Thiocarbamoyl in organic synthesis: Synthesis of some new arylazothiophene and arylazopyrazole derivatives

Article abstract of DOI:10.1080/10426500701839536

Arylazothiocarbamoyl derivatives 4a-e were utilized for the synthesis of several new thiophene and pyrazole derivatives. Compound 4 reacted with phenacyl bromide, ethyl bromoacetate, chloroacetonitrile, chloroacetone and hydrazine hydrate to yield thiophe

Full text of DOI:10.1080/10426500701839536

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Thiocarbamoyl in Organic
Synthesis: Synthesis of Some
New Arylazothiophene and
Arylazopyrazole Derivatives
A. A. Fadda a , E. Abdel-Latif a & Rasha E. El-
Mekawy a
a Chemistry Department, Faculty of Science,
Mansoura University, Mansoura, Egypt
Published online: 28 Jul 2008.
To cite this article: A. A. Fadda , E. Abdel-Latif & Rasha E. El-Mekawy (2008):
Thiocarbamoyl in Organic Synthesis: Synthesis of Some New Arylazothiophene and
Arylazopyrazole Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
183:8, 1940-1953
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Phosphorus, Sulfur, and Silicon, 183:1940–1953, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701839536
Thiocarbamoyl in Organic Synthesis: Synthesis of Some
New Arylazothiophene and Arylazopyrazole Derivatives
A. A. Fadda, E. Abdel-Latif, and Rasha E. El-Mekawy
Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
Arylazothiocarbamoyl derivatives 4a–e were utilized for the synthesis of several new
thiophene and pyrazole derivatives. Compound 4 reacted with phenacyl bromide,
ethyl bromoacetate, chloroacetonitrile, chloroacetone and hydrazine hydrate to yield
thiophene and pyrazole derivatives 7, 10, 12, 14, and 16, respectively.
Keywords Benzoylacetone; phenylisothiocyanate; pyrazole; thiophene
INTRODUCTION
Aryl isothiocyanates are versatile reagents, which have been used
as synthetic intermediate to prepare biologically active heterocyclic
compounds.1 As a part of our program of developing new, simple, and
efficient procedures for the synthesis of new aromatic compounds using
readily available aryl isothiocyanates, we have recently affected recy-
clization of thiocarbamoyl in pyrazoles and thiazoles.2−5 This procedure
appears to be a fundamental type of thiocarbamoyl-into- pyrazole ring
transformation.
RESULTS AND DISCUSSION
We have been particularly interested in studying if reactions of such
thiocarbamoyl might be extended to include more general synthesis of
other classes of organic compounds and its utility as synthetic inter-
mediate for the synthesis of new heterocyclic compounds. The present
work reports on the synthesis of several new arylazothiophene and ary-
lazopyrazole derivatives by the reaction of thiocarbamoyl of the type 4
with compounds containing an active methylene group in the presence
of a base. Reactions of this type have not been reported previously, but
Received 15 August 2007; accepted 8 September 2007.
Address correspondence to A. A. Fadda, Chemistry Department, Faculty of Science,
Mansoura University, Mansoura, Egypt. E-mail afadda2@yahoo.com
1940

Arylazothiophene and Arylazopyrazole Derivatives
1941
they were found to give products in excellent yields under very mild
conditions. Moreover, the resulting thiophene and pyrazole derivatives
have latent functional substituents, which have potential for further
chemical transformations and new routes for the preparation of substi-
tuted thiophene and pyrazole derivatives with possible biological activ-
ity. Now, we have extended our synthetic program to the synthesis of
otherwise inaccessible heterocyclic ring system utilizing phenyl isoth-
iocyanate as a key starting material. It is known that a great vari-
ety of reactants bearing the N=C=S fragment undergoes cyclization
on reaction with α-halocarbonyl compounds to afford thiazoles, 2,3-
dihydrothiazoles,6 which have been shown to exhibit antiprotozoal,7
and fungicidal properties.8
Thus, the base-prompted reaction of the acidic methylene compound
1 with phenyl isothiocyanate in dry DMF at room temperature in basic
medium led to the formation of the non-isolable intermediate 2 which
gave thiocarbamoyl derivative 3 upon treatment with dilute HCl. Treat-
ment of 3 with aromatic diazonium salts in the presence of sodium
acetate affected acetyl cleavage with the formation of arylazothiocar-
bamoyl derivatives 4a–e rather than the expected product 5. This result
is in agreement with the previously reported work9−14 (Scheme 1).
SCHEME 1

1942
A. A. Fadda et al.
Assignment of the product 3 was based on elemental analysis, IR
and 1H-NMR spectral data. The IR spectrum showed absorption bands
at 3229, 3125, 1600, and 1283 cm−1 attributable to the enolic OH,
1
NH, C=O, C=S, functions, respectively. H NMR spectrum of 3 dis-
played multiplet signals at σ 7.1–7.5 ppm for aromatic protons and
exchangeable proton at 11.9 ppm for NH proton. Its mass spectrum
showed molecular ion peak m/z = 297 (M+, 14%). On the other hand,
the structure of the newly prepared hydrazone derivatives 4a–e was
based on their correct elemental analysis and spectral data. In general,
the IR spectra showed absorption bands due to C=O, C=S and NH
1
at 1640, 1280, and 3250 cm−1, respectively. The H NMR spectrum of
compound 4a displayed multiplet signals at σ 6.8–7.8 ppm for aromatic
protons and two exchangeable protons at σ 13.9 and 16.4 ppm for two
NH protons. An additional conformation for the correct structure was
supported by its mass spectroscopic measurements. The mass spectrum
showed the molecular ion peak (m/z = 359, M+).
In this paper, we describe a generally applicable extension of this
synthetic approach, first reported by Hantzsch and Weber.15 Thus, the
base-prompted reaction of compounds 4a with potassium carbonate in
dry DMF at room temperature affords the non-isolable intermediate
6a. Stirring of 6 with phenacyl bromide in DMF overnight yielded a
product 7a, which analyzed correctly for C29H21N3OS. The structure
7a was inferred from its spectral data. Thus, the IR spectrum showed
absorption bands at 3150, 1660, and 1600 cm−1 corresponding to NH,
1
CO, and N=N functions. Its H-NMR spectrum showed two multiplet
signals integrated for (20H) centered at 7.4 and 8.0 (aromatic protons)
and a singlet (1H) at σ 10.2. On shaking the compound with D2O, the
broad band signal at σ 10.2 disappeared. Based on the foregoing data,
structure 7a was assigned to this product. The structure 7a was further
confirmed by alternative synthesis. Thus, it was found that stirring of
4a with phenacyl bromide in the presence of potassium carbonate in
ethanol at room temperature produced acyclic intermediate 8a. Struc-
ture 8a was suggested for the reaction product based on both elemental
and spectral analyses. The IR spectrum showed the presence of carbonyl
absorption bands at 1640 and 1623 cm−1, N = N function at 1600 cm−1
,
respectively.
Refluxing 8a in ethanol with few drops of TEA led to the formation of
a product identical in all respects (m.p. mixed m.p., IR) to 7a. Similarly,
compounds 7b–e were synthesized by pathway (1) (Scheme 2).
The addition of two or more equivalents of ethyl bromoacetate,
chloroacetonitrile, chloroacetone leads only to thiophenes10, 12, and
14 in good yields. Thus, condensation of the intermediate salt with an
equimolar amount of chloroacetyl chloride or with chloroacetic acid in

Arylazothiophene and Arylazopyrazole Derivatives
1943
SCHEME 2
ethanol, a product that analyzed for C25H23N3O3S was isolated in each
case in good yield. The acyclic structure 9a was established based on its
IR spectrum that showed bands related to NH and CO functions. Its 1H
NMR spectrum reveals a multiplet at (σ ppm) 6.8–7.7 (15H, aromatic),
a triplet signal at σ 1.3 (3H, CH3), singlet at σ 3.7 (2H), quartet at σ 4.3
(2H, CH2) and a D2O exchangeable NH at σ 12.9 ppm. Alternatively,
treatment of the intermediate 6a with ethyl bromoacetate in ethanol
gives a single product, which is identical in all respects to 9a (m.p. mixed
m.p. and IR spectrum). The mass spectrum of 9a showed a molecular
formula C25H23N3O3S (M+ = 445). Refluxing of 9a in ethanol with a
catalytic amount of TEA or leaving it in DMF containing potassium
carbonate at room temperature overnight afforded the corresponding
thiophene derivative 10a. In a similar manner, 10a–e were prepared
by pathway (1).
Similarly, when the intermediate potassium salt 6a is stirred with
chloroacetonitrile in ethanol at room temperature, the corresponding
acyclic intermediate 11a is exclusively isolated in good yield. The struc-
ture 11 has been confirmed based on elemental and spectral data, e.g.
the IR spectrum exhibits bands at 3200 (NH), 2220, and 1695 cm−1
1
(cyano and carbonyl group). Its H NMR spectrum reveals CH2 sig-
nals at σ 3.23 ppm. Furthermore, heating of the intermediate 11a in
ethanol containing a catalytic amount of TEA affords the thiophene
derivative 12a. The thiophene structure 12a was established based on
its IR spectrum, which showed bands related to NH and CN functions.
1
Its H NMR spectrum reveals a multiplet at (σ ppm) 7.31–7.56 (15H,

1944
A. A. Fadda et al.
SCHEME 3
aromatic), broad signals at σ 14.2 ppm (1H, NH). On the other hand, it
has been found that compounds 12a–e are directly formed by treatment
of 6a–e with chloroacetonitrile in dimethylformamide and in the pres-
ence of potassium carbonate at room temperature overnight by pathway
(1) (Scheme 3).
Compound 6a reacted readily with chloroacetone in the presence of
ethanol at room temperature to afford the acyclic intermediate 13a by
KCl elimination. Refluxing 13 in ethanol with a catalytic amount of
TEA gave the thiophene derivative 14a whose structure was confirmed
by its alternative synthesis. Thus, stirring 6a–e with chloroacetone in
DMF overnight affords the thiophene derivative 14a–e in reasonably
good yield (Scheme 4).
On the other hand, treatment of the key intermediate 4b with hy-
drazine hydrate in DMF gave a single product, which analyzed correctly
for C22H19N5 (16b). The structure of 16b was inferred from its spectral
data. Thus, the infrared spectrum of 16b showed a band at 3189 and
3229 cm−1, corresponding to the NH groups, and avoided a band due
1
to the carbonyl group. The H NMR spectrum revealed a singlet at σ
2.3 assigned for the methyl protons, a broad band located at σ 10.1
and 12.0 assignable to the NH protons, and a multiplet at σ 7.0–8.2,
assigned for aromatic protons. The formation of 16a–e is assumed to
proceed via the replacement of the SH group by the hydrazine moiety
to give the intermediate 15 which then cyclized via the carbonyl group

Arylazothiophene and Arylazopyrazole Derivatives
1945
SCHEME 4
to afford the final isolable products 16a–e. In fact, the structure of 16
was further confirmed by alternative synthesis. Thus, it has been found
that treatment of 4a with hydrazine hydrate for long time in ethanol
produced the intermediate 15a. Refluxing 15a in ethanol containing a
catalytic amount of TEA or in DMF lead to the formation of a product
identical in all respects (m.p., mixed m.p., IR) with 16a.16 Structure
15a is suggested for the reaction product based on both elemental and
spectral analyses. The infrared spectrum of compound 15a showed ab-
sorption at 1640 (CO), 3340 (NH), 3418, and 3550 cm−1(NH2) groups,
1
and the H- NMR spectrum revealed a broad signal at σ 6.4 assigned
for NH2 protons, a multiplet at σ 7.2–7.8 for aromatic protons, and a
singlet at σ 12.7 and 14.0 ppm for NH protons (Scheme 5).
These results indicate that the reaction of thiocarbamoyls and bifunc-
tional reagents provides an excellent route for the synthesis of five—
otherwise not easily accessible—arylazothiophenes and pyrazoles. The
compounds synthesized will be subjected to biological testing.
EXPERIMENTAL
All melting points are uncorrected. FTIR spectra (KBr disk) were
recorded on a Nicolet Magna. IR-Model 550 Spectrophotometers,
1H NMR spectra in DMSO, were determined on Brucker Wpsy 200
MHZ spectrometer with TMS as internal standard and the chemical
shifts are in σ ppm. Mass spectra were recorded at 70 eV with a Varian
MAT 311.

1946
A. A. Fadda et al.
SCHEME 5
Synthesis of Thiocarbamoyl Derivative (3)
To a cold suspension of potassium hydroxide (1.4 g, 25 mmol) in DMF (30
ml) was added the benzoyl acetone (4.05 g, 25 mmol), followed by phenyl
isothiocyanate (3.375 g, 25 mmol). The mixture was stirred overnight
at room temperature and then poured onto ice-cold water. Acidification
using dilute HCl until the medium becomes acidic gave solid product 3,
which was filtered off, washed with water, dried and crystallized from
aqueous ethanol to give compound 3 (cf. Table I).
Coupling of (3) with Aromatic Diazonium Salts. Formation of
Monoazothiocarbamoyl Derivatives (4a–e)—General
Procedure
A well–stirred solution of aromatic amines (20 mmol) in concentrated
HCl (6 ml) and water (4 ml) was cooled in an ice bath and diazotized
with a solution of sodium nitrite (1.39 g, 20 mmol) in water (5 ml).
The above cold diazonium solution was added drop wise to a well
stirred cold solution of 3 in ethanol (10 ml) containing sodium acetate
(1.75 g, 20 mmol). The reaction mixture was stirred for 1–2 h until

1947

1948

1949

1950

1951

1952
A. A. Fadda et al.
reach complete coupling reaction. The crude product was filtered off,
dried well, and recrystallized from ethanol. The results are given in
Table I.
Synthesis of the Acyclic Intermediate 8a, 9a, 11a, and 13a
Equimolecular quantities of 4a (3.59 g, 10 mmol) in ethanol containing
potassium carbonate (1.39 g, 10 mmol) and phenacyl bromide and/or
ethyl bromoacetate and/or chloroacetonitrile and/or chloroacetone were
stirred for 6 h at room temperature, then left to stand at the same
temperature for 24 h. The separated solid product was washed with
water, dried, and crystallized from ethanol to give 8a, 9a, 11a, and
13a, respectively (cf. Table I).
Synthesis of Thiophene Derivatives
Pathway (1)
A mixture of equimolecular amounts of 4a– e and α-halo compounds
(10 mmol) was stirred in DMF (20 ml) containing potassium carbonate
(1.39 g, 10 mmol) overnight. The reaction mixture was poured onto ice-
cold water, acidified by dilute HCl, filtered off, and recrystallized from
ethanol to give the corresponding thiophene derivatives (cf. Table I).
Pathway (2)
Refluxing the acyclic intermediate 8a, 9a, 11a, and 13a in ethanol
(20 ml) containing a catalytic amount of TEA for 3 h afforded the cor-
responding thiophene derivatives 7a, 10a, 12a, and 14a.
1-Phenylamino-1-hydrazone-2-(arylazo)-2-benzoylethylene (15a). A
mixture of 4a (3.55 g, 50 mmol) and hydrazine hydrate (1.6 g, 50 mmol)
in ethanol was stirred for 4 h at room temperature. The reaction mixture
was then cooled and the solid product was filtered off and recrystallized
from ethanol to give compound 15a (cf. Table I).
Synthesis of Arylazopyrazoles (16a–e)
Method A
A mixture of 4a–e (50 mmol), hydrazine hydrate (1.6 g, 50 mmol)
in DMF was refluxed for 4 h. The reaction mixture then poured onto
ice water (200 ml). The solid product was filtered off and recrystallized
from ethanol:DMF (1:1) to give the corresponding derivatives 16a–e,
respectively (cf. Table I).

Arylazothiophene and Arylazopyrazole Derivatives
1953
Method B
Refluxing the acyclic intermediate 15a in ethanol (20 ml) containing
a catalytic amount of TEA for 3h gave the pyrazole derivative 16a.
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