An efficient synthesis of new thiazole based heterocycles

Article abstract of DOI:10.3987/COM-10-12032

Synthesis of new aminopyrazole, pyrazolo[3,4-d]-1,2,3-triazine, 1,3,4-thiadiazole, thiophene and 1,2-dihydropyridine derivatives containing thiazole template has been carried out by simple, efficient and good yielding routes starting from the versatile an

Full text of DOI:10.3987/COM-10-12032

HETEROCYCLES, Vol. 81, No. 10, 2010
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HETEROCYCLES, Vol. 81, No. 10, 2010, pp. 2369 - 2376. © The Japan Institute of Heterocyclic Chemistry
Received, 1st August, 2010, Accepted, 18th August, 2010, Published online, 18th August, 2010
DOI: 10.3987/COM-10-12032
AN EFFICIENT SYNTHESIS OF NEW THIAZOLE BASED
HETEROCYCLES
Yahia N. Mabkhot,1 Nabila A. Kheder,2,3 and Ahmad M. Farag2,*
1Department of Chemistry, Faculty of Science, King Saud University, 2455,
Riyadh 11751, Saudi Arabia
2Department of Chemistry, Faculty of Science, Cairo University, Giza 12613,
Egypt; 3On leave toDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy,
King Khalid University, Abha, Saudi Arabia
E-mail: afarag49@yahoo.com
Abstract – Synthesis of new aminopyrazole, pyrazolo[3,4-d]-1,2,3-triazine, 1,3,4-
thiadiazole, thiophene and 1,2-dihydropyridine derivatives containing thiazole
template has been carried out by simple, efficient and good yielding routes starting
from the versatile and readily accessible 2-cyano-N-(thiazol-2-yl)acetamide.
Thiazoles and their derivatives have attracted continuing interest over the years because of their diverse
biological activities.1,2 They found application in drug development for the treatment of allergies,3
hypertension,4 inflammation,5 schizophrenia,6 bacterial7 and HIV infections.8 They are also used as
hypnotics,9 for the treatment of pain,10 and as inhibitors of LFA-1/ICAM-1 mediated cell adhesion.11 In
addition, thiazole derivatives show strong FabI and FabK inhibitory effects with potent antibacterial
activity.12 In view of the above mentioned findings, and as a continuation of our interest in the synthesis of
a variety of heterocyclic ring systems for biological evaluation,13-28 we report in the present work the
synthesis of some heterocycles containing thiazole template. During our search, we have found that
2-cyano-N-(thiazol-2-yl)acetamide (1) 29 is a versatile, readily accessible building block for synthesis of the
target compounds.
Treatment of the acetamide 1 with 2-oxo-N'-phenylpropanehydrazonoyl chloride (2)30 in ethanolic sodium
ethoxide, at room temperature, furnished a single product identified as the aminopyrazole derivative 4a.
The IR spectrum of the reaction product exhibited absorption bands at 3443, 3331, 3191, 1692 and 1638
cm-1 due to amino, amide-NH and two carbonyl groups, respectively. Prompted by the foregoing results
and to generalize this reaction, we have also studied the behaviour of the acetamide 1 towards the
2-oxo-2-(phenylamino)-N'-p-tolylacetohydrazonoyl chloride (5a),31 under the same experimental

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HETEROCYCLES, Vol. 81, No. 10, 2010
conditions, which led to the respective aminopyrazole derivative 4b. When the aminopyrazole 4a was
treated with nitrous acid, it furnished one isolable product which was analysed correctly for C15H10N6O2S.
The structure of the isolated product was assigned as 5-acetyl-7-phenyl-3-(thiazol-2-yl)-3H- pyrazolo[3,4-
d]-1,2,3-triazin-4(7H)one (7), based on its elemental analyses and spectral data. For example, the IR
spectrum of the reaction product revealed the disappearance of the amino and amide-NH absorption bands
in the region 3450-3000 cm-1 and showed two strong carbonyl bands at 1729 and 1680 cm-1.
Cl
S
N
H
NH
O
CN
N
EtONa/EtOH
R
N
Ar
2, 5a
1
S
O
R
N
S
O
R
N
N
N
H
N
N
N
H
H2N
4a,b
CN HN
Ar
Ar
3
NaNO2 /HCl
AcOH
O
S
R
N
R
O
HCl
S
N
N
N
N
N
R
N
H
N
N
N
Ar
Cl N2
Ar
6
7
2,4a,7
4b,5a
4a (63%), 4b (68%), 7(61%)
MeCO
PhNHCO
4-MePh
Ph
Ar
Scheme 1
The nucleophilic addition of the acetamide 1 to an equimolar amount of phenyl isothiocyanate in DMF, in
the presence of potassium hydroxide, afforded the corresponding potassium salt intermediate 8. Cyclization
of the intermediate 8, in situ, with the hydrazonyl chloride 5b gave 5-(1-cyano-2-oxo-2-(thiazol-2-
ylamino)ethylidene)-N,4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carboxamide (11) as depicted in
Scheme 2. The IR spectrum of the product 11 revealed, absorption bands at 3385, 3065, 2193 1682 and
1647 cm-1 corresponding to two NH, nitrile and two carbonyl groups, respectively. Its 1H NMR spectrum
displayed two D2O-exchangeable signals at  10.85 and 11.68 due to two NH protons, in addition to an
aromatic multiplet in the region  7.05-7.77. The aforementioned results indicate that the reaction of the
intermediate potassium salt 8 with the hydrazonayl chloride 5b proceeds, via elimination of potassium
chloride and aniline, respectively.

HETEROCYCLES, Vol. 81, No. 10, 2010
2371
Similarly 1-phenyl-2-bromoethanone (12)32 reacted with the intermediate potassium salt 8, formed in situ
under the same experimental conditions, and afforded the corresponding aminothiophene derivative 14
1
(Scheme 2). The IR spectrum of compound 14 revealed absence of nitrile absorption band while, its H
NMR spectrum showed three D2O-exchangeable signals at  8.80, 11.98 and 13.19 due to NH2 and two
amide proton, respectively in addition to an aromatic multipelt in the region  7.05-8.04.
O
S
CN
SK
PhNCS
KOH
1
N
H
N
PhHN
8
O
N
Ph
PhCOCH2Br
PhHN
5b
N
H
12
Cl
- KBr
- KCl
O
S
CN
S
S
O
N
N
CN
H
N
N
PhHN
H
Ph
PhHN
S
Ph
N
N
CONHPh
O
H
13
9
O
S
PhHN
H
S
CN
Ph
N
H
Ph
H
N
N
N
NHPh
S
O
N
NH2
S
O
N
CONHPh
14 (68%)
10
PhNH2
CN
O
S
N
NH
Ph
S
N
CONHPh
N
11 (76%)
Scheme 2
Refluxing of equimolar amounts of the acetamide 1 and 2-benzylidenemalononitrile (15a),33 in the
presence of a catalytic amount of piperidine afforded 1 : 1 cycloadduct (Scheme 3). The structure of the
isolated cycloadduct was identified as 6-amino-2-oxo-4-phenyl-1-(thiazol-2-yl)-1,2-dihydropyridine-3,5-
dicarbonitrile (18a) on the basis of its elemental analyses and spectral data. Compound 18a is assumed to be

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HETEROCYCLES, Vol. 81, No. 10, 2010
formed via an initial Michael type adduct 16a followed by an intramolecular cyclization and subsequent
oxidation to the final product (Scheme 3).
When compound 1 was treated with 2-cyano-3-phenyl-2-propenoic acid ethyl ester (15b),33 in ethanol and
in the presence of a catalytic amount of piperidine, it gave the corresponding pyridine-3,5-dicarbonitrile
18b (Scheme 3).
S
O
N
N
H
CN
CN
CN
CN
1
Ph
Ph
CO2Et
15b
15a
S
O
O
CN
S
CN
N
N
NH
NC
Ph
H
O
N
Ph
CN
16a
EtO CN
16b
-EtOH
O
N
CN
Ph
O
S
S
N
CN
Ph
N
N
H
HN
CN
O
NC
H
17a
-H2
17b
-H2
O
N
CN
O
N
CN
S
S
N
Ph
Ph
N
HO
CN
18b (68%)
H2N
CN
18a (90%)
Scheme 3
Compound 18b was formed initially via Michael type addition followed by elimination of ethanol molecule
and subsequent dehydrogenation. The IR spectrum of the reaction product revealed the absence of amino
absorption bands and exhibited absorption bands at 1715 and 2222 cm-1 due to amid carbonyl and two
nitrile groups, respectively. Moreover, its 1H NMR spectrum showed a broad D2O-exchangable signal at 
12.6 due to OH proton in addition to aromatic multiplet in the region  7.24-8.74.

HETEROCYCLES, Vol. 81, No. 10, 2010
2373
In conclusion, the reactivity of 2-cyano-N-(thiazol-2-yl)acetamide (1) was investigated, as a versatile and
readily accessible building block, for the synthesis of new heterocycles incorporating thiazole ring of
biological and pharmaceutical importance.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting point apparatus (Weiss-Gallenkamp, London,
UK). The infrared spectra were recorded in potassium bromide disks on a pye Unicam SP 3300 and
Shimadzu FT IR 8101 PC infrared spectrophotometers (Pye Unicam Ltd. Cambridge, England and
Shimadzu, Tokyo, Japan, respectively). The NMR spectra were recorded on a Varian Mercury VX-300
NMR spectrometer (Varian, Palo Alto, CA, USA). 1H spectra were run at 300 MHz in deuterated dimethyl
sulphoxide (DMSO-d6). Chemical shifts were related to that of the solvent. Mass spectra were recorded on
a Shimadzu GCMS-QP 1000 EX mass spectrometer (Shimadzu) at 70 eV. Elemental analyses were carried
out at the Micro-analytical Center of Cairo University, Giza, Egypt. 2-Cyano-N-(thiazol-2-yl)acetamide
(1)29 is commercially available. Hydrazonoyl chlorides 230 5a, 5b31 1-phenyl-2-bromoethanone (12),32
2-benzylidenemalononitrile (15a)33 and 2-cyano-3-phenyl-2-propenoic acid ethyl ester (15b)33 were
prepared according to the literature procedures.
Reaction of acetamide 1 with hydrazonoyl halides 2 and 5a.
General procedure
2-Cyano-N-(thiazol-2-yl)acetamide (1) (0.33 g, 2 mmol) was added to an ethanolic sodium ethoxide
solution [prepared from sodium metal (46 mg, 2 mmol) and absolute EtOH (20 mL)] with stirring. After
stirring the resulting solution for 15 min., compound 2 or 5a (2 mmol) was added portionwise and the
reaction mixture was stirred further for 12 h at room temperature. The resulted solid product was filtered off,
washed with water and dried. Recrystallization from the DMF/EtOH afforded the corresponding pyrazole
derivatives 4a and 4b, respectively.
3-Acetyl-5-amino-1-phenyl-N-(thiazol-2-yl)-1H-pyrazole-4-carboxamide (4a).
Yield (63%), mp 246-247 oC; IR (KBr) v 3443-3331 (NH2), 3191 (NH), 1692 (C=O), 1638 (C=O) cm-1; 1H
NMR (DMSO-d6)  2.43 (s, 3H, CH3), 4.01 (s, 2H, D2O-exchangeable, NH2), 7.08-7.86 (m, 7H, ArH), 12.2
(s, 1H, D2O-exchangeable NH). Anal. Calcd for C15H13N5O2S: C, 55.03; H, 4.00; N, 21.39. Found: C,
55.13; H, 4.05; N, 21.35%.
5-Amino-N3-phenyl-N4-(thiazol-2-yl)-1-(p-tolyl)-1H-pyrazole-3,4-dicarboxamide (4b).
o
Yield (68%), mp 279-280 C; IR (KBr) v 3314-3356 (NH2), 3200 (NH), 3036 (NH), 1692 (C=O), 1672
1
(C=O) cm-1; H NMR (DMSO-d6)  2.26 (s, 3H, CH3), 7.12-7.56 (m, 13H, ArH+ NH2), 11.25 (s, 1H,
D2O-exchangeable, NH), 14.0 (s, 1H, D2O-exchangeable NH); MS m/z (%) 418 (M+, 32.78), 99 (7.78), 84
(23.89). Anal. Calcd for C21H18N6O2S: C, 60.27; H, 4.34; N, 20.08. Found: C, 60.21; H, 4.24; N, 20.18%.

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5-Acetyl-7-phenyl-3-(thiazol-2- yl)-3H-pyrazolo[3,4-d]-1,2,3-triazin-4(7H)-one (7).
To a solution of 5-aminopyrazole 4a (0.33 g, 1 mmol) in acetic acid (5 mL) was added HCl (6 M, 1 mL).
The mixture was then cooled to 0-5 oC and sodium nitrite (69 mg) was added portionwise while stirring.
The reaction mixture was left to stand in an ice bath for 1 h and was then diluted with water, filtered off,
washed with water and finally recrystallized from DMF/EtOH to afford compound 7: Yield (61%), mp
o
1
265-266 C; IR (KBr) v 1729 (C=O), 1680 (C=O) cm-1; H NMR (DMSO-d6)  2.53 (s, 3H, CH3),
7.10-7.87 (m, 7H, ArH). Anal. Calcd for C15H10N6O2S: C, 53.25; H, 2.98; N, 24.84. Found: C, 53.15; H,
2.92; N, 24.86%.
5-(1-Cyano-2-oxo-2-(thiazol-2-ylamino)ethylidene)-N,4-diphenyl-4,5-dihydro-1,3,4-thiadiazole-2-carb-
oxamide (11) and 4-amino-5-benzoyl-2-(phenylamino)-N-(thiazol-2-yl)thiophene-3- carboxamide (14).
General Procedure
To a stirred solution of potassium hydroxide (0.11 g, 2 mmol) in DMF (20 mL) was added the acetamide 1
(0.33 g, 2 mmol). After stirring for 30 min, phenyl isothiocyanate (0.27 g, 0.24 mL, 2 mmol) was added to
the resulting mixture. Stirring was continued for 6 h, and then 2-oxo-N'-phenyl-2-(phenylamino)-
acetohydrazonoyl chloride (5b) (0.55 g, 2 mmol) or 2-bromo-1-phenylethanone (12) (0.40 g, 2 mmol) was
added portionwise over a period of 30 min. After the addition was complete, the reaction mixture was
stirred for additional 12 h, during which the reactant went into solution and a yellow product precipitated.
The solid product was filtered off, washed with EtOH and dried. Recrystallization from DMF/EtOH
afforded compounds 11 and 14, respectively.
o
11: Yield (76%), mp 293-295 C; IR (KBr) v 3385 (NH), 3065 (NH), 2193 (C≡N), 1682, 1647 (2C=O)
cm-1; 1H NMR (DMSO-d6)  7.05-7.77 (m, 12H, ArH), 10.85 (s, 1H, D2O-exchangeable, NH), 11.68 (s, 1H,
D2O-exchangeable NH); MS m/z (%) 448 (M++1, 2.88), 446 (25.21), 127 (5.47). Anal. Calcd for
C21H14N6O2S2: C, 56.49; H, 3.16; N, 18.82. Found: C, 56.42; H, 3.25; N, 18.77%.
14: Yield (68%), mp 232-233 oC; IR (KBr) v 3625 (NH), 3550-3600 (NH2), 1663, 1645 (2C=O) cm-1; 1H
NMR (DMSO-d6)  7.05-8.04 (m, 12H, ArH), 8.80 (s, 2H, D2O-exchangeable NH2), 11.98 (s, 1H,
D2O-exchangeable, NH), 13.19 (s, 1H, D2O-exchangeable, NH); MS m/z (%) 421 (2.89), 420 (M+, 11.04),
127 (33.5), 84 (6.84). Anal. Calcd for C21H16N4O2S2: C, 59.98; H, 3.84; N, 13.32. Found: C, 59.88; H, 3.80;
N, 13.38%.
6-Amino-2-oxo-4-phenyl-1-(thiazol-2-yl)-1,2-dihydropyridine-3,5-dicarbonitrile (18a).
To a solution of 2-benzylidenemalononitrile (15a) (0.77 g, 5 mmol) in EtOH (20 mL) was added an
equimolar amount of acetamide 1 (0.84 g, 5 mmol), and few drops of piperidine and the reaction mixture
was heated under reflux for 2 h. The solid product was collected by filtration, washed with EtOH and then
crystallized from DMF to afford compound 18a in 90% yield, mp > 300 oC (DMF); IR (KBr) v 3312 and

HETEROCYCLES, Vol. 81, No. 10, 2010
2375
3350 (NH2), 2216 (C≡N), 2208 (C≡N), 1666 (C=O) cm−1; 1H NMR (DMSO-d6)  7.57-7.60 (m, 5 H, ArH),
7.94-7.93 (d, 1H, J = 3.0 Hz), 8.00-7.99 (d, 1H, J = 3.0 Hz), 8.77 (s, 2H, D2O-exchangeable NH2). Anal.
Calcd for C16H9N5OS: C, 60.18; H, 2.84; N, 21.93. Found: C, 60.25; H, 2.92; N, 21.85%.
6-Hydroxy-2-oxo-4-phenyl-1-(thiazol-2-yl)-1,2-dihydropyridine-3,5-dicarbonitrile (18b).
To a solution of 2-cyano-3-phenyl-2-propenoic acid ethyl ester (15b) (1.0 g, 5 mmol) in EtOH (20 mL) was
added an eqimolar amount of the acetamide 1 (0.84 g, 5 mmol), and few drops of piperidine and the reaction
mixture was heated under reflux for 2 h. The solid product that obtained was collected by filtration, washed
o
with EtOH and then crystallized from DMF to afford 18b in 68% yield, mp > 300 C; IR (KBr) v 2226
1
(2C≡N), 1693 (C=O), 1641 (C=O) cm−1; H NMR (DMSO-d6)  8.53-9.34 (m, 7H, ArH), 14.24 (s, 1H,
D2O-exchangeable OH); MS m/z (%) 321 (18.1), 320 (M+, 100.0), 127(11.6). Anal. Calcd for C16H8N4O2S:
C, 59.99; H, 2.52; N, 17.49. Found: C, 60.08; H, 2.48; N, 17.39%.
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