Studies on thiazolopyridines. Part 5: Synthesis of hitherto unknown thiazolinone and thiazolo[3,2-a]pyridine derivatives having in their structure the morpholin-4-yl moiety

Article abstract of DOI:10.1080/10426500490468092

Condensation of thiazolinone 1 with, benzaldehydes 2a,b in ethanolic piperidine afforded the methylidene derivatives 3a,b. Cyclocondensation of compound 3b with malononitrile furnished the novel thiazolo[3,2-a]-pyridine 5. Also, compound 3b was condensed with dimethylformamide-dimethylacetal (DMF-DMA) and triethylorthoformate to yield N,N-dimethylamino 6 and ethoxymethylene 7 derivatives respectively. The novel thiazolo[3,2-a]pyridines 10a,b were obtained by cyclocondensation of compounds 3a,b with benzylidenemalononitriles 8a,b. Similarly, cyclocondensation of compound 3b with benzylidenemalononitrile 11 afforded the thiazolopyridines 12a-c. Ternary condensation of compound (12), 4-morpholinobenzaldehyde 2b and malononitrile (1:1:1 molar ratio) produced, the thiazolopyridines 14a-c. When compound 10b was subjected to react with malononitrile in dioxane/piperidine under reflux the novel condensed heterocyclic system 18 was obtained. Treatment of ortho-aminocarbonitrile 10b with formic acid, aromatic aldehyde and triethylorthoformate furnished the thiazolo[2′,3′:1,6]pyrido[2,3-d] pyrimidine 20, azomethine 21a,b and ethoxymethylene 22 derivatives respectively. The structure of the synthesized compounds was established by analytical and spectral data.

Full text of DOI:10.1080/10426500490468092

This article was downloaded by: [Dalhousie University]
On: 12 January 2013, At: 01:14
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
STUDIES ON THIAZOLOPYRIDINES. PART 5: SYNTHESIS
OF HITHERTO UNKNOWN THIAZOLINONE AND
THIAZOLO[3,2-a]PYRIDINE DERIVATIVES HAVING IN
THEIR STRUCTURE THE MORPHOLIN-4-YL MOIETY
R. Q. Lamphon a , M. S. A. El-Gaby b , M. M. Khafagy c , G. A. M. El-Hag Ali c , A. A. El-
Maghraby c , H. A. Eyada c & M. H. M. Helal c
a King Abdel-Aziz University, Madine Munawarah, Saudia
b Al-Azhar University at Assiut, Assiut, Egypt
c Al-Azhar University, Nasr City, Cairo, Egypt
Version of record first published: 16 Aug 2010.
To cite this article: R. Q. Lamphon , M. S. A. El-Gaby , M. M. Khafagy , G. A. M. El-Hag Ali , A. A. El-Maghraby , H. A. Eyada
& M. H. M. Helal (2004): STUDIES ON THIAZOLOPYRIDINES. PART 5: SYNTHESIS OF HITHERTO UNKNOWN THIAZOLINONE AND
THIAZOLO[3,2-a]PYRIDINE DERIVATIVES HAVING IN THEIR STRUCTURE THE MORPHOLIN-4-YL MOIETY, Phosphorus, Sulfur, and
Silicon and the Related Elements, 179:7, 1279-1292
To link to this article: http://dx.doi.org/10.1080/10426500490468092
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims,
proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 179:1279–1292, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490468092
STUDIES ON THIAZOLOPYRIDINES. PART 5:
SYNTHESIS OF HITHERTO UNKNOWN
THIAZOLINONE AND THIAZOLO[3,2-a]PYRIDINE
DERIVATIVES HAVING IN THEIR STRUCTURE
THE MORPHOLIN-4-YL MOIETY
R. Q. Lamphon,a M. S. A. El-Gaby,b M. M. Khafagy,c
G. A. M. El-Hag Ali,c A. A. El-Maghraby,c H. A. Eyada,c
and M. H. M. Helalc
King Abdel-Aziz University, Madine Munawarah, Saudia;a
Al-Azhar University at Assiut, Assiut, Egypt;b
and Al-Azhar University, Nasr City, Cairo, Egyptc
(Received September 17, 2003; accepted November 7, 2003)
Condensation of thiazolinone 1 with benzaldehydes 2a,b in ethano-
lic piperidine afforded the methylidene derivatives 3a,b. Cyclocon-
densation of compound 3b with malononitrile furnished the novel
thiazolo[3,2-a]-pyridine 5. Also, compound 3b was condensed with
dimethylformamide-dimethylacetal (DMF-DMA) and triethylortho-
formate to yield N,N-dimethylamino 6 and ethoxymethylene 7 deriva-
tives respectively. The novel thiazolo[3,2-a]pyridines 10a,b were
obtained by cyclocondensation of compounds 3a,b with benzylidene-
malononitriles 8a,b. Similarly, cyclocondensation of compound 3b with
benzylidenemalononitrile 11 afforded the thiazolopyridines 12a–c.
Ternary condensation of compound (12), 4-morpholinobenzaldehyde 2b
and malononitrile (1:1:1 molar ratio) produced the thiazolopyridines
14a–c. When compound 10b was subjected to react with malononi-
trile in dioxane/piperidine under reflux the novel condensed hetero-
cyclic system 18 was obtained. Treatment of ortho-aminocarbonitrile
10b with formic acid, aromatic aldehyde and triethylorthoformate fur-
nished the thiazolo[2ꢁ,3ꢁ:1,6] pyrido[2,3-d] pyrimidine 20, azomethine
21a,b and ethoxymethylene 22 derivatives respectively. The structure of
the synthesized compounds was established by analytical and spectral
data.
Keywords: Condensed thiazole derivatives; morpholine; thiazoline;
thiazolo[3,2-a]pyridine
Address correspondence to M. S. A. El-Gaby, Department of Chemistry, Faculty of Sci-
ence, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail: m-elgaby@hotmail.com
1279

1280
R. Q. Lamphon et al.
Morpholine derivatives have been reported to possess antimicrobial,1
hypoglycemic,2 antagonists of leukocyte,3 tyrosine kinase inhibitory,4
potent and selective M2 muscarinic receptor antagonist,5 hypo-
lipidemic,6 and inhibition of collagen-induced blood aggregation7
activities. Also, morpholine derivatives have medical bactericide,
fungicide, virucide, and anthelmintic8 activities. In addition morpho-
lines are commerically important as basic dyes for acrylic fibers,9 hair
dyes,10 sensitizers of photopolymerizable compounds11 and inflam-
mation inhibitors.12 Thiazolo[3,2-a]pyridine derivatives were reported
to furnish various biological and pharmacological activities such as
antimicrobial,13 bactericide,14 coronary dilator, antihypertensive, and
muscle relaxant15 activities. In continuation with our work on the
synthesis of heterocyclic compounds from readily available starting
materials,16−20 we report here on the synthesis of some novel thiazoli-
none and thiazolo[3,2-a]pyridine derivatives having in their structure
the morpholin-4-yl moiety in order to investigate the antimicrobial
activity.
RESULTS AND DISCUSSION
Condensation of thiazolinone 1 with 4-piperidinobenzaldehyde 2a and
4-morpholinobenzaldehyde 2b in ethanol and piperidine afforded the
methylidene derivatives 3a and 3b respectively. In the mass spectrum
of compound 3b, the molecular ion peak was observed at m/z 313 (78%)
and the base peak was found in the spectrum at m/z 314 (M + 1; 100%).
Cyclocondensation of compound 3b with malononitrile in ethanol in the
presence of triethylamine under reflux furnished the novel thiazolo[3,2-
a]-pyridine derivative 5, Scheme (1). Analytical and spectral data are
consistent with the structure of thiazolopyridine 5 and excluded the
other possible structure 4. The infrared spectrum revealed the pres-
ence of carbonyl function group at 1701 cm−1, as well as amino, and
1
carbonitrile function groups. Also, the H NMR spectrum of the reac-
tion product recorded in DMSO-d6 displayed a signal at δ 4.44 for an
pyridine-H in addition to N(CH2)2, O(CH2)2, aromatic, methylidene,
amino, and imino protons. The molecular ion peak of compound 5 was
observed at m/z 379 (25%) corresponding to the molecular formula
C19H17N5O2S and the base peak at m/z 378 (M-1). The formation of
thiazolopyridine 5 is assumed to proceed via the addition of the ac-
tive methylene in malononitrile to the cyano function group in 3b fol-
lowed by intramolecular cyclization at the cyano group and tautomer-
ization to furnish 5, Scheme (1). Also, compound 5 was obtained by
another synthetic route via the ternary condensation of compound 1,

Studies on Thiazolopyridines
1281
4-morpholinobenzaldehyde 2b and malononitrile (1:1:1 molar ratio) un-
der reflux in ethanol in the presence of triethylamine.
SCHEME 1
The reactivity of compound 3b towards some electrophilic reagents
was studied. Condensation of compound 3b with dimethylformamide-
dimethylacetal (DMF-DMA) in refluxing m-xylene produced the
N,N-dimethylamino derivative 6. The 1H NMR spectrum of compound
6 indicated the presence of N,N-dimethyl protons and the absence
of methylene protons which present in the parent compound. In a

1282
R. Q. Lamphon et al.
similar manner, compound 3b reacted with triethyl orthoformate to
yield ethoxymethylene derivative 7 (Scheme 2).
SCHEME 2
Cyclocondensation of compounds 3a,b with benzylidenemalono-
nitriles 8a,b (1:1 molar ratio) in ethanolic piperidine at reflux temper-
ature yielded the novel thiazolo[3,2-a]pyridines 10a,b in good yields
(Scheme 3). Structural elucidation of compounds 10a,b was accom-
plished from their analytical and spectral data. The infrared spectra
indicated the presence of amino, cyano and carbonyl function groups.
Also, the 1H NMR spectrum of compound 10a recorded in DMSO-
d6 displayed a signal at δ 4.43, attributed to the pyridin-H. In the
mass spectrum of compound 10b a molecular ion peak was observed
at m/z 525 (0.2%; M+-HCN). The formation of 10 is assumed to proceed
via Michael addition of methylene function group in 3 to the benzylidene
8 to yield Michael adduct 9 followed by intramolecular cyclization21,22
at the cyano group to form thiazolopyridine 10 (Scheme 3). Also, thia-
zolopyridines 10 were synthesized by another synthetic route through
ternary condensation of compound 3, benzaldehyde 2 and malononi-
trile (1:1:1 molar ratio) in ethanolic piperidine under reflux. Similarly,
cyclocondensation of compound 3b with benzylidenemalononitriles 11
in refluxing ethanol containing piperidine afforded the novel thiazolo-
pyridines 12a–c. The mass spectrum of compound 12a exhibited a
molecular ion peak at m/z 481 (15%) and base peak at m/z 279. Also,

Studies on Thiazolopyridines
1283
SCHEME 3

1284
R. Q. Lamphon et al.
ternary condensation of thiazolidine 13, 4-morpholinobenzaldehyde 2b
and malononitrile (1:1:1 molar ratio) under reflux in ethanolic piperi-
dine afforded the thiazolopyridines 14a–c (Scheme 3).
Our investigation was extended to study the reactivity of thiazolopy-
ridine 10b, which contain chalcone and ortho-amino carbonitrile moi-
eties, towards malononitrile. Thus, three possible structures 15, 16
and 18 can be formulated when compound 10b was subjected to re-
act with malononitrile in dioxane in the presence of piperidine under
reflux (Scheme 4). The structure of the novel condensed system 18 was
established and the other possible structures 15 and 16 were easily
eliminated on the basis of analytical and spectral data. The infrared
spectrum indicated the lack of a ring carbonyl function group and the
presence of amino and cyano function groups. Also, the 1H NMR spec-
trum of compound 18 recorded in DMSO-d6 revealed the presence of
a singlet at δ 4.19 attributed to pyridine-H in addition to morpholinyl,
amino, methylidene, and aromatic protons. The formation of 18 is as-
sumed to proceed through initial condensation of malononitrile with
carbonyl function group in 10b to form intermediate 17 followed by in-
tramolecular cyclization to one of the cyano group and tautomerization
to furnish 18 (Scheme 4).
Refluxing of ortho-aminocarbonitrile 10b with formic acid furnished
the corresponding thiazolo[2ꢁ,3ꢁ:1,6]pyrido[2,3-d]pyrimidine derivative
20. The formation of 20 is supposed to proceed through intermediate
amide formation23 19, resulting from the partial hydrolysis of cyano
functionality present at position six of 10b, followed by intramolecu-
lar cyclization with formic acid to give 20 (Scheme 5). Condensation
of compound 10b with aromatic aldehyde in dioxane containing a cat-
alytic amount of triethylamine yielded the novel azomethine deriva-
tives 21a,b. Also, fusion of compound 10b with triethyl orthoformate
afforded the ethoxymethylene derivative 22 (Scheme 5).
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded (KBr) on a
Perkin Elmer 1650 spectrophotometer. 1H NMR spectra were recorded
on Varian Gemini spectrometer 200 (200 MHz), using DMSO-d6 as a
solvent and TMS as internal standard. Chemical shifts are expressed
as δ ppm units. Mass spectra were recorded on a gas chromatographic
GC-MS qp 1000 Ex Shimadzu instrument at 70 eV. Microanalytical data
were obtained from the Microanalytical Data Unit at Cairo University.
Physical data for the synthesized compounds are given in Table I. Also,
the spectral data are collected in Table II.

Studies on Thiazolopyridines
1285
SCHEME 4

1286
R. Q. Lamphon et al.
SCHEME 5
2-Cyanomethyl-5-[4-(piperidin-1-yl) or 4-(Morpholin-4-
yl)benzylidenyl]-4,5-dihydro-4-thiazolinones (3a,b)
A mixture of compound 124 (0.01 mmol) and benzaldehyde 2a25 or 2b25
(0.01 mmol) and piperidine (0.5 mL) in absolute ethanol (40 mL) was
heated under reflux for 1 h, the solid product which produced on heating
was collected to give 3a and 3b respectively.
MS (3b): 313 (M+; 78%), 314 (M + 1; base peak), 315 (M + 2; 18.8%),
255 (87.6%), 219 (12.5%), 161 (82.2%), 86 (2.8%) and 80 (27%).

Studies on Thiazolopyridines
1287
TABLE I Physical Data for the Synthesized Compounds
Elemental analyses
calcd./found %
Compd.
no.
m.p.
(◦C)
Yield
(%)
Solvent
cryst.
Molecular formula
(mol. wt.)
C
H
N
3a
3b
235-7
210-1
260-2
190-2
250-2
262-4
>300
290-1
230-2
234-6
276-8
240-2
238-9
150-2
152-4
260-2
243-4
170-2
67
74
82
71
74
65
76
84
64
56
79
83
80
87
67
62
69
57
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Ethanol
Ethanol
Dioxane
C17H17N3OS
(311.41)
C16H15N3O2S
(313.38)
C19H17N5O2S
(379.44)
C19H20N4O2S
(368.46)
65.57
65.40
61.32
61.30
60.14
60.20
61.94
61.80
61.77
61.80
70.05
70.10
65.20
65.20
67.34
67.30
62.21
62.20
69.61
69.70
67.34
67.40
64.32
64.30
69.61
69.70
65.98
65.80
64.12
64.00
69.70
69.60
71.28
71.20
65.11
65.10
5.50
5.50
4.82
4.70
4.52
4.50
5.47
5.40
5.18
5.00
5.88
5.80
5.11
5.10
4.81
4.80
4.02
4.10
4.48
4.40
4.81
4.80
4.15
4.00
4.48
4.50
4.70
4.70
4.86
4.70
5.23
5.00
4.96
4.90
5.30
5.20
13.49
13.50
13.41
13.40
18.46
18.30
15.21
15.10
11.37
11.40
15.32
15.40
15.21
15.30
14.54
14.60
7.06
5
6
7
C
19H19N3O3S
(369.45)
10a
10b
12a
12b
12c
14a
14b
14c
18
C
32H32N6OS
(548.72)
C
30H28N6O3S
(552.66)
C27H23N5O2S
(481.58)
26H20ClN5O2S
(502.00)
C30H23N5O2S
(517.61)
C
7.20
13.53
13.40
14.54
14.60
14.42
14.60
13.53
13.40
18.65
18.70
14.47
14.30
12.83
12.90
12.17
12.20
13.81
13.60
C
27H23N5O2S
(481.58)
C
26H20FN5O2S
(485.54)
C
30H23N5O2S
(517.61)
C
33H28N8O2S
(600.71)
20
C31H28N6O4S
(580.67)
21a
21b
22
C
C
C
38H34N6O3S
(654.80)
41H34N6O3S
(690.83)
33H32N6O4S
(608.72)
5-Amino-7-imino-2-[4-(morpholin-4-yl)benzylidenyl]-3-
oxo-2,3-dihydro-thiazolo[3,2-a]pyridin-6-carbonitrile (5)
Method A: A mixture of compound 3b (0.01 mmol), malononitrile
(0.01 mmol), and triethylamine (0.5 mL) in absolute ethanol (30 mL)

1288
R. Q. Lamphon et al.
TABLE II Spectral Data of the Synthesized Compounds
Compd.
no.
IR /ν
(cm−1
)
1H NMR (δ/ppm) (DMSO-d6)
max
3a
2929, 2851 (CH-aliph),
2201 (C N), 1702 (C O).
1.59 (s, 6H, 3CH2), 3.34 (s, 4H, N(CH2)2),
4.04 (s, 2H, CH2), 7.02–7.51 (m, 5H, 4H-Ar
and methine proton).
3b
5
2958, 2851 (CH-aliph),
2198 (C N), 1709 (C O).
3392, 3319, 3284 (NH,
NH2), 2961, 2846 (CH
aliph), 2184 (C N), 1701
(C O), 1649 (C N).
3.31 (s, 4H, N(CH2)2), 3.75 (s, 4H, O(CH2)2),
4.44 (d, 1H, pyridine-H), 6.93, 7.21 (2d, 4H,
Ar-H), 7.12 (s, 1H, methine proton), 7.52 (s,
2H, NH2), 7.72 (s, 1H, NH).
6
7
2923, 2854 (CH-aliph),
2183 (C N), 1681 (C O).
3.10 (s, 6H, N(CH3)2), 3.38 (s, 4H, N(CH2)2),
3.75 (s, 4H, O(CH2)2), 6.91–7.60 (m, 5H, 4H-
Ar and methine proton), 7.99 (s,
1H, methine-H).
2962, 2846 (CH-aliph),
2198 (C N), 1705 (C O).
1.11 (t, 3H, CH3), 3.30 (s, 4H, N(CH2)2),
3.74 (s, 4H, O(CH2)2), 4.05 (q, 2H, OCH2),
6.97–8.15 (m, 6H, 4H-Ar and two methine
protons).
10a
3421, 3327 (NH2), 2929,
2851 (CH-aliph), 2202
(C N), 1696 (C O).
1.61 (s, 12H, 6CH2), 3.36 (s, 8H, two
N(CH2)2), 4.43 (s, 1H, pyridine-H), 6.91–7.53
(m, 10H, 8H-Ar and NH2), 7.71 (s, 1H,
methine-H).
10b
12a
12b
12c
14a
3394, 3322 (NH2), 2961,
2848 (CH-aliph), 2184
(C N), 1702 (C O).
3398, 3323 (NH2), 2961,
2847 (CH-aliph), 2185
(C N), 1702 (C O).
3387, 3330 (NH2), 2959,
2852 (CH-aliph), 2194
(C N), 1713 (C O).
3396, 3324 (NH2), 2958,
2850 (CH-aliph), 2191
(C N), 1687 (C O).
3.38 (s, 8H, two N(CH2)2), 3.76 (s, 8H, two
3.38 (O(CH2)2), 4.47 (s, 1H, pyridine-H), 6.99–
7.85 (m, 11H, 8H-Ar, NH2 and methine-H).
3.39 (s, 4H, N(CH2)2), 3.75 (s, 4H, O(CH2)2),
4.45 (s, 1H, pyridine-H), 6.90–7.80 (m, 10H,
8H-Ar and NH2), 8.00 (s, 1H, methine-H).
3.25 (s, 4H, N(CH2)2), 3.73 (s, 4H, O(CH2)2,
4.42 (s, 1H, pyridine-H), 6.92–8.10 (m, 14H,
11H-Ar, NH2 and methine-H).
2.33 (s, 3H, CH3), 3.34 (s, 4H, N(CH2)2),
3.75 (s, 4H, O(CH2)2), 4.46 (s, 1H, pyridine
-H), 6.93–7.53 (m, 10H, 8H-Ar and NH2),
7.75 (s, 1H, methine-H).
3415, 3327 (NH2), 2959,
2851 (CH-aliph), 2193
(C N), 1701 (C O).
14b
14c
18
3413, 3320 (NH2), 2959,
2853 (CH-aliph), 2194
(C N), 1692 (C O).
3400, 3331 (NH2), 2959,
2852 (CH-aliph), 2210
(C N), 1695 (C O).
3330, 3209 (NH2), 2957,
2855 (CH-aliph), 2214
(C N).
3.25 (s, 4H, N(CH2)2), 3.75 (s, 4H, O(CH2)2),
4.44 (s, 1H, pyridine-H), 6.92 (m, 10H, 8H-
Ar and NH2), 7.78 (s, 1H, methine-H).
3.35 (s, 8H, two N(CH2)2), 3.76 (s, 8H, two
O(CH2)2), 4.19 (s, 1H, pyridine-H), 7.07,
7.90 (2d, 8H, Ar-H), 7.42 (s, 1H, methine-H),
8.13 (s, 2H, NH2).
(Continued on next page)

Studies on Thiazolopyridines
1289
TABLE II Spectral Data of the Synthesized Compounds
Compd.
no.
IR /ν
(cm−1
)
1H NMR (δ/ppm) (DMSO-d6)
max
20
3165 (NH), 2957, 2852
(CH-aliph), 2214 (C N),
1678 (C O, broad).
3.34 (s, 8H, two N(CH2)2), 3.74 (s, 8H, two
O(CH2)2), 4.10 (s, 1H, pyridine-H), 6.92–7.90
(m, 9H, 8H-Ar and methine-H), 8.01 (s, 1H,
NH), 8.14 (s, 1H, CH-pyrimidine).
21a
2960, 2853 (CH-aliph),
2.21 (s, 3H, CH3), 3.28 (m, 8H, two
2214 (C N), 1704 (C O).
N(CH2)2), 3.74 (s, 8H, two O(CH2)2), 4.15 (s,
1H, pyridine-H), 6.90–7.80 (m, 9H, 8H-Ar
and methine-H), 8.20 (s, 1H, CH N).
21b
22
2957, 2852 (CH-aliph),
2203 (C N), 1703 (C O).
2962, 2854 (CH-aliph),
2214 (C N), 1712 (C O).
1.22 (t, 3H, CH3), 3.38 (s, 8H, two N(CH2)2,
3.73 (s, 8H, two O(CH2)2), 4.10 (q, 2H,
OCH2), 4.67 (s, 1H, pyridine-H), 6.97–7.89
(m, 9H, 8H-Ar and methine-H), 8.13 (s, 1H,
CH N).
was heated under reflux for 10 min, the solid product which produced
on heating was collected to give 5.
MS (5): 379 (M+; 25%), 378 (M-1; base peak), 216 (75%), 147 (34%),
131 (28%) and 77 (30%).
Method B: A mixture of compound 1 (0.01 mmol), benzaldehyde 2b
(0.01 mmol), malononitrile (0.01 mmol), and triethylamine (0.5 mL) in
absolute ethanol (30 mL) was heated under reflux for 10 min and the
solid product was collected to give 5.
3-Dimethylamino-2-[5-(4-(morpholin-4-yl)benzylidenyl)-
4-oxo-4,5-dihydro-thiazol-2-yl]acrylonitrile (6)
A mixture of compound 3b (0.01 mmol) and dimethylformamide-
dimethylacetal (0.01 mmol) in dry m-xylene (30 mL) was refluxed for
3 h, then cooled and the precipitated product was filtered off, washed
with ether to give 6.
3-Ethoxy-2-[5-(4-(morpholin-4-yl)benzylidenyl)-4-oxo-
4,5-dihydro-thiaol-2-yl]acrylonitrile (7)
A mixture of compound 3b (0.01 mmol) and triethyl orthoformate (5 mL)
was heated under reflux for 3 h, then allowed to cool and poured into
pet. ether 40/60 and the solid product was collected to give 7.

1290
R. Q. Lamphon et al.
5-Amino-3-oxo-2-[4-(piperidin-1-yl)benzylidenyl]-7-[4-
(piperidin-1-yl)phenyl]-2,3-dihydro-7H-thiazolo[3,2-
a]pyridin-6,8-dicarbonitrile (10a) and 5-Amino-3-
oxo-2-[4-(morpholin-4-yl)benzylidenyl]-7-[4-(morpholin-
4-yl)phenyl]-2,3-dihydro-7H-thiazolo[3,2-a]pyridin-6,8-
dicarbonitrile (10b)
Method A: General Procedure:
A mixture of compound 3
(0.01 mmol), benzylidenemalononitrile 8 (0.01 mmol), and piperidine
(0.01 mmol) in absolute ethanol (30 mL) was heated under reflux for
2 h, the solid product which produced on heating was collected to give
10.
MS (10b): 525 (M-HCN; 0.2%), 313 (31%), 255 (28%), 176 (44%), 162
(40%) and (86; base peak).
Method B: A mixture of compound 3 (0.01 mmol), malononitrile
(0.01 mmol), benzaldehyde 2 (0.01 mmol), and piperidine (0.01 mmol)
in absolute ethanol was heated under reflux for 2 h, the solid product
which produced on heating was collected to give 10.
5-Amino-3-oxo-2-[4-(morpholin-4-yl)benzylidenyl]-7-aryl-
2,3-dihydro-7H-thiazolo[3,2-a]pyridin-6,8-dicarbonitriles
(12a--c): General Procedure
A mixture of compound 3b (0.01 mmol), benzylidenemalononitrile 11
(0.01 mmol), and piperidine (0.01 mmol) in absolute ethanol (30 mL)
was heated under reflux for 3 h. The solid product which produced on
heating was collected to give 12.
MS (12a): 481 (M+; 15%), 417 (94%), 337 (78%), 279 (base peak), 170
(80%), 149 (57%) and 104 (27%).
5-Amino-2-arylmethylidene-7-[4-(morpholin-4-
yl)phenyl]-3-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyridin-
6,8-dicarbonitriles (14a--c): General procedure
A mixture of compound 322 (0.01 mmol), benzaldehyde 2b (0.01 mmol),
malononitrile (0.01 mmol), and piperidine (0.01 mmol) in absolute
ethanol (30 mL) was heated under reflux for 30 min and the precip-
itate was collected by filtration to give 14a–c.
4-Amino-2-[4-(morpholin-4-yl)benzylidenyl]-7-[4-
(morpholin-4-yl)-phenyl]-2,7-dihydro-1-thia-5,8b-diaza-
acenaphthylene-3,6,8-tricarbonitrile (18)
A mixture of compound 10b (0.01 mmol), malononitrile (0.01 mmol),
and piperidine (0.01 mmol) in dioxane (20 mL) was heated under reflux

Studies on Thiazolopyridines
1291
for 3 h, then allowed to cool. The solid product was collected to give
18.
8-[4-(Morpholin-4-yl)benzylidenyl]-5-[4-(morpholin-4-
yl)phenyl]-3,4,8,9-tetrahydro-5H-4-oxo-thiazolo[2’,3’:1,6]
pyrido[2,3-d]-pyrimidin-6-carbonitrile (20)
A mixture of compound 10b (0.01 mmol) in formic acid (10 mL) was
heated under reflux for 12 h. The reaction mixture was concentrated in
vacuo and the solid product was collected, washed with water to give
20.
2-[4-(Morpholin-4-yl)benzylidenyl]-5-arylideneamino-7-
[4-(morpholin-4-yl)phenyl]-3-oxo-2,3-dihydro-7H-
thiazolo[3,2-a]-pyridin-6,8-dicarbonitriles (21a,b)
A mixture of compound 10b (0.01 mmol) and aromatic aldehydes
(0.01 mmol) in dioxane (20 mL) and a few drops of piperidine was re-
fluxed for 3 h, then allowed to cool and poured into cold water (60 mL)
and the solid product was collected to give 21a,b.
5-Ethoxmethyleneamino-2-[4-(morpholin-4-
yl)benzylidenyl]-7-[4-(morpholin-4-yl)phenyl]-3-oxo-2,3-
dihydro-7H-thiazolo[3,2-a]-pyridin-6,8-dicarbonitrile (22)
A mixture of compound 10b (0.01 mmol) and triethyl orthoformate
(3 mL) was heated under reflux for 1 h. The solid product was collected
to give 22.
REFERENCES
[1] P. Magdolen, P. Zahradnik, and P. Foltinova, Pharmazie, 55(11), 803 (2000).
[2] K. H. Pfoertner, K. Bernauer, F. Kaufmann, and E. Lorch, Helv. Chim. Acta, 68(3),
584 (1985).
[3] M. Winn, E. B. Reilly, G. Liu, et al., J. Med. Chem., 44, 4393 (2001).
[4] L. Sun, N. Tran, F. Tang, et al., J. Med. Chem., 41, 2588 (1998).
[5] T. Watanabe, A. Kakefuda, I. Kinoyama, et al., Chem. Pharm. Bull., 45, 1458 (1997).
[6] W. D. Vaccaro, D. A. Burnett, and J. W. Clader, PCT Int. Appl. WO 9619, 450 (Cl.
C07D205/08); Chem. Abstr., 125, 142526z (1996).
[7] D. M. Duchworth, R. M. Hindley, Eur. Pat. Appl. EP. 68, 669 (Cl. C07C91/16), 05
Jan 1983, GB Appl. 81/19, 112, 20 Jun 1981; Chem. Abstr., 98, 160401h (1983).
[8] E. M. Karpitschka, W. Kloetzer, H. Link, et al., Eur. Pat. Appl. EP. 200, 947 (Cl.
C07D233/56) 17 Dec 1986, CH Appl., 85/1778, 26 Apr 1985; Chem. Abstr., 107,
198319e (1987).

1292
R. Q. Lamphon et al.
[9] M. Takahashi and T. Uemura, Japan, Kokai, 71, 13, 409 (Cl. 23A0, 48B111), 12 Feb
1975, Appl. 7363, 759, 08 Jun 1973; Chem. Abstr., 88, 51964s (1978).
[10] H. Moeller, H. Hoeffkes, and B. Meinigke, Ger. Offen. DE 19, 630, 274 (Cl. A61K7/13),
29 Jan 1998, Appl. 19, 630, 274, 26 Jul 1996; Chem. Abstr., 128(11), 132250c (1998).
[11] A. G. Anderson, Eur. Pat. Appl. EP 39, 025 (Cl. C07C97/10), 04 Nov 1981, US Appl.
142, 173, 21 Apr 1980; Chem. Abstr., 96, 77549a (1982).
[12] G. Schmidt, W. Opitz, and H. Jacobi, Ger. Offen. 2, 836, 613 (Cl. C07D295/14), 13
Mar 1980, Appl, 22, Aug 1978; Chem. Abstr., 93, 186789n (1980).
[13] U. Olthoff, K. Matthey, and B. Ditscher, Ger (East) 84, 850 (Cl. C07D), 05 Oct 1971,
Appl. WP C07D/148314, 16 Jun 1970; Chem. Abstr., 78, 72121y (1973).
[14] K. Sato and U. Nagai, Jpn. Kokai Tokkyo Koho JP 6222, 798 [8722, 798] (Cl.
C07K7/00), 30 Jan 1987, Appl. 85/163, 306, 24 Jul 1985; Chem. Abstr., 107, 115975s
(1987).
[15] H. Meyer, F. Bossert, W. Vater, and K. Stoepel, Ger. Offen., 2, 210, 633 (Cl. C07D),
20 Sep 1973, Appl. P. 2210, 633, 06 Mar 1972; Chem. Abstr., 79, 146519d (1973).
[16] M. S. A. El-Gaby, A. M. Gaber, A. A. Atall, and K. A. Abd Al-Wahab, Il Farmaco, 57,
613 (2002).
[17] M. S. A. El-Gaby, J. A. Micky, N. M. Taha, and M. A. M. Sh. El-Sharief, J. Chin.
Chem. Soc., 49, 407 (2002).
[18] M. S. A. El-Gaby, J. A. Micky, N. M. Taha, and M. A. M. Sh. El-Sharief, Acta Chem.
Slov., 49, 159 (2002).
[19] M. S. A. El-Gaby, Y. A. Ammar, A. M. Sh. El-Sharief, M. A. Zahran, and A. A.
Khames, Heteroatom Chem., 13(7), 611 (2002).
[20] M. S. A. El-Gaby, A. A. Atalla, A. M. Gaber, and K. A. Abd Al-Wahab, IL Farmaco,
55, 596 (2000).
[21] A. A. El-Maghraby, G. A. M. El-Hag Ali, A. H. Ahmed, and M. S. A. El-Gaby, Phos-
phorus, Sulfur and Silicon, 117, 293 (2002).
[22] G. A. M. El-Hag Ali, A. Khali, A. H. Ahmed, and M. S. A. El-Gaby, Acta Chim. Slov.,
49, 365 (2002).
[23] C. G. Dave and R. D. Shah, J. Heterocyclic Chem., 35, 1295 (1998).
[24] M. H. Elnagdi, M. R. H. Elmoghayar, A. G. Hammam, and S. A. Khallaf, J. Hetero-
cylic Chem., 16, 1541 (1979).
[25] D. J. Gale and J. F. K. Wilshire, Aust. J. Chem., 23, 1063 (1970).