Novel synthesis of pyrano[2,3-d]thiazole, thiazolo[3,2-a]pyridine, and pyrazolo [3′,4′:4,5] thiazolo[3,2-a]pyridine derivatives

Article abstract of DOI:10.1080/10426500802059331

Cyclocondensation of 2-cyanomethyl-4-thiazolidinone (1) with tetracyanoethylene (2) furnished pyrano[2,3-d]thiazole derivative (4). Benzo[e]pyrano[2,3-d]thiazole derivative (6) was obtained by cyclization of compound (1) with salicylaldehyde. In a similar manner, condensation of compound (1) with 2-hydroxy-1-naphthaldehyde in refluxing ethanol yielded naphtho[e]pyrano[2,3-d]thiazole derivative (7). Interaction of compound (9) with benzylidenemalononitriles (10) (1:1 molar ratio) at reflux temperature in ethanol in the presence of piperidine afforded thiazolo[3,2-a]pyridines (12a-c). Treatment of compound (12a) with hydrazines furnished pyrazolo[3′, 4′:4,5] thiazolo[3,2-a]pyridines (14a,b). The reaction of compound (1) with benzyli-denecyanoacetate (16) yielded 5-hydroxythiazolo[3,2-a]pyridine derivative (21). Cyclization of bis(thiazolinone) (23) with benzylidenemalononitriles (10) produced bis(thiazolopyridine) derivatives (25a,b). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500802059331

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Phosphorus, Sulfur, and Silicon
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Novel Synthesis of Pyrano[2,3-
d]Thiazole, Thiazolo[3,2-
a]Pyridine, and Pyrazolo
[3′,4′:4,5] Thiazolo[3,2-
a]Pyridine Derivatives
G. A. M. El-Hag Ali a , M. T. Abd El-Rahman a , M. H.
M. Helal a & M. S. A. El-Gaby b
a Chemistry Department, Faculty of Science, Al-
Azhar University, Nasr City, Cairo, Egypt
b Chemistry Department, Faculty of Science, Al-
Azhar University at Assiut, Assiut, Egypt
Published online: 03 Nov 2008.
To cite this article: G. A. M. El-Hag Ali , M. T. Abd El-Rahman , M. H. M. Helal & M. S.
A. El-Gaby (2008) Novel Synthesis of Pyrano[2,3-d]Thiazole, Thiazolo[3,2-a]Pyridine,
and Pyrazolo [3′,4′:4,5] Thiazolo[3,2-a]Pyridine Derivatives, Phosphorus, Sulfur, and
Silicon and the Related Elements, 183:12, 3023-3036
To link to this article: http://dx.doi.org/10.1080/10426500802059331
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Phosphorus, Sulfur, and Silicon, 183:3023–3036, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802059331
Novel Synthesis of Pyrano[2,3-d]Thiazole,
Thiazolo[3,2-a]Pyridine, and Pyrazolo [3ꢀ,4ꢀ:4,5]
Thiazolo[3,2-a]Pyridine Derivatives
G. A. M. El-Hag Ali,1 M. T. Abd El-Rahman,1 M. H. M.
Helal,1and M. S. A. El-Gaby2
1Chemistry Department, Faculty of Science, Al-Azhar University, Nasr
City, Cairo, Egypt
2Chemistry Department, Faculty of Science, Al-Azhar University at
Assiut, Assiut, Egypt
Cyclocondensation of 2-cyanomethyl-4-thiazolidinone (1) with tetracyanoethylene
(2) furnished pyrano[2,3-d]thiazole derivative (4). Benzo[e]pyrano[2,3-d]thiazole
derivative (6) was obtained by cyclization of compound (1) with salicylaldehyde. In
a similar manner, condensation of compound (1) with 2-hydroxy-1-naphthaldehyde
in refluxing ethanol yielded naphtho[e]pyrano[2,3-d]thiazole derivative (7). Inter-
action of compound (9) with benzylidenemalononitriles (10) (1 : 1 molar ratio) at
reflux temperature in ethanol in the presence of piperidine afforded thiazolo[3,2-
a]pyridines (12a−c). Treatment of compound (12a) with hydrazines furnished
pyrazolo[3ꢀ,4ꢀ:4,5] thiazolo[3,2-a]pyridines (14a,b). The reaction of compound
(1) with benzyli-denecyanoacetate (16) yielded 5-hydroxythiazolo[3,2-a]pyridine
derivative (21). Cyclization of bis(thiazolinone) (23) with benzylidenemalononi-
triles (10) produced bis(thiazolopyridine) derivatives (25a,b).
Keywords Pyrano[2,3-d]thiazole; thiazolinone; thiazolo[3,2-a]pyridine
INTRODUCTION
Pyrano[2,3-d]thiazoles are reported to possess antimicrobial, bac-
tericidal and fungicidal1 properties. Thiazolo[3,2-a]-pyridine deriva-
tives have also been reported to show antimi-crobial,2 antifungal,3
anticancer,4 and antihypertensive5 activities. In continuation of
our work,6−8we report here the synthesis of versatile hith-
erto unknown pyrano[2,3-d]thiazole, thiazolo[3,2-a]pyridine and
pyrazolo[3ꢀ,4ꢀ:4,5]thiazolo[3,2-a]pyridine derivatives.
Received 29 September 2007; accepted 11 December 2007.
Address correspondence to M. S. A. El-Gaby, Chemistry Department, Faculty of Sci-
ence, Al-Azhar University at Assiut, Assiut 71524, Egypt. E-mail: m elgaby@hotmail.com
3023

3024
G. A. M. El-Hag Ali et al.
RESULTS AND DISCUSSION
Treatment of 2-cyanomethyl-4-thiazolinone (1) with tetracyanoethy-
lene (2) in ethanol in the presence of triethyl-amine at reflux temper-
ature afforded the novel pyrano[2,3-d]-thiazole derivative (4) and not
thiazolo[3,2-a]pyridine (5). The molecular structure of (4) was estab-
lished on the basis of elemental analysis and spectral data. Its infrared
spectrum showed no absorption band assignable to C=O group and in-
1
dicated the presence of NH2 group. On the basis of HNMR spectrum
the latter product was recommended to exist predominantly in the form
1
(4A) rather than methylene form (4). Its HNMR indicated the pres-
ence of methylene-H at δ = 6.83 ppm besides the expected signals for
NH2 and NH protons. In addition, the mass spectrum of compound (4)
revealed a molecular ion peak at m/z = 268 (10.0%) and the base peak
CHART 1 Fragmentation pattern of compound 4.

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3025
SCHEME 1
was found in the spectrum at m/z = 86, Chart 1. The formation of (4)
is assumed to proceed through an initial Michael addition of the ac-
tive methylene function group of (1) at C5 to the activated double bond
in (2) to form the non-isolable acyclic intermediate (3) followed by in-
tramolecular cyclization via the addition of hydroxy group to one of the
two cyano groups and tautomerization to form (4), Scheme 1.
Cyclization of compound (1) with salicylaldehyde in ethanol under
reflux in the presence of piperidine yielded the benzo[e]pyrano[2,3-
d]thiazole derivative (6). Assignment of benzopyranothiazole (6) was
based on the basis of elemental and spectral data. Its infrared spec-
trum exhibited the absence of any C=O stretching absorption while
it showed the presence of OH group stretching at 3168 cm−1. Also,
its mass spectrum showed a molecular ion peak at m/z = 244 (1.98%)
together with base peak at m/z = 63, Chart 2. The formation of (6) is as-
sumed to proceed through the in situ intramolecular cyclization of the
non-isolable intermediate (5) via nucleophilic addition of the hydroxy
group to the carbonyl group, Scheme 2. In a similar manner, com-
pound (1) underwent cyclocondensation on treatment with 2-hydroxy-
1-naphthaldehyde in refluxing ethanol in the presence of piperidine
to yield the naphtho[e]pyrano[2,3-d]-thiazole derivative (7). Its mass
spectrum revealed a molecular ion peak at m/z = 294 (2.57%) and the
base peak was observed in the spectrum at m/z = 66, Chart 3.
The benzylidene derivative (9) was obtained in a good yield by re-
fluxing of compound (1) with 4-nitro-4ꢀ-carbox-aldehyde diphenylether
(8) in ethanol in the presence of piperidine. The molecular structure of

3026
G. A. M. El-Hag Ali et al.
CHART 2 Fragmentation pattern of compound 6.
compound (9) was confirmed by its analytical and spectral data. Its
mass spectrum showed a molecular ion peak at m/z = 365 (25.73%) and
the base peak was found in the spectrum at m/z = 66. Cyclocondensa-
tion of compound (9) with benzylidenemalononitriles (10) (1 : 1 molar
ratio) in ethanol in the presence of piperidine at reflux temperature
afforded the novel thiazolo[3,2-a]pyridine derivatives (12a−c). The
molecular structure of thiazolopyridines (12) was elucidated through
their elemental analysis and spectral data. Mass spectrum of com-
pound (12a) exhibited a molecular ion peak at m/z = 656 (1.38%) and
the base peak was observed in the spectrum at m/z = 76 (phenyl group).

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3027
SCHEME 2
Also, mass spectrum of compound(12b) showed a molecular ion peak
at m/z = 553 (4.95%) together with base peak at m/z = 57. The for-
mation of (12) is assumed to proceed via Michael addition of the
active methylene group in (1) at C2 to the activated double bond of
(10) to form the acyclic intermediate (11) followed by intramolecular
cyclization6 through the addition of the endocyclic nitrogen of thia-
zole to the cyano function group and tautomerization to yield (12),
Scheme (3). The behavior of compound (12a), which contains α,β-
unsaturated ketone, towards hydrazines was examined. Treatment
of compound (12a) with hydrazine hydrate in refluxing ethanol fur-
nished the pyrazolo[3ꢀ,4ꢀ:4,5]thiazolo[3,2-a]pyridine derivative (14a).
The molecular structure of compound (14a) was assigned on the basis
of its elemental analysis and spectral data. Its infrared spectrum indi-
cated the absence of carbonyl group stretching absorption that might
be expected to appear at the range of ν 1700−1730 cm−1. In addition,
1
its HNMR of compound (14a; DMSO-d6) revealed the presence of a
pyridine H-7 proton at δ = 4.81 ppm besides the expected signals for
the NH2, NH and aromatic protons. Also, mass spectrum of compound
(14a) showed a molecular ion peak at m/z = 668 (2.07%) together

3028
G. A. M. El-Hag Ali et al.
CHART 3 Fragmentation pattern of compound 7.
with base peak at m/z = 257. The formation of (14a) is assumed to
proceed via Michael addition of hydrazine to the activated double bond
of (12a) to form the non-isolable acyclic intermediate (13) followed by
intramolecular cyclization through dehydration and auto-oxidation un-
der the experimental conditions. In a similar manner, compound (12a)
was allowed to react with benzoyl hydrazine in ethanol at reflux tem-
perature to give the pyrazolo[3ꢀ,4ꢀ:4,5]thiazolo[3,2-a]pyridine deriva-
tive (14b). Refluxing of compound (12a) with formic acid8 afforded
the corresponding thiazolo[2ꢀ,3ꢀ:1,6]pyrido[2,3-d]pyrimidine derivative
(15), Scheme 3.
The reaction of compound (1) with equimolar amount of benzyli-
denecyanoacetate (16) in refluxing ethanol in the presence of piperidine
afforded the 5-hydroxy-thiazolo[3,2-a]-pyridine derivative (21). Both el-
emental and spectral data supported the proposed structure (21) and

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3029
SCHEME 3

3030
G. A. M. El-Hag Ali et al.
SCHEME 4
ruled out the other possible structures (17), (18), and (19). The infrared
spectrum of compound (21) revealed absorption bands at 3400, 2208,
and 1700 cm−1 due to hydroxyl, cyano and carbonyl function groups, re-
spectively. Also, its 1HNMR spectrum (DMSO-d6) indicated the absence

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3031
SCHEME 5
of ethoxycarbonyl moiety and showed the presence of methylene, hy-
droxyl, and aromatic protons. In addition, its mass spectrum exhibited
a molecular ion peak at m/z = 432 (2.22%), and the base peak was found
in the spectrum at m/z = 76 which is characteristic for C6H4 moiety.
The formation of (21) is assumed to proceed via the Michael addition
of active methylene group in (1) at C2 to the activated double bond of
(16) to form Michael adduct (20) followed by intramolecular cyclization
through elimination of ethanol, Scheme 4.
Condensation of compound (1) with 4,4ꢀ-bis(carboxaldehyde)
diphenylether (22) in ethanol in the presence of piperidine furnished
bisbenzylidene derivative (23). Its mass spectrum revealed a molecu-
lar ion peak at m/z = 470 (23%). Cyclocondensation of compound (23)
with benzylidenemalononitriles (10) (1 : 2 molar ratio) at reflux tem-
perature in the presence of piperidine yielded the bis(thiazolopyridine)

3032
G. A. M. El-Hag Ali et al.
derivatives (25a,b) on the basis of their elemental and spectral data.
Mass spectrum of compound (25a) showed a molecular ion peak at
m/z = 778 (1.78%), which is characteristic for the molecular formula
C44H26N8O3S2. The formation of (25) is assumed to proceed via the
in situ intramolecular cyclization6 of the non-isolable Michael adduct
(24), Scheme 5.
CONCLUSION
2-Cyanomethyl-4-thiazolinone (1) was used as starting material for the
synthesis of some novel pyrano [2,3-d] thiazole, thiazolo [3,2-a] pyridine
and pyrazolo [3ꢀ,4ꢀ:4,5] thiazolo [3,2-a] pyridine derivatives through its
reaction with some electrophilic reagents.
EXPERIMENTAL
Melting points are recorded on a Fisher-John melting points appara-
tus and are uncorrected. IR spectra were recorded on a Shimadzu 470
1
spectrometer using KBr pellets. HNMR spectrum were recorded on
a Varian Gemini spectrometer 200 (200 MHz) using TMS as inter-
nal standard and mass spectra on a Jeol-JMS-600 mass spectrometer.
Elemental analyses were performed on a Perkin-Elmer 240 C micro-
analyzer. The physical and spectral data are collected in Tables I and
II, respectively.
Synthesis of 5-Amino-2-cyanomethylene-2, 3-dihydropyrano-
[2,3-d]thiazole-6,7,7-tricarbonitrile (4)
A mixture of compound 18 (0.01 mol) and tetracyano-ethylene 2 (0.01
mol) and triethylamine (0.01 mol) in ethanol (40 mL) was heated under
reflux for 1 h., the solid product, which was produced on heating was
collected and recrystallized to give 4.
Synthesis of 2-Cyanomethylene-3a-hydroxy-benzo[e] pyrano-
[2,3-d]thiazole (6), 2-Cyanomethylene-3a-hydroxy-naphtho[e]-
pyrano[2,3-d]thiazole (7)—General Procedure
A mixture of compound 1 (0.01 mol), ortho hydroxy-carboxaldehyde
(0.01 mol), and piperidine (0.01 mol) in ethanol (40 mL) was heated
under reflux for 3 h., the solid product which produced on heating was
collected and recrystallized to give 6 and 7.

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3033
TABLE I Physical and Analytical Data for the Synthesized
Compounds
Elemental
Molecular
formula
(Mol. Wt.)
analyses
M.p.
(◦C)
Yield Solvent
Compd. no.
4
(%)
cryst.
C% H% N%
>300
>300
>300
63
DMF
C11H4N6OS (268)
49.25 1.49 31.34
49.20 1.40 31.20
59.01 3.27 11.47
59.10 3.20 11.40
6
71
65
DMF
DMF
C12H8N2O2S (244)
7
C
C
C
16H10N2O2S (294) 65.30 3.40 9.52
65.20 3.30 9.60
18H11N3O4S (365) 59.17 3.01 11.50
59.10 3.20 11.40
34H20N6O7S (656) 62.19 3.04 12.80
62.10 3.10 12.70
9
210−212 82 Dioxane
12a
12b
12c
14a
14b
15
236−238 84
240−241 60
252−254 74
270−272 79
292−293 70
152−153 62
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
C
28H16ClN5O4S (553.5) 60.70 2.89 12.64
60.60 2.80 12.40
C
C
C
C
C
32H19N5O4S (569) 67.48 3.33 12.30
67.40 3.20 12.20
34H20N8O6S (668) 61.07 2.99 16.76
61.10 2.90 16.70
41H24N8O7S (772) 63.73 3.10 14.50
63.60 3.00 14.40
35H20N6O8S (684) 61.40 2.92 12.28
61.30 2.80 12.20
21
166−168 61 Dioxane
>300 78 Dioxane
21H12N4O5S (432) 58.33 2.77 12.96
58.20 2.70 12.80
23
C
C
C
24H14N4O3S2 (470) 61.27 2.97 11.91
61.20 2.80 11.80
44H26N8O3S2 (778) 67.86 3.34 14.39
67.80 3.30 14.30
46H30N8O3S2 (806) 68.48 3.72 13.89
68.40 3.60 13.80
25a
25b
290−292 70
272−274 55
AcOH
AcOH
Synthesis of 2-Cyanomethylene-5-[4-(4-nitrophenoxy)
benzylidene]-4-thiazolinone (9)
A mixture of compound 1 (0.01 mol), compound 89 (0.01 mol) and piperi-
dine (0.01 mL) in ethanol (40 mL) was heated under reflux for 1 h., the
solid product which produced on heating was collected and recrystal-
lized to give 9.

3034
G. A. M. El-Hag Ali et al.
TABLE II Spectral Data of the Synthesized Compounds
1H NMR (DMSO-d6)
Compd. No.
IR / ν
(cm−1
)
(δ / ppm)
max
4
3400, 3324, 3176 (NH/
NH2), 2926 (CH-aliph.),
2202 (C N).
4.23 (hump, 2H, NH2;
exchange-able), 6.83 (s,
1H, methylidene-H),
7.34 (s, 1H, NH,
exchange-able).
6
7
9
3364, 3168 (OH/NH),
2204 (C N).
3240 (OH), 2208 (C N),
1638 (C N).
3076 (CH-arom.), 2926
(CH-
Insoluble
Insoluble
4.05 (s, 2H, CH2),
7.15.−8.30 (m, 9H,
Ar-H +
aliph.),2198(C N),1720
(C=O).
methylidene-H).
4.69(s,1H,pyridine-H),
7.41.−7.62(m, 16H,
Ar-H), 7.78 (s, 1H,
methylid-ene-H), 7.87
(s, 2H, NH2;
12a
3382,3284 (NH2), 2198
(C N), 1720 (C O).
exchangeable).
—
12b
12c
3334,3200 (NH2), 2200
(C N), 1714 (C O).
3382,3300 (NH2),2196
(C N), 1718 (C O).
4.71 (s, 1H, pyridine-H),
7.15.−8.32 (m, 18H,
Ar-H + methylidene-H
+ NH2).
14a
3330, 3204 (NH2), 2210
(C N).
4.49 (s, 1H, pyridine-H),
6.83.−8.39 (m, 18H,
Ar-H + NH2), 11.96 (s,
1H, NH; exchangeable).
4.59 (s, 1H, pyridine-H),
7.09.−8.36 (m, 23H,
Ar-H + NH2).
14b
15
3328, 3198 (NH2), 2214
(C N).
3386 (NH), 2200 (C N),
1718, 1660 (2 C O).
4.98 (s, 1H, pyridine-H),
7.15.−8.30 (m, 18H,
Ar-H + methylidene-H
+ pyrimidine-H), 11.62
(s, 1H, NH;
exchangeable).
21
23
3400 (OH), 2208 (C N),
1720 (C O).
4.10 (s, 2H, CH2), 4.96 (s,
1H, pyridine-H),
7.09−8.31 (m, 8H,
Ar-H), 8.68 (s, 1H, OH;
exchangeable).
4.05 (s, 4H, 2CH2),
7.23−7.99 (m, 10H,
Ar-H + methylidene-H)
2198 (C N), 1708 (C O).
(Continued on next page)

Pyranothiazoles, Thiazolo Pyridines, and Pyrazolo Thiazolo Pyridines
3035
TABLE II Spectral Data of the Synthesized Compounds (Continued)
1H NMR (DMSO-d6)
Compd. No.
IR / ν
(cm−1
)
(δ / ppm)
max
25a
3390,3300 (NH2), 2200
(C N), 1722 (C O).
3472,3350 (NH2), 2200
(C N), 1716 (C O).
—
25b
1.61 (s, 6H, 2CH3), 4.43
(s, 1H, pyridine-H),
6.91−7.71 (m, 22H +
Ar-H + methylidene-H
+ 2 NH2).
Synthesis of
5-Amino-3-oxo-2-[4-(4-nitrophenoxy)benzylidene]-7-aryl-2,3-
dihydro-7H-thiazolo[3,2-a]pyridine-6,8-dicar-bonitriles
(12a−c)—General Procedure
A mixture of compound 9 (0.01 mol), benzylidene malononitrile 10 (0.01
mol) and piperidine (0.01 mol) in ethanol (40 mL) was heated under re-
flux for 3 h. The solid product which produced on heating was collected
and recrystallized to give 12.
Synthesis of 8-Amino-3,6-bis[4-(4-nitrophenoxy)phenyl]-1H,
6H-pyrazolo[3ꢀ,4ꢀ:4,5]thiazolo[3,2-a]pyridine-5,7-dicarbonit-rile
(14a), and 8-Amino-1-benzoyl-3,6-bis[4-(4-nitropheno-xy)
phenyl]-6H-pyrazolo[3ꢀ,4ꢀ:4,5]thiazolo[3,2-a]pyridine-5,7-
dicarbonitrile (14b)—General Procedure
A mixture of compound 12a (0.01 mol) and hydrazine hydrate or ben-
zoyl hydrazine (0.01 mol) in ethanol (30 mL) was heated under reflux
for 1 h. The solid product which produced on heating was collected and
recrystallized to give 14a and 14b, respectively.
Synthesis of 8-[4-(P-nitrophneoxy)benzylidene]-5-[4-(4-nitro-
phenoxy)phenyl]-3,4,8,9-tetrahydro-5H-4,9-dioxo-thiazolo[2ꢀ,
3ꢀ:1,6]pyrido[2,3-d]pyrimidine-6-carbonitrile (15)
A mixture of compound 12a (0.01 mol) in formic acid (10 mL) was heated
under reflux for 24 h. The reaction mixture was concentrated and the
solid product was collected, washed with water and recrystallized to
give 15.

3036
G. A. M. El-Hag Ali et al.
Synthesis of 6,8-Dicyano-5-hydroxy-7-[4-(4-nitrophenoxy)-
phenyl]2,3-dihydro-3-oxo-7H-thiazolo[3,2-a]pyridine (21)
A mixture of compound 1 (0.01 mol), arylidene 16 (0.01 mol) and piperi-
dine (0.01 mol) in ethanol (40 mL) was heated under reflux for 0.5 h.
The solid product which produced on heating was collected and recrys-
tallized to give 21.
Synthesis of 4,4ꢀ-[2-Cyanomethyl-4,5-dihydro-5-methylid-ene-
4-thiazolinone-5-yl]diphenylether (23)
A mixture of thiazolidinone 1 (0.02 mol), 4,4ꢀ-bis(carbox-aldehyde)-
diphenylether 229 (0.01 mol), and piperidine (0.01 mol) in ethanol
(40 mL) was heated under reflux for 3 h. The solid obtained after cooling
was filtered and dried and recrystallized to give 23.
Synthesis of 4,4ꢀ-Bis[5-amino-7-aryl-2-methylidene-2,3-dihy-
dro-7H-3-oxo-thiazolo[3,2-a]pyridine-6,8-dicyano-2-yl]diphen-
ylether Derivatives (25a,b)—General Procedure
A mixture of 23 (0.01 mol), arylidenemalononitrile 10 (0.02 mol) and
piperidine (0.01 mol) in ethanol (40 mL) was heated under reflux for
3 h. The solid product which produced on heating was collected and
recrystallized to give 25a,b.
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