Efficient synthesis of new functionalized 2-(hetaryl)thiazoles

Article abstract of DOI:10.1080/00397911.2011.591036

An efficient synthesis of the hitherto unknown ring system, 2-heteroaryl-thiazoles, is described via the reaction of 3-oxo-N-(4- phenylthiazol-2-yl)butanamide (1) with diazotized heterocyclic amine, phenyl isothiocyanate, dimethylformamide-dimethylacetal,

Full text of DOI:10.1080/00397911.2011.591036

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Efficient Synthesis of New
Functionalized 2-(Hetaryl)thiazoles
Samir Bondock a b , Hossam El-Azab a , Ez-Eldin M. Kandeel a &
Mohamed A. Metwally a
a Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
b Chemistry Department, Faculty of Science, King Khalid University,
Abha, Saudi Arabia
Accepted author version posted online: 24 Jan 2012. Version of
record first published: 05 Sep 2012
To cite this article: Samir Bondock, Hossam El-Azab, Ez-Eldin M. Kandeel & Mohamed A. Metwally
(2013): Efficient Synthesis of New Functionalized 2-(Hetaryl)thiazoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:1, 59-71
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Synthetic Communications1, 43: 59–71, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.591036
EFFICIENT SYNTHESIS OF NEW FUNCTIONALIZED
2-(HETARYL)THIAZOLES
Samir Bondock,1,2 Hossam El-Azab,1 Ez-Eldin M. Kandeel,1
and Mohamed A. Metwally1
1Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
2Chemistry Department, Faculty of Science, King Khalid University, Abha,
Saudi Arabia
GRAPHICAL ABSTRACT
Abstract An efficient synthesis of the hitherto unknown ring system, 2-heteroaryl-thiazoles,
is described via the reaction of 3-oxo-N-(4-phenylthiazol-2-yl)butanamide (1) with
diazotized heterocyclic amine, phenyl isothiocyanate, dimethylformamide–dimethylacetal,
and hydrazine hydrate, and the reaction of 2-chloro-N-(4-phenylthiazol-2-yl)acetamide
(13) with some sulfur nucleophiles and malononitrile. The structures of the compounds
prepared were determined by analytical and spectral analyses.
Keywords Japp–Klingmann; phenyl isothiocyanate; pyrazole; pyridine; thiazole
Received May 9, 2011.
Address correspondence to Samir Bondock, Chemistry Department, Faculty of Science, Mansoura
University, ET-35516, Mansoura, Egypt. E-mail: Bondock@mans.edu.eg
59

60
S. BONDOCK ET AL.
INTRODUCTION
2-Aminothiazoles have received considerable attention because of their impor-
tance as versatile reagents.[1–5] The thiazole ring system is a common structural
moiety found in numerous biologically active molecules.[6] This heterocyclic moiety
has been employed in the preparation of different drugs required for the treatment of
hypertension.[7] Some of the thiazole analogs are used as fungicides, inhibiting the
in vivo growth of Xanthomonas, and as ingredients of herbicides or schistosomicidal
and anthelmintic drugs.[8] They have been utilized for the treatment of pain,[9] as
fibrinogen receptor antagonists with antithrombotic activity,[10] and as inhibitors
of bacterial DNA gyrase B.[11] In the light of these facts and in continuation of
our interest in the synthesis of heterocycles containing a thiazole moiety,[12–20] we
report herein the results of our study of the reaction of 3-oxo-N-(4-phenylthiazol-2-
yl)butanamide (2) and 2-chloro-N-(4-phenylthiazol-2-yl)acetamide (13) with some
electrophilic and nucleophilic reagents. The aim of the present article is to present
an efficient synthesis of novel 2-heteroaryl-thiazoles, which have not been reported.
RESULTS AND DISCUSSION
The starting material, 3-oxo-N-(4-phenylthiazol-2-yl)butanamide (2), used in
this study was prepared by the solvent-free reaction of 2-amino-4-phenylthiazole (1)
with ethyl acetoacetate at 150 ꢀC according to a literature procedure.[21] The chemical
behavior of the versatile starting material 2 was tested toward many chemical reac-
tions, for example, coupling reaction with aromatic and heterocyclic diazonium salts,
phenyl isothiocyanate, and dimethylformamide–dimethylacetal (DMF-DMA).
Compound 2 possesses two active sites (active methylene C-2 and thiazole C-5)
for electrophilic substitution reaction by aromatic diazonium salts. The methylene
group in compound 2 proved to be more reactive toward coupling reaction with dia-
zonium salts than the thiazole C-5. Thus, compound 2 coupled smoothly with 1 mol of
the diazonium salts of aniline, p-toulidine, and p-anisidine in pyridine to afford the
corresponding arylhydrazone derivatives 3a–c by reaction at the methylene site
(Scheme 1). The structure of the arylhydrazone products 3a–c were verified by elemen-
tal analyses and spectroscopic methods. For example, the infrared (IR) spectrum of 3c
revealed absorption bands at 3216, 3102, 1674, and 1656 cmꢁ1 due to two (NH) and
1
two carbonyl functions. Its H NMR spectrum displayed, in addition to aromatic
proton signals, four singlet signals at d 2.40, 3.79, 13.36, and 13.70 ppm characteristic
for the CH3, OCH3, hydrazone NH, and amidic NH protons, respectively.
It has been reported[22] that condensation of 2-arylhydrazonoketones with
active methylene nitriles affords pyridazinones. In this context, compounds 3a–c
were allowed to react with ethyl cyanoacetate in refluxing ethanolic piperidine sol-
ution, sodium ethoxide, or glacial acetic acid containing ammonium acetate, in an
attempt to get the pyridazinones 4a–c. Unfortunately, the starting arylhydrazonoke-
tones 3a–c were recovered.
We turned our attention to study the reactivity of 2 toward diazotized hetero-
cyclic amine, namely, 3-amino-4,6-dimethyl-pyrazolo[3,4-b]-pyridine (4d) as a poss-
ible synthetic route to attain a bridged head nitrogen heterocyclic system. Thus,
coupling of 4d with butanamide 2 in pyridine afforded the corresponding

2-(HETARYL)THIAZOLES
61
Scheme 1. Synthetic route to pyrido[20,30:3,4]pyrazolo-[5,1-c][1,2,4]trazine-3-carboxamide (6).
pyrido[20,30:3,4]pyrazolo[5,1-c]triazine derivative 6 via the hetarylhydrazonoketone
intermediate 5. The mass spectrum of 6 clearly showed the molecular ion peak at
m=z 415 (Mþ) corresponding to the molecular weight of the molecular formula
C21H17N7OS.
The base-promoted nucleophilic addition of butanamide 2 to an equimolar
amount of phenyl isothiocyanate in dimethylformamide containing potassium
hydroxide afforded the corresponding thiocarbamoyl derivative 7 after neutraliza-
tion with dilute HCl. The structure of 7 was confirmed on the basis of its elemental
analysis and spectral data. The IR spectrum of 7 showed absorption bands at 3445,
3227, 1675, 1654, and 1288 cmꢁ1, indicating the presence of two (NH), two (C O),
=
=
and (C S) groups, respectively. Moreover, its mass spectrum showed the molecular
ion peak at m=z 369 (Mþ), corresponding to the molecular formula C18H15N3O2S2.
Treatment of thiocarbamoyl derivative 7 with hydrazine hydrate in refluxing
ethanol afforded the isolable product (tested by thin-layer chromatography, TLC),
identified as 3-methyl-5-(phenylamino)-N-(4-phenylthiazol-2-yl)-1H-pyrazole-4-
carboxamide (8). The IR spectrum of compound 8 showed absorption bands at
3365, 3278, 3150, and 1652 cmꢁ1 due to three NH and amidic carbonyl functions.
Its 1H NMR revealed a singlet signal at d 2.12 due to CH3 protons, D2O-exchangeable
signals at 9.17, 11.37, and 13.12 due to three NH protons, and an aromatic multiplet
and thiazole-H5 in the region d 6.95–7.84 ppm.
Treatment of 7 with the phenyl diazonium chloride in ethanol buffered with
sodium acetate effected acetyl group cleavage (Japp–Klingmann reaction) with the
formation of the corresponding phenylhydrazonothiocarbamoyl derivative 9. The
chemical structure of 9 was assigned on the basis of the spectral and elemental analy-
ses. The IR spectrum showed absorption bands at 3412, 3234, 3154, 1658, and
1288 cmꢁ1 due to three NH, amidic carbonyl and thiocarbonyl functions, respectively.

62
S. BONDOCK ET AL.
1
The H NMR spectrum revealed the lack of acetyl signal and the presence of three
singlet signals exchangeable with D2O at d 9.98, 12.46, and 13.26 ppm due to three
NH protons, beside the expected multiplet signal for an aromatic protons and
thiazole-H5 in the region 7.16–7.91 ppm.
The reaction of thiocarbamoyl derivatives with a-halocarbonyl compounds
provides a facile one-pot synthesis of thiazole derivatives. Thus, treatment of thioa-
cetanilide 9 with chloroacetyl chloride in dimethylformamide containing a catalytic
amount of triethylamine at room temperature afforded the thiazolidin-5-one 10. The
structure of the latter product was established by the presence of a strong absorption
band at 1735 cmꢁ1 in the IR spectrum. This is considered to be a strong confirmation
for the thiazolidinone nucleus formation. Another of evidence for the cyclization is
1
the presence of a singlet signal, equivalent to two protons in the H NMR spectrum
at d 4.24 ppm, which represents the C-4 protons of the thiazolidinone nucleus.
Enaminones are versatile intermediates for the synthesis of a variety of biologically
important natural products, fine chemicals, and pharmacecuticals.[23] In this context, the
reactivity of butanamide 2 toward DMF-DMA as a possible synthetic route to
enaminone was investigated. Thus, when butanamide 2 was treated with DMF-DMA
in boiling dioxane, it afforded the corresponding enaminone, namely 2-(N,N-
dimethylaminomethylene)-3-oxo-N-(4-phenylthiazol-2-yl)butanamide (11). The IR
spectrum of the latter product revealed absorption bands at 3172, 1682, and 1656cmꢁ1
1
due to NH and two carbonyl functions. Its H NMR revealed signals at d 2.47, 3.21,
and 3.26ppm due to acetyl CH3 protons and N,N-dimethyl protons, in addition to the
D2O-exchangeable signal at d 13.72 ppm due to the amidic NH proton, and an aromatic
multiplet, thiazole H5, and olefinic proton in the region d 7.26–8.35ppm.
Compound 11 was treated with hydrazine hydrate, in refluxing ethanol, to
afford the pyrazole derivative 12 (Scheme 2). The IR spectrum of pyrazole 12 revealed
Scheme 2. Synthetic pathway to pyrazolo 8, 12, and thiazolidin-5-one 10 derivatives.

2-(HETARYL)THIAZOLES
63
absorption bands at 3235, 3100, and 1661 cmꢁ1 due to two NH and amidic carbonyl
functions. Its 1H NMR revealed two singlets at d 2.14, and 8.98 ppm due to CH3 pro-
tons and pyrazole-H5, beside two D2O-exchangeable signals at d 9.56 and 11.75 due
to NH protons, and an aromatic multiplet in the region d 6.68–7.85 ppm. Morever, its
mass spectrum showed a molecular ion peak at m=z 284 (Mþ) corresponding to the
molecular weight of the molecular formula C14H12N4OS.
In addition, a-chloroacetamides are highly reactive compounds.[24,25] They are
extensively utilized as reactants or reaction intermediates because the imino and
chloride functions of these compounds are suitably situated to enable reactions with
common bidendate reagents to form a variety of heterocyclic compounds. Moreover,
the active hydrogen at C-2 of these compounds can take part in a variety of conden-
sation and substitution reactions. In this context, we synthesized 2-chloro-N-
(4-phenylthiazol-2-yl)acetamide (13),[26] via treatment of 2-amino-4-phenylthiazole
(1) with chloroacetyl chloride in DMF containing anhydrous potassium carbonate,
to investigate its reactivity toward some sulfur nucleophiles and malononitrile.
Thus, treatment of 2-chloroacetamide 13 with 4,6-dimethyl-2-mercaptonicoti-
nonitrile in refluxing acetone containing sodium carbonate gave the corresponding
sulfide derivative 14, which underwent cyclization on heating in ethanolic sodium
ethoxide solution to afford the corresponding thieno[2,3-b]pyridine derivative 15
(Scheme 3). The chemical structures of compounds 14 and 15 were established on
the basis of their elemental analyses and spectral data.
The IR spectrum of 14 is characterized by the presence of a strong absorption
bands at 3107, 2223, and 1689 cmꢁ1 due to NH, nitrile, and carbonyl functions, respect-
ively. Its 1H NMR spectrum displayed two singlet signals at d 2.35 and 2.40 due to the
two methyl protons, a singlet signal at d 4.28 due to the thiomethylene protons (SCH2),
Scheme 3. Synthetic route to thieno[2,3-b]pyridine 15, thiomorpholine-3,5-dione 17, and pyrrole 19
derivatives.

64
S. BONDOCK ET AL.
a multiplet in the region d 7.10–7.92 due to an aromatic and thiazole-H5 protons, and a
singlet signal at d 12.57 ppm exchangeable with D2O due to a NH proton.
The IR spectrum of 15 clearly indicated the lack of a cyano absorption band
and revealed the characteristics of NH2 and NH absorption bands at 3509, 3403,
and 3347 cmꢁ1 in addition to the carbonyl absorption band at 1623 cmꢁ1. The strong
decrease in the carbonyl absorption frequency is attributed to the highly chelated
1
intramolecular H-bond structure. Its H NMR spectrum confirmed the lack of the
singlet signal that characterized the methylene protons and showed two singlet sig-
nals due to the two methyl protons at d 2.40 and 2.80 in addition to a singlet signal
at d 7.00 for the pyridine-H5 proton and multiplet signal at d 7.40–7.90 ppm for the
aromatic and thiazole H5 protons. Also, its mass spectrum showed a molecular ion
peak at m=z 490 (Mþ) corresponding to the molecular weight of the molecular for-
mula C24H22N6O2S2.
The plausible mechanism for the formation of thieno[2,3-b]pyridine 15 is
attributed to an initial alkylation of 13 with mercaptonicotinonitrile to form the iso-
lable thioether 14, which underwent intramolecular cyclization via nucleophilic
addition of the active methylene group to the nitrile function and tautomerization
according to the Thorpe–Ziegler reaction.[27]
In a similar manner, the reaction of 13 with ethyl thioglycolate in acetone con-
taining anhydrous potassium carbonate afforded the corresponding sulfide 16, which
could be easily converted to thiomorpholine-3,5-dione 17 upon boiling in ethanolic
triethylamine solution. The structures of isolated products 16 and 17 were verified by
elemental analyses and spectroscopic data. For example, the IR spectrum of 17
revealed the lack of both an imino and carbonyl ester groups and the presence of
1
absorption band at 1669 cmꢁ1 due to an amidic carbonyl group. Its H NMR spec-
trum displayed, in addition to the aromatic proton signals, a singlet signal at d
5.24 ppm integrated for four protons due to the two methylene protons of
thiomorpholine-3,5-dione ring.
Finally, the reaction of 13 with malononitrile in refluxing dioxane containing a
catalytic amount of triethylamine furnished the functionalized pyrrole derivative 19.
The IR spectrum of the latter product showed the characteristic absorption bands of
amino (NH2), cyano (CN) and carbonyl (CO) groups at 3424, 3329, 2198, and
1
1692 cmꢁ1, respectively. Its H NMR spectrum displayed a singlet signal at d 4.10
due to the methylene protons (CH2, ring), a broad singlet signal at d 6.85 ppm
exchangeable with D2O due to the NH2 protons, and thiazole H-5 proton, aromatic
protons as multiplet signal in the region d 7.40–7.60 ppm.
Compound 19 was thought to be formed via the initial displacement of the
chloride ion by the active methylene group of malononitrile to form the nonisolable
intermediate 18, which in situ undergoes intramolecular cyclization via nucleophilic
addition of the imino group to the nitrile function and tautomerization. Moreover,
the formation of pyrrolidinone 19 is also in the line with previous report by Schaefer
and Gewald.[28]
In conclusion, we have described an efficient synthesis of new pyrido[20,30:
3,4]pyrazolo[5,1-c]triazine, pyrazole, thiazole, thieno[2,3-b]pyridine, thiomorpholine,
and pyrrole derivatives containing thiazole template via the reaction of two versatile,
and readily accessible starting materials, 3-oxo-N-(4-phenylthiazol-2-yl)butanamide
and 2-chloro-N-(4-phenylthiazol-2-yl)acetamide with some chemical reagents.

2-(HETARYL)THIAZOLES
65
EXPERIMENTAL
All melting points were measured on an electrothermal Gallenkamp melting-
point apparatus. The IR spectra were recorded in potassium bromide disks on a
Mattson 5000 FTIR spectrometer. The NMR spectra were recorded on a Brucker
1
WP 300 NMR spectrometer. H spectra were run at 300 MHz and 13C spectra were
run at 75.5 MHz in dimethylsulfoxide (DMSO-d6) or CDCl3 or CF3COOD as sol-
vent. Chemical shifts were related to that of the solvent. The mass spectrum were
recorded on a Finnigan MAT 212 mass spectrometer at 70 eV. Elemental analyses
were carried out at the Microanalytical Center of Cairo University, Giza, Egypt,
and the results were in a good agreement (ꢂ0.3%) with the calculated values. The
starting materials 3-oxo-N-(4-phenylthiazol-2-yl)butanamide (2)[21] and 2-chloro-
N-(4-phenylthiazol-2-yl)acetamide (13)[26] were prepared according to the literature.
General Procedure for the Synthesis of Arylhydrazone
Derivatives (3a–c)
The appropriate diazonium salt of aromatic amines (2 mmol) was added to a
cold solution of butanamide 2 (0.52 g, 2 mmol) in 30 ml pyridine. The addition
was carried out portionwise with stirring at 0–5 ꢀC over a period of 30 min. After
complete addition, the reaction mixture was stirred for a further 2 h and then diluted
with water. The precipitated solid was collected by filtration, washed with water,
dried, and finally recrystallized from a mixture of EtOH-DMF (2:1) to afford the
arylhydrazones 3a–c.
2-(Phenylhydrazono)-3-oxo-N-(4ꢀ-phenylthiazol-2-yl)butanamide (3a).
Yellow crystals, yield 55%, mp 220–221 C. IR (n=cmꢁ1): 3208 (NH), 3097 (NH),
ꢀ
1
=
=
1670 (C O), 1652 (C O). H NMR (CDCl3): d 2.31 (s, 3H, CH3), 7.18–7.95 (m,
11H, Ar-H and thiazole-H5), 13.52 (bs, 1H, NH), 13.75 (s, 1H, NH). 13C NMR
(CDCl3): d 26.5, 108.6, 114.8, 118.2, 125.3, 127.8, 128.3, 128.6, 134.1, 140.1, 145.2,
148.3, 158.1, 160.2, 192.5. MS (EI, 70 eV): m=z (%) ¼ 364 (Mþ, 19.2), 321 (25.0),
256 (14.3), 203 (6.4), 176 (49.8), 149 (30.1), 134 (18.02), 111 (35.1), 97 (69.4), 85
(47.5), 73 (74.0), 55 (94.7). Anal. calcd. for C19H16N4O2S (364.42): C, 62.62; H,
4.43; N, 15.37. Found: C, 62.48; H, 4.49; N, 15.26.
2-(4-Methylphenylhydrazono)-3-oxo-N-(4-phenylthiazol-2-yl)butanamide
(3b). Reddish brown crystals, yield 62%, mp 200–201 C. IR (n=cmꢁ1): 3225 (NH),
ꢀ
ꢀ
1
=
=
3105 (NH), 1672 (C O), 1621 (C O). H NMR (CDCl3): d 2.12 (s, 3H, CH3), 2.35
(s, 3H, CH3), 7.14–7.91 (m, 10H, Ar-H and thiazole-H5), 13.43 (bs, 1H, NH), 13.71
(s, 1H, NH). 13C NMR (CDCl3): d 21.3, 26.4, 108.8, 117.0, 127.2, 128.1, 129.8,
133.9, 136.8, 142.2, 148.2, 158.3, 160.4, 192.1. MS (EI, 70 eV): m=z (%) ¼ 378 (Mþ,
36.7), 335 (28.9), 239 (9.1), 203 (36.5), 176 (88.0), 134 (29.6), 97 (59.1), 83 (63.7), 77
(29.2), 57 (100). Anal. calcd. for C20H18N4O2S (378.45): C, 63.47; H, 4.79; N,
14.80. Found: C, 63.63; H, 4.67; N, 14.86.
2-(4-Methoxyphenylhydrazono)-3-oxo-N-(4-phenylthiazol-2-yl)
butanamide (3c). Red crystals, yield 70%, mp 210–211 C. IR (n=cmꢁ1): 3216
ꢀ
ꢀ
1
=
=
(NH), 3102 (NH), 1674 (C O), 1656 (C O). H NMR (DMSO-d6): d 2.40 (s, 3H,
CH3), 3.79 (s, 3H, OCH3), 7.00–8.05 (m, 10H, Ar-H and thiazole-H5), 13.36 (s,

66
S. BONDOCK ET AL.
1H, NH), 13.7 (s, 1H, NH). 13C NMR (DMSO-d6): d 26.3, 56.1, 108.9, 114.8, 119.4,
124.7, 127.3, 128.2, 133.7, 139.4, 141.0, 148.7, 158.6, 161.3, 192.4. Anal. calcd. for
C20H18N4O3S (394.45): C, 60.90; H, 4.60; N, 14.20. Found: C, 60.98; H, 4.52;
N, 14.12.
Synthesis of 4,8,10-Trimethyl-N-(4-phenylthiazol-2-
yl)pyrido[2’,3’:3,4]pyrazolo-[5,1-c][[1,2,4]triazine-3-carboxamide (6)
The diazonium salt of 3-amino-4,6-dimethylpyrazolo[3,4-b]pyridine 4d
(2 mmol) [prepared by addition of a cold solution of sodium nitrite (0.138 g,
2 mmol) dissolved in 3 ml water to a stirred ice-cold solution of 3-amino-4,6-
dimethylpyrazolo[3,4-b]pyridine (0.324 g, 2 mmol), dissolved in 3 ml concentrated
HCl and 2 ml water] was added to a cold solution of butanamide 2 (0.52 g, 2 mmol)
in 30 ml pyridine. The addition was carried out portionwise with stirring at 0–5 ꢀC
over a period of 30 min. After complete addition, the reaction mixture was stirred
for a further 4 h, then kept in an ice chest for 24 h, and finally diluted with water.
The precipitated solid was collected by filtration, washed with water, dried, and
finally recrystallized from ethanol to afford compound 6.
Yellow crystals, yield 42%, mp > 300 C. IR (n=cmꢁ1): 3349 (NH), 1686
ꢀ
ꢀ
1
=
(C O). H NMR (DMSO-d6): d 2.32 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.41 (s, 3H,
CH3), 7.16–8.16 (m, 7H, Ar-H, pyridine-H3 and thiazole-H5), 13.84 (s, 1H, NH).
13C NMR (DMSO-d6): d 10.2, 20.1, 21.6, 96.1, 108.5, 115.3, 117.4, 124.7, 127.2,
128.1, 131.8, 133.5, 133.8, 140.5, 157.9, 159.2, 161.0, 161.9, 164.8. MS (EI, 70 eV):
m=z (%) ¼ 415 (Mþ, 55.9), 382 (24.8), 240 (38.2), 175 (37.3), 168 (40.1), 154 (29.8),
134 (100), 104 (47.6), 91 (19.3), 76 (57.5), 66 (62.9). Anal. calcd. for C21H17N7OS
(415.47): C, 60.71; H, 4.12; N, 23.60. Found: C, 60.80; H, 4.15; N, 23.57.
Synthesis of 3-Oxo-2-(phenylthiocarbamoyl)-N-(4-phenylthiazol-2-
yl)butanamide (7)
Butanamide 2 (0.52 g, 2 mmol) was added to a stirred solution of potassium
hydroxide (0.11 g, 2 mmol) in 20 ml dimethylformamide. After the mixture had
been stirred for 30 min, phenyl isothiocyanate (0.27 g, 2 mmol) was added to the
mixture. Stirring was continued for 24 h, and then the mixture was poured over
crushed ice containing hydrochloric acid. The solid product formed was filtered
off, washed with water, dried, and finally recrystallized from ethanol to afford
compound 7.
Yellow crystals, yield 87%, mp 127–128 C. IR (n=cmꢁ1): 3445 (NH), 3327
ꢀ
ꢀ
1
=
=
=
(NH), 1675 (C O), 1654 (C O), 1288 (C S). H NMR (CDCl3): d 2.34 (s, 3H,
CH3), 4.47 (s, 1H, CH), 7.25–7.96 (m, 11H, Ar-H and thiazole-H5), 11.76 (s, 1H,
NH), 12.96 (s, 1H, NH). 13C NMR (CDCl3): d 29.8, 72.7, 108.4, 122.6, 124.7,
127.2, 127.8, 128.1, 128.3, 133.6, 140.7, 156.3, 160.7, 162.5, 167.5, 198.8. MS (EI,
70 eV): m=z (%) ¼ 395 (Mþ, 24.6), 352 (36.1), 303 (15.5), 259 (46.2), 235 (12.3),
175 (100), 160 (41.7), 92 (30.2), 77 (57.5), 43 (69.6). Anal. calcd. for C20H17N3O2S2
(395.50): C, 60.74; H, 4.33; N, 10.62. Found: C, 60.81; H, 4.27; N, 10.58.

2-(HETARYL)THIAZOLES
67
Synthesis of 3-Methyl-5-(phenylamino)-N-(4-phenylthiazol-2-yl)-1H-
pyrazole-4-carboxamide (8)
Hydrazine hydrate (80%, 0.1 ml, 1 mmol) was added to a solution of the com-
pound 7 (0.395 g, 1 mmol) in 20 ml ethanol. The reaction mixture was heated under
reflux for 6 h and then left to cool. The solid product was filtered off, washed with
ethanol, dried, and recrystallized from ethanol to afford compound 8.
Yellow crystals, yield 78%, mp 192–193 C. IR (n=cmꢁ1): 3365 (NH), 3278 (NH),
ꢀ
ꢀ
1
=
3150 (NH), 1652 (C O). H NMR (CDCl3): d 2.12 (s, 3H, CH3), 6.95–7.84 (m, 11H,
Ar-H and thiazole-H5), 9.17 (s, 1H, pyrazole NH), 11.37 (s, 1H, NH), 13.12 (s, 1H,
NH). 13C NMR (CDCl3): d 12.8, 93.8, 108.7, 116.4, 120.1, 124.7, 127.2, 128.1,
129.2, 133.8, 139.6, 141.1, 143.3, 148.9, 157.8, 159.6, 160.2. Anal. calcd. for
C20H17N5OS (375.45): C, 63.98; H, 4.56; N, 18.65. Found: C, 63.98; H, 4.56; N, 18.65.
Synthesis of 3-(Phenylamino)-2-(phenylhydrazono)-N-
(4-phenylthiazol-2-yl)-3-thioxopropanamide (9)
The diazonium salt of aniline (2 mmol) was added to a cold solution of com-
pound 8 (0.75 g, 2 mmol) in 50 ml ethanol buffered with sodium acetate trihydrate
(3 g). The addition was carried out portionwise with stirring at 0–5 ꢀC over a period
of 30 min. After complete addition, the reaction mixture was stirred for a further 2 h,
then kept in an ice chest for 6 h, and finally diluted with water. The precipitated solid
was collected by filtration, washed with water, dried, and finally recrystallized etha-
nol to afford compound 9.
Orange crystals, yield 76%, mp 170–171 C. IR (n=cmꢁ1): 3412 (NH), 3234
ꢀ
ꢀ
1
=
=
(NH), 3154 (NH), 1658 (C O), 1288 (C S). H NMR (CDCl3): d 7.16–7.91 (m,
16H, Ar-H and thiazole-H5), 9.98 (s, 1H, NH), 12.46 (s, 1H, NH), 13.26 (s, 1H,
NH). 13C NMR (CDCl3): d 109.2, 115.5, 122.4, 124.7, 127.2, 128.1, 128.6, 128.8,
129.2, 133.7, 139.2, 145.8, 149.7, 155.7, 156.4, 159.4, 160.4. MS (EI, 70 eV): m=z
(%) ¼ 457 (Mþ, 11. 6), 297 (13.5), 282 (100), 254 (15.6), 175 (45.6), 160 (36.8), 135
(59.3), 92 (46.2), 77 (42.8). Anal. calcd. for C24H19N5OS2 (457.57): C, 63.00; H,
4.19; N, 15.31. Found: C, 63.08; H, 4.12; N, 15.39.
Synthesis of 2-(5-Oxo-3-phenylthiazolidin-2-ylidene)-2-(phenylazo)-
N-(4-phenylthiazol-2-yl)acetamide (10)
Chloroacetyl chloride (0.224 g, 2 mmol) was added dropwise with stirring to a
solution of compound 9 (0.814 g, 2 mmol) in 25 ml dimethylformamide containing
0.5 ml of triethylamine at room temperature. Stirring was continued for a further
4 h, and then the reaction mixture was poured into ice-cooled water. The precipitated
solid was collected by filtration, washed with water, dried, and finally recrystallized
from ethanol to afford compound 10.
Yellow crystals, yield 75%, mp 154–155 C IR (n=cmꢁ1): 3175 (NH), 1735
ꢀ
ꢀ
1
=
=
=
(C O, ring), 1656 (C O), 1585 (N N). H NMR (CDCl3): d 4.24 (s, 2H, CH2 ring),
7.26–7.96 (m, 16H, Ar-H and thiazole-H5), 13.15 (s, 1H, NH). 13C NMR (CDCl3): d
49.5, 108.8, 114.4, 120.2, 123.0, 124.8, 127.5, 127.8, 128.2, 128.3, 129.0, 133.6, 138.5,
150.1, 153.1, 159.3, 161.1, 163.5, 170.1, 198.2. MS (EI, 70 eV): m=z (%) ¼ 497 (Mþ,

68
S. BONDOCK ET AL.
12.8), 392 (27.1), 337 (24.9), 322 (32.8), 294 (65.2), 176 (100), 160 (76.9), 105 (57.5),
77 (81.2). Anal. calcd. for C24H19N5OS2 (497.59): C, 62.76; H, 3.85; N, 14.07.
Found: C, 62.68; H, 3.78; N, 14.16.
Synthesis of 2-(N,N-Dimethylaminomethylene)-3-oxo-N-
(4-phenylthiazol-2-yl)butanamide (11)
A mixture of butanamide 2 (1.3 g, 5 mmol) and DMF-DMA (0.53 ml, 5 mmol)
in 25 ml dioxane was refluxed for 3 h and then left to cool. The yellow precipitated
product was filtered off, washed with light petroleum ether, dried, and recrystallized
from a mixture of ethanol–dioxane (1:1) to afford the enaminone 11.
Yellow crystals, yield 64%, mp 230–231 C IR (n=cmꢁ1): 3172 (NH), 1682
ꢀ
ꢀ
1
=
=
(C O), 1656 (C O). H NMR (CDCl3): d 2.47 (s, 3H, CH3), 3.21 (s, 3H, NCH3),
3.26 (s, 3H, NCH3), 7.26–8.35 (m, 7H, Ar-H, thiazole-H5 and olefinic CH ¼),
13.72 (s, 1H, NH). 13C NMR (CDCl3): d 29.4, 45.3, 108.3, 115.2, 124.7, 127.5,
128.1, 133.8, 154.2, 156.1, 158.7, 162.3, 193.7. Anal. calcd. for C16H17N3O2S
(315.39): C, 60.93; H, 5.43; N, 13.32. Found: C, 60.87; H, 5.38; N, 13.40.
Synthesis of 3-Methyl-N-(4-phenylthiazol-2-yl)-1H-pyrazole-4-
carboxamide (12)
A mixture of enaminone 11 (0.63 g, 2 mmol) and hydrazine hydrate (0.2 ml,
4 mmol) in 25 ml absolute ethanol was refluxed for 2 h. The solid product, which
separated during heating, was collected by filtration, washed with ethanol, dried,
and finally recrystallized from ethanol to afford comꢀpound 12.
Dark brown crystals, yield 68%, mp 242–243 C. IR (n=cmꢁ1): 3235 (NH),
ꢀ
1
=
3100 (NH), 1661 (C O). H NMR (CDCl3): d 2.14 (s, 3H, CH3), 7.12–7.96 (m,
6H, Ar-H and thiazole-H5), 8.98 (s, 1H, pyrazole-H5), 9.26 (s, 1H, pyrazole NH),
13.21 (s, 1H, NH). 13C NMR (CDCl3): d 92.2, 108.4, 116.4, 120.2, 124.7, 127.6,
128.2, 129.3, 131.2, 133.9, 140.1, 143.8, 154.3, 157.8, 160.3. MS (EI, 70 eV): m=z
(%) ¼ 284 (Mþ, 5.5), 264 (13.8), 236 (24.3), 176 (31.9), 161 (10.9), 134 (32.9), 111
(46.6), 98 (67.3), 77 (24.7), 71 (79.9), 57 (100), 55 (93.7). Anal. calcd. for C14H12N4OS
(284.34): C, 59.14; H, 4.25; N, 19.70. Found: C, 59.02; H, 4.14; N, 19.86.
Synthesis of 2-(3-Cyano-4,6-dimethylpyridin-2-ylthio)-N-
(4-phenylthiazol-2-yl)acetamide (14)
A mixture of 2-chloro-N-(4-phenylthiazol-2-yl)acetamide (13) (0.504 g, 2 mmol),
4,6-dimethyl-2-mercaptonicotinonitrile (0.328 g, 2 mmol), and anhydrous potassium
carbonate (0.35 g, 2.5 mmol) in 30 ml acetone was refluxed for 4 h. The excess acetone
was evaporated under reduced pressure. The residue was collected by filtration, washed
with water, dried, and finally recrystallized from ethanol to afford compound 14.
Yellow crystals, yield 75%, mp 178–179 ꢀC. IR (n=cmꢁ1): 3107 (NH), 2223
1
=
(CN), 1689 (C O). HNMR (DMSO-d6): d 2.35 (s, 3H, CH3), 2.40 (s, 3H, CH3),
4.28 (s, 2H, SCH2), 6.75 (s, 1H, pyridine-H5), 7.1–7.92 (m, 6H, Ar-H and
thiazole-H5), 12.57 (s, 1H, NH).13C NMR (DMSO-d6): d 20.4, 24.3, 38.5, 105.2,
108.6, 115.5, 124.8, 125.6, 127.2, 128.1, 133.8, 143.3, 154.7, 157.6, 159.9, 162.3,

2-(HETARYL)THIAZOLES
69
165.2. Anal. calcd. for C19H16N4OS2 (380.49): C, 59.98; H, 4.24; N, 14.73. Found: C,
60.28; H, 4.29; N, 14.84.
Synthesis of 3-Amino-4,6-dimethyl-N-(4-phenylthiazol-2-
yl)thieno[2,3-b]pyridine-2-carboxamide (15)
The nicotinonitrile derivative 14 (1.9 g, 5 mmol) was added to solution of an
equimolar amount of sodium ethoxide (prepared from dissolving 0.125 g sodium
in 30 ml absolute ethanol). The solution was refluxed for 2 h, left to cool, and diluted
with 50 ml cooled water containing a few drops of dilute HCl. The solid obtained
was filtered off, washed with ethanol, dried, and finally recrystallized from a mixture
of EtOH-DMF (1:2) mixture to afford compound 15.
Yellow crystals, yield 77%, mp 270–271 C. IR (n=cmꢁ1): 3509 (NH), 3403, 3347
ꢀ
ꢀ
1
=
(NH2), 1623 (C O). H NMR (CDCl3=CF3COOD): d 2.40 (s, 3H, CH3), 2.80 (s, 3H,
CH3), 7.00 (s, 1H, pyridine-H5), 7.40–7.90 (m, 6H, Ar-H and thiazole-H5). 13C NMR
(CDCl3=CF3COOD): d 19.2, 24.3, 106.0, 108.7, 123.5, 124.6, 124.9, 127.3, 128.2,
133.9, 145.9, 146.5, 147.0, 153.5, 155.7, 160.1, 163.5. Anal. calcd. for C19H16N4OS2
(380.49): C, 59.98; H, 4.24; N, 14.73. Found: C, 60.21; H, 4.09; N, 14.88.
Synthesis of Ethyl 2-(2-Oxo-2-(4-phenylthiazol-
2-ylamino)ethylthio)acetate (16)
A
mixture of 2-chloro-N-(4-phenylthiazol-2-yl)acetamide (13) (0.504 g,
2 mmol), ethyl thioglycolate (0.24 g, 2 mmol), and anhydrous potassium carbonate
(0.35 g, 2.5 mmol) in 30 ml acetone was refluxed for 4 h. The excess acetone was eva-
porated under reduced pressure. The residue was collected by filtration, washed with
water, dried, and finally recrystallized from ethanol to afford compound 16.
ꢁ1
ꢀ
=
ꢀ
Yellow crystals, yield 75%, mp 112–113 C. IR (n=cm ): 3362 (NH), 1724 (C O,
1
=
ester), 1677 (C O, amide). H NMR (CDCl3): d 1.40 (t, J ¼ 7.2 Hz, 3H, CH3), 4.29 (s,
2H, SCH2), 4.65 (q, J ¼ 7.2 Hz, 2H, OCH2), 4.78 (s, 2H, SCH2), 7.35–7.86 (m, 6H,
Ar-H and thiazole-H5), 12.76 (s, 1H, NH). 13C NMR (CDCl3): d 14.1, 33.4, 37.9,
62.0, 108.6, 124.7, 127.2, 128.3, 133.6, 154.6, 159.6, 165.1, 172.3. Anal. calcd. for
C15H16N2O3S2 (336.43): C, 53.55; H, 4.79; N, 8.33. Found: C, 53.44; H, 4.85; N, 8.41.
Synthesis of 4-(4-Phenylthiazol-2-yl)thiomorpholine-3,5-dione (17)
A few drops of triethylamine were added to a solution of sulfide 16 (0.672 g,
2 mmol) in 25 ml ethanol. The reaction mixture was heated under reflux for 8 h
and then left to cool. The solid product was filtered off, washed with ethanol, dried,
and finally recrystallized from ethanol to afford compoundꢁ117.
ꢀ
=
ꢀ
Yellow crystals, yield 85%, mp 132–133 C. IR (n=cm ): 1669 (C O, amide).
1H NMR (CDCl3): d 5.24 (s, 4H, 2CH2 ring), 7.18–7.92 (m, 6H, Ar-H and
thiazole-H5). 13C NMR (CDCl3): d 30.5, 109.2, 125.8, 128.2, 128.8, 133.8, 159.1,
162.6, 170.0. MS (EI, 70 eV): m=z (%) ¼ 290 (Mþ, 29.5), 262 (13.9), 248 (18.6), 174
(75.9), 160 (100), 130 (50.2), 77 (55.6). Anal. calcd. for C13H10N2O2S2 (290.36): C,
53.77; H, 3.47; N, 9.65. Found: C, 53.68; H, 3.41; N, 9.59.

70
S. BONDOCK ET AL.
Synthesis of 2-Amino-5-oxo-1-(4-phenylthiazol-2-yl)-4,5-dihydro-1H-
pyrrole-3-carbonitrile (19)
Triethylamine 0.5 ml was added to a mixture of 2-chloro-N-(4-phenylthiazol-2-
yl)acetamide (13) (0.504 g, 2 mmol) and malononitrile (0.132 g, 2 mmol) in 25 ml
dioxane. The reaction mixture was heated under reflux for 6 h, left to cool, and then
poured into ice-cold water. The solid product that formed was filtered off, washed
with dilute ethanol, dried, and recrystallized from dioxane to afford compound 19.
Yellow crystals, yield 76%, mp 276–277 C. IR (n=cmꢁ1): 3424, 3329 (NH2),
ꢀ
ꢀ
1
=
2198 (CN), 1692 (C O, pyrrole ring). H NMR (DMSO-d6): d 4.10 (s, 2H, CH2),
6.85 (s, 2H, NH2), 7.40–7.60 (m, 6H, Ar-H and thiazole-H5). 13C NMR (DMSO-d6):
d 39.4, 83.2, 105.6, 115.9, 125.9, 127.6, 128.4, 128.8, 137.3, 160.1, 161.6, 164.7, 168.2
MS (EI, 70 eV): m=z (%) ¼ 282 (Mþ, 15.7), 254 (35.6), 216 (63.3), 176 (100), 108
(32.8), 122 (28.0), 77 (69.1), 66 (55.4). Anal. calcd. for C14H10N4OS (282.32): C,
59.56; H, 3.57; N, 19.85. Found: C, 59.68; H, 3.43; N, 19.67.
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