Convenient synthesis and reactions of some 7,9-dimethylthieno-[2,3-b:4,5-b' ]dipyridines

Article abstract of DOI:10.3184/030823409X12532880131016

3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxaldehyde was prepared and from it various functionalised thieno[2,3-b:4,5-b']dipyridines were synthesised, using the Friedlaender and related reactions. Ethyl 2,7,9- trimethylthieno[2,3-b:4,5-b']dipyridine

Full text of DOI:10.3184/030823409X12532880131016

JOURNAL OF CHEMICAL RESEARCH 2009
OCTOBER, 649–652
RESEARCH PAPER 649
Convenient synthesis and reactions of some 7,9-dimethylthieno-
[2,3-b:4,5-b'ꢀ]dipyridines
Adel M. Kamal El-Deana*, Gehan Ahmed Ali Mickyb, Abo Bakr Abdel-Hadi Ahmedc and
Rasha Hassan Ahmedb
aChemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
bChemistry Department, Faculty of Science, Alazhar University, Cairo, Egypt
cChemistry Department, Faculty of Science, Alazhar University, Assiut Branch, Assiut, Egypt
3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxaldehyde was prepared and from it various functionalised
thieno[2,3-b:4,5-b']dipyridines were synthesised, using the Friedländer and related reactions. Ethyl 2,7,9-
trimethylthieno[2,3-b:4,5-b']dipyridine-3-carboxylate was transformed into a variety of thieno[2,3-b:4,5-b']dipyridine
systems with heterocyclic rings attached at C-3 or fused at C2–C3.
Keywords: pyrazoles, 1,3,4-oxadiazoles, fused pyridines, thiophenes, pyrroles, quinolines, pyridazines, Friedländer reactions
Fused pyridines and, in particular, thienopyridines are well-
known as biologically active compounds. Thus, in the
series of thienopyridines and related condensed analogues,
antithrombotic,1,2 antihistamine (antianaphylactic),3 anti-
bacterial,4 antiallergic5 and neuroprotective6 agents have
been found. Polysubstituted and partially hydrogenated
pyridothienopyridines are new heterocycles with potential
biological activity.7,8 Their syntheses, however, are based
on a multistep approach and often require inaccessible
reagents. In continuation of our work in the synthesis and
studies of thienopyridines9-11 and pyridothienopyridines
(thienodipyridines),12 we report here a new approach to the
synthesis of thieno[2,3-b:4,5-b']dipyridines.
Compound 3 underwent Friedländer reactions with various
reagents, specifically ethyl acetoacetate, acetyl acetone and
diethyl malonate, in ethanol in the presence of catalytic
piperidine to give thieno[2,3-b:4,5-b']dipyridine derivatives
4a–c in good yields. Also it reacted with cyclohexanone and
deoxybenzoin in ethanol in the presence of sodium hydroxide
to give 2,4-dimethyl-6,7,8,9-tetrahydropyrido[2',3':2,3]thieno-
[4,5-b]quinoline (4d) in 78% yield and 7,9-dimethyl-2,3-
diphenylthieno[2,3-b:4,5-b']dipyridine (4e) in 64% yield,
respectively. The IR spectra of 4a–e revealed the disappearance
of bands characteristic of NH2 in the starting material and the
appearance of absorption at 1715 cm-1 of the ester carbonyl
group in 4a and at 1700 cm-1 for the ketonic carbonyl group
in 4b; and in the case of 4d and 4e showed the disappearance
of bands characteristic of NH21and aldehydic carbonyl groups
in the starting material. The H NMR of 4a showed triplet
and quartet signals at 1.40 and 4.33 characteristic of the OEt
group, methyl singlets at d 2.6 (3H) and 2.9 (6H), and two
singlets at d 6.95 and 8.45 for the pyridine protons. The mass
spectrum of 4a showed the molecular ion as base peak at m/z
Results and discussion
Reaction of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-
3-carbonitrile (1) with chloroacetaldehyde in ethanolic
sodium hydroxide afforded 2-(3-cyano-4,6-dimethylpyridin-
2-ylthio)acetaldehyde (2), which cyclised in the presence
of sodium ethoxide to give 3-amino-4,6-dimethylthieno
[2,3-b]pyridine-2-carbaldehyde (3). The IR spectrum of
compound 2 showed a C≡N absorption band at 2210 cm-1,
which disappeared when cyclised to give the thienopyridine
3 and was replaced by bands at 3430 and 3310 cm-1 for NH2.
1
300. The H NMR of 4b revealed new signals at d 2.6 and
3.0 for Me and COMe protons.
The amino-carboxaldehyde 3 was allowed to react with
malononitrile in ethanol in the presence of piperidine as
catalyst; 2-amino-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-
3-carbonitrile (5) was produced. The IR of compound 5
showed absorption bands at 3450 and 3350 cm-1 for NH2 and
at 2200 for CN.
1
The H NMR of 2 showed a CHO group and a signal at d
3.7 for CH2 which disappeared when compound 2 cyclised
to form the thienopyridine 3, then showing a new signal at
6.8 for NH2.
Me
Me
Me
Me
CN
NH2
N
NH2
CN
CN
b
c
d
a
Me
S
N
H
Me
Me
CHO
Me
N
SCH2CHO
N
S
S
N
1
2
3
5
e
X
Y
Me
Me
Me
N
4a
4b
4c
4d
4e
Me CO2Et
Me COMe
OH CO2Et
-(CH2)4-
H
N
N
N
O
X
Y
NH2
+
Me
Me
Me
CO2Et
CN
N
S
N
S
S
Ph Ph
6
4
7
Scheme 1 Reagents and conditions: a,: ClCH2CHO/EtOH/NaOH, 10°C; b, EtONa/EtOH, reflux; c,: XCOCH2Y; d,: CH2(CN)2;
e, NCCH2CO2Et; c-e: all in piperidine/EtOH, reflux.
* Correspondent. E-mail: a.eldean@aun.edu.eg

650 JOURNAL OF CHEMICAL RESEARCH 2009
When ethyl cyanoacetate was used instead of malononitrile,
a mixture of ethyl 2-amino-7,9-dimethylthieno[2,3-b:4,5-b']
dipyridine-3-carboxylate (6) and 7,9-dimethyl-2-oxo-1,2-
dihydrothieno[2,3-b:4,5-b']dipyridine-3-carbonitrile (7) was
formed (Scheme 1).The mixture of 6 and 7 was separated
by column chromatography using ethyl acetate: methylene
chloride (1:1) as eluent in 48 and 38% yields. The IR of
compound 6 showed bands at 3420 and 3320 cm-1 for NH2
and 1690 for C=O. The 1H NMR revealed a triplet at d 1.5 for
CH3 and a quartet at 4.55 for the ethyl ester. The MS showed a
peak at m/z 300 (M+–1, 100%).
Heatingthecarbohydrazide8withcarbondisulfideinpyridine
on a steam bath afforded 5-(2,7,9-trimethylthieno[2,3-b:
4,5-b']dipyridin-3-yl)-1,3,4-oxadiazole-2(3H)-thione (11) in
fair yield. The thione 11 was alkylated using a-halogenated
carbonylcompounds,viz.ethylchloroacetate,phenacylbromide
and chloroacetone, to afford compound 12a–c respectively.
IR of compounds 12a–c revealed no band characteristic of the
NH group in the starting material and showed the appearance
of new carbonyl absorption bands. Also, compound 8
condensed with acetylacetone and with anisaldehyde to give
the N-acylpyrazole 13 and the acylhydrazone 14, respectively
(Scheme 2).
Treatment of the ester 4a with bromine in acetic acid in
the presence of sodium acetate resulted in bromination of the
methyl group adjacent to the ester function to give ethyl 2-
bromomethyl-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-3-
carboxylate (15). The NMR of showed a signal at d 4.0 for the
CH2Br group. Compound 15, when refluxed with hydrazine
hydrate, underwent nucleophilic substitution of bromine by
hydrazinefollowedbycyclisationwitheliminationofethanolto
give 2,4-dimethyl-6,7,8,9-tetrahydropyrido[2",3":2',3']thieno-
[4',5':2,3]pyrido[5,6-d]pyridazine (16) in 60% yield. The IR
of compound 16 showed the ester carbonyl group replaced by
a band at 1660 cm-1; the ethoxy signals in the NMR were also
absent. Furthermore, the bromine atom in compound 15 was
exchanged by a SH group on reflux with thiourea followed
by treatment with sodium hydroxide solution and then
acidification with dilute HCl. (Scheme 2)
Hydrazinolysis of compound 4a using hydrazine hydrate in
ethanol afforded the trimethylthieno[2,3-b:4,5-b']dipyridine-
8-carbohydrazide 8. Its IR showed bands at 3350–3200
1
(NHNH2) and 1650 cm-1 (C=O) The H NMR showed the
disappearance of signals characteristic of the ethoxy group
present in the starting material and the appearance of signals
at d 4.5 for NH2 and 8.9 for NH which were exchangeable
with D2O. (Scheme 2)
Carbohydrazide 8 was converted into 2,7,9-trimethyl-
thieno[2,3-b:4,5-b']dipyridine-3-carboazide (9) by treatment
with nitrous acid in acetic acid at 0-5°C. The IR showed bands
at 2150 (N3) and 1700 cm-1 (C=O). When the azide 9 was heated
in xylene it first underwent a Curtius rearrangement to give an
intermediate isocyanate, followed by cyclisation to the adjacent
methyl group to produce the pyrrolopyridothienopyridine 10.
1
The H NMR of compound 10 showed the presence of a 2H
singlet signal at d 3.3 for the methylene group and at 5.4 a
signal for NH exchangeable by D2O.
Me
Me
Me
N
Me
N
N
Me
e
O
N
H
Me
N
S
CON3
Me
N
S
Me
N
S
NCO
9
10
d
Me
Me
N
Me
N
N
d
Me
O
N
Me
O
N
Me
Me
b
f
N
S
N
Me
N
S
Me
Me
S
CONHNH2
S
N
NH
Me
13
11
8
c
g
Me
a
Me
N
Me
O
N
Me
R
H
CHR
N
12a CO2Et
12b COMe
12c COPh
4a
O
SCH2R
Me
N
S
N
Me
N
S
N
N
12a-c
h
14, R =C6H4-OMe-p
Me
N
Me
Me
N
N
N
CH2SH
CO2Et
N
a
CH2Br
CO2Et
NH
NH
i
Me
S
Me
N
S
Me
S
15
O
16
17
Scheme 2 Reagents and conditions: a, N2H4.H2O/EtOH, reflux; b, (Ac)2CH2/EtOH; c, anisaldehyde/EtOH/AcOH, D; d, NaNO2,
AcOH at 5-10°C; e, xylene, D; f, CS2/pyridine, steam bath; g, RCH2Cl(Br)/EtOH/AcONa; h, Br2/AcOH/AcONa; i, thiourea/EtOH, D,
then NaOH/H2O, then dil. HCl.

JOURNAL OF CHEMICAL RESEARCH 2009 651
The solid product was collected and recrystallised from dioxan as
brown crystals (0.85 g, 67%), m.p. 200–202°C. IR: nmax 3450, 3350
(NH2), 2200 cm-1 (CN). NMR (DMSO-d6): dH 2,5 (s, CH3), 2.9 (2 s,
2CH3), 6.8 (s, NH2), 7.0, 8.50 (2 s, 2 CH-pyridine). MS: m/z (%) 254
(M+, 100%). Anal. Calcd for C13H10N4S: C, 61.40; H, 3.96; N, 22.03;
S, 12.61. Found: C, 61.63; H, 4.18; N, 21.80; S, 12.84%.
Experimental
Melting points were measured on a Fisher–Johns apparatus.
Elemental analyses (C, H, N and S) were determined on an Elementar
Analysensystem GmbH-VarioEL V.3 microanalyser in the central
laboratory of Assiut University. The IR spectra were obtained
on a Pye-Unicam SP-100 spectrophotometer using the KBr disc
technique. NMR spectra were recorded on a Varian EM-390 90 MHz
spectrometer in a suitable deuteriated solvent using TMS as internal
standard (chemical shifts in ppm). MS spectra were recorded on
JEOL JMS-600 apparatus.
2-(3-Cyano-4,6-dimethylpyridin-2-ylthio)acetaldehyde (2): To a
solution of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
(1)13 (1.64 g, 0.01 mol) in sodium hydroxide (20 mL, 10%)
chloroacetaldehyde (50% solution, 2 mL) was added and the reaction
mixture was stirred at room temperature for 10 h. After dilution with
water (100 mL) the solid product was collected and recrystallised
from ethanol as yellowish crystals (1.2 g, 58%), m.p. 100°C. IR:
nmax 2210 (CN), 1720 cm-1 (C=O). NMR (CDCl3): dH 2.5, 2.6 (2 s,
6H, 2CH3), 3.9 (2H, CH2), 6.9 (s, 1H, CH pyridine), 9.5 (1H, CHO).
Anal. Calcd for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58; S, 15.54.
Found: C, 58.01; H, 5.09; N, 13.71; S, 15.32%.
3-Amino-4,6-dimethylthieno[2,3-b]pyridine-2-carbaldehyde (3):
The acetaldehyde derivative 2 (2.1 g, 0.01 mol) was stirred at room
temperature for 5 h in ethanol (20 mL) containing sodium ethoxide
(1.36 g, 0.02 mol). Dilution with water (100 mL) precipitated a
solid product which was collected and recrystallised from ethanol as
brown crystals (2 g, 95%), m.p. 130°C. IR: nmax 3520, 3410 (NH2),
1670 cm-1 (C=O). 1H NMR (DMSO-d6): 2.5, 2.7 (2 s, 2CH3), 6.8 (s,
NH2), 7.15 (s, pyridine CH) and 9.7 (s, 1H, CHO). Anal. Calcd for
C10H10N2OS: C, 58.23; H, 4.89; N, 13.58; S, 15.54. Found: C, 58.42;
H, 4.69; N, 13.72; S, 15.71%.
7,9-Dimethylthieno[2,3-b:4,5-b']dipyridines (4a–c); general procedure
The amino-aldehyde 3 (1.0 g, 5 mmol) was heated for 4 h under
reflux in ethanol (20 mL) containing a few drops of piperidine with
the appropriate a-methylene carbonyl compound (ethyl acetoacetate,
pentane-2,4-dione, or diethyl malonate, 5 mmol). After cooling,
the solid product was filtered off and recrystallised from the
indicated solvent.
Ethyl 2-amino-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-3-carboxyl-
ate (6) and 7,9-Dimethyl-2-oxo-1,2-dihydrothieno[2,3-b:4,5-b']
dipyridine-3-carbonitrile (7): To compound 3 (1.0 g, 5 mmol) and
ethyl cyanoacetate (0.57 g, 005 mol) in ethanol (15 mL), a few drops
of piperidine was added. The mixture was heated under reflux for
3 h, and then allowed to cool. The solid product was collected and
chromatographed on silica gel using ethyl acetate as eluent to give the
ester 6 as yellowish orange crystals (0.72 g, 48%), m.p. 198–200°C,
and the nitrile 7 as red crystals m.p 238°C. (0.49 g, 38%).
Compound 6: IR: nmax 3420, 3320 (NH2), 1690 cm-1 (CO). 1H NMR
(DMSO-d6): dH 1.5 (t, CH3), 2.55, 2.9 (2 s, 2CH3), 4.55 (q, CH2), 6.5
(s, NH2), 7.0, 8.5 (2 s, CH pyridine). MS: m/z (%) 300 (M+–1, 100%).
Anal. Calcd for C15H15N3O2S: C, 59.78; H, 5.02; N, 13.94; S, 10.64.
Found: C, 60.01; H, 4.83; N, 14.17; S, 10.81%.
Compound 7: IR: nmax 3350 (NH), 2220 (CN), 1670 cm-1 (CO).
NMR (CF3CO2D): dH 2.7, 3.2 (2 s, 2CH3), 7.2, 8.5 (2 s, CH pyridine).
MS: m/z (%) 254 (M+–1, 100%). Anal. Calcd for C13H9N3OS: C,
61.16; H, 3.55; N, 16.46; S, 12.56. Found: C, 60.93; H, 3.32; N, 16.67;
S, 12.76%.
2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridine-3-carbohydrazide
(8): The ester 4a (3 g, 0.01 mol) and hydrazine hydrate (80%, 1.9 mL,
0.03 mol) in ethanol (20 mL) were heated under reflux for 5 h, and
then allowed to cool. The solid product was collected as yellowish
crystals (2.1 g 74%), m.p. 260°C. IR: nmax 3350–3200 (NHNH2) and
1650 cm-1 (C=O). NMR (DMSO-d6): dH 2.3, 2.5, 2.9 (3 s, 3 CH3),
4.5 (broad, NH2), 6.9, 8.0 (s, 2CH pyridine), 8.9 (s, NH). Anal. Calcd
for C14H14N4OS: C, 58.72; H, 4.93; N, 19.57; S, 11.20. Found: C,
58.95; H, 5.16; N, 19.39; S, 11.00%.
2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridine-8-carboazide (9):
The hydrazide 8 (1.43 g, 5 mmol) was dissolved in acetic acid (10 mL),
cooled to 5–10°C, and sodium nitrite (0.69 g, 0.01 mol) in H2O
(2 mL) was added dropwise with stirring over 10 minutes.
The reaction mixture was allowed to stand for 2 h, and the solid
product (1.17 g, 79%), m.p. 140°C (decomp.), was filtered off and
used without further purification. IR: nmax 2150 (N3) and 1700 cm-1
(C=O). 1H NMR (CDCl3): dH 2.6 (s, CH3), 2.9 (2 s, 2CH3), 6.95, 9.2
(2 s, 2CH pyridine).
7,9-Dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]thieno[2,3-b:4,5-b']
dipyridin-2-one (10): The carboazide 9 (1.0 g, 4 mmol) (15 mL) was
heated under reflux in dry xylene for 1 h. The solid product which
separated while hot was filtered off and recrystallised from dioxan as
brown crystals (0.88 g, 82%), m.p >300°C. IR: nmax 3250 (NH) and
1600 cm-1 (C=O). NMR (DMSO-d6): dH 2.55, 2.9 (2 s, 2CH3), 5.4 (s,
NH), 6.95 and 8.5 (2 s, 2CH pyridine). Anal. Calcd for C14H11N3OS:
C, 62.44; H, 4.12; N, 15.60; S, 11.91. Found: C, 62.28; H, 4.34; N,
15.83; S, 12.14%.
5-(2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridin-3-yl)-1,3,4-oxadiazole-
2(3H)-thione (11): The carbohydrazide 8 (1.43 g, 5 mmol) and carbon
disulfide (1 mL) in pyridine (10 mL) were heated on a steam bath
for 8 h, then allowed to cool. The solid product which separated was
collected and recrystallised from ethanol as yellowish crystals (1.2 g,
74%), m.p. >300°C. IR: nmax 3400 cm-1 (NH). NMR (CF3CO2D): dH
2.65, 2.75, 3.0 (3 s, 3CH3), 7.1, 8.3 (2 s, CH pyridine). Anal. Calcd
for C15H12N4OS2: C, 54.86; H, 3.68; N, 17.06; S, 19.53. Found: C,
55.09; H, 3.81; N, 16.86; S, 19.75%.
Ethyl 2,7,9-trimethylthieno[2,3-b:4,5-b']dipyridine-3-carboxylate
(4a): White crystals (1.2 g, 87%) from ethanol, m.p. 160–162°C.
IR: nmax 2950 (CH aliphatic) and 1710 cm-1 (C=O). NMR (CDCl3):
dH 1.40 (t, CH3 of OEt), 2,6 (s, CH3), 2.9 (2 s, 2CH3), 4.33 (q, CH2
of OEt), 6.95, 8.45 (2 s, 2CH pyridine). MS: m/z (%) 300 (M+, 100),
272 (M – C2H4)+, 255 (M – OEt)+, 227 (M – CO2Et)+. Anal. Calcd
for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33; S, 10.67. Found: C,
64.19; H, 5.60; N, 9.54; S, 10.45%.
3-Acetyl-2,7,9-trimethylthieno[2,3-b:4,5-b']dipyridine (4b): White
crystals (1.05 g, 78%) from ethanol, m.p. 163–165°C. NMR (CDCl3):
dH 2.6 (s, 2CH3), 2.85 (s, CH3), 3.0 (s, CH3), 7.0, 8.35 (2 s, 2 CH
pyridine). Anal. Calcd for C15H14N2OS: C, 66.64; H, 5.22; N, 10.36;
S, 11.86. Found: C, 66.86; H, 5.00; N, 10.526; S, 12.08%.
2-Hydroxy-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-3-carboxylate
(4c):Yellowish white solid (1.0 g, 66%), from dioxan, m.p > 300°C. IR:
n
max 2400 (OH) and 1690–1660 cm-1 (C=O). NMR (CDCl3): dH 1.35
(t, CH3 ester), 2,5 (s, CH3), 2.9 (2 s, 2CH3), 4.4 (q, CH2 ester), 6.95,
8.55 (2 s, 2CH pyridine), 10 (s, OH). Anal. Calcd for C15H14N2O3S: C,
59.59; H, 4.67; N, 9.27; S, 10.60. Found: C, 59.78; H, 4.89; N, 9.03;
S, 10.38%.
2,4-Dimethyl-6,7,8,9-tetrahydropyrido[2',3':2,3]thieno[4,5-b]
quinoline (4d): Compound 3 (1 g, 5 mmol) and cyclohexanone (0.5 g,
5 mmol) were stirred together in ethanolic sodium hydroxide (10%,
20 mL) room temperature for 6 h, and then water (100 mL) was added.
The solid product that separated was collected and recrystallised
from ethanol, forming white crystals (1.0 g, 78%), m.p 158–160°C.
NMR (MHz, CDCl3): dH 1.8 (m, 2CH2), 2.5, 2.7 (2 s, 2CH3), 2.95
(m, 2CH2), 6.95, 7.8 (2 s, pyridine H). MS: m/z (%) 268 (M+, 100).
Anal. Calcd for C16H16N2S: C, 71.61; H, 6.01; N, 10.44; S, 11.95.
Found: C, 71.38; H, 5.79; N, 10.66; S, 12.17%.
7,9-Dimethyl-2,3-diphenylthieno[2,3-b:4,5-b']dipyridine (4e): The
synthetic procedure was similar to described above, employing
deoxybenzoin (5 mmol) instead of cyclohexane. Compound 4e (1.17 g,
64%) m.p. 290°C. NMR (CF3CO2D): dH 2.7, 3.0 (2 s, 2CH3), 7.1–7.5
(m, 5H, ArH), 7.0, 8.1 (2 s, pyridine H). Anal. Calcd for C24H18N2S:
C, 78.66; H, 4.95; N, 7.64; S, 8.75. Found: C, 78.90; H, 5.16; N,
7.41; S, 8.52%.
Alkylation of the thione 11: general procedure
The compound 11 (1.6 g, 5 mmol), the halogenated compound
(5 mmol) and sodium acetate (0.5 g, 0.06 mmol) were heated to reflux
in ethanol for 2 h, then allowed to cool. The solid product 12 was
filtered off, washed with water several times, dried and recrystallised
from ethanol.
Ethyl
2-[5-[(2,7,9-trimethylthieno[2,3-b:4,5-b']dipyridin-3-yl)-
[1,3,4]oxadiazol-2-yl]sulfanyl]acetate (12a): White crystals (1.76 g,
85%), m.p 188–190°C. IR: nmax 2950 (CH aliphatic), 1725 cm-1
(CO). NMR (CDCl3): dH 1.3 (t, CH3 ester), 2.6 (s, CH3), 3.0 (s,
2CH3), 4.15 (q, CH2 ester), 7.0, 8.5 (2 s, 2CH pyridine). Anal. Calcd
for C19H18N4O3S2: C, 55.06; H, 4.38; N, 13.52; S, 15.47. Found: C,
54.88; H, 4.61; N, 13.75; S, 15.33%.
1-[[5-(2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridin-3-yl)-1,3,4-
oxadiazol-2-yl]sulfanyl]propan-2-one (12b): White crystals (1.65
g, 86%), m.p. 230–232°C. IR: nmax 2950 (CH aliphatic), 1700 cm-1
(CO). NMR (CF3CO2D): dH 2.7, 3.1, 3.3, 3.55 (4 s, 4CH3), 4.6 (s,
2-Amino-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-3-carbonitrile
(5):Tocompound3(1.0g, 5mmol)andmalononitrile(0.33g, 005mol)
in ethanol (25 mL), a few drops of piperidine were added.
The mixture was heated under reflux for 3 h, and then allowed to cool.

652 JOURNAL OF CHEMICAL RESEARCH 2009
SCH2), 7.9, 9.1 (2 s, CH pyridine). Anal. Calcd for C18H16N4O2S2:
C, 56.23; H, 4.19; N, 14.57; S, 16.68. Found: C, 56.00; H, 4.36; N,
14.72; S, 16.46%.
2-[[5-(2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridin-3-yl)-1,3,4-
oxadiazol-2-yl]sulfanyl]-1-phenylethanone (12c): White crystals
(1.8 g, 80%), m.p. 200–202°C. IR: nmax 3050 (CH aromatic), 1690
cm-1 (CO). NMR (CF3CO2D): dH 2.7, 2.9, 3.0 (3 s, 3CH3), 4.3 (s,
SCH2), 7.1, 8.7 (2 s, CH-pyridine), 7.4–8.2 (m, Ar-H). Anal. Calcd
for C23H18N4O2S2: C, 61.86; H, 4.06; N, 12.55; S, 14.36. Found: C,
62.05; H, 4.27; N, 12.33; S, 14.14%.
1-(2,7,9-Trimethylthieno[2,3-b:4,5-b']dipyridine-3-carbonyl)-3,5-
dimethylpyrazole (13): The hydrazide 8 (1.43 g, 5 mmol) and
acetyl acetone (0.05 g, 5 mmol) were refluxed for 5 h in ethanol
(15 mL), then allowed to cool. The solid product was filtered off and
recrystallised from ethanol as yellowish white crystals (1.35 g, 77%)
yield, m.p 180°C. IR: nmax 1680 cm-1 (CO). NMR (CDCl3): d = 2.3,
3.05, 3.15 (3 s, 3CH3), 2.9 (s, 2CH3), 6.2 (s, CH-pyrazole), 7.1, 8.2
(2 s, 2CH pyridine). Anal. Calcd for C19H18N4OS: C, 65.12; H, 5.18;
N, 15.99; S, 9.15. Found: C, 64.88; H, 5.39; N, 16.22; S, 8.94%.
and recrystallisation from ethanol the solid product (0.85 g, 60%)
had m.p 240–242°C. IR: nmax 3450, 3240 (2NH), 1660 cm-1 (CO).
NMR (DMSO-d6): dH 2.5, 2.9 (2 s, 2CH3), 3.2 (s, CH2), 7.1, 8.3
(2 s, 2CH pyridine), 9.6, 10.5 (2 s, 2NH).Anal. Calcd for C14H12N4OS:
C, 59.14; H, 4.25; N, 19.70; S, 11.28. Found: C, 58.91; H, 4.02; N,
19.94; S, 11.05%.
Ethyl 2-mercaptomethyl-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-
3-carboxylate (17): The bromomethyl compound 15 (1.9 g, 5 mmol)
in ethanol (20 mL) was heated under reflux for 5 h with an excess
of thiourea (0.76 g, 0.01 mol), and then allowed to cool. The solid
product was filtered off and washed several times with water to remove
unreacted thiourea. The residue was dissolved in aqueous NaOH
(20 mL, 10%) and then acidified with HCl (0.1 N) to just neutral.
The solid precipitated product was collected and recrystallised from
ethanol as yellow crystals (1.16 g, 70%), m.p 170–172°C. IR: nmax
2550 (SH), 1710 cm-1 (CO). NMR (DMSO-d6): dH 1.4 (t, CH3 ester),
2.5, 2.85 (2 s, 2CH3), 4.3 (s, CH2), 4.45 (q, CH2 ester), 7.1, 8.7 (2 s,
2CH pyridine). Anal. Calcd for C16H16N2O2S2: C, 57.81; H, 4.85; N,
8.43; S, 19.29. Found: C, 57.80; H, 4.65; N, 8.42; S, 19.51%.
N'-Anisylidene
2,7,9-trimethylthieno[2,3-b:4,5-b']dipyridine-3-
carbohydrazide (14): The hydrazide 8 (1.43 g, 5 mmol) and
anisaldehyde (0.68 g, 5 mmol) in ethanol (15 mL) were mixed, and
a few drops of acetic acid were added. The mixture was heated to
reflux for 3 h, and then allowed to cool. The solid product was filtered
off and recrystallised from ethanol as yellow–white crystals (1.7 g,
86%), m.p. 268–270°C. IR: nmax 3350 (NH), 1670 cm-1 (CO). NMR
(DMSO-d6): dH 2.3, 2.5, 2.9 (3 s, 3CH3), 3.9 (s, OCH3), 6.8, 7.2 (2 d,
CHaromatic), 7.0, 8.5 (2 s, 2CH pyridine), 11.5 (s, NH). Anal. Calcd
for: C22H20N4O2S: C, 65.33; H, 4.98; N, 13.85; S, 7.93. Found: C,
65.11; H, 5.21; N, 13.63; S, 8.14%.
Ethyl 2-bromomethyl-7,9-dimethylthieno[2,3-b:4,5-b']dipyridine-
3-carboxylate (15): To the ester 4a (1.5 g, 5 mmol) and sodium acetate
(1 g, 0.012 mol) in acetic acid (20 mL), bromine (1 g. 0.006 mol) in
acetic acid (5 mL) was added dropwise with stirring over 15 min.
After addition was complete stirring was continued for an additional
1 h. The reaction mixture was poured into cold water (100 mL).
The solid product was filtered off and recrystallised from ethanol as
yellow crystals (1.5 g, 80%), m.p 154–156°C. IR: nmax 1720 cm-1
(CO). NMR (CDCl3): dH 1.3(t, CH3 ester), 4.5 (q, CH2 ester), 2.5,
2.8 (2 s, 2CH3), 4.0 (s, CH2Br), 7.0, 8.6 (2 s, 2CH pyridine). Anal.
Calcd for C16H15BrN2O2S: C, 50.67; H, 3.99; Br, 21.07; N, 7.39; S,
8.45. Found: C, 50.88; H, 4.23; Br, 20.86; N, 7.61; S, 8.65%.
Received 27 April 2009; accepted 18 September 2009
Paper 09/0552 doi: 10.3184/030823409X12532880131016
Published online: 8 October 2009
References
1
2
3
4
5
6
7
J. Gosteli and A. Warm, Eur. Pat. Appl. EP 360 293 (1990) (Chem. Abstr.,
1990, 113, 97 595).
M. Baronyi, M. Csatari Nagy, L. Molnar, A. Gajary and E. Alattyani,
PCT Int. Appl. WO 9 851 689 (1998) (Chem. Abstr., 1999, 130, 25 057).
G. Wagner, H. Vieweg and S. Leistner, Pharmazie, 1993, 48, 576 (Chem.
Abstr., 1994, 120, 134 330n).
G. Malicorne, J. Bompart, L. Giral and E. Despaux, Eur. J. Med. Chem.,
1991, 26, 3.
E. Kretzschmar, G. Laban, P. Meisel, R. Grupe and W. Kirsten, Ger. (East)
DD 272 082 (1989) (Chem. Abstr., 1990 112, 198 357).
W. Lösel, O. Roos, D. Arndts and G. Schingnitz, Ger. Offen. DE:4 104
257 (1993), (Chem. Abstr., 1993, 118, 6878u).
V.A. Artemov, V.L. Ivanov, L.A. Rodinovskaya, A.M. Shestopalov and
V.P. Litvinov, Chem. Heterocycl. Compds. (Engl. Transl.), 1996, 32, 483.
A.D. Dunn and R. Norrie, J. Prakt. Chem., 1992, 334, 483.
A.M. Kamal El-Dean, A.A. Geies, H.S. El-Kashef, J.C. Lancelot,
P. Dallemagene and S. Rault, J. Heterocyclic Chem., 2000, 37, 1521.
8
9
10 A.M. Kamal El-Dean, A.A. Geies and Y.A. El-Osaily, Phosphorus, Sulfur,
Silicon Related Elements, 2006, 181, 2013.
11 N.M. Rageh, N.M. Ismail and A.M. Kamal El-Dean, Can. J. Anal. Sci.
Spectroscopy, 2004, 49, 240.
12 A.M. Kamal El-Dean and M.E. Abdel-Moneam, J. Chem. Res., 23 (2004).
13 U. Schmidt and H. Kubitzek, Chem. Ber., 1960, 93, 1559.
2,4-Dimethyl-7,8-dihydropyrido[2″,3″:2',3']thieno[4',5':2,3]-
pyrido[5,6-d]pyridazin-9(6H)-one (16): The bromomethyl compound
15 (1.9 g, 5 mmol) in hydrazine hydrate (80%, 5 mL) was heated
under reflux for 2 h, then ethanol (20 mL) was added and reflux was
continued for additional 2 h, then allowed to cool. Afte collection and