Studies on thiazolopyridines. Part 4: Synthesis of hitherto unknown 1,4-bis(thiazolopyridine)benzene derivatives

Article abstract of DOI:10.1080/10426500307827

2-Cyanomethyl-4-thiazolinone (1) was condensed with terephthalaldehyde (2) (2:1 molar ratio) and produced 1,4-bis(2-cyanomethyl-4,5-dihydro-5-methylidene-4-thiazolinone-5-yl) benzene (3). Treatment of compound (3) with benzylidenemalononitrile (4) (1:2 mo

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Studies on Thiazolopyridines. Part 4: Synthesis of
Hitherto Unknown 1,4-Bis(thiazolopyridine)benzene
Derivatives
Mohamed S. A. El-Gaby a , Moustafa M. Khafagy b , Gameel A. M. El-Hag Ali b , Hassan A.
Eyada b , Ahmed A. El-Maghraby b & Mohamed H. M. Helal b
a Al-Azhar University at Assiut, Assiut, Egypt
b Al-Azhar University, Nasr City, Cairo, Egypt
Version of record first published: 27 Oct 2010.
To cite this article: Mohamed S. A. El-Gaby , Moustafa M. Khafagy , Gameel A. M. El-Hag Ali , Hassan A. Eyada , Ahmed
A. El-Maghraby & Mohamed H. M. Helal (2003): Studies on Thiazolopyridines. Part 4: Synthesis of Hitherto Unknown 1,4-
Bis(thiazolopyridine)benzene Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:8, 1681-1688
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Phosphorus, Sulfur, and Silicon, 178:1681–1688, 2003
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200729
STUDIES ON THIAZOLOPYRIDINES. PART 4:
SYNTHESIS OF HITHERTO UNKNOWN
1,4-BIS(THIAZOLOPYRIDINE)BENZENE DERIVATIVES
Mohamed S. A. El-Gaby,a Moustafa M. Khafagy,b
Gameel A. M. El-Hag Ali,b Hassan A. Eyada,b
Ahmed A. El-Maghraby,b and Mohamed H. M. Helalb
Al-Azhar University at Assiut, Assiut, Egypta and Al-Azhar
University Nasr City, Cairo, Egyptb
2-Cyanomethyl-4-thiazolinone (1) was condensed with terephthalalde-
hyde (2) (2:1 molar ratio) and produced 1,4-bis(2-cyanomethyl-4,5-
dihydro-5-methylidene-4-thiazolinone-5-yl) benzene (3). Treatment of
compound (3) with benzylidenemalononitrile (4) (1:2 molar ratio) fur-
nished the novel bisthiazolopyridines (6a–e). Condensation of com-
pound (1) with aromatic aldehyde yielded the benzylidene derivatives
(7a–f), which on treatment with compound (8) (2:1 molar ratio) afforded
the novel bisthiazolopyridines (10a–f). Structures of the synthesized
compounds have been established by elemental analyses and spectral
data.
Keywords: Bisthiazolopyridines; thiazolinones
A considerable number of bisheterocyclic compounds exhibited vari-
ous biological activities including antibacterial, fungicidal, tubercu-
lostatic, and plant growth regulative properties.1–4 It also was re-
ported that bisheterocyclic compounds display much better antibac-
terial activity than heterocyelic compounds.5 Some thiazolo[3,2-a]
pyridines have been reported to possess antibacterial,6 bactericide,7
coronary dilator, antihypertensive, and muscle relaxant8 activities.
It is observed from the literature that 7H-thiazolo[3,2-a] pyridines
have been prepared from 2-alkoxycarbonylmethylidene-5-(arylmethyl-
idene)-1,3-thiazolidin-4-one and arylmethylidenemalononitriles.9–12
On this basis and in continuation of our research13–17 program on
Address correspondence to M.S.A. El-Gaby, Department of Chemistry, Faculty of Sci-
ence, Al-Azhar University of Assiut, Assiut 71524, Egypt. E-mail: m elgaby@hotmail.com
1681

1682
M. S. A. El-Gaby et al.
the synthesis of heterocyclic compounds for antimicrobial activity,
we report here the synthesis of novel bisthiazolo[3,2-a] pyridine
derivatives.
RESULTS AND DISCUSSION
The reaction of 2–cyanomethyl-4-thiazolinone (1) with terephthalalde-
hyde (2) (2:1 equivalents) in refluxing ethanol using piperidine as
base yielded the corresponding 1,4-bis(2-cyanomethyl-4,5-dihydro-5-
methylidene-4-thiazolinone-5-yl) benzene (3). The IR spectrum of this
product exhibited the presence of the absorption band of the nitrile
function and a band for C O (thiazolinone) was observed. It’s 1H
NMR spectrum recorded in DMSO-d6 revealed the presence of sig-
nals of methylene and aromatic protons. When a solution of (3) and
benzylidenemalononitrile (4) (1:2 molar ratio) was heated to reflux
in absolute ethanol, in the presence of catalytic amounts of piperi-
dine for 3 h the 1,4-bis[5-amino 7-aryl-2-methylidene-2,3-dihydro-7H-3-
oxo thiazolo[3,2-a] pyridin-6,8-dicarbonitrile-2-yl] benzene derivatives
6a–e were isolated. The novel compounds 6 were synthesized in
good yields as stable crystalline solids and easily recrystallized from
dioxane. The structure of compounds 6a–e were characterized by
elemental and spectroscopic analysis. Thus, IR spectra of compounds 6
revealed the presence of characteristic bands for amino, cyano and car-
1
bonyl functional groups. H NMR spectrum of compound 6a showed
signal in the region δ 4.26 ppm, attributed to the pyridine-H. The
formation of 6 is assumed to proceed via Michael addition of nu-
cleophilic carbon atom of cyanomethyl in 3 to the benzylidene (4)
to form Michael intermediate18,19 5 followed by intramolecular nu-
cleophilic attack at the cyano group to form bisthiazolopyridines (6)
(Scheme 1).
5-Arylmethylidene-2-cyanomethyl-4,5-dihydro-4-thiazolinones (7a–
f) were obtained by condensation of 2-cyanomethyl-4-thiazolinone
(1) with aromatic aldehydes in ethanol containing piperidine
as catalyst under reflux. Reaction of benzylidene derivative (8)
with excess of (1) in absolute ethanol in the presence of tri-
ethylamine gave 1,4-bis[5-amino-2-arylmethylidene-2,3-dihydro-7H-3-
oxo-thiazolo[3,2-a]pyridin-6,8-dicarbonitrile-7-yl] benzene derivatives
(10a–f) in good yields (Scheme 2). The formation of 10 is a assumed
to proceed via initial formation of Michael adduct 9 followed by in-
tramolecular cyclization at the cyano group to form compounds 10
(Scheme 2).

Studies on Thiazolopyridines
1683
SCHEME 1
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded on a
Shimadzu-440 infrared spectrophotometer (ν; cm−1) using the KBr
technique (Shimadzu, Japan). 1HNMR spectra were recorded in DMSO-
d6 at 200 MHz on a Varian Gemini NMR spectrometer (δ, ppm) us-
ing TMS as an internal standard. Elemental analyses were carried
out by the Microanalytical Research Center, Faculty of Science, Cairo

1684
M. S. A. El-Gaby et al.
SCHEME 2
University. The characteristics data for the prepared compounds are
given in Table I.
1,4-Bis(2-cyanomethyl-4,5-dihydro-5-methylidene-4-
thiazolinone-5-yl) Benzene (3)
A mixture of thiazolinone 120 (0.02 mmol), terephthalaldehyde 2
(0.01 mmol), and piperidine (0.5 mL) in absolute ethanol (50 mL) was
heated under reflux for 3 h. The product obtained after cooling was
filtered, dried, and recrystallized from ethanol to give 3 (Table I).

Studies on Thiazolopyridines
1685
TABLE I Physical and Analytical Data for the Synthesized Compounds
Calculated/found (%)
Compd.
no.
m.p.
(◦C)
Yield
(%)
Solvent
cryst.
Mol. formula
(mol. wt.)
C
H
N
3
204–205
>300
78
72
65
60
53
80
56
63
69
60
63
64
67
70
82
86
62
59
E
D
D
D
D
D
E
E
E
E
E
E
D
D
D
D
D
D
C18H10N4O2S2
(378.43)
C38H20Br2N8O2S2
(844.58)
C38H20Cl2N8O2S2
(755.67)
C38H20Cl2N8O2S2
(755.67)
57.13 2.66 14.80
57.20 2.60 14.10
54.04 2.39 13.27
54.10 2.20 13.30
60.40 2.67 14.83
60.40 2.70 14.70
60.40 2.64 14.83
60.30 2.60 14.80
70.21 3.33 14.24
70.21 3.29 14.20
70.21 3.33 14.24
70.20 3.20 14.20
6a
6b
>300
6c
>300
6d
6e
>300
C46H26N8O2S2
(786.90)
>300
C
46H26N8O2S2
(786.90)
7a
167–168
160–162
162–164
166–165
167–168
155
C
12H7BrN2OS
(307.18)
46.92 2.30
46.80 2.10
9.12
9.30
7b
C
C
12H7Cl N2OS
(262.72)
12H7Cl N2OS
(262.72)
54.86 2.69 10.66
54.80 2.50 10.40
54.86 2.69 10.66
54.90 2.60 10.50
56.92 3.67 10.21
56.70 3.60 10.20
69.05 3.62 10.06
69.10 3.60 10.10
69.05 3.62 10.06
69.10 3.60 10.20
54.04 2.39 13.27
54.20 2.10 13.20
60.40 2.67 14.83
60.30 2.60 14.80
60.40 2.67 14.83
60.40 2.60 14.80
61.69 3.36 14.39
61.70 3.20 14.70
70.21 3.33 14.24
70.10 3.30 14.25
70.21 3.33 14.24
70.20 3.30 14.30
7c
7d
7e
C13H10 N2O3S
(274.30)
C
16H10 N2OS
(278.33)
7f
C
16H10N2OS
(278.33)
10a
10b
10c
10d
10e
10f
>300
C
38H20Br2N8O2S2
(844.58)
C38H20Cl2N8O2S2
(755.67)
38H20Cl2N8O2S2
(755.67)
>300
>300
C
>300
C
C
C
40H26N8O6S2
(778.83)
46H26N8O2S2
(786.90)
46H26N8O2S2
(786.90)
>300
>300
D = dioxane; E = ethanol.
1,4-Bis{5-amino-7-aryl-2-methylidene-2,3-dihydro-7H-3-
oxo thiazolo[3,2-a] pyridin-6,8-dicarbonitrile-2-yl}
Benzene Derivatives (6a–e)
A mixture of 3 (0.01 mmol), arylidenemalononitrile 4 (0.02 mmol), and
piperidine (0.5 mL) in absolute ethanol (50 mL) was heated under reflux

1686
M. S. A. El-Gaby et al.
TABLE II Spectral Data of the Synthesized Compounds
Compd.
no.
IR (νmax, cm−1
)
1H-NMR (δ, ppm) (DMSO-d6)
3
2950 (CH-aliph), 2200 (C N),
1695 (C O)
4.02 (s, 4H, 2 CH2 CN), 7.31–8.11
(m, 6H, 4H-Ar and 2H-methine)
6a
6b
6c
6d
6e
3468, 3433, 3267 (NH2), 2928
(CH-aliph), 2200 (C N), 1713
(C O)
3472, 3330, 3250 (NH2), 2922
(CH-aliph), 2199 (C N), 1714
(C O)
3412, 3301, 3229(NH2), 2929
(CH-aliph), 2197 (C N), 1713
(C O)
3464, 3323, 3264 (NH2), 2928
(CH-aliph), 2198 (C N), 1714
(C O)
3437, 3325, 3237 (NH2), 2926
(CH-aliph), 2197 (C N), 1714
(C O)
2950 (CH-aliph), 2199 (C N),
1715 (C O)
2981 (CH-aliph), 2204 (C N),
1720 (C O)
2934 (CH-aliph), 2200 (C N),
1718 (C O)
4.26 (s, 2H, pyridine-H), 4.98 (s, 2H,
NH2), 7.29–8.17 (m, 14H, 12H-Ar and
2H-methine), 10.10 (Hump, 2H, NH2)
4.80 (s, 2H, pyridine-H), 5.07 (s, 2H,
NH2), 7.39–8.09 (m, 14H, 12H-Ar and
2H-methine), 8.59 (s, 2H, NH2)
4.79 (s, 2H, pyridine-H), 4.89 (s, 2H,
NH2), 7.10–8.11 (m, 20H, 18H-Ar and
2H-methine), 10.05 (s, 2H, NH2)
4.60 (s, 2H, pyridine-H), 5.30 (s, 2H,
NH2) 7.20–8.06 (m, 20H, 18 H-Ar-H
and 2H-methine), 10.05 (s, 2H, NH2)
4.04 (s, 2H, CH2 CN), 7.12–7.85 (m, 5H,
4H-Ar and methine-H)
7a
7b
7c
7d
3483–2985 (broad, OH), 2200
(C N), 1707 (C O)
3.84 (s, 3H, OCH3), 4.76 (s, 2H, CH2, CN),
6.67–7.89 (m, 4H, 3H-Ar and
methine-H), 10.00 (s, 1H, OH)
7e
7f
2924 (CH-aliph), 2202 (C N),
1711 (C O)
2971 (CH-aliph), 2202 (C N),
1713 (C O)
10a
3446, 3336, 3266 (NH2), 2198
(C N), 1707 (C O)
4.79 (s, 2H, pyridine-H), 7.45–8.14
(m, 14H, 12H-Ar and 2H-methine),
8.60, 10.20 (2s, 4H, 2 NH2)
10b
10c
10d
10e
10f
3452, 3385, 3208 (NH2), 2900
(CH-aliph), 2196 (C N), 1715
(C O)
3431, 3413, 3347 (NH2), 2920
(CH-aliph), 2199 (C N), 1716
(C O)
3379, 3337, 3223 (NH2), 2934
(CH-aliph), 2200 (C N), 1709
(C O)
3397, 3363, 3337 (NH2), 2924
(CH-aliph), 2199 (C N), 1712
(C O)
5.13 (s, 2H, pyridine-H), 7.44–8.16
(m, 14H, 12H-Ar and 2H-methine),
8.61, 10.10 (2s, 4H, 2 NH2)
4.83, 4.85 (2s, 2H, pyridine-H), 7.49–8.17
(m, 14H, 12H-Ar and 2H-methine),
8.59, 10.09 (2s, 4H, 2 NH2)
4.83, 4.85 (2s, 2H, pyridine-H), 7.50–8.15
(m, 20H, 18H-Ar and 2H-methine),
8.59, 10.10 (2s, 4H, 2 NH2)
3339, 3214, 3170 (NH2), 2199
(C N), 1715 (C O)

Studies on Thiazolopyridines
1687
for 3 h. The solid product which was produced on heating was collected
and recrystallized form dioxane to give 6a–e (Table I).
5-Arylmethylidene-2-cyanomethyl-4,5-dihydro-4-
thiazolinones (7a–f)
A mixture of 1 (0.01 mmol), aromatic aldehyde (0.01 mmol), and piperi-
dine (0.5 mL) in absolute ethanol (30 mL) was heated under reflux for
1 h. then allowed to cool to room temperature. The precipitate was col-
lected by filtration and recrystallized from ethanol/benzene to give 7a–f
(Table I).
1,4-Bis{5-amino-2-arylmethylidene-2,3-dihydro-7H-3-
oxo-thiazolo[3,2-a] pyridin-6,8-dicarbonitrile-7-yl}
Benzene Derivatives (10a–f)
A mixture of 7 (0.02 mmol), benzylidene 8 (0.01 mmol), and triethy-
lamine (0.5 mL) in absolute ethanol (30 mL) was heated under reflux
for 3 h. The reaction mixture was then cooled, poured into crushed ice,
and neutralized with dilute HCl to give 10a–f, which were recrystal-
lized from dioxane (Table I).
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