An eco-friendly protocol for synthesis of thiourea derivatives: 1-benzoyl-3-benzylguanidine and 1-benzoyl-3-benzyl-O-ethylisourea. A possible non-purely thermal microwave assisted reaction

Article abstract of DOI:10.1016/j.tet.2005.12.037

1-Benzoyl-3-benzylguanidine and 1-benzoyl-3-benzyl-O-ethylisourea were synthesized in good yields (68 and 76%, respectively) from 1-benzoyl-3- benzylthiourea and benzoyl-ethylthiocarbamate in dry media conditions using KF-Al₂O₃ under

Full text of DOI:10.1016/j.tet.2005.12.037

Tetrahedron 62 (2006) 2616–2621
An eco-friendly protocol for synthesis of thiourea derivatives:
1-benzoyl-3-benzylguanidine and
-benzoyl-3-benzyl-O-ethylisourea. A possible non-purely
1
thermal microwave assisted reaction
a
Heiddy Marquez, Andr e´ Loupy, Osmar Calderon and Eduardo R. P e´ rez
b
c
d,
*
a
Instituto de Qu ´ı mica, UFRJ, CT Bloco A, Laborat o´ rio 641, Rio de Janeiro, Brasil
Laboratoire des R e´ actions S e´ lectives sur Supports, ICMMO, UMR 8615, B aˆ t. 410, Universit e´ Paris-Sud, 91405 Orsay, France
b
c
Laboratorio de S ´ı ntesis Org a´ nica, Facultad de Qu ´ı mica, Universidad de La Habana, 10400 Cuba
Faculdade de Ci eˆ ncias e Tecnologia, UNESP, C.P. 467, Presidente Prudente, 19060-080 SP, Brasil
d
Received 19 September 2005; revised 22 November 2005; accepted 15 December 2005
Available online 9 January 2006
Abstract—1-Benzoyl-3-benzylguanidine and 1-benzoyl-3-benzyl-O-ethylisourea were synthesized in good yields (68 and 76%,
respectively) from 1-benzoyl-3-benzylthiourea and benzoyl-ethylthiocarbamate in dry media conditions using KF–Al O under microwave
2
3
irradiation. Strong nucleophilic amines promoted the sulfur elimination by attack on the thiocarbonyl group in both thiourea and
thiocarbamates to afford guanidines and isourea, respectively. Transesterification products were obtained from p-TsOH catalyzed reaction of
thiocarbamate with alcohols under MW-solvent-free conditions. Very important non-purely thermal MW specific effects were evidenced and
attributed to stabilization by coulombic interactions between materials and waves.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Microwave (MW) activation has been used for guanidines
1
9
20
preparation under both dry and in solution. However, in
the first case, several reaction steps and the use of the very
toxic isocyanates were required, whereas the second work
described the use of non-volatile solvents and hazardous
diamines as guanidine precursors at high temperatures (O
150 8C).
Substituted guanidines are interesting compounds that are
utilized in medicine as analgesic and antihypertensive
1
–3
4
5
compounds. In analytical chemistry, guanidines have been
used as extraction agents for periodate ions. In addition,
guanidines are also useful in organic synthesis.
6
7
–9
The substituents on the guanidine group influence the
physico-chemical properties and biological activities of
these molecules. For instance, the introduction of an acyl
group on one of the guanidine nitrogen atoms markedly
Alkylisoureas like 2a are hydantoin derivatives. This class
of compounds has been used as anti-convulsants in the
2
1–22
treatment of epilepsy and heart arrhythmia.
other hand, alkylisoureas are useful materials for ester
On the
1
0
23
reduces the guanidine basicity.
preparation by O-alkylation of carboxylic acids. The first
synthesis of hydantoins was described as early as 1911,
24
using KOH–EtOH, which resulted in very low yields.
Several methods have been reported for the preparation of
1
1–15
guanidines in solution.
N-benzoylthioureas into guanidines has been disclosed in
Recently, the conversion of
Recently, the synthesis of phenytoin, a hydantoin analogue,
25
has also been reported by using MW activation. Classical
preparations of alkylisoureas require of carbodiimides as
16
good yields using Bi(NO ) $5H O as a catalyst. Solid-
2
3
3
1
phase syntheses of trisubstituted guanidines and N-acyl-
7
26
starting materials and long reaction times. Improvements
0
18
N -carbamoylguanidines have been also reported.
were introduced by using of the solid supported carbodii-
26
2
mides and microwave irradiation.
7
Keywords: 1-Benzoyl-3-benzylguanidine; 1-Benzoyl-3-benzyl-O-ethyl-
isourea; Thiocarbamates; Microwave irradiation; Solvent-free conditions.
The use of MW technology together with solvent-free
conditions allows improvements in yields, selectivity and
*
Corresponding author. Tel.: C55 18 229 5355; fax: C55 18 221 5682;
e-mail: eperez@prudente.unesp.br
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.037

H. Marquez et al. / Tetrahedron 62 (2006) 2616–2621
2617
O
NH2
O
S
BnNH2
+
H2S
N
O
N
N
NH2
KF–Al O (2:3)
H
H
2
3
2
0 min,100
C
°
1
1a
68%
N
O
S
BnNH2
+ H2S
C H
2
5
N
2
OC H5
N
O
KF–Al O (2:3)
H
H
2
3
°
1
0 min, 100 C
76%
2
2a
Scheme 1. Synthesis of 1-benzoyl-3-benzylguanidine 1a and 1-benzoyl-3-benzyl-O-ethylisourea 2a.
work up, with shortened reaction times when compared with
2
classical methods.
2. Results and discussions
8–34
Microwave experiments were carried out in open vessels
with an efficient mechanical stirring (which avoids all
problems of non-homogeneity in temperature). Several
inorganic supports were tested in order to achieve the best
product yields. The support/substrate relative amounts were
previously optimized. Experiments were replicated to
ensure reproducibility. In order to check the possible
intervention of the specific non-purely thermal MW
This work describes the synthesis of 1-benzoyl-3-benzyl-
guanidine 1a and 1-benzoyl-3-benzyl-O-ethylisourea 2a
from the corresponding thiourea derivatives 1 and 2,
respectively, under MW irradiation under solvent-free
conditions using potassium fluoride impregnated onto
alumina as the catalyst (Scheme 1) (Scheme 2). A special
aim of the present work is the reaction of thiocarbamates 2
with alcohols to yield the transesterification products 2b and
3
7,38
effects,
the same reactions were performed using an
oil bath controlled using a thermostat under similar
conditions. Table 1 shows the results obtained for the
synthesis of 1a or/and 2a. A single-mode focused MW
reactor was used to ensure a higher reproducibility and a
better control of the reaction parameters (power,
temperature).
2
c (Scheme 3), which constitutes an extension of the
previous non-classical synthesis of thiourea related com-
3
5–36
pounds.
=
/
The best yields (68 and 76% for guanidine 1a and
alkylisourea 2a, respectively) were obtained using KF
impregnated on alumina. Experiments performed at higher
output power and for longer exposure times were
unsuccessful (higher yields were not observed and
decomposition products were detected by TLC analysis).
No reaction was observed below 100 8C. Figure 1 showed
the profiles of rises in temperature and emitted power during
microwave assisted synthesis of 1a. An emitted MW power
value of 60 W was sufficient to maintain a constant
temperature of 120 8C.
δ+
N
N
.
.
I
δ–
C
S
C
S
GS1
TS1
=/
(-)
+
N
K
N
+
.
.
K
II
(-)
C
In all cases, it has been found that reactions proceed with
considerable lower yields under similar temperature
conditions by conventional heating demonstrating that the
effect of MW is evidently not only purely thermal.
C
S
S
GS2
TS2
Scheme 2. Rate determining steps in the mechanism of amine addition to
the thiocarbonyl functionality in neutral I or basic II medium.
Microwaves are electromagnetic waves generated by an
alternating electric field of high frequency. The energy
R´OH
O
S
R´ = b) PhCH
2
O
S
c) n-C18H37
C H
2
5
+
C H OH
2 5
N
O
p-TsOH (10%)
N
OR´
H
0
H
120 C
2
2b, 2c
Scheme 3. Acid-catalyzed transesterification of 2 under MW irradiation without solvent.

2618
H. Marquez et al. / Tetrahedron 62 (2006) 2616–2621
Table 1. Synthesis of 1a and 2a under MW irradiation by reacting 1 and 2 with benzylamine
a
b
Reagent
2 mmol)
Support
t (min)
T (8C)
Product
Activation mode
c
D
Yield (%)
MW
(
1
No support
20
20
15
120
100
120
—
!10
—
51
168
59
1a
KF–Al
2
O
3
2
No support
3
5
3
100
120
100
100
!10
21
17
40
52
67
76
2
a
KF–Al
2
O
3
1
0
—
a
b
c
KF–Al
Yields of isolated products.
Conventional heating controlled using a thermostat oil bath wash under similar conditions.
2
3
O Z3/2 w/w.
–
For the base-activated reaction (i.e., of KF–alumina), the
enhancement of polarity of the system during the reaction is
provided by ionic dissociation of the ion pairs from GS2
toward TS2 II, which is more polar due to the negative
4
3
charge delocalization.
In both cases, the most important phenomenon is the
stabilization of the transition states by dipole–dipole
electrostatic interactions with the electric field, which
therefore could be responsible for an enhancement of
reactivity by a decrease of the activation energy (Scheme 2).
A special interest lies in the reaction of 2 with BnNH2
yielding the corresponding 2a with H S elimination. On the
2
other hand, when catalyzed by p-TsOH, the reaction of
compound 2 with alcohols leads to the transesterification
product, without sulfur elimination. Thus, two other
thiocarbamates 2b and 2c were synthesized through
transterification of 2 (Scheme 3) in order to confirm the
reactivity of thiocarbamates toward molecules with differ-
ent nucleophilic strength. This reaction has afforded the
corresponding thiocarbamates in high yields and short
reaction times (Table 2). Therefore, the present microwave
assisted-acid catalyzed transesterification of thiocarbamate
Figure 1. Profile of rise in temperature for the MW assisted solvent-free
synthesis of 1a.
K1
associated with a MW photon (1 J mol by application of
Planck’s law: EZhn with nZ2450 MHz) is far too small to
induce any excitation of molecules. It can, however, induce
thermal effects due to some internal friction between polar
molecules during their changes in orientation with each
alternation of the electric field. In addition, they can induce
some electrostatic interactions with polar materials by
dipole–dipole interactions, rather similar to the behavior of
44
was more efficient than the reported classical procedure.
3
9
a dipolar solvent.
The main results for thiocarbamates transesterification are
displayed in Table 2.
By analogy and extension of the interpretation of solvent
effects, the reactions can be facilitated when there is an
increase of the polarity of the system during the progress of
the reaction between the ground state and the transition
state. An increase in MW efficiency could result therefore
from both thermal effects (which provide adequate thermal
energy) and specific polar electrostatic (non-purely thermal)
The dielectric environment during MW-assisted transester-
ification of 2 aid the formation of polar intermediates
formed during the acid-catalyzed transesterification
reaction. The rapid microwave induced volatilization of
the leaving alcohol (ethanol) molecule would shift the
equilibrium favorably to formation of the transesterification
3
4
4
5
effects.
product.
The specific MW effects we have evidenced here are
consistent with the consideration of the mechanism and with
the assumption that MW effects are increased when the
polarity of a system is increased during the progress of the
Reactions carried out without acid catalysis showed low
yields of the transesterification product presumably due the
elimination of the ethanol molecule and formation of the
isothiocyanate occurring before the nucleophilic attack of
the benzyl alcohol (reactions 1–4 in Table 2). This thermal
process seems to be more rapid under microwaves
irradiation (reactions 1–2 in Table 2) and showed a strong
dependence on the exposition time (reactions 3–4 in
Table 2) yielding decomposition at 20 and 180 min of
irradiation. When the reaction was conducted under
classical heating (120 8C) for 24 h a 61% of 2b was
obtained together some decomposition products. This
3
7,38,40,41
reaction (Scheme 2):
–
For the support (base)-free reaction, the rate determining
step is the nucleophilic attack of the amine on thiocarbonyl
moiety I. One can thus expect an important MW effect due
to the enhancement of polarity of the system provided by the
dipolar transition state TS1 when compared to neutral
3
7–42
ground state GS1.

H. Marquez et al. / Tetrahedron 62 (2006) 2616–2621
2619
Table 2. Results of synthesis of thiocarbamates 2b and 2c by reaction of 2 (2 mmol) with benzyl and octadecyl alcohol under MW irradiation
0
R OH (mmol)
BnOH (2)
Catalyst (mmol)
Time (min)
T (8C)
MW, yield (%)
D, Yield (%)
—
—
—
—
10
10
20
180
10
5
10
10
20
20
100
120
100
120
100
120
120
120
120
120
52
64
—
—
25
28
a
b
—
64
70
88
94
61
85
52
0
1
1
1
.2
—
45
50
48
27
41
BnOH (4)
n-C18
n-C18
H37OH (2)
—
1
c
H
37OH (2)
Comparison with classical heating (D).
Decomposition products.
a
b
D 24 h/120 8C, 61%.
Higher alcohol amounts did not affect the product yield.
c
behavior will be carefully investigated and the results will
be opportunely communicated.
4.2. Typical procedure for synthesis of 1a and 2a from
benzoylthiourea 1 and thiocarbamate 2 under micro-
wave irradiation
Benzoylthiourea 1 (2 mmol) or ethyl benzoylthiocarbamate
2 was dissolved in acetone. An equimolar amount of
benzylamine was added and the mixtures were smoothly
mixed with 1 g of KF–alumina (3/2). The solvent was
removed under reduced pressure. The resulting mixture was
placed into a Pyrex-glass open vessel and irradiated in the
monomode MW reactor for the reaction times and
temperatures as indicated in Table 1. The products were
extracted from the support with acetone and precipitated
using ice water.
3
. Conclusion
In conclusion, we describe herein an efficient and eco-
friendly protocol for the synthesis of 1,3-substituted
guanidines, alkylisoureas and thiocarbamates in good
yields. Special interests lie in the procedures for preparation
of guanidines and alkylisoureas, where a non-purely thermal
effect of the microwave irradiation is evidenced. In addition,
transesterification of ethyl thiocarbamate with benzyl and
octadecyl alcohols give the corresponding transesterificated
products, resulting in a useful procedure toward other
thiocarbamates.
Benzoylthiourea 1 and ethyl-N-benzoylthiocarbamate 2
were obtained according to the standard procedure
previously reported in the literature.
3
5–36
4.3. Typical procedure for microwave assisted transes-
terification of thiocarbamate 2. Synthesis of 2b and 2c
4
. Experimental
4
.1. General methods
Equimolar amounts (2 mmol) of alcohol and ethyl
benzoylthiocarbamate 2 were dissolved in acetone. The
solvent was removed under reduced pressure. 1 mmol of
p-TsOH was added slowly. The resulting mixture was
placed into a Pyrex-glass open vessel and irradiated in a
monomode MW reactor for reaction times and temperatures
as indicated in Table 2. The reaction mixture was extracted
with petroleum ether (bp 60 8C)–cyclohexane (1/1),
yielding a white compound. The product was dissolved in
dichloromethane and filtered to separate insoluble p-TsOH.
After solvent evaporation, the white precipitate was purified
by a column silica gel chromatography using toluene–
methanol (5/1) as eluent.
Reactions were performed in a Prolabo monomode reactor
3
0
Synthewavee 402 device. The temperature was measured
during the reaction by an optical fiber introduced inside the
stirrer or by infrared detection, which indicates the surface
temperature after previous calibration of emissivity in each
case with an optical fiber (FTI-10 device from Fiso). All
reactions were carried out in a cylindrical Pyrex tube with
mechanical stirring to establish homogeneity in tempera-
ture. The emitted power was monitored (between 15 and
3
00 W) to maintain a constant temperature.
Melting points were obtained using Electrothermal 9100
apparatus. H NMR spectra were recorded on a Bruker AC
1
4.4. Comparison between microwave activation and
conventional heating for compounds 1a, 2a–c
1
3
spectrometer at 250 MHz. C NMR spectra and DEPT
experiments were determined at 62 MHz. Chemical shifts
are expressed in d (ppm) using tetramethylsilane (TMS),
which was used as an internal standard. IR spectra (nmax
In order to compare the results of MW irradiation versus
conventional heating (D), the same reactions were
performed inside a preheated thermostated oil bath at the
same temperature as under MW irradiation. The reaction
was achieved for the same reaction time. The temperature
was controlled with the same optical fiber thermometer as
for the calibration of MW’s emissivity and the profile of
temperature rise was adjusted to be similar to that registered
K1
cm ) were recorded on Bruker IR S48 using KBr pellets.
EI mass (70 eV) spectra were obtained on HP5989A
spectrometers. The reactions were followed by silica-gel
plates (Merck 60F250) TLC performed using chloroform–
ethyl acetate (8/2) as the eluent. All the chemicals were
purchased from Aldrich and used as received.

2620
H. Marquez et al. / Tetrahedron 62 (2006) 2616–2621
under microwave irradiation. The treatment and analysis
remained identical.
CNPq and FAPESP (Brazil) for financial and general
support.
4
4
.5. Spectroscopic data
.5.1. N-Benzoylthiourea 1. Yield 73% (from acetone–
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1
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(
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.5.3. 1-Benzoyl-3-benzylguanidine 1a. Mp 184–185 8C;
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(
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.5.5. N-Benzoyl-benzylthiocarbamate 2b. Mp 104–
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.5.6. N-Benzoyl-stearylthiocarbamate 2c. Mp 67.5–68.5
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(
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2 2 2 2
29.0 (CH), 133.1 (Cipso and CH), 162.7 (CO), 189.7 (CS);
K1
FT-IR (KBr): nmax (cm )Z3256, 3021, 1704, 1604, 1538,
1
300. Anal. Calcd for C H NO S (433.54): C, 72.02; H,
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9
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