(S)-5-Benzyl- and 5-benzylidene-imidazo-4-one derivatives synthesized and studied for an understanding of their thermal reactivity

Article abstract of DOI:10.1039/c4ra11046c

Flash vacuum as well as static pyrolysis were used to gain insight into the mechanisms of decomposition of the title compounds. They were synthesized by the use of microwave techniques that allowed better yields than the established methods. Since the benzyl compounds always open a radical channel in the thermal processes, consequently lowering the yields of other important intramolecular processes, we also started the pyrolysis with benzylidene derivatives. Detection and quantification of products accompanied by kinetic analyses were carried out for both types of compounds. The activation energies as well as the entropy contributions have been determined. Moreover, DFT calculations provided support for and corroborating of the proposed thermal pathways.

Full text of DOI:10.1039/c4ra11046c

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(S)-5-Benzyl- and 5-benzylidene-imidazo-4-one
derivatives synthesized and studied for an
understanding of their thermal reactivity†
Cite this: RSC Adv., 2014, 4, 60092
a
a
A. J. Pepino, W. J. Pelaez, M. S. Faillace,a N. M. Ceballos,a E. L. Moyanob
*
´
and G. A. Arguelloa
¨
Flash vacuum as well as static pyrolysis were used to gain insight into the mechanisms of decomposition of
the title compounds. They were synthesized by the use of microwave techniques that allowed better yields
than the established methods. Since the benzyl compounds always open a radical channel in the thermal
processes, consequently lowering the yields of other important intramolecular processes, we also started
the pyrolysis with benzylidene derivatives. Detection and quantification of products accompanied by
kinetic analyses were carried out for both types of compounds. The activation energies as well as the
entropy contributions have been determined. Moreover, DFT calculations provided support for and
corroborating of the proposed thermal pathways.
Received 23rd September 2014
Accepted 6th November 2014
DOI: 10.1039/c4ra11046c
www.rsc.org/advances
cores in an attempt to get a comprehensive explanation on
the reactivity of this useful nucleus.
Introduction
In a very recent paper,1 we reported an efficient dehydrogena-
tion reaction that allowed the synthesis of the 5-benzylidene-2-
thioxoimidazolidin-4-one (1) core mediated by eco-friendly
techniques such as Microwave Induced Pyrolysis (MIP) and
Flash Vacuum Pyrolysis (FVP) (Scheme 1).
The interest in the synthesis of (S)-5-benzyl-imidazo-4-ones
is based upon two important features. First, the widespread
use of this heterocyclic nucleus in the preparation of pharma-
ceutically active compounds such as antimycobacterials,2
immunomodulators,3 anticonvulsivants,4 and antifungals.5
Second, it affords an interesting route towards the formation of
an exocyclic double bond at C5 which is difficult to obtain using
conventional methods. In this regard, there have been many
attempts and reactions proposed to induce the formation of the
exocyclic double bond in similar heterocyclic systems, but they
invariably need the use of a co-reactant or a catalyst, such as
rhodium,6 iridium,7 or even more complex catalysts.8
In the present contribution we synthesized other (S)-5-
benzyl-thioxoimidazolidin-4-one and imidazolidine-2,4-dione
Dehydrogenation reactions are quite common in high-
temperature pyrolysis, because of the decrease in energy in
the system due to aromatization and/or the formation of stable
products;9 however, selective dehydrogenations are scarce and
few examples have been studied.
Scheme 1 Synthesis of 5-benzylidene-2-thioxoimidazolidin-4-one 1
by selective dehydrogenation of (S)-5-benzyl-3-phenyl-2-thio-
xoimidazolidin-4-one 2.
Our previous study, led us to put forward questions like
whether the dehydrogenation reaction is a general mechanism,
or whether the substitution of the benzyl imidazo core is of
prime importance. Besides, it is also interesting to look into the
role played by the 3p electrons and orbitals available in the
sulfur atom of the thioxo compounds during the thermal
transformations. We have also reported that 1,3-heterocycles in
which the sulfur atom is changed by an oxygen atom, react at
higher temperatures than cis or trans-thioxo analogs when
subjected to FVP (Scheme 2, 3).10,11 As a result of the higher
temperatures required for the dioxo compounds, competitive
pathways open up. In the case of (S)-5-benzyl-imidazo-4-ones,
this competitive pathway is a radical process that dramatically
a
´
´
´
INFIQC-Dpto. de Fisicoquımica, Facultad de Ciencias Quımicas, UNC, Cordoba,
5000, Argentina. E-mail: waldemar31@fcq.unc.edu.ar
b
´
´
´
´
INFIQC-Dpto. de Quımica Organica, Facultad de Ciencias Quımicas, UNC, Cordoba,
5000, Argentina
† Electronic supplementary information (ESI) available: Rate constants obtained
by FVP from 7 and 8 (Tables S1 and S2), characterization of compounds 7, 8,
˚
11, 12, 25, 27, 28, 31, and 35 and Cartesian coordinates (A) obtained from the
B3LyP(6-31+G(d,p)) computational calculations are provided. See DOI:
10.1039/c4ra11046c
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Results and discussion
Synthesis of (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-2,4-
dione (7) and (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]thiazol-
5(6H)-one (11)
Our synthetic work was focused on the obtainment of 2-oxoi-
midazolidinones and 2-thioxoimidazolidinones substituted in
position 3 by a chloroethyl group. It was expected that these
molecules would suffer dehydrogenation or dehydrochlorina-
tion reactions allowing us to study the mechanisms and
energetic requirements of both class of thermal reactions. (S)-5-
Benzyl-3-(2-chloroethyl)imidazolidine-2,4-dione 7 was prepared
by modication of known general methodologies17,18 but
employing microwave irradiation (MW) as an alternative
approach.
(S)-5-Benzyl-3-(2-chloroethyl)imidazolidine-2,4-dione 7 was
prepared by carefully reacting L-phenylalanine 13 with 2-chlor-
oethylisocyanate 14 in CH3NO2 (Scheme 3). The synthesis is
tricky because of the intrinsic high reactivity of 14 which
decomposes easily, as we demonstrated recently.19
Since the thio-analog of 14 was unavailable to us, we devel-
oped a 2-step strategy to obtain (S)-5-benzyl-3-(2-chloroethyl)-2-
thioxoimidazolidin-4-one 9. In spite of our efforts, the attempts
were unsuccessful because the end product was always the bicy-
clic compound 11. We formed (S)-5-benzyl-2-thioxoimidazolidin-
4-one 20 from L-phenylalanine 13 and thiourea 23 and reacted it
with 1,2-dichloroethane. Although several conditions and
temperatures were used, the method afforded only the cyclization
to the (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one 11
(Scheme 3).
Scheme 2 FVP of cis and trans-2-thio(oxo)quinazolin-4-ones.
reduces the yield of the products formed by intramolecular
reactions. For his reason, we also synthesized the 5-
benzylidene-imidazo-4-ones that acted as initial reagent in the
thermal decomposition.
The fact that FVP is both a very useful technique to study
reaction mechanisms and
a powerful tool for synthetic
purposes has been highlighted in several excellent reviews12–14
and books.15,16 The purpose of this work is to study the thermal
behavior of (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-2,4-
dione 7 and 5-benzylidene-3-chloroethyl-2-oxoimidazolidin-4-
one 8 (Fig. 1) in order to better understand their chemistry, in
particular the structural requirements that allow dehydroge-
nation or dehydrochlorination reactions to occur under FVP
conditions.
We pursued further to compare the results with the corre-
sponding thio-derivatives (namely (S)-5-benzyl-3-(2-chloroethyl)-2-
thioxoimidazolidin-4-one 9 and 5-benzylidene-3-(2-chloroethyl)-2-
thioxoimidazolidin-4-one 10), though our syntheses have resulted
without exception in the cyclic compounds (S)-6-benzyl-2,3-dihy-
droimidazo[2,1-b]thiazol-5(6H)-one 11 and 6-benzylidene-2,3-
dihydroimidazo[2,1-b]thiazol-5(6H)-one 12 which are neverthe-
less interesting because they allowed us to evaluate different kind
(exocyclic and endocyclic) of dehydrogenations as well as to
obtain essential information about the energetics required.
Synthesis of 5-benzylidene-3-(2-chloroethyl) imidazolidine-
2,4-dione (8) and 5-benzylidene-2,3-dihydroimidazo[2,1-b]
thiazol-6(5H)-one (12)
5-Benzylidene-3-(2-chloroethyl)imidazolidine-2,4-dione 8 was
prepared by modifying existing procedures20,21 in order to
increase the yield of the reaction and by trying a one pot
synthesis (Scheme 4). First, we attempted to obtain 8 in a two-
step reaction, preparing the 5-benzylidene-imidazolidine-2,4-
dione 15 by MW irradiation (72%) which later reacted with
Fig. 1 Structures of (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-2,4-
dione 7 and 5-benzylidene-3-chloroethyl-2-oxoimidazolidin-4-one Scheme 3 Synthesis of (S)-5-benzyl-3-(2-chloroethyl)-2-oxoimida-
8, (2-chloroethyl)-2-thioxoimidazolidinones (9 and 10) and 2,3-dihy- zolidin-4-one 7 and (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]thiazol-
droimidazo[2,1-b]thiazol-5(6H)-ones (11 and 12).
5(6H)-one 11.
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Thus, the thioxoimidazolidinone precursor 22 was prepared
from 18 and 21 using MW irradiation at 140 ꢀC (90%), and then
ꢀ
reacted with 16 under MW irradiation at 175 C yielding 12 in
55% overall yield (paths (a) and (b)). On the other hand, 12
could be also obtained from the imidazothiazolone 24 and
benzaldehyde in 64% overall yield (paths (c and d)). Here again,
the simplest one-pot reaction was the best procedure to obtain
12 in the highest yield (68%, path (e)).
The difficulties found in the preparation of both 2-thio-
xoimidazolidinones 9 and 10 can be attributed to multiple
reasons. One of them is the high reactivity of the thiol tautomer
of the thioxoimidazolidinone precursors (20–22), towards the
alkylation that led to the bicyclic imidazothiazolones (11, 12
and 24) without detection of 2-chloroethyl-2-thioxo-
imidazolidin-4-ones (Schemes 3 and 5). These ndings agree
with literature data,24,25 especially when the alkylation reaction
is performed with dibromoalkanes where the corresponding
bicyclic compounds are obtained.26 Although we have per-
formed the reactions with 1,2-dichloroethane, which is less
reactive than 1,2-dibromoethane, the cyclization could not be
avoided. Many attempts to perform a sequence of protection
and deprotection reactions of the thiol group in 20 and 22 led to
unsuccessful results.
Scheme
4 Synthesis of 5-benzylidene-3-chloroethyl-2-oxoimida-
zolidin-4-one 8 by different methodologies.
1,2-dichloroethane 16 in the presence of Et3N yielding 8 in an
overall 41% yield (paths (a) and (b)).
A second methodology involved the preparation of the 3-(2-
chloroethyl)imidazolidine-2,4-dione 17 (20%) and later its
reaction with benzaldehyde 18,which yielded the desired
product (paths (c) and (d), 14%). Nevertheless, the simplest one
pot reaction of the three reagents proved to be the best proce-
dure to obtain 8 in 55% yield (path E) with a ratio between
isomers Z : E > 98% as reported elsewhere for other benzylidene
analogs.1
The use of equivalent procedures to afford 5-benzylidene-3-
(2-chloroethyl)-2-thioxoimidazolidin-4-one 10, resulted in the
bicyclic product 6-benzylidene-2,3-dihydroimidazo[2,1-b]thia-
zol-5(6H)-one 12.22,23 The synthesis of 12 was performed in three
different ways in order to nd the best methodology (Scheme 5).
Reactivity by ash vacuum pyrolysis
(S)-5-Benzyl-3-(2-chloroethyl)imidazolidine-2,4-dione
7
was
subjected to ash vacuum pyrolysis (FVP) (Scheme 6). Sakai-
zumi et al.,27 reported that the main product of the vacuum
pyrolysis of 2-chloroethylisocyanate 14 is vinyl isocyanate
produced by dehydrochlorination oꢀf the precursor between
ꢀ
100–900 C, with a maximum at 800 C. In our case, FVP reac-
ꢀ
tions of 7 below 500 C were unsuccessful, recovering only the
starting material. Above 500 ꢀC the two expected reactions took
place, namely the dehydrochlorination leading to 25 and the
dehydrogenation leading to 8, though their yields were low
(Scheme 6 and Table 1).
ꢀ
At 550 C, C5–C6 cleavage of 7 becomes dominant and the
main product observed was 1,2-diphenylethane 26, resulting
from the dimerization of benzyl radicals. At 575 ꢀC a new
product (27) involving both extrusions appears. We propose that
Scheme
thiazol-6(5H)-one 12.
5 Synthesis of 5-benzylidene-2,3-dihydroimidazo[2,1-b] Scheme 6 Pyrolysis of (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-
2,4-dione 7 between 500–600 ꢀC.
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Table 1 FVP reactions of 7
Table 2 FVP reactions of 8
Yield of productsa, %
Yield of productsa, %
27 28
3.7 2.2
T (ꢀC)
7
26
8+25
Minor compounds T (ꢀC)
8
31
500
550
96.7
73.8
67.1
54.5
11.0
4.1
—
3.3 (40 : 60)c
2.9 (45 : 55)c
3.2 (38 : 62)c
4.8 (79 : 21)c
7.2 (76 : 24)c
6.2 (74 : 26)c
—
—
27
27, 28
27, 28
27, 28
525
550
575
600
650
675
700b
750b
94.1
74.4
53.5
45.7
33.7
26.5
19.8
16.8
0
1.9
7.5
6.3
10.4
12.8
14.1
14.7
12.2
14.8
20.0
39.4
43.1
4.8
11.7
11.9
21.7
23.8
24.2
27.9
18.9
27.3
36.1
34.2
36.9
34.3
34.0
575
600b
625b
650b
Determined by GC-MS analysis. b The presence of coke was observed.
a
c
Ratio 8 : 25.
a
b
Determined by GC-MS analysis. The presence of coke was detected.
27 principally originates from 8, because the dominance of the
benzylic C5–C6 cleavage in 25 would increase the amount of 26
which is the main product of the reaction. However, a further
obtained also in the FVP of 7. One of them (27) corresponds to
the dehydrochlorination process (path A), and the other (28)
arises from an intra-molecular aromatic insertion (path B).
These results corroborate our previous assumption about the
origin of 27 in the FVP of 7.
Over 550 ꢀC, a new product, 31 is obtained. It could arise
from dehydrochlorination when the precursor is 28 and/or from
aromatic insertion when the precursor is 27. At present we
cannot distinguish between paths A or B to produce 31 and
perhaps both routes take place. It is important to note that this
compound was not detected when the FVP started from 7
probably due to the characteristics of the FVP technique that
allows the isolation of kinetically controlled products due to the
short contact times.
ꢀ
increase in temperature (over 600 C) yields another heterocy-
clic compound (28) which is formed through an intra-molecular
aromatic insertion (intermediates 29 and 30). This appears to be
an exclusive product from benzylidene hydantoines since to the
best of our knowledge, we have found no literature evidence of
this process occurring in other cores. We have already observed
this kind of reaction in the FVP of 5-benzyl-3-phenyl-2-thio-
xoimidazolidin-4-one.1 Compounds similar to 28 are interesting
in pharmaceutical chemistry because of their antifungal activ-
ities28 and for this reason many other synthetic methods have
been described.29
Compounds 8 and 27 were obtained as a mixture of the Z and
E isomers under all conditions. 1H-NMR analysis of those
mixtures indicated that in thermal equilibrium, the ratio
between isomers Z : E is approximately 98 : 2 as was previously
observed by us in the case of 5-benzylidene-3-phenyl-2-
thioxoimidazolidin-4-one 1.1
Reactivity by static pyrolysis
Earlier work,1 reported the decomposition of 2 by MIP and
conrmed the selectivity of the dehydrogenation process
observed by FVP. As compounds 7 and 8 do not react at the
highest temperatures reached by the microwave assisted reac-
In order to obtain relevant information on the mechanism
without the interference of the radical reactions, i.e., to
suppress the formation of 1,2-diphenylethane 26, FVP of 5-
ꢀ
tions (300 C), we studied their decomposition by static pyrol-
benzylidene-3-(2-chloroethyl)imidazolidine-2,4-dione
performed (Scheme 7 and Table 2).
8
was
ysis using a sealed tube with the main goal of increasing the
yield of products 27, 28 and 31. Due to the long contact times of
the static pyrolysis, complex mixtures were obtained in the
whole range of temperatures studied (Schemes 6 and 7, static
pyrolysis). The reaction mixtures were therefore analyzed by
GC/MS.
As can be seen in Scheme 7, two main products were
obtained under FVP at all temperatures, both described and
ꢀ
The static pyrolysis of 7 and 8 were performed at 500 C in
glass cells. Aer 10 minutes 77% conversion of 7 into products
8, 25, 26, 27, 28, a new compound 32 and different products of
fragmentation and recombination such as stilbene 33 and
benzonitrile 34 was reached (Scheme 6, static pyrolysis). Simi-
larly, compound 8 yielded compounds 27, 28, 32, benzonitrile
34 and other trace components (Scheme 7, static pyrolysis). The
new compound 32 could arise from the hydrogenation of 27 or
by elimination of chlorine followed by hydrogenation. In order
to evaluate its source, the same procedure was performed in
deactivated quartz cells. In these cases, the amount of 32 was
much lower than in glass cells, suggesting that 32 is formed by
hydrogen abstraction from the surface of the glass reactor.
Scheme 7 Pyrolysis of 5-benzylidene-3-(2-chloroethyl) imidazoli-
dine-2,4-dione 8 at 400–750 ꢀC.
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Although it was not possible to increase the yield of the efforts to achieve volatilization of the sample failed. Neverthe-
desired products by static experiments, relevant information less, for 11 it was possible and the FVP reactions were carried
about the stability of compounds 8, 25–28, 31 was retrieved. out at 350 ꢀC affording as main products 1,2-diphenylethane 26,
Compounds 27 and 28 appear to be the most stable ones, while 5-benzylidene-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one
12
8, 25 and 31 decompose under these conditions.
and (S)-6-benzylimidazo[2,1-b]thiazol-5(6H)-one 35 among
others (which included even coke, Scheme 8).
Exocyclic (12) and endocyclic (35) dehydrogenation reactions
are competing with the radical fragmentation of the weak C5–C6
in 11. Exocyclic dehydrogenation appears to be more easily
achieved than the other processes. According to the yields
obtained, the relatively low amount of 35 could also be due to its
inherent instability, which would, upon reaction, generate more
fragmentation products. We propose this hypothesis due to the
fact tꢀhat in the static pyrolysis performed at low temperatures
(150 C, 10 min) 35 was not detected. Calculations to estimate
the energies required for each process are therefore needed to
support or discard the mechanisms.
The reaction temperatures required for any pyrolysis of 11
are lower than those required for 7. This fact allows us to obtain
a smaller number of kinetically controlled products thus
improving the selectivity of the process. This is one of the most
relevant pieces of information obtained from static experi-
ments, where oxo derivatives aꢀre much more stable (requiring
temperatures higher than 400 C to react) in comparison with
their thio analogues. As it was stated above, this behavior was
also observed for cis and trans-2-thio(oxo)quinazolin-4-ones 3.10
It is well known that charge density can be distributed over
the molecule by the appropriate interaction with the electron
lone pairs or with 3p orbitals available on heteroatoms. The
more electronegative the atom containing the lone pair is, the
less able it is to donate electron density. For this reason, sulfur
is a more effective stabilizer of charge density than oxygen. We
Kinetic measurements from ash vacuum pyrolysis
More information on the reaction mechanism was derived from
kinetic measurements carried out on 7 and 8 through the use of
FVP. The rate constants for the reactions of 7 and 8 are given in
Tables S1 and S2 in ESI data,† while the activation parameters
in Table 3. Rate constants were measured at particular
temperatures from the change of the relative concentrations of
1
the starting materials as determined by H NMR and GC and
averaged over at least three determinations. Reaction times
were calculated as V0/m (contact time), V0 being the volume of
the reaction tube inside the hot zone and m, the carrier gas ow.
Arrhenius parameters were derived via the classical equation
(ln k vs. 1/T). In order to validate the system, the kinetic
parameters from the pyrolysis of ethyl acetate were measured
and compared with those reported for a static system; these
results, together with a detailed description of the methodology,
have been described elsewhere.1
Even though the calculated parameters describe the sum of
various processes, they highlight the differences between the
reactions of two imidazolidine-2,4-dione derivatives. For
compound 7 the positive value of activation entropy (DS# ¼ 0.8
e.u.) indicates that the mechanism is driven by a radical process
like the one proposed for the formation of the main product
observed (26) while for 8 this value is negative (ꢁ36.0 e.u.) in
agreement with a concerted mechanism. In fact, the parameters
obtained for 8, are similar to those reported in the gas phase
reaction for 5-benzyl-3-phenyl-2-thioxoimidazolidin-4-one 2,
where a concerted H2 elimination was proposed.1
From the calculation of DG#, it is possible to conclude that
radical mechanisms affording benzyl radicals have a slightly
smaller free energy demand than the concerted ones yielding
dehydrogenation or dehydrochlorination products. This can be
rationalized by the increasingly important contribution of the
entropy term, because at higher temperatures it cannot be
neglected in the calculation of DG#.
On the other hand, (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]-
thiazol-5(6H)-one 11 and 5-benzylidene-2,3-dihydroimidazo-
[2,1-b]thiazol-6(5H)-one 12 were subjected to pyrolysis in gas
phase. Unfortunately, the low vapour pressures and the lability
of these compounds difficult the study and promoted decom-
Scheme 8 Pyrolysis of (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]thia-
position of substrates in the sample probe. In the case of 12 all zol-5(6H)-one 11.
Table 3 Activation parameters for FVP reactions of 7 and 8
Comp.
Ea (kcal molꢁ1
)
log(A)/DS# (u.e.)
DH#a (kcal molꢁ1
)
DG#a (kcal molꢁ1
)
7
8
45.6
14.5
13.41/0.80
5.37/ꢁ36.0
43.9
12.8
43.2
44.2
a
Determined at 600 ꢀC.
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believe that this is the reason why the imidazothiazolone 11
Calculations through concerted routes (Table 4) show that
reacts at lower temperatures than the oxygenated ones, afford- the dehydrochlorination (path B, 25TS ¼ 53.5 kcal molꢁ1
)
ing the same kind of products.
requires less energy than the dehydrogenation which is ach-
ieved from the enol 7OH (path C, 7TS ¼ 76.9 kcal molꢁ1). This
trend corresponds to the experimental results obtained at low
temperatures (500–575 ꢀC) where the ratio 8/25 is lower than
one (Table 1). On the other hand, the most energetic process
calculated was the cleavage of the C5–C6 bond to afford benzyl
radicals through path A, which is in disagreement with the
experimental results, where 1,2-diphenylethane 26 is the main
product; however, it is important to remember that at high
temperatures the positive term TDS# is not negligible and it
could compensate the energy requirement to the cleavage.
Starting from 8, we postulate different concerted ways for
the synthesis of 27 and 28. The energy required for the dehy-
drochlorination is almost the same than for 7 (path E, 27TS ¼
54.0 kcal molꢁ1); nevertheless, the energy required to reach
Theoretical study
Quantum chemical calculations, using the DFT level of theory
(B3LYP/6-31+G(d,p) functional), have been carried out in order
to investigate the reaction mechanisms in the gas phase pyrol-
ysis of imidazolidine-2,4-dione derivatives (7, 8) as well as the
imidazothiazolone 11. In all cases, full geometry optimizations
were performed, followed by harmonic frequency calculations
at the same level of theory, which also allowed characterization
of the nature of the stationary points.
With the exception of our recent work, there are, to the best
of our knowledge, no previous mechanistic studies on the gas
phase dehydrogenation of benzyl imidazolidinones.1 Therefore,
we propose the set of reactions depicted in Scheme 9 to account
for the whole reaction mechanism of imidazolidinones. We
suggest three main paths for reaction of 7, namely, a stepwise
one, via a radical intermediate (path A) that has to do with the
dissociation of the C5–C6 bond, and two concerted routes (paths
B or C) that lead to the dehydrochlorination and dehydroge-
nation compounds, respectively. For all possible reaction
mechanisms, radical routes are expected to give positive
entropies of activation and concerted mechanisms negative
values, as was stated above.
the concerted transition state 28TS (path G, 112.0 kcal molꢁ1
)
is too high to be achieved and its formation seemed rather
unlikely; for this reason, a lower energy possibility (path F)
postulates rst the loss of radical hydrogen (91.7 kcal molꢁ1
)
and then a radical insertion to the aromatic ring, with
formation of a new ve-membered heterocycle. Thus, a
comparison of the energy barriers for dehydrochlorination
and aromatic insertion allows us to propose that compound 31
would be principally obtained from 28 rather than being
formed from 27.
Scheme 9 Reaction mechanism for pyrolysis of 7 and 8.
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Table 4 B3LYP energies of transient species involved in the proposed mechanisms for FVP of 7 and 8
Path
A
B
C
D
E
F
G
H
I
Species
7C–C
110.0
25TS
53.5
7TS
76.9
8TS
45.2
25OHTS
73.2
27OHTS
44.1
27TS
54.0
29
91.7
28TS
112.0
30TS
ꢃ50
29TS
ꢃ90
DEa
Values in kcal molꢁ1
.
a
methodology to form C–C double bonds through simple dehy-
drogenation and dehydrohalogenation process.
We found that thio compounds react at lower temperatures
than the oxygenated counterparts. This fact was explained by
the capacity of sulfur atoms to conjugate electrons as well as
charge density.
Through experimental observations and quantum chemical
calculations, we were able to rationalize the sequence and the
energy requirements of the different processes for each
compound. For (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-2,4-
dione (7) the sequence established was cleavage of benzylic
bond, dehydrochlorination and exo-dehydrogenation to afford
the benzyliden derivative; while for (S)-6-benzyl-2,3-dihy-
droimidazo[2,1-b]thiazol-5(6H)-one (11) it was exocyclic dehy-
drogenation, cleavage of benzylic bond and a new endocyclic
dehydrogenation.
Scheme 10 Proposed mechanisms for the FVP reaction of 11 at
B3LyP/6-31+G(d,p) theoretical level.
Experimental
General methods
The reaction paths of compound 11 were calculated and
led us to conclude that the concerted endocyclic dehydroge-
nation to afford 35 is the most energetic process (Scheme 10,
path B, 35TS ¼ 130.1 kcal molꢁ1) (cf. the C5–C6 cleavage, path
C, 11C–C ¼ 110.0 kcal molꢁ1 and the exocyclic dehydrogena-
tion, path A, 11TS ¼ 70.2 kcal molꢁ1 and 12TS ¼ 45.2 kcal
molꢁ1). These calculations are in agreement with the fact that
compound 12 is obtained in 56% yield while 26 and 35 are
obtained in low yields, 20% and 14% respectively. Despite the
fact that the experimental energy barrier obtained was much
lower than the calculated numbers, we believe that the overall
trend of the calculations is quite signicant, because we can
explain not only the percentage of products obtained but also
corroborate our assumptions about the dehydrogenation,
cyclization1 and tautomerization11 performed in our previous
studies.
FVP reactions were carried out in a Vycor glass reactor using a
tube furnace with a temperature-control device. Oxygen-free dry
nitrogen was used as the carrier gas. Contact times were around
10ꢁ2 s and a pressure of 0.02 Torr was used. Products were
trapped at liquid air temperature, extracted with a solvent, and
subjected to different analyses or separation techniques. In all
FVP experiments, the recovery of material was >90%. Static
pyrolysis were performed by introducing each of the substrates
into the reaction tube (1.5 ꢂ 12 cm Pyrex) that was then cooled in
liquid nitrogen and sealed under vacuum. The sealed ampoule
was nally placed in the Vycor glass reactor. The products of
pyrolysis were then extracted with solvent (acetone-d6) and sub-
jected to different analyses or separation techniques. Reactions
under microwave irradiation were performed in cylindrical
borosilicate tubes (F ¼ 1.5 cm) located in a Anton Paar Mono-
wave 300 reactor (2.455 GHz), with adjustable power within the
range 0–300 W and a wave guide (monomode) tted with a stir-
ring device and IR and Ruby temperature detectors. (S)-5-Benzyl-
3-(2-chloroethyl)imidazolidine-2,4-dione 7, 5-benzylidene-3-(2-
Conclusions
New synthetic methodologies to obtain 3-(2-chloroethyl) chloroethyl)imidazolidine-2,4-dione 8, (S)-6-benzyl-2,3-dihy-
imidazolidine-2,4-dione (7 and 8) and 2,3-dihydroimidazo[2,1- droimidazo[2,1-b]thiazol-5(6H)-one 11 and 5-benzylidene-2,3-
b]thiazol-5(6H)-one (11 and 12) derivatives are described dihydroimidazo[2,1-b]thiazol-6(5H)-one 12 were prepared by
together with studies of their reactivity. Under thermal condi- modifying a procedure described in the literature.17,18 All
tions, these compounds undergo fragmentation, dehydrogena- compounds were characterized by standard spectroscopic tech-
tion, dehydrochlorination and cyclization or a combination of niques (1H NMR, 13C NMR, HMBC, HSQC, UV, IR) and mass
these reactions to give the corresponding dehydrogenated spectrometry, and all data are in agreement with the proposed
1
products. This work shows once again the scope of the FVP structures. H, 13C, HSQC and HMBC spectra were recorded in
60098 | RSC Adv., 2014, 4, 60092–60101
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acetone-d6 with a Bruker Advance II 400 MHz spectrometer (BBI
probe, z gradient) (1H at 400.16 MHz and 13C at 100.56 MHz).
Chemical shis are reported in parts per million (ppm) down-
eld from TMS. The spectra were measured at 22 ꢀC. Absorption
spectra of the solutions were recorded with a UV-1601 Shimadzu
spectrophotometer using a quartz cell with an optical path length
of 1 cm and acetonitrile as solvent. Infrared solid spectra were
recorded with an FTIR Bruker IFS 28v spectrometer, with a
resolution of 2 cmꢁ1 in the range from 4000 to 400 cmꢁ1 by using
KBr disks. All calculations were performed with the Gaussian 09
program system30 by using a DFT-B3LYP/6-31+G(d,p) approach.
Transition-state theory was used to evaluate the energy of the
different channels. The transition states were characterized by
the presence of one negative frequency and the internal reac-
tion's coordinate (IRC) method was applied to verify that the
correct states were connected. Though we knew that more precise
methods were available, we had to make a compromise between
the size of the molecules under study and the computational
cost. Gas chromatography/mass spectrometry (GC/MS) analyses
were performed with a Shimadzu GC/MS-QP 5050 spectrometer
equipped with a VF column (30 m ꢂ 0.25 ꢂ mm ꢂ 5 m) by using
helium as eluent at a ow rate of 1.1 mL minꢁ1. The injector and
ion souꢁrc1e temperature was 280 ꢀC, the oven heating ramp was 15
Method (a) and (b). In a cylindrical borosilicate tube were
placed benzaldehyde 18 (0.5 mL, 4.9 mmol), imidazolidine-2,4-
dione 19 (410 mg, 4.1 mmol) and saturated NaHCO3 solution
(1.0 mL). Aer introduction into the Anton Paar microwave
reactor, the mixture was irradiated at 140 ꢀC for 10 min. The
crude was partitioned with ethyl acetate (3 ꢂ 15 mL) and the
organic layer dried over anhydrous Mg2SO4 to obtain the pure 5-
benzylidene-imidazolidine-2,4-dione 15 (60.1 mg, 72%). Then,
compound 15 (0.3 mmol), 1,2-dichloroethane 16 (1.0 mL, 12.6
mmol) and Et3N (1 mL) were placed in the borosilicate tube and
irradiated at 175 ꢀC for 10 min. The reaction products were
extracted performing the same procedure as before to obtain
the pure 5-benzylidene-3-(2-chloroethyl)imidazolidine-2,4-
dione 8 (42.8 mg, 57%, global yield: 41%).
Method (c) and (d). In a cylindrical borosilicate tube
thioxoimidazolidin-4-one 19 (713 mg, 7.1 mmol), 1,2-dichloro-
ethane 16 (1.2 mL, 15.1 mmol) and K2CO3 (2.9 g, 21.1 mmol)
ꢀ
were placed. The mixture was irradiated at 175 C for 10 min.
The reaction products were extracted as in method A and B to
obtain the pure 3-(2-chloroethyl)imidazolidine-2,4-dione 17
(760 mg, 20%). Then, compound 17 (4.7 mmol), benzaldehyde
18 (0.5 mL, 4.5 mmol) and NaHCO3 saturated solution (1.0 mL)
were introduced in the borosilicate tube and irradiated at 140
ꢀC for 10 min. The reaction crude was extracted to obtain the
pure 5-benzylidene-3-(2-chloroethyl)imidazolidine-2,4-dione 8
(70%, global yield: 14%).
ꢀ
ꢀC min from 150 up to 280 C, and the interface temperature
ꢁ5
ꢀ
was 280 C. The pressure in the MS instrument was 10 Torr,
precluding ion-molecule reactions from taking place, and MS
recordings were made in the electron impact mode (EI) at ioni-
zation energy of 70 eV.
Method (e). In a cylindrical borosilicate tube, benzaldehyde
18 (1.0 mL, 9.8 mmol), imidazolidine-2,4-dione 19 (634 mg, 3.4
mmol), 1,2-dichloroethane 16 (1.0 mL, 12.6 mmol) and Et3N (1.0
mL) were placed. Subsequently the mixture was irradiated at 175
ꢀC during 20 min. The reaction mixture was extracted to obtain
the pure 5-benzylidene-3-(2-chloroethyl)imidazolidine-2,4-dione
8 (55%) as white powder. nmax (KBr)/cmꢁ1 ¼ 1720 (C]O st),
Synthesis of (S)-5-benzyl-3-(2-chloroethyl)imidazolidine-2,4-
dione (7)
L-Phenylalanine 13 (496 mg, 3.0 mmol) and 2-chlor-
oethylisocyanate 14 (446 mg, 3.3 mmol) were placed in a
cylindrical borosilicate tube in that order. Nitromethane (0.3
mL) was added solely to homogenize the mixture. The tube was
then introduced into the Anton Paar microwave reactor. The
mixtꢀure was stirred at room temperature and then irradiated at
100 C for 10 min. The reaction products were extracted with
ethyl acetate (3 ꢂ 15 mL), the organic layer was dried over
anhydrous Mg2SO4, and aer removal of the solvent under
reduced pressure, the solid was recrystallized from toluene to
give the pure title compound 7 (310 mg, 41%) as white powder.
nmax (KBr)/cmꢁ1 ¼ 3292 (NH st), 2924 (C–H sp3 st), 1773 (C]O
st), 1721 (C]O st). lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 191 [(1 ꢂ
102 ꢄ 0.006)106]. 1H NMR dH (ppm) (400.16 MHz, acetone-d6, 22
ꢀC) ¼ 7.24 (m, 5H, Ar-H), 4.42 (m, 1H, C5–H), 3.55 (m, 4H, CH2–
CH2–Cl), 3.15 (dd, J1 ¼ 14.1 Hz, J2 ¼ 4.5 Hz, 1H, C6–Ha), 2.99
(dd, J1 ¼ 14.1 Hz, J2 ¼ 6.1 Hz, 1H, C6–Hb). 13C NMR dc (ppm)
(100.56 MHz, acetone-d6) ¼ 173.9, 156.9, 136.5, 130.6 (ꢂ2),
129.1(ꢂ2), 127.7, 58.7, 40.8, 40.3, 38.0. GC-MS t (min) ¼ 7.82, m/
z (EI, %): 65(10), 91(100), 92(11), 252(5, M+c), 254(2, M+c + 2).
2925 (C–H sp3 st). lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 315 [(1.81 ꢄ
1
0.01)104]. H NMR dH (ppm) (400.16 MHz, acetone-d6, 22 C) ¼
ꢀ
9.65 (broad s. 1H, N–H), 7.63 (d, J ¼ 7.2, 2H, Ar-Ho), 7.43 (t, J ¼
7.4 Hz, 2H, Ar-Hm), 7.36 (t, J ¼ 7.4 Hz, 1H, Ar-Hp), 6.63 (s, 1H, ]
C6–H); 3.90 (m, 4H, CH2–CH2–Cl). 13C NMR dc (ppm) (100.56
MHz, DMSO-d6) ¼ 163.8, 154.3, 129.3 (ꢂ2), 128.9 (ꢂ2), 128.6,
109.9, 40.6, 39.9. GC-MS t (min) ¼ 9.10, m/z (EI, %): 63(13), 64(5),
89(37), 90(44), 91(7), 116(28), 117(100), 118(16), 144(5), 172(13),
187 (18), 188 (33), 250 (68, M+c), 251(14), 252(23).
Synthesis of 5-benzyl-2-thioxoimidazolidin-4-one (20)
In a cylindrical borosilicate tube, L-phenylalanine 7 (4.0 g, 24.0
mmol), thiourea 23 (5.6 g, 73.7 mmol) and tert-butylammonium
perchlorate (341 mg, 1.0 mmol) were placed. Aer introduction
into the Anton Paar microwave reactor, it was irradiated at 190 ꢀC
for 15 min. The reaction products were extracted with ethyl acetate
(3 ꢂ 15 mL) and the organic layer dried over anhydrous Mg2SO4 to
obtain the pure 5-benzyl-2-thioxoimidazolidin-4-one, 20 (95%).
Synthesis of 5-benzylidene-3-(2-chloroethyl) imidazolidine-
2,4-dione (8)
Synthesis of (S)-6-benzyl-2,3-dihydroimidazo[2,1-b]thiazol-
5(6H)-one (11)
8 was prepared by three different ways modifying existing First, compound 20 (118 mg, 0.6 mmol), 1,2-dichloroethane 16
procedures.18,19
(0.3 mL, 3.8 mmol) and Et3N (0.1 mL) were placed in the
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ꢀ
microwave vial and subjected to 15 min irradiation at 100 C. mmol), 1,2-dichloroethane 16 (1.0 mL, 12.6 mmol) and Et3N
ꢀ
The reaction products were extracted to obtain the pure 6- (1.0 mL). The mixture was irradiated with MW at 175 C for 15
benzyl-2,3-dihydroimidazo[2,1-b]thiazol-5(6H)-one 11 (61%, min. The reaction products were extracted as usual to obtain the
global yield: 58%). In other vial, compound 20 (436.7 mg, 2.1 pure 5-benzylidene-2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one
mmol), 1,2-dichloroethane 16 (0.3 mL, 3.8 mmol), K2CO3 (815 12 (547 mg, 68%) as yellow powder. nmax (KBr)/cmꢁ1 ¼ 1713 (C]
mg, 8.2 mmol) and acetone (1.0 mL) were placed. The mixture O st), 2906 (C–H sp3 st). lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 366
1
was stirred at room temperature for 48 h. The reaction products [(4.67 ꢄ 0.01)104]. H NMR dH (ppm) (400.16 MHz, acetone-d6,
were extracted to obtain the pure 6-benzyl-2,3-dihydroimidazo 22 ꢀC) ¼ 8.16 (m, 2H, Ar-Ho), 7.42 (m, 3H, Ar-Hp, Ar-Hm), 6.73 (s,
[2,1-b]thiazol-5(6H)-one 11 (229 mg, 47%, global yield: 45%). 1H, ]C6–H), 3.98 (m, 4H, CH2–CH2–Cl). 13C NMR dc (ppm)
The last procedure consisted in placing compound 20 (450 mg, (100.56 MHz, acetone-d6) ¼ 132.4 (ꢂ2), 130.3, 129.4(ꢂ2), 122.9,
2.2 mmol), 1,2-dichloroethane 16 (0.3 mL, 3.8 mmol) and K2CO3 41.6, 35.1. m/z (EI, %) ¼ 51(5), 59(6), 60(10), 63(10), 76(5), 86(18),
(810 mg, 8.2 mmol) in the borosilicate tube. The mixture was 89(40), 90(11), 102(7), 115(7), 116(60), 117(8), 122(7), 142(14),
irradiated with MW at 110 ꢀC for 30 minutes. The reaction 147(6), 174(12), 201(16), 202(57, M+c – CH2]CH2), 203(7),
products were extracted as usual to obtain the pure 6-benzyl-2,3- 229(11), 230(100, M+c).
dihydroimidazo[2,1-b]thiazol-5(6H)-one 11 (52%, global yield:
49%). nmax (KBr)/cmꢁ1 ¼ 1708 (C]O st), 1769 (C]O st), 2925
(C–H sp3 st), 3276 (N–H st). lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 267
Thermal reactions of 7, 8 and 11
1
[(4.61 ꢄ 0.01)104]. H NMR dH (ppm) (400.16 MHz, acetone-d6,
Flash vacuum pyrolysis reaction. In a typical experiment,
ꢀ
22 C) ¼ 7.52 (m, 5H, Ar-H), 4.43 (m, 1H, C5–H), 3.58 (m, 4H, samples of 7, 8 or 11 (30 mg) were pyrolyzed. Aer the reaction,
CH2–CH2–Cl), 3.16 (dd, J1 ¼ 15.1 Hz, J2 ¼ 5.4 Hz, 1H, C6–Ha), the crudes were extracted with acetone-d6 and subjected to GC/
3.01 (dd, J1 ¼ 15.2 Hz, J2 ¼ 6.3 Hz, 1H, C6–Hb). 13C NMR dc MS and NMR analysis. The mixtures were also puried by
(ppm) (100.56 MHz, acetone-d6) ¼ 173.9, 156.9, 136.5, 130.6 preparative thin-layer chromatography (dichloromethane/
(ꢂ2), 129.1 (ꢂ2), 127.7, 58.7, 40.8, 40.3, 38.0. GC-MS t (min) ¼ hexane, 6 : 4) to afford products 25, 27, 28, 31, 33 and 35.
7.52. m/z (EI, %) ¼ 51(3), 65(8), 77(3), 91(100), 92(9), 206(17, M+c
– CH^CH), 232 (2, M+c).
Static pyrolysis. Each of the substrates (7; 5.0 mg, 20.0
mmolar 8; 5.0 mg, 21.6 mmol) were introduced into the reaction
tube (1.5 ꢂ 12 cm Pyrex), cooled in liquid nitrogen, sealed
under vacuum (0.06 mbar) and then placed in the Vycor glass
Synthesis of 5-benzylidene-2,3-dihydroimidazo[2,1-b]thiazol-
6(5H)-one (12)
ꢀ
reactor for 10 min at 400 C for 7 and 400 ꢀC and 500 ꢀC for 8.
The pyrolysis products were then extracted with solvent
Method (a) and (b). In a microwave vial, benzaldehyde 18 (acetone-d6) and subjected to different analyses or separation
(0.5 mL, 4.9 mmol), 2-thioxoimidazolidin-4-one 21 (649 g, 5.6 techniques to afford products 8, 25, 26, 27, 28 and 32.
mmol) and saturated NaHCO3 solution (1.0 mL) were placed. Compounds 26, 33, 34, 36, 37 and 38 were characterized by
Aer introduction into the Anton Paar microwave reactor, it was comparison with authentic samples.
irradiated at 140 ꢀC for 10 min. The reaction products were
Data for 5-benzyl-3-vinylimidazolidine-2,4-dione, 25. GC/MS t
extracted with ethyl acetate (3 ꢂ 15 mL) and the organic layer (min) ¼ 6.20, m/z (EI, %) ¼ 42(6), 43(30), 44(6), 58(8), 65(11),
dried over anhydrous Mg2SO4 to obtain the pure 5-benzylidene- 83(9), 91(100), 92(14), 100(24), 117(13), 149(7), 216(8, M+c).
2-thioxoimidazolidin-4-one 22 (61.2 mg, 90%). Then,
Data for (Z)-5-benzylidene-3-vinylimidazolidine-2,4-dione, 27.
compound 22 (0.3 mmol), 1,2-dichloroethane 16 (1.0 mL, 12.6 lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 316 [(1.87 ꢄ 0.01)104] Mꢁ1
mmol) and Et3N (1.0 mL) were placed in a vial and irradiated cmꢁ1. 1H NMR dH (ppm) (400.16 MHz, acetone-d6, 22 ꢀC) ¼ 5.50
with MW at 175 ꢀC for 10 min. The reaction products were (dd, J1 ¼ 410.1 Hz, J2 ¼ 16.3 Hz, 2H); 6.67 (s, 1H); 6.76 (c, J1 ¼
extracted to obtain the pure 5-benzylidene-2,3-dihydroimidazo 16.3 Hz, J2 ¼ 9.8 Hz, 1H); 7.38 (t, J ¼ 7.3 Hz, 1H); 7.45 (t, J ¼ 7.2,
[2,1-b]thiazol-6(5H)-one 12 (61%, global yield: 55%).
2H); 7.66 (d, J ¼ 7.3, 2H) ppm. 13C NMR dc (ppm) (100.56 MHz,
Method (c) and (d). In a microwave vial, thioxoimidazolidin- DMSO-d6) ¼ 102.9, 110.4, 124.3, 128.8, 128.9 (ꢂ2), 129.3. GC-MS
4-one 23 (705 mg, 6.8 mmol), 1,2-dichloroethane (1.3 mL, 16.4 t (min) ¼ 7.10, m/z (EI, %) ¼ 63(10), 64(5), 89(31), 90(37),
mmol) and K2CO3 (2.5 g, 18.0 mmol) were placed. The mixture 116(24), 117(100), 118(9), 172(9), 213(8), 214(84, M+c).
was irradiated at 175 ꢀC for 10 min. The reaction products were
Data for 2-(2-chloroethyl)-1H-imidazo[1,5-a]indole-1,3(2H)-
extracted to obtain the pure 2,3-dihydroimidazo[2,1-b]thiazol- dione, 28. lmax/nm [3/Mꢁ1 cmꢁ1](CH3CN) ¼ 202 [(2.54 ꢄ 0.01)
5(6H)-one 24 (680 mg, 80%). Then, compound 24 (4.8 mmol) 105], 235 [(4.26 ꢄ 0.01)104], 319 [(7.12 ꢄ 0.01)104]. H NMR dH
1
ꢀ
and benzaldehyde 18 (0.5 mL, 4.9 mmol), in presence of (ppm) (400.16 MHz, acetone-d6, 22 C) ¼ 4.00 (m, 4H); 7.33 (s,
NaHCO3 (1.0 mL), were placed in the borosilicate tube and 1H); 7.37 (t, J ¼ 7.8 Hz, 1H); 7.58 (t, J ¼ 7.7 Hz, 1H); 7.85 (t, J ¼
irradiated at 140 ꢀC for 10 min. The reaction products were 7.6 Hz, 2H) ppm. 13C NMR dc (ppm) (100.56 MHz, DMSO-d6) ¼
extracted with ethyl acetate (3 ꢂ 15 mL) and the organic layer 41.2, 41.6, 109.1, 124.9, 129.2, 113.7, 125.3, 133.5, 133.7, 149.5,
dried over anhydrous Mg2SO4 to obtain the pure 5-benzylidene- 159.54 ppm. GC-MS t (min) ¼ 6.06, m/z (EI, %) ¼ 62(5), 63(5),
2,3-dihydroimidazo[2,1-b]thiazol-6(5H)-one 12 (80%, global 88(10), 89(6), 114(13), 115(45), 116(6), 143(100), 144(12), 199(6),
yield: 64%).
Method (e). In a cylindrical vial were placed benzaldehyde 18
248(23, M+c), 250(8).
Data for 2-vinyl-1H-imidazo[1,5-a]indole-1,3(2H)-dione, 31.
(1.0 mL, 9.8 mmol), 2-thioxoimidazolidin-4-one 21 (0.5 g, 3.5 This compound was characterized by GC-MS t (min) ¼ 5.91, m/z
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(EI, %) ¼ 43(10), 44(6), 62(9), 88(20), 89(6), 114(18), 115(68), 17 K. Faghihi, K. Zamani and A. Mobinikhaledi, Turk. J. Chem.,
116(8), 143(100), 144(11), 212(40, M+c), 213(15).
2004, 28, 345–350.
Data for (Z)-5-benzylidene-3-ethylimidazolidine-2,4-dione, 32. 18 K. Schologl, F. Wessel, O. Kraupp and H. Storma, J. Med.
This compound was characterized by GC-MS t (min) ¼ 6.89, m/z
Pharm. Chem., 1961, 4, 231–258.
´
(EI, %) ¼ 43(24), 44(15), 63(9), 89(25), 90(34), 116(19), 117(100), 19 G. A. Martinez Cordoba, L. A. Ramos, S. E. Ulic, J. L. Jios,
118(11), 187(6), 188(6), 215(1), 216(81, M+c), 217(13).
C. O. DellaVedova, A. J. Pepino, M. A. Burgos Paci,
´
¨
Data for 6-benzylimidazo[2,1-b]thiazol-5(6H)-one, 35. GC/MS t
(min) ¼ 6.89, m/z (EI, %) ¼ 44(9), 91(36), 105(15), 116(14),
G. A. Arguello, M. Ge, H. Beckers and H. Willner, J. Phys.
Chem. A, 2011, 115, 8608–8615.
´
119(39), 128(9), 142(9), 143(29), 157(8), 191(9), 201(7), 202(16), 20 J. Marton, J. Enisz, S. Hoszta and T. Tımar, J. Agric. Food
107(30), 208(8), 220(8), 221(100), 222(17), 229(7), 230(25, M+c).
Chem., 1993, 41, 148–152.
21 J. C. Thenmozhiyal, P. T.-H. Wong and W.-K. Chui, J. Med.
Chem., 2004, 47, 1527–1535.
22 J. C. Kim, L. K. Yun, Y. S. Koh, U. C. Yoon, M. Y. Pack and
K. H. Moon, Yakhak Hoechi, 1983, 27, 309–314.
Acknowledgements
Thanks are due for the nancial support provided by CONICET,
FONCyT, SECyT-UNC. A.J.P. and M.S.F. acknowledge doctoral
fellowships from CONICET.
´
¨
23 K. Kiec-Kononowicz, J. K. Wojciechowska, C. E. Mullerc,
´
U. Geis, W. Ksiazek and E. Szymanska, J. Heterocycl. Chem.,
1999, 36, 257–264.
´
´
24 E. Szymanska, K. Kiec-Kononowicz, A. Białecka and
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25 E. Szymanska and K. Kiec-Kononowicz, Il Farmaco, 2002, 57,
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¨
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2 K. Kiec-Kononowicz and E. Szymanska, Il Farmaco, 2002, 57,
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26 K. Kiec-Kononowicz, J. K. Wojciechowska, C. E. Muller,
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