Microwave-assisted synthesis of symmetrical and unsymmetrical N,N 0-disubstituted thioureas and ureas over MgO in dry media

Article abstract of DOI:10.1007/s00706-011-0583-6

Under mild microwave irradiation conditions a variety of symmetrical and unsymmetrical A,N′-disubsti-tuted thioureas and ureas were prepared via the reaction of Af-monosubstituted hydroxylamines with isocyanate and isothiocyanate derivatives over MgO under solvent-free conditions. This new method afforded satisfactory results with good yields, short reaction time, and simplicity in the experimental procedure.

Full text of DOI:10.1007/s00706-011-0583-6

Monatsh Chem (2012) 143:251–254
DOI 10.1007/s00706-011-0583-6
ORIGINAL PAPER
Microwave-assisted synthesis of symmetrical and unsymmetrical
N,N0-disubstituted thioureas and ureas over MgO in dry media
•
Hassan Valizadeh Leila Dinparast
Received: 10 May 2010 / Accepted: 12 July 2011 / Published online: 12 August 2011
Ó Springer-Verlag 2011
Abstract Under mild microwave irradiation conditions a
variety of symmetrical and unsymmetrical N,N0-disubsti-
tuted thioureas and ureas were prepared via the reaction of
N-monosubstituted hydroxylamines with isocyanate and
isothiocyanate derivatives over MgO under solvent-free
conditions. This new method afforded satisfactory results
with good yields, short reaction time, and simplicity in the
experimental procedure.
become an established tool in organic synthesis [2–4],
because of the rate enhancements, higher yields, and often
improved selectivity with respect to conventional reaction
conditions. In addition, solvent-free MWI processes are also
clean and efficient; moreover, the use of organic or inorganic
solid supports has received increased attention [5, 6].
Thiourea and urea derivatives are important synthetic
intermediates for amidines or guanidines [7]. Thioureas
have also been used as neutral receptors for various anions
[8] and natural product mimics. There are many methods
for the preparation of disubstituted ureas [9–14] and
thioureas [15–19] including condensation of amine
hydrochlorides with potassium thiocyanate [20]. The most
direct approach involves interaction of carbon disulfide
with primary amines [9]. However, this reaction is often
associated with several by-products depending on the
reaction conditions employed [9]. To the best of our
knowledge, there are no reports on the use of N-substituted
hydroxylamines in the reaction with isothiocyanate and
isocyanate derivatives for the synthesis of the related N,N0-
disubstituted thioureas and ureas.
Keywords N-Monosubstituted hydroxylamines ꢀ
Isocyanate ꢀ Isothiocyanate ꢀ Microwave irradiation ꢀ
Solvent-free
Introduction
Green chemistry has been attracting great interest from
chemists because of the potential environmental benefits of
using such methods. A number of procedures involving new
eco-friendly reagents and catalysts, selected media such as
water, supercritical fluids, ionic liquids, solvent-free reac-
tions, non-classical modes of activation such as ultrasound or
microwaves are now recommended for green chemistry.
There are several advantages of performing organic reac-
tions in a solventless system such as short reaction time,
increased safety, and economic advantages from the absence
of solvent [1]. Recently, microwave irradiation (MWI) has
In continuation of our work in studying organic reac-
tions in ionic liquids, water, or solventless systems as a
green reaction medium [21–27], we wish to report here the
synthesis of symmetrical and unsymmetrical N,N0-disub-
stituted thioureas and ureas from the reaction of N-
substituted hydroxylamines with isothiocyanate and iso-
cyanate derivatives over MgO as basic solid support in a
solventless system under MWI (Scheme 1).
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0583-6) contains supplementary
material, which is available to authorized users.
Results and discussions
H. Valizadeh (&) ꢀ L. Dinparast
Department of Chemistry, Faculty of Sciences,
Azarbaijan University of Tarbiat Moallem, Tabriz, Iran
e-mail: hvalizadeh2@yahoo.com
In a pilot experiment, N-methylhydroxylamine (2a) and
phenylisothiocyanate (1a) were mixed with excess of MgO
123

252
H. Valizadeh, L. Dinparast
Scheme 1
X
X
MgO, Solvent-free
MWI
R2NHOH
R1
N
C
X
+
+
R1HN
NHR2
R1HN
NHR1
1
2
3
4
1a: R1 = Ph, X = S
1b: R1 = Ph, X = O
3a
1
2
: R = Ph, R = Me, X = S
4a: R1 = Ph, X = S
4b: R1 = Ph, X = O
: R2 = Me
: R2 = Ph
3b: R1 = Ph, R2 = Me, X = O
3c: R1 = Et, R2 = Me, X = S
2a
2b
: R1 = Et, X = S
1c
: R1 = Et, X = S
4c
1
1
2
1d
3d
3e
: R = Et, X = O
: R = Et, R = Ph, X = S
: R1 = Et, X = O
4d
1
: R = Et, R2 = Me, X = O
3f: R1 = Et, R2 = Ph, X = O
Table 1 Microwave-assisted synthesis of thioureas and ureas over MgO in solventless system
Entry
Reactant 1
Reactant 2
MWI or thermal heating
Time/min
Product 3, yielda/%
Product 4, yielda/%
1
1a
1a
1b
1b
1c
1c
1d
1d
1a
1c
1a
1c
2a
2b
2a
2b
2a
2b
2a
2b
2a
2a
2a
2a
MWI
3
3a (76)
–
4a (9)
4a (81)
4b (8)
4b (78)
4c (13)
4c (12)
4d (10)
4d (9)
–
2
MWI
4.5
3.5
3
3
MWI
3b (75)
–
4
MWI
5
MWI
3.5
4
3c (71)
3d (76)
3e (74)
3f (72)
3a (22)
3c (23)
3a (25)
3c (21)
6
MWI
7
MWI
3.5
4
8
MWI
9
MWI (neat conditions)
MWI (neat conditions)
Thermal heating
Thermal heating
60
60
300
300
10
11
12
a
–
–
–
Isolated yields after recrystallization
and irradiated by microwave to obtain N-methyl-N0-phen-
ylthiourea (3a) in 76% yield and N,N0-diphenylthiourea (4a)
as a minor product in less than 10% yield (Table 1). By this
method, other isocyanates and isothiocyanates with N-
(phenyl and methyl)hydroxylamines gave satisfactory
results (Table 1, entries 2–8). In order to exhibit the catalytic
effect of MgO, the condensation of N-methylhydroxylamine
with two isothiocyanates (1a and 1c) was studied in the
absence of MgO under MWI conditions. It was found that
MgO was more effective, and very poor yield of the corre-
sponding thioureas were isolated in these conditions
(Table 1, entries 9–10). In the absence of MWI, the reactions
proceeded in longer reaction times at 80 °C in lower yields in
comparison with MWI conditions (Table 1, entries 11–12).
So MWI can shorten the reaction time and also assist the
reaction process effectively. We conducted these reactions
on a 25-mmol scale and found that they underwent a smooth
transformation to the thiourea and urea derivatives in good
yields. Thus, the present procedure is amenable to scaling up.
Optimization of the reaction conditions was studied with
different molar ratios of MgO and under different microwave
powers. The best ratio was found to be 200 mol% of MgO
under 200-W microwave power. Increasing the power of
microwave decreases the yields of the products.
A plausible mechanism for the formation of the
selected products 3a and 4a over MgO is outlined in
Scheme 2. Intermediate A apparently results from the
initial nucleophilic attack of N-methylhydroxylamine on
phenylisothiocyanate in the presence of MgO as base cat-
alyst. Subsequent nucleophilic addition of intermediate
A to another phenylisothiocyanate yields the intermediate
B, which fragments to CSO, aniline, and 3a as a major
product. The fragmentation of B perhaps accrued in the
Mg2+
S
S
PhHN
Me
S
S
O
NHPh
MeNHOH
+
C
N
NHMe
PhN
C
S
NPh
O
NHPh
O2-Mg2+
B
A
- CSO
S
PhNH2
+
O2-Mg2+
S
MeHN
NHPh
S
3a
PhNH2
+
C
PhHN
NHPh
NPh
4a
Scheme 2
123

Synthesis of N,N0-disubstituted thioureas and ureas
253
presence of water or oxygen present in the open reaction
vessel under MWI. The compound N,N0-diphenylthiourea
(4a) was obtained from the nucleophilic attack of aniline
on unreacted phenylisothiocyanate in very low yield.
to 10 cm3 acetone containing 1.61 g MgO (40 mmol) and
stirred for 10 min at room temperature. After evaporation
of acetone the mixture was subjected to MWI at 200 W for
a few minutes (depending on the reactants, see Table 1).
The completion of reaction was monitored by TLC using
EtOAc/petroleum 1:2 as eluent. After completion of the
reaction, the mixture was cooled to room temperature and
extracted with ether or ethyl acetate. The extracts were
concentrated on a rotary evaporator and the crude mixture
was purified by silica gel (Merck 230–240 mesh) column
chromatography using a 1:2 ethyl acetate/n-hexane mixture
as eluent to give pure products 3a–3f and 4a–4d, which
were characterized by their spectroscopic data (1H NMR,
13C NMR, and IR), elemental analysis, and by comparison
of their melting points with those reported in the literature
(Table 2).
Conclusion
Under solvent-free conditions, microwave-assisted synthe-
sis of symmetrical and unsymmetrical N,N0-disubstituted
thioureas and ureas over MgO can be achieved from N-
monosubstituted hydroxylamines and isocyanates and iso-
thiocyanates efficiently. The advantages of this protocol are
mild reaction conditions, short reaction times, simple work-
up procedure, absence of organic solvent, and good yields.
Therefore, we believe that the new synthetic method
reported here constitutes an environmentally greener and
safer process than existing approaches.
Acknowledgments The partial financial assistance from the
Research Vice Chancellor of Azarbaijan University of Tarbiat
Moallem is gratefully acknowledged.
Experimental
References
All reagents were purchased from Merck and used without
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