Synthesis and spectral characterization of novel thiazolopyridine and pyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2011.615445

Novel thiazolo [3,2-a]pyridine and thiazolo[3,2-a]pyrimidine derivatives, pyrazolo[3,4-b]pyrano[2,3-d]thiazole, and coumarin derivatives were synthesized from readily obtainable starting materials such as (Z)-2-ethoxycarbonyl methyl-5-(4-chlorobenzylidene)-2-thiazolidin-4(H)one 3 and (Z)-4-(4- hydroxybenzylidene)-2-imino-2-thiazolidin-4(H)one 11.

Full text of DOI:10.1080/00397911.2011.615445

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Synthesis and Spectral Characterization
of Novel Thiazolopyridine and
Pyrimidine Derivatives
Mahmoud R. Mahmoud a , Ahmed K. El-Ziaty a & Ahmed M. Hussein a
a Synthetic Organic Chemistry Laboratory, Chemistry Department,
Faculty of Science, Ain Shams University, Cairo, Egypt
Accepted author version posted online: 22 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Mahmoud R. Mahmoud , Ahmed K. El-Ziaty & Ahmed M. Hussein (2013): Synthesis
and Spectral Characterization of Novel Thiazolopyridine and Pyrimidine Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:7, 961-978
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Synthetic Communications1, 43: 961–978, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.615445
SYNTHESIS AND SPECTRAL CHARACTERIZATION OF
NOVEL THIAZOLOPYRIDINE AND PYRIMIDINE
DERIVATIVES
Mahmoud R. Mahmoud, Ahmed K. El-Ziaty, and Ahmed
M. Hussein
Synthetic Organic Chemistry Laboratory, Chemistry Department, Faculty of
Science, Ain Shams University, Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract Novel thiazolo [3,2-a]pyridine and thiazolo[3,2-a]pyrimidine derivatives, pyra-
zolo[3,4-b]pyrano[2,3-d]thiazole, and coumarin derivatives were synthesized from readily
obtainable starting materials such as
chlorobenzylidene)-2-thiazolidin-4(H)one
2-imino-2-thiazolidin-4(H)one 11.
(Z)-2-ethoxycarbonyl methyl-5-(4-
and (Z)-4-(4-hydroxybenzylidene)-
3
Keywords Activated nitrile; thiazolopyridine; thiazolopyridopyrimidine
INTRODUCTION
Acute and chronic inflammation and different types of arthritis are inflamma-
tory disorders that deal a big blow to humanity, and continual search for new
Received June 28, 2011.
Address correspondence to Ahmed K. El-Ziaty, Synthetic Organic Chemistry Laboratory,
Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt.
E-mail: ahm512@sci.asu.edu.eg
961

962
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
nonsteroidal anti-inflammatory agents is the only way to protect against this threat.
In the past few decades the literature has been enriched with newer agents that are
structurally different from the presently known anti-inflammatory drugs, but the
search for better candidates in terms of higher efficacy and selectivity with lesser side
effects continues to be an area of research for scientists worldwide.
The thiazolopyridine ring system is found in a broad range of biologically
active compounds.[1] Thiazolo[3,2-a]pyridine derivatives exhibit a broad spectrum
of potent anticancer activity and are useful for chemotherapy of various cancers,
such as leukemia, lung cancer, and melanoma.[2] Because of their biological impor-
tance, thiazolo[3,2-a]pyridine derivatives have become synthetic targets for many
organic and medicinal chemists.[3–10]
RESULTS AND DISCUSSION
In this context, the reaction of acrylonitriles with 2-thiazolidine derivatives has
previously been said to afford the thiazolopyridine derivatives in moderate yields.[11–13]
We report here that no thiazolopyridine could be isolated in the reaction of 2-ethoxy-
carbonyl methylthiazolidin-4one 1 with 2-cyano-3-(4-chlorophenyl)-2-propenonitrile
2 in refluxing ethanol in the presence of catalytic amount of piperidine and instead
we have found that the reaction product was the arylidene derivative of thiazolidinone
3 as the sole product (Scheme 1).
at 1762 cmꢀ1 and tC
=
=
The IR spectrum of 3 exhibit tC
O(ester)
O(unsaturated cyclic
at 1686 cmꢀ1 and devoid the coupling bands of NH2. H-NMR spectrum
1
amide)
(DMSO-d6) of 3 revealed a signals at d 12.3 (br.s, 1H, NH, exchangeable with
=
=
D2O), 7.66-7.59 (m, 4Harom), 7.5(s, 1H, C CH), 5.63 (s,1H, C CH), 4.16-4.09 (q,
2H, J ¼ 8.5 Hz), 1.24-1.19 (t, 3H, J ¼ 8.5 Hz) which completely in accord with the
assigned structure.
Scheme 1. Formation of 5-(4-chlorobenzylidene)-2-ethoxy carbonyl methyl-D2-thiazolidin-4(H)one 3.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
963
Figure 1. EI fragmentation pattern of (Z)-5-(4-chlorobenzylidene)-2-ethoxycarbonyl methyl-D2-
thiazolidin-4(H)one 3.
The EI-MS of 3 show the correct molecular ion peak at m=z ¼ 309 (38.6%)
together with M þ 1 and M þ 2 peaks at m=z ¼ 310 (8.6%), 311 (15.1%) respectively.
=
The base peak at m=z ¼ 168(100%) attributable for the radical cation Ar-CH C ¼ S.
Moreover, the structure of compound 3 was confirmed by comparison with an
authentic specimen resulting from the condensation of 2-ethoxycarbonyl methyl-D2-
thiazolidin-4(H)one 2 with 4-chlorobenzaldehyde in refluxing ethanol in the presence
of a catalytic amount of piperidine (mp 180–182ꢁC undepressed on admixture with
an authentic sample).
5-Amino-2-(4-chlorobenzylidene)-7-(N,N-dimethyl-4-aminophenyl)-8-ethoxy-
carbonyl-3-oxo-2H,3H,7H-thiazolo [3,2-a]pyridine-6-carbonitrile 4 (Arꢀ ¼ C6H4
NMe2-4) was obtained in fairly good yield (58%) upon treatment of compound 3 with
a -cyano-N,N-dimethyl-4-aminocinnamonitrile in refluxing ethanol in the presence of
catalytic amount of piperidine (Scheme 2).
The structure of thiazolo[3,2-a]pyridine derivative 4 was deduced from analyti-
cal and spectroscopic data.
1H NMR spectrum (DMSO-d6) of compound 4 revealed signals from low to
upfield at d (ppm) 12.2 as a singlet integrated for 2 H that disappeared with D2O,
a multiplet for 9H at d ranging from 7.6 to 7.5 ppm for aromatic protons with
one olefinic proton, a singlet at d 5.6 integrated for one benzylic proton, a quartet
at d 4.1–4.09 ppm integrated for 2H (methylene protons of ethyl group), a singlet
for 6H at d 3.3 ppm that represents an N(CH3)2 group, and a triplet for 3H at d
1.2–1.1 ppm for (methyl protons of the ethyl group).
On the other hand, full analysis of the mass spectrum of compound 4 shows
the correct molecular ion peak at m=z ¼ 506 (34.4%) with M þ 1 and M þ 2 peaks
at m=z ¼ 507 (13.5%) and 508 (6.9%). The base peak at m=z ¼ 395 (100%) are
attributable to the cation (M-Ar.).
The formation of thiazolo[3,2-a]pyridine derivative 4 could be explained as
shown in (Scheme 3).

964
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
Scheme 2.
Figure 2. EI-MS fragmentation pattern for compound 4.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
965
Scheme 3. The pathway of the formation of 5-amino-2-(4-chlorobenzylidene)-7-(N,N-dimethyl-4-amino-
phenyl)-8-ethoxy carbonyl-3-oxo-2H,3H,7H-thiazolo[3,2-a]pyridine-6-carbonitrile 4.
The structure of compound 4 was chemically supported via its reaction with
one-carbon donor reagents. Thus treatment of compound 4 with triethyl orthofor-
mate in freshly distilled acetic anhydride under reflux for 10h yielded
2-(4-chlorobenzylidine)-7-(N,N-dimethyl-4-aminophenyl)-8-ethoxycarbonyl-5-ethoxy
methylene amino-3-oxo-2H,3H,7H-thiazolo[3,2-a]pyridine-6-carbonitrile5 (Scheme 2).
Figure 3. EI fragmentation pattern for compound 7.

966
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
The IR spectrum of 5 is devoid of the stretching absorption bands character-
istic for the amino group but retained ꢀt1CꢂN at 2207 cmꢀ1, tC O(ester) at
=
1725 cmꢀ1, tC O(cyclic amide) at 1691 cm , and tC N at 1634 cmꢀ1. The highest
recorded peak in the mass spectrum of compound 5 at m=z ¼ 562 (54.6%) represents
the molecular ion peak, which upon loss of ethoxy radical and carbon monoxide
molecule afforded the cation [M-COOEt] peak at m=z ¼ 489 (22.4%). The base peak
=
=
1
at m=z ¼ 451 (100%) was attributable to the cation [M-Ar.]. H NMR spectrum of 5
(DMSO-d6) shows the disappearance of amino protons and retained signals charac-
teristic of two different ethyl protons.
Compound 5, when subjected to react with cyclohexyl amine in boiling etha-
nol, afforded the thiazolopyridopyrimidine derivative 6 (Scheme 2).
The IR spectrum of 6 is devoid of the stretching absorption bands character-
=
istic of the nitrile group and the carbonyl ester group and displayed tC O of cyclic
and open amide.
On the other hand, treatment of compound 4 with carbon disulphide in ethanolic
KOH afforded 8-amino-2-(4-chlorobenzylidene)-9-(N,N-dimethyl-4-aminophenyl)
-10-ethoxycarbonyl-3-oxo-9H-thiazolo[3,2-a]pyrido[2,3-d]1,3-thiazin-6(H)thione 7.
The structure of compound 7 was substantiated by analytical data and con-
firmed by IR and mass spectroscopy. Thus, the IR spectrum of 7 displayed tNH at
3423, 3242 cmꢀ1(w), tC O(ester) at 1732 cmꢀ1, tC O(a, b-unsat. cyclic ketone) at 1683 cmꢀ1
,
=
=
and tC S at 1213 cmꢀ1 and is devoid of the stretching absorption band for the cyano
group which indicates that the cyano group was involved in the reaction pathway.
The mass spectrum of compound 7 shows the correct molecular ion peak at m=
z ¼ 582 (0.82%) together with the peak at m=z ¼ 506 (26.9%) attributable to the rad-
ical cation [M.þ-CS2], and the base peak at m=z ¼ 395 (100%) was obtained upon loss
of the CS2 molecule followed by removal of the chlorophenyl radical.
The reaction of compound 3 with cyanoethanoic hydrazide in refluxing diox-
ane in the presence of a catalytic amount of triethyl amine afforded pyrazolo[3,4-
b]pyrano[2,3-d]thiazole derivative 8 (Scheme 4). The EI fragmentation for compound
8 shows the correct molecular ion peak at m=z ¼ 408 (11.0%).
=
When compound 3 was subjected to react with 4-amino-6-(4-chlorophenyl)-2-
hydrazinopyrimidine-5-carbonitrile 9 in refluxing ethanol, a sulfur-free compound
was obtained with molecular formula C25H19Cl2N7O3 [M.þ ¼ 536] (Scheme 4). The
assigned structure 10 was based on many arguments such as the analytical and
spectroscopic data.
1HNMR spectrum of compound 10 (DMSO-d6) revealed signals at d (ppm)
12.2 (s, 1H, NH, exchangeable with D2O), 7.6–7.15 (m, 9Haromþone olefinic H),
5.6 (s, 2H, NH2, exchangeable with D2O), 4.17–4.09 (q, 2H, J ¼ 4.2 Hz), 3.4 (s,
2H), and 1.2–1.16 (t, 3H, J ¼ 5.4 Hz). Furthermore, the greatest recorded peak in
the mass spectrum of 10 at m=z ¼ 535 (21.4%) represented the molecular ion peak.
In the context of our investigation of thiazolopyrimidines, the author attempted
to prepare thiazolopyrimidine derivatives according to the published procedure.[13]
Thus, treatment of 2-imino-4-oxo-2-thiazolidine with a-cyano-4-hydroxycin
namonitrile in refluxing ethanol in the presence of a catalytic amount of piperidine
afforded (Z)-5-(4-hydroxybenzylidene)-2-imino-2-thiazolidin-4(H)-one 11 as the sole
product in fairly good yield (Scheme 5).

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
967
Scheme 4. Formation of ethyl [8a-amino-4-(4-chlorophenyl)-3-oxo-1,2,3,3a,4,8a,hexahydropyrazolo[40,
30,5,6]pyrano[2,3-d][1,3]thiazol-6-yl] acetate 8 and (Z)-ethyl-2-(5-(4-chlorobenzylidine)-1-(4-amino-6-(4-
chloeophenyl)-5-cyanopyrimidine-2-ylamino)-4-oxo-4,5-dihydro-1H-imidazol-2-yl)acetate 10.
Figure 4. Mass fragmentation pattern for compound 10.

968
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
Scheme 5. Formation of 4-(4-hydroxy benzylidene)-2-imino-2-thiazolidine-4(H)one 11.
The structure of compound 11 is substantiated from microanalytical data and
was confirmed by IR and mass spectroscopy. Thus, the IR spectrum of 11 exhibit
tOH(phenolic) br. 3520–2820 cmꢀ1, tNH at 3212 cmꢀ1, and tC
at 1658 cmꢀ1. The
=
O
mass spectrum of 11 shows the molecular ion peak at m=z ¼ 220 (12.76%) together
with the base peak at m=z ¼ 150 (100%).
5-Amino-2-(4-hydroxybenzylidine)-7-(4-chlorophenyl)-3-oxo-7H-thiazolo[3,2-
a]pyrimidine-6-carbonitrile 12 could be obtained in moderate yield upon treatment
Figure 5. EI-MS of (Z)-5-(4-hydroxybenzylidene)-2-imino 4-oxo-2-thiazolidine 11.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
969
of compound 11 with a-cyano-4-chlorocinnamonitrile in boiling dioxane in the
presence of a catalytic amount of piperidine (Scheme 6). The structure of 12 was elu-
cidated from analytical data and confirmed by the study of its IR and mass spec-
troscopy. It was reported[14 15]
that treatment of compound 2-alkylthio or
,
2-imino-4-oxo-5-arylidineD2-thiazolidines with primary amines gave the 2-substidu-
ted imino-4-oxo-thiazolidines. Herein, treatment of compound 11 with cyclohexyl
amine in refluxing dioxane afforded 2-cyclohexyl amino-4-oxo-5-(4-hydroxybenzyli-
dene)-D2-thiazoline 13 (Scheme 6).
The structure of 13 was confirmed from the spectral data. The EI-MS shows
the correct molecular ion peak at m=z ¼ 302(10.43%), which upon loss of cyclohexyl
radical yielded the cation at m=z ¼ 219 (55.1%). Loss of isocyanate and cyanide rad-
ical gave the base peak at m=z ¼ 150 (100%).
Scheme 6. Reactions on 4-(4-hydroxy benzylidene)-2-imino-2-thiazolidine-4(H)one 11.

970
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
A tentative explanation for the formation of 13 is that it forms via the nucleo-
philic addition of nitrogen nucleophile to the positively polarized carbon of the
=
C NH group followed by elimination of the NH3 molecule (Scheme 7).
Several authors reported the formation of piperdino and morpholino salts of
5-aryl methylene-2-thioxo-4-oxo-1,3-thiazolidines by reacting the 3H-thiazolines
with the required secondary amine in acetone or methyl acetate solution.[14]
Treatment of (Z)-2-imino-5-(4-hydroxybenzylidene)-4-oxo-thiazolidine 11 with
piperidine or morpholine afforded (Z)-2-(piperidin-1-yl)thiazol-4(5H)one 14a and
(Z)-2-(morpholin-1-yl) thiazol-4(5H)one 14b.
The EI-MS of compounds 14a and 14b shows the correct molecular ion peaks
that agree with the proposed structure.
Furthermore, 1HNMR spectrum of 14a (DMSO-d6) revealed the following sig-
nals at d (ppm): 10 (brs, 1H, OH, exchangeable with D2O), 7.52 (s, 1H, ¼CH),
7.49–7.48 (d, 2Harom. J ¼ 8.8 Hz), 6.89–6.87 (d, 2Harom. J ¼ 8.8 Hz), 3.59–3.56 (t,4H,
CH2N, J ¼ 5.6 Hz), 1.66–1.48 (m, 6H).
1H NMR spectrum of 14b (DMSO-d6) shows signals at d (ppm) 10.3 (brs, 1H,
OH, exchangeable with D2O), 7.95 (s, 1H), aromatic protons as doublet integrated
for 2H at d 7.59–7.46 ppm, doublet for 2H at d 6.92–6.88 ppm, and two triplets each
integrated for 4H at d 3.89–3.86 ppm (CH2OCH2) and 3.56–3.55 ppm (CH2NCH2).
Conversion of 2-piperidino or morpholino-5-aryl methylene-4-oxo-thiazolidine
14a and b into the potassium salt 15 have been done on the basis of the higher acidity
of the 3H-compound by treating compounds 14a and b with ethanolic potassium
hydroxide solution (Scheme 6).
Formation of the potassium salt 15 implies that the substituent at the 2-
position is knocked out through the reaction. The route of conversion of 14a and b into
potassium salt of 5-arylidene-2,4-dioxothiazolidine 15 is represented in (Scheme 8).
Structure of the potassium salt 15 is evidenced by spectral data. Thus, its IR
=
spectrum shows tC at relative lower frequencies as compared with the extra con-
O
jugation performed by the newly formed negative charge (1655 cmꢀ1).
Ample evidence for the structure of the potassium salt is forthcoming from
alkylation of 15 with ethyl chloroacetate in boiling dioxane, which gave the
N-alkylation product 16.
Figure 6. EI-MS pattern of compounds 14a and b.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
971
2
Scheme 7. The pathway of the formation of 2-cyclohexylamino-5-(4-hydroxybenzylidine)-4-oxo-4 -
thiazoline 13.
The IR spectrum of 2,4-dioxo-5-(4-hydroxy benzylidene)-3-ethoxycarbonyl
methyl-2-thiazolidine 16 displayed stretching carbonyl absorption frequencies
characteristic of cyclic imide and ester groups.
1HNMR spectrum was completely in accordance with the assigned structure
16, since it revealed the signals at d (ppm) 10.1 (s, 1H, OH, exchangeable with
Figure 7. EI-MS pattern of compound 16.

972
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
Scheme 8. The pathway of the formation of potassium salt 15.
Figure 8. EI fragmentation pattern for compound 17.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
973
D2O), 7.5 (s, 1H, ¼CH), 7.48–7.45 (d, 2Harom., J ¼ 9 Hz), 6.9–6.87 (d, 2Harom.
,
J ¼ 9 Hz), 3.9–3.86 (q, 2H, J ¼ 12 Hz), 3.59 (brs, 2H, CH2COOEt), and 1.6 (t, 3H,
J ¼ 11.8 Hz).
The greatest recorded m=z value at 307 (2.49%) corresponding to the molecular
ion peak, as well as the base peak at m=z ¼ 150 (100%), is characteristic of the radical
=
cation Ar-CH C¼S.
Treatment of 2-imino-5-(4-hydroxybenzylidene)-4-oxo-thiazolidine 11 with
cyanoacetic acid hydrazide in boiling dioxane in the presence of a catalytic amount
of triethylamine afforded N-[5-(4-hydroxybenzylidene)-4-oxo-thiazolin-2-yl]cyanoa-
cetic acid hydrazide 17.
The EI mass spectrum of 17 shows the correct molecular ion peak at 302
(0.15%).
Compound 17 got further chemical support from the reaction with salicylalde-
hyde in refluxing ethanol in the presence of a catalytic amount of piperidine and
furnished the coumarin derivative 18 (Scheme 6).
Structure 18 was substantiated from the correct analytical and spectroscopic
data. Thus, the IR spectrum of 18 displayed the stretching absorption bands charac-
=
teristic for NH, CO (d-lactone), CO cyclic amide, CO amide, and C N groups and
was devoid of the absorption band for the cyano group. Furthermore, the mass spec-
trum of compound 18 shows the correct molecular ion peak at m=z ¼ 408 (24.96%),
which in accord with the assigned structure.
EXPERIMENTAL
Melting points are uncorrected and were measured by an electric melting-point
apparatus (G-K). The IR spectra were recorded on a Pye-Unicam SP1200 spectro-
1
photometer using KBr Wafer technique. The H NMR spectra were determined
on a Varian Gemini 200-MHz NMR spectrophotometer using CDCl3 or DMSO-d6
as solvent and tetramethylsilane (TMS) as an internal standard. All chemical shifts
are in parts per million (ppm) downfield from TMS. The elemental analysis were car-
ried out at the Faculty of Science, Ain Shams University. Mass Spectra (MS) were
recorded on a Shimadzu GC-MS QP1000EX instrument in the Microanalytical Lab-
oratory, Cairo University. The monitoring of the progress of all reactions and hom-
ogeneity of the synthesized compound was carried out by thin-layer chromato
graphy (TLC).
5-(4-Chlorobenzylidene)-2-ethoxy Carbonyl Methyl-D2-
thiazolidin-4(H)one 3
A mixture of 1 (1.88 g, 0.01 mol) and 2 (1.87 g, 0.01 mol) in absolute ethanol
(30 ml) and drops of piperidine was heated under reflux for 2 h. The product that
deposited during reflux was filtered off, washed with methanol, dried, and recrystal-
lized from dioxane to give 3 as yellow crystals; mp: 180–182 ꢁC, yield 63%. Anal.
calcd. for C14H12ClNO3S (309.5): C, 54.28; H, 3.88; Cl, 11.47; N, 4.52; S, 10.34.
Found: C, 54.18; H, 3.82; Cl, 11.45; N, 4.32; S, 10.20. IR (tcmꢀ1): 1762 cmꢀ1
(C Oester), 1686 cmꢀ1 (unsaturated cyclic imide). MS m=z (%): 309 (M.þ; 38.6),
=
310 (M þ 1, 8.6), 311 (M þ 2, 15.1), 168 (100), 133 (14.2), 89 (23.7). 1H NMR

974
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
(DMSO-d6) d (ppm): 12.3 (br.s, 1H, NH, exchangeable with D2O), 7.66–s7.59 (dd,
=
4Harom.), 7.5 (s, 1H, C CH), 5.63 (s, 1H), 4.16–s4.09 (q, 2H, J ¼ 8.5 Hz),
1.24–1.19 (t, 3H, J ¼ 8.5 Hz).
Authentic Sample
A mixture of 2-ethoxy carbonyl methyl-D2-thiazolidin-4(H)one (1.87 g,
0.01 mol) and 4-chlorobenzaldehyde (1.41 g, 0.01 mol) in absolute ethanol (30 ml)
and piperidine (0.5 ml) was heated under reflux for 3 h. The precipitate was collected
by suction, washed by methanol, dried, and then recrystallized from dioxane to
give 3 as yellow crystals (identity, TLC, mp, no depression in mixed mp and IR
comparison).
5-Amino-2-(4-chlorobenzylidene)-7-(N,N-dimethyl-
4-aminophenyl)-8-ethoxycarbonyl-3-oxo-2H,3H,7H-thiazolo
[3,2-a]pyridine-6-carbonitrile 4
A mixture of compound 3 (3.09 g, 0.01 mol) and a-cyano-4-(N,N-dimethyl-
4-amino)cinnamonitrile (1.97 g, 0.01 mol) in absolute ethanol (50 ml) containing
1 ml piperidine was heated under reflux for 5 h. The solid obtained during the heated
reflux was collected by suction, washed with ethanol, dried, and then recrystallized
from dioxane to give 4 as pale yellow crystals; mp 280–282 ꢁC, yield 60%. Anal.
calcd. for C26H23ClN4O3S (506.5): C, 61.60; H, 4.54; N, 11.06; S, 6.31. Found: C,
61.41; H, 4.25; N, 11.32; S, 6.27. IR (t cmꢀ1): 3412, 3374, 3281 cmꢀ1 (NH2),
2193 cmꢀ1 (Cꢂ N), 1689 cmꢀ1 (C Oester), 1641 cmꢀ1 (C O unsaturated cyclic
imide). MS m=z (%): 506 (M.þ, 34.4), 507 (M þ 1, 13.5), 508 (M þ 2, 6.9), 395
(100), 386 (33), 177 (49.3). 1H NMR (DMSO-d6) d (ppm): 12.2 (brs, 2H, disappeared
with D2O), 7.6–7.5 (m, 8Harom.þolefinic H), 5.6 (s, 1H, benzylic proton), 4.1–4.09 (q,
2H, J ¼ 7.2 Hz), 3.3 [s, 6H, N(CH3)2], 1.2–1.1 (t, 3H, J ¼ 7.2 Hz).
=
=
2-(4-Chlorobenzylidene)-7-(N,N-dimethyl-4-aminophenyl)-8-
ethoxycarbonyl-5-ethoxymethyleneamino-3-oxo-2H,
3H,7H-thiazolo[3,2-a]pyridine-6-carbonitrile 5
A mixture of 4 (1.07 g, 1.9 mmol) and triethylortho formate (10 ml, 0.067 mol)
in freshly distilled acetic anhydride (10 ml) was heated under reflux for 10 h. The pale
green solid deposited during reflux was collected by suction, washed with light pet-
roleum ether (bp 80–100 ꢁC), and then recrystallized from benzene to give 5; mp:
239–242 ꢁC, yield 57%. Anal. calcd. for C29H27ClN4O4S (562.5): C, 61.86; H, 4.8;
N, 9.95; S, 5.68. Found: C, 62.09; H, 4.7; N, 9.62; S, 5.64. IR (t cmꢀ1): 3200,
3100 cmꢀ1 (NH2), 2207 cmꢀ1 (Cꢂ N), 1725 cmꢀ1 (C Oester), 1691 cmꢀ1 (C O cyclic
=
=
imide), 1634 cmꢀ1 (C N). MS m=z (%):562 (M , 54.6), 489 (22.4), 451 (100). H
.þ
1
=
=
NMR (DMSO-d6) d (ppm): 8.29 (s, 1H, CH N), 7.65–6.65 (m, 8Harom.þolefinic),
H), 4.7 (s, 1H), 4.4–4.34 (q, 2H, J ¼ 7.2 Hz), 4.33–4.03 (q, 2H, J ¼ 6.5 Hz), 2.9 (s,
6H, NM2), 1.33–1.31 (t, 3H, J ¼ 7.2 Hz), 1.1–1.05 (t, 3H, J ¼ 5.6 Hz).

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
975
Thiazolopyridopyrimidine Derivative 6
A solution of 5 (5.62 g, 0.01 mol) and cyclohexyl amine (1 ml, 0.01 mol) in
absolute ethanol (30 ml) was heated under reflux for 6 h. The solid separated after
cooling was filtered off, washed several times with ethanol, and then recrystallized
from dioxane to give 6; mp: 250–252 ꢁC, yield 63%. Anal. calcd. for C37H41ClN6O2S
(668.5): C, 66.41; H, 6.13; N, 12.56; S, 4.78. Found: C, 66.70; H, 6.05; N, 12.37; S,
4.32. IR (t cmꢀ1): 3288 cmꢀ1 (NH), 1651 cmꢀ1 (CO); MS m=z (%): 558 (M.þ-Ar. 45),
425 (41.3), 342 (69), 113 (48), 83(51), 56(100).
8-Amino-2-(4-chlorobenzylidene)-9-(N,N-dimethyl-
4-aminophenyl)-10-ethoxycarbonyl-3-oxo-9H-thiazolo[3,2-a]
pyrido[2,3-d]-1,3-thiazin-6(H)-thione 7
A mixture of 4 (5.06 g, 0.01 mol) and carbon disulphide (5 ml) in ethanolic
KOH 10% (20 ml) was refluxed on water bath for 5 h. The solid deposited after cool-
ing was collected and recrystallized from ethanol to give 7 as yellow crystals; mp:
250–253 ꢁC, yield 60%. Anal. calcd. for C27H23ClN4O3S3 (582.5): C, 55.62; H,
3.94; N, 9.61; S, 16.48. Found: C, 55.80; H, 3.756; N, 9.50; S, 16.26. IR (t cmꢀ1):
3423, 3242 cmꢀ1 (NH), 1732 cmꢀ1 (C Oester), 1683 cmꢀ1 (C O), 1213(C S). MS
=
=
=
m=z (%): 582 (M.þ, 8.02), 506 (26.9), 395 (100), 177 (38.37).
Ethyl [8a-Amino-4-(4-chlorophenyl)-3-oxo-1,2,3,3a,4,8a,hexa-
hydropyrazolo[4’,3’,5,6]pyrano[2,3-d][1,3]thiazol-6-yl] acetate 8
A mixture of 3 (3.09 g, 0.01 mol) and cyanoethanoic hydrazide (0.99 g,
0.01 mol) in dioxane and triethylamine (0.1 ml) was refluxed for 4 h. The solid
deposited was collected and recrystallized from dioxane to give 8 as yellow crystals;
mp: 180–183 ꢁC, yield 66%. Anal. calcd. for C17H17ClN4O4S (408.5): C, 49.93; H,
4.16; N, 13.70; S, 7.83. Found: C, 49.71; H, 4.12; N, 13.58; S, 7.72. IR (t cmꢀ1):
3378, 3270 cmꢀ1(NH2), 1705 cmꢀ1 (C Oester), 1661 cmꢀ1 (C O cyclic imide). MS
=
=
m=z (%): 408 (11), 379 (10), 351 (20), 335 (3.9), 308 (50), 292 (11.5), 68 (100).
(Z)-Ethyl-2-(5-(4-chlorobenzylidine)-1-(4-amino-6-(4-chlorophenyl)-5-
cyanopyrimidine-2-ylamino)-4-oxo-4,5-dihydro-1h-imidazol-
2-yl)acetate 10
A
solution of
3
(3.09 g, 0.01 mol) and 4-amino-2-hydrazino-
6-(4-chlorophenyl)pyrimidin-5-carbonitrile (2.6 g, 0.01 mol) in absolute ethanol
(50 ml) was heated under reflux for 6 h. The solid separated during reflux was col-
lected by suction, washed by methanol, and then recrystallized from ethanol to give
10 as pale yellow crystals; mp: 280–283 ꢁC, yield 58%. Anal. calcd. for
C25H19Cl2N7O3 (536): C, 55.97; H, 3.54; N, 18.28. Found: C, 56.16; H, 3.33; N,
18.47. IR (t cmꢀ1): 3423, 3324, 3168 cmꢀ1 (NH2), 2207 cmꢀ1 (CꢂN), 1693 cmꢀ1
.þ
(C Oester), 1660 cmꢀ1 (C O unsaturated cyclic amide). MS m=z (%): 536 (M ,
=
=
1
21.4), 309 (57.1), 260 (100), 237 (46.4), 231 (75), 195 (64.3), 135 (57.1). H NMR
(DMSO-d6) d (ppm): 12.2 (s, 1H, NH), 7.6–7.5 (m, 8Harom þ one olefinic H), 5.6

976
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
(br. s, 2H, NH2, exchangeable with D2O), 4.17–4.09 (q, 2H, J ¼ 4.2 Hz), 3.4 (s, 2H,
CH2COOEt), 1.2–1.16 (t, 3H, J ¼ 5.4 Hz).
4-(4-Hydroxy Benzylidene)-2-imino-2-thiazolidine-4(H)one 11
A solution of 2-imino-4-oxo D2-thiazolidine (1.16 g, 0.01 mol) and a-cyano-4-
hydroxy cinnamonitrile (1.7 g, 0.01 mol) in absolute ethanol (20 ml) and drops of pip-
eridine was heated under reflux for 3 h. The solid separated was filtered off, washed
with ethanol, dried, and recrystallized from dioxane to give 11 as pale yellow crys-
tals; mp: 220–222 ꢁC, yield 50%. Anal. calcd. for C10H8N2O2S (220): C, 54.54; H,
3.63; N, 12.72. Found: C, 54.39; H, 3.62; N, 12.52. IR (ꢀt1cmꢀ1): 3520–2820 (br)
cmꢀ1 (OHꢀ), 3212 cmꢀ1 (NH), 1658 cmꢀ1 (C O), 1593 cm (C N). MS m=z (%):
=
=
220 (M. þ, 30.4), 177 (4.9), 150 (100), 121 (17.28), 77 (4.23).
Authentic Sample
A mixture of 2-imino-4-oxo D2-thiazolidine (1.16 g, 0.01 mol) and 4-hydroxy
benzaldehyde (1.22 g) in absolute ethanol (20 ml) and drops of triethyl amine was
heated under reflux for 4 h. The solid deposited was filtered off and recrystallized
from dioxane to give 11 as yellow crystals. (identity, IR, TLC, mp, and mixed mp).
5-Amino-2-(4-hydroxybenzylidine)-7-(chlorophenyl)-3-oxo-7H-
thiazolo[3,2-a]pyrimidin-6-carbonitrile 12
A solution of 11 (2.20 g, 0.01 mol) and a-cyano-4-chlorocinnamonitrile in dioxane
(30 ml) in the presence of piperidine (0.5 ml) was heated under reflux for 8 h. The solid
deposited after cooling was collected by filtration and then recrystallized from dioxane
to give 12 as colorless crystals; mp: 280–282 ꢁC, yield 65%. Anal. calcd. for
C20H13ClN4O2S (408.5): C, 58.75; H, 3.18; N, 13.7. Found: C, 58.88; H, 3.21; N, 13.9.
IR(t cmꢀ1): 3600–2692 (br)cmꢀ1(OH, NH2), 2214 cmꢀ1 (CꢂN), 1666 cmꢀ1(unsaturated
cyclic amide). MS m=z (%): 391 (M.þ-OH, 72.36), 389 (100), 168 (23.54), 150 (47.98).
2
2-Cyclohexylamino-5-(4-hydroxybenzylidine)-4-oxo-4 -thiazoline 13
A mixture of 11 (2.2 g, 0.01 mol) and cyclohexyl amine (0.99 g, 0.01 mol) in diox-
ane (20 ml) was refluxed for 6 h. The reaction mixture was concentrated and after cool-
ing the separated solid was collected by filtration, dried, and recrystallized from dilute
acetic acid to give 13 as green crystals; mp: 260–262 ꢁC, yield 54%. Anal. calcd. for
C16H18N2O2S (302): C, 63.57; H, 5.96; N, 9.27; S, 10.59. Found: C, 63.79; H, 5.73;
N, 10.35; S, 10.41. IR (KBr, cmꢀ1): br. centered at 3242 cmꢀ1(tNH,OH), 1660 cmꢀ1
(CO). MS m=z (%): 302 (M.þ, 10.43), 219 (55.1), 150 (100), 98 (20.13), 55 (30.24).
2-Piperidino (or Morpholino)-5-(4-hydroxy benzylidene)-4-oxo-D2-
thiazolines 14a and 14b
Piperidine (5 ml, 0.01 mol) or morpholine (5.2 ml, 0.01 mol) was added to a sol-
ution of compound 11 (2.2 g, 0.01 mol) in dioxane (25 ml) and the mixture was
refluxed for 8 h. The solid that separated after cooling was collected by filtration,
dried, and recrystallized from the proper solvent to give 14a and 14b, respectively.

THIAZOLOPYRIDINE AND PYRIMIDINE DERIVATIVES
977
2-Piperidino-5-(4-hydroxybenzylidene)-4-oxo-D2-thiazoline 14a. Recrys-
tallized from dioxane as yellow crystals; mp: 250–252 ꢁC, yield 75%. Anal. calcd. for
C15H16N2O2S (288): C, 62.5; H, 5.56; N, 9.72; S, 11.11. Found: C, 62.81; H, 5.32; N,
9.5; S, 10.83. IR (t cmꢀ1): 3520-2863 (br) cmꢀ1 (OH), 1674 cmꢀ1 (CO). MS m=z (%):
288 (M.þ, 12.86), 150 (100), 121 (7.7). 1H NMR (DMSO-d6) d (ppm): 10.4 (br.s, 1H,
OH, exchangeable with D2O), 7.52 (s, 1H, ¼CH), 7.49–7.48 (d, 2Harom, J ¼ 8.8 Hz),
6.89–6.87 (d, 2Harom., J ¼ 8.8 Hz), 3.89–3.86 (t, 2H, CH2N, J ¼ 5.6 Hz), 3.59–3.56 (t,
2H, CH2N, J ¼ 5.6), 1.66–1.48 (m, 6H, aliphatic H).
2-Morpholino-5-(4-hydroxybenzylidene)-4-oxo-D2-thiazoline 14b.Recrys-
tallized from dioxane as intense yellow crystals; mp: 240–243 ꢁC, yield 77%. Anal.
calcd. for C14H14N2O3S (290): C, 57.93; H, 4.82; N, 9.65; S, 11.03. Found: C,
58.11; H, 4.62; N, 9.46; S, 10.88. IR (t cmꢀ1): 3520–2863 (br) cmꢀ1 (OH),
1663 cmꢀ1 (CO). MS m=z (%): 290 (M.þ, 9.58), 150 (100), 121 (7.7). 1H NMR
(DMSO-d6) d (ppm): 10.3 (br.s, 1H, OH, exchangeable with D2O), 7.95 (s, 1HCH¼),
), 7.59–7.46 (d, 2Harom, J ¼ 9 Hz), 6.92–6.88 (d, 2H, J ¼ 9 Hz), 3.89–3.86 (t, 4H,
CH2OCH2), 3.56–3.55 (t, 4H, CH2NCH2).
Reaction of 13a and b with Potassium Hydroxide: Formation of
Potassium Salt 15
A mixture of 2-piperidino or 2-morpholino-5-(4-hydroxybenzylidene)-4-oxo-D2-
thiazolines 14a and b (2.8 g, 0.01 mol) and KOH (0.5 g, 0.02 mol) in ethanol (20 ml)
was heated under reflux for 1 h. The solid deposited after concentration and cooling
was collected and dried. Yield 50%. IR (t cmꢀ1): 1655 cmꢀ1 (C O cyclic amide).
=
2,4-Dioxo-5-(4-hydroxybenzylidene)-3-ethoxycarbonyl
Methyl-2-thiazolidine 16
A mixture of the salt 15 (2.86 g, 0.01 mol) and ethyl chloroacetate (1.13 g, 0.01 mol)
in dioxane (20 ml) was heated for 5 h. The solid that separated was filtered off, washed
several times with water, and recrystallized from ethanol to give 16 as pale yellow crys-
tals; mp: 132–134 ꢁC, yield 40%. Anal. Calcd. for C14H13NO5S (307): C, 54.72; H, 4.23;
N, 4.56; S, 10.42. Found: C, 54.89; H, 4.03; N, 4.6; S,ꢀ110.21. IR (t cmꢀ1): 3450 (br) cmꢀ1
ꢀ1
.þ
(OH), 1720cmꢀ1 (C O), 1663 cm (C O), 1650 cm (C O). MS m=z (%): 307 (M ,
=
=
=
2.49), 221 (4.73), 150 (100), 121 (23.9), 93 (7.8), 77 (13.0). 1HNMR (DMSO-d6) d (ppm):
10.1 (s, 1H, OH, exchangeable with D2O), 7.5 (s, 1H, ¼CH), 7.48–7.45 (d, 2Harom.
,
J ¼ 9 Hz), 6.9–6.87 (d, 2Harom., J¼ 9 Hz), 3.9–3.86 (q, 2H, CH2CH3, J ¼ 12Hz), 3.59
(br.s, 2H, CH2COOEt), 1.6 (t,3H, J ¼ 11.8 Hz).
N-[5-(4-Hydroxybenzylidene)-4-oxo-2-thiazolin-2-yl] Cyanoacetic
Hydrazide 17
A mixture of 11 (2.2 g, 0.01 mol) and cyanoacetic acid hydrazide (0.99 ml,
0.01 mol) in dioxane (20 ml) and drops of triethyl amine was refluxed for 8 h. The solid
separated on hot was collected by filtration and recrystallized from ethanol to give 17
as pale yellow crystals, mp: 205–207 ꢁC, yield 60%. Anal. calcd. for C13H10N4O3S
(302): C, 51.65; H, 3.31; N, 18.54. Found: C, 51.51; H, 3.22; N, 18.49. IR (t cmꢀ1):

978
M. R. MAHMOUD, A. K. EL-ZIATY, AND A. M. HUSSEIN
3339, 3310, 3257 cmꢀ1 (tNH,OH), 2215 cmꢀ1 (Cꢂ N), 1685 cmꢀ1(br.) (C O). MS m=z
=
(%): 302 (M.þ, 0.15), 220 (38.53), 150 (100), 121 (25.34).
(Z)-N’-(5-(4-Hydroxybenzylidine)-4-oxo-4,5-dihydrothiazol-2-
yl)-2-oxo-2H-chromene-3-carbohydrazide 18
Salicylaldehyde (1.22 g, 0.01 mol) was added with drops of piperidine to a sol-
ution of compound 17 (3.02 g, 0.01 mol) in ethanol (30 ml), and the whole mixture
was refluxed for 2 h. After concentration and cooling, the separated solid was col-
lected by filtration, washed with ethanol, dried, and recrystallized from ethanol to
give 18 as orange crystals; mp: 180–182 ꢁC, yield 55%. Anal. calcd. for C20H13N3O5S
(407): C, 58.96; H, 3.19; N, 10.32; S, 7.86. Found: C, 59.2; H, 3.09; N, 10.11; S, 7.55.
IR (t cmꢀ1): 3197 cmꢀ1 (NH), 1740 cmꢀ1 (COd-lactone), 1682 cmꢀ1 (COthiazolidinone),
1
1662 cmꢀ1. MS m=z (%): 408 (M þ 1, 24.96). H NMR (DMSO-d6) d (ppm): 11.1
(s, 1H, OH, exchangeable with D2O), 8.9 (s, 1H, CH ¼), 7.6 (br.s, 2H, exchangeable
with D2O), 7.7–6.9 (m, 9Harom.þC4’-H).
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