Diastereoselective synthesis of benzofuran-3(2H)-one-hydantoin dyads

Article abstract of DOI:10.1016/j.tet.2013.04.111

A convenient diastereoselective rearrangement of the racemic (R/S)-spiro[chroman-2,4′-imidazolidine]-2′,4,5′-triones 3a-c into (2′R,5S)- and (2′S,5R)-5-(3-oxo-2,3-dihydrobenzofuran-2-yl) imidazolidine-2,4-diones 4a-c under alkali conditions is described.

Full text of DOI:10.1016/j.tet.2013.04.111

Tetrahedron 69 (2013) 5413e5420
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Diastereoselective synthesis of benzofuran-3(2H)-one-hydantoin
dyads
a
b
a
b
ꢀ
*
Oualid Talhi , Jose A. Fernandes , Diana C.G.A. Pinto , Filipe A. Almeida Paz ,
Artur S.M. Silva a
,
a QOPNA, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
b CICECO, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
a r t i c l e i n f o
a b s t r a c t
A convenient diastereoselective rearrangement of the racemic (R/S)-spiro[chroman-2,40-imidazolidine]-
20,4,50-triones 3aec into (20R,5S)- and (20S,5R)-5-(3-oxo-2,3-dihydrobenzofuran-2-yl)imidazolidine-2,4-
Article history:
Received 17 February 2013
Received in revised form 20 April 2013
Accepted 24 April 2013
diones 4aec under alkali conditions is described. The obtained
s bridged benzofuran-3(2H)-one-hy-
dantoin dyads 4aec are subsequently transformed into conjugated benzofuran-3(2H)-one-hydantoin
p
Available online 30 April 2013
dyads 5aec by a diastereoselective dehydrogenation using I2 (catalytic)/DMSO system to predominantly
yield the (Z)-isomer. The novel single and double bonded benzofuran-3(2H)-one-hydantoin conjugate
structures 4aec and 5aec were unambiguously elucidated by single-crystal X-ray diffraction and 2D
NMR techniques allowing an in-depth stereochemical and mechanistic discussions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Benzofuran-3(2H)-one
Hydantoin
Diastereoselective synthesis
X-ray crystallography
2D NMR
1. Introduction
The structural diversity of natural and synthetic heterocycles
has become a key topic in organic, bioorganic and medicinal
chemistry. Recent investigations are focused at the synthesis of
new conjugates of small bioactive molecules derived from well-
known organic compounds, such as flavonoids, stilbenes, couma-
rins, alkaloids, terpenoids, peptides and glycosides.1 Indeed, the
structural combination of two or more of these medicinal relevant
molecules in one organic framework usually leads to additive and/
or new biological properties different from those of the parent
material. Although, uncommonly encountered in nature, the titled
dihydrobenzofuran-3-one and hydantoin are important oxygen
and nitrogen containing heterocycles, which play outstanding bi-
ological roles.2e6 The dihydrobenzofuran-3-one nucleus (Fig. 1) is
represented by aurones, a natural flavonoid-type of compounds
showing two possible (E)- and (Z)-isomers. Hydantoins are imida-
zolidine derived compounds sharing two carbonyl functions at
positions C-2 and C-4 with substituents bonded via carbon C-5
and/or nitrogen N-1, N-3 atoms (Fig. 1).3
Fig. 1. Dihydrobenzofuran-3-one and hydantoin heterocyclic systems.
and update new synthetic routes.2,7 Filloux et al.7c reported a mul-
ticatalytic, one-pot, enantioselective Michael/Stetter synthesis of
dihydrobenzofuran-3-one by reaction of salicylaldehydes with
electron deficient alkynes. A one-pot, three-component sequential
reaction is updated for the synthesis of diversely 1,3,5- and 1,3,5,5-
poly-substituted hydantoins from azides, iso(thio)cyanates and
substituted a
-haloacetic carboxylic acids.8a This methodology and
others similar are appropriately designated for the synthesis of
spiro hydantoins, being particularly useful synthetic precursors to
perform other interesting chemical alterations and, for this pur-
pose, we consider their use as starting material in the present
study.8
Recent interests have considered the biological significance of
dihydrobenzofuran-3-one and hydantoin compounds to develop
The development of natural mimic heterocyclic combinations,
using greener synthetic methods, is an attractive goal in the me-
dicinal chemistry area. In this framework, we point fingers to
the covalently combined heterocycles and their stereoselective
* Corresponding author. Tel.: þ351 234 370714; fax: þ351 234 370084; e-mail
address: artur.silva@ua.pt (A.S.M. Silva).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.111

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O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
synthetic endpoint. Indeed, the available literature is carelessly
taking into consideration the stereoselective organic access to
single bonded or conjugated heterocyclic dyads. The geometrical
2. Results and discussion
s
p
Spiro bicyclic chromanoneehydantoins 3aec have only been
reported in the primary literature by Filliatre and Servens.8b They
reported the synthesis of 10,30-dicyclohexylspiro[chroman-2,40-
imidazolidine]-20,4,50-trione 3a by the action of chromone-2-
carboxylic acid 1 on N,N-dicyclohexylcarbodiimide 2a in a two-
step procedure.8b In their method the isolation of 2-chromone-N-
acylurea as intermediate is required at the first stage in order to
carry out a subsequent intramolecular N-cyclization affording the
desired spiro bicyclic chromanoneehydantoin 3a. Alternatively, we
have herein shorten the protocol into a one-step synthetic route of
10,30-disubstituted-spiro[chroman-2,40-imidazolidine]-20,4,50-tri-
ones 3aec via the organo-catalytic coupling of the cheap chro-
factor remains a critical issue to arguably justify certain structur-
eeactivity relationships. From this point of view, Singh et al.9 have
reported the synthesis and antitumour activity of various
chromone-based conjugated combinations with indole, pyrazole
and pyrimidine moieties. Nevertheless the (E/Z)-isomeric aspect
was completely omitted regarding to the undertaken Knoevenagel
condensation route, and its influence as an important geometrical
parameter on the newly discovered antitumour activity. Indirubin
derivatives,10a the active ingredients of Danggui Longhui Wan (a
mixture of plants that is used in traditional Chinese medicine to
treat chronic diseases), are p-conjugated hybrids of indolin-(2 and
3)-ones exhibiting potent cyclin-dependent kinases and cancer cell
proliferation inhibitory effect. Many published studies are devoted
to investigate the synthetic routes and the biological manifesta-
tions of natural indirubin derivatives and related compounds, but
the structural relevance of the (E/Z) geometry remains unexplored
to date (Fig. 2).10
mone-2-carboxylic acid 1 with carbodiimides 2aec using
a catalytic amount of 4-pyrrolidinopyridine (Scheme 2). Our im-
proved procedure delivers high yields (66e88%) and readily iso-
lated materials 3aec after recrystallization. The formation of
compounds 3aec has been rationalized on the basis of density
functional theory (DFT) studies,8c by a mechanism involving three
steps: a nucleophilic addition of chromone-2-carboxylic acid 1 on
the carbodiimide C]N double bond followed by an O/N acyl shift
of the intermediate 6 to give the chromone-2-N-acylurea 7, which
is reported as an experimentally isolated product.8b The last step
consists in an intramolecular cyclization via aza-Michael addition
at position C-2 of the chromone, which has led to the creation of
a spiro asymmetric carbon joining both of the chromanone and
hydantoin rings at positions C-2/C-40 3aec. A racemic (R/S) mixture
is resulted from the equiprobable C-2 nucleophilic attack of the
nitrogen atom on both sides of the sp2 plan in the 2-chromone-N-
acylurea intermediate 7 (Scheme 2). The crystal structures of the
representative compounds 3a and 3c confirm their presence as
racemic mixtures (Fig. 3). Both (R)- and (S)-absolute configurations
(1:1 ratio) at the C-2 asymmetric spiro carbon can be recognized
from the centrosymmetric monoclinic crystal space groups P21/c
and C2/c in which compounds 3a and 3c crystallize, respectively.
Fig. 2. Synthetic and natural conjugated heterocyclic dyads.
Due to the valuable biological outcome of such conjugated
heterocyclic dyads, our attention is directed towards designing
mimic skeletons. Herein we combine both the biologically active
dihydobenzofuran-3-one and hydantoin in a single bonded 4aec or
double bonded dyads 5aec bearing asymmetric or diastereomeric
centres, respectively. The synthetic strategy is based on a three-step
reaction sequence, starting from the readily accessible spiro bicyclic
chromanoneehydantoin 3aec to be diastereoselectively trans-
formed into the benzofuran-3(2H)-one-hydantoin dyads 4aec and
5aec (Scheme 1). The stereochemical course of the relevant
transformations is investigated by means of high-resolution spec-
troscopic techniques allowing the discussion of their formation
mechanism.
Scheme 2. Synthesis of spiro[chroman-2,40-imidazolidine]-20,4,50-triones 3aec and
the proposed mechanism for their formation as a racemic mixture.
Our synthetic approach concerns the ring transformation of the
spiro bicyclic chromanoneehydantoin scaffolds 3aec into the
benzofuran-3(2H)-one-hydantoin 4aec. This rather rare rear-
rangement is performed by treatment of 3aec with sodium eth-
oxide. The transformation permits the creation of a second
asymmetric centre in the resulting C20eC5
s bridged benzofuran-
3(2H)-one-hydantoins 4aec, which are obtained in acceptable
yields (47e63%) after column chromatography purification and
recrystallization (Scheme 3). The O1/C2 to O1/C3 rearrange-
ment was initially monitored by 1H NMR analysis. The 1H NMR
spectra of benzofuran-3(2H)-one-hydantoins 4aec present two
signals as doublets at 4.55e5.34 and 4.89e4.93 ppm, with a small
vicinal coupling constant (3J¼1.9e2.0 Hz), attributed to the proton
Scheme 1. Reaction sequence to synthesize benzofuran-3-one-hydantoin dyads.

O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
5415
Fig. 3. Molecular structures of compounds C23H28N2O4 (3a) and C25H20N2O4 (3c).
While for 3a the asymmetric unit coincides with a whole molecule, for 3c the asym-
metric unit comprises two crystallographic independent molecules (only one is rep-
resented for clarity). Asymmetric carbons are depicted by an asterisk (*). Non-
hydrogen atoms are represented as thermal ellipsoids drawn at the 50% probability
level, while hydrogen atoms are represented as small spheres with arbitrary radii.
Fig. 4. Molecular structures of compounds C23H28N2O4 (4a) and C25H20N2O4 (4c).
While for 4a the asymmetric unit is composed of a whole molecule co-crystallizing
with an ethanol molecule (not shown), for 4c the asymmetric unit comprises in-
stead four crystallographic independent molecules (for clarity, only one is repre-
sented). Asymmetric carbons are depicted by an asterisk (*). Non-hydrogen atoms are
represented as thermal ellipsoids drawn at the 50% probability level, while hydrogen
atoms are represented as small spheres with arbitrary radii.
resonances of H-5 and H-20 of the C20eC5
s single bond, re-
spectively. The aforementioned 1H NMR patterns of compounds
4aec are the sole difference in comparison with the 1H NMR
spectra of the starting material 3aec, which display a clear AB spin
system [assigned at 2.89e3.14 ppm and 3.22e3.30 ppm
(2J¼16.7e16.9 Hz)] due to the geminal diastereotopic protons of the
chromanone C-3 methylene group. 1H NMR data are otherwise
useless to discuss the ambiguous stereochemical aspect of the
eventual chromanone/dihydrobenzofuran-3-one rearrangement.
Fig. 5. Asymmetric unit of compound 4a showing the (20R,5S)-enantiomer and the
corresponding Newman gauche projection.
Scheme 3. Synthesis of 1,3-disubstituted-5-(3-oxo-2,3-dihydrobenzofuran-2-yl)imi-
dazolidine-2,4-diones 4aec.
The reaction of the racemic 3aec compounds must logically
generate the rearranged products 4aec as 1:1 mixture of two di-
astereomers, thus two pairs of enantiomers are expected. In fact,
a unique racemic pair of enantiomer (20R,5S and 20S,5R) is de-
termined by single-crystal X-ray diffraction studies of compounds
4a and 4c (Fig. 4). Convincible crystallographic data reveal that the
Fig. 6. Main connectivities observed in the HMBC spectra of compounds 4aec.
differentiate between the carbonyl groups. For instance in all
compounds 4aec the carbonyl C-30 is coupled to H-40
(7.69e7.74 ppm) proving its position in the benzofuran-3(2H)-one
ring. In the case of compounds 4a and 4b, H-1000 (3.81 and 4.22 ppm)
correlates to both carbonyls of the hydantoin ring C-2 and C-4,
while H-100 shows only a weak HMBC correlation with carbonyl C-2,
therefore allowing the assignment of the 1-N- and 3-N-cyclohexyl/
isopropyl hydantoin substituents.
Appreciable information is gained from the NOESY spectrum of
4a. Strong NOE effects between H-20 (4.90 ppm) and H-5
(4.56 ppm) are present, consistently proving the relative C20eC5
gauche conformation in solution and as previously described for
ꢁ
centrosymmetric space groups, triclinic Pı in 4a and monoclinic
P21/n in 4c, impose both of (R)- and (S)-absolute configurations at
the asymmetric carbons C-20 and C-5 in a 1:1 ratio. Aside, the
crystallization conditions of the candidate compounds 4a and 4c in
ethanol at 6 ꢀC, yielded crystals exhibiting a preferential enrich-
ment of the gauche conformer relatively to the central
s single
0
bond C20eC5 with dihedral angle (CH2 eCH5) of 64ꢀ calculated
from the crystallographic parameters (Fig. 5).
The HSQC experiment of the
s bridged benzofuran-3(2H)-one-
hydantoin 4aec indicated that both H-20 and H-5 are carried by two
different carbons C-20 at 80.6e82.3 ppm and C-5 at 59.9e62.1 ppm,
respectively. The neighbouring carbon resonances of H-20 and H-5
are assigned from the main HMBC correlations (Fig. 6): (i) H-5
correlates with three carbonyl groups C-2 (153.6e156.2 ppm) and
C-4 (166.2e168.1 ppm) from the hydantoin moiety and C-30
(196.8e196.9 ppm) from the benzofuran-3(2H)-one moiety; and
(ii) H-20 correlates with carbonyls C-4 and C-30 together with C-80
(172.5e176.6 ppm) and C-5. Further HMBC features enable to
the crystals (Figs. 4 and 5). The
s bridged benzofuran-3(2H)-one-
hydantoin molecules 4aec adopt the desirable gauche conformer
in order to increase their chemical stability by adjusting between
both electronegative atoms repulsion forces and heterocyclic ten-
sions at the same time.
From a chemical stability perspective, the spiro bicyclic pre-
cursors 3aec have a high tension that may favour an expected

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O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
rearrangement or opening the heterocycles. The formation of the
rearranged products 4aec can be envisaged by an initial deproto-
nation of the active methylene group in 3aec by the strong base
sodium ethoxide, followed by a chromanone ring-opening of 9 and
a five-membered ring closure of 10 to finally afford the benzofuran-
3(2H)-one-hydantoin 4aec (Scheme 4). The reaction using de-
rivative 3c (with the tolyl substituent) was the unique case where
a small amount (5%) of the opened conjugated-form (Z)-1,3-ditolyl-
5-[2-(2-hydroxyphenyl)-2-oxoethylidene]imidazolidine-2,4-dione
8c was isolated and established by NMR analysis and analytical
data. These results unequivocally confirm the chromanone ring-
opening of the spiro bicyclic compounds 3aec to give the in-
termediate 10 (Scheme 4). In such a spiro bicyclic structure, the
heterolytic cleavage is found more susceptible to occur over the
highly polarized OeC
s bond of the chromanone than the NeC one
of the hydantoin nucleus making this latter more chemically stable.
Scheme 5. Stereochemical features of the diastereoselective rearrangement of 3aec
into 4aec.
leading to a racemic character of the carbon C-20 (R/S in a 1:1 ratio).
However the adjacent C-5 asymmetric carbon is most likely taking
the opposite configuration (R or S) of C-20 as clearly seen in the
O10eC20eC5eH5 arrangement of compounds’ 4aec gauche con-
formation (Figs. 4 and 5).
The final step of our synthetic strategy consisted in the con-
struction of a rigid
p double bond between the benzofuran-3(2H)-
Scheme 4. Proposed mechanism for diastereoselective rearrangement of 3aec onto
4aec.
one and the hydantoin rings. We have attempted the de-
hydrogenation of compounds 4aec using a catalytic amount of
iodine in refluxing DMSO. The desired 1,3-disubstituted-5-(3-
The rationale behind the diastereoselective rearrangement of
the spiro bicyclic chromanoneehydantoin 3aec into the benzofu-
ran-3(2H)-one-hydantoin 4aec is mainly deduced from the iso-
lated conjugated-form 8c. Unless considered as an intermediate of
reaction, the opened conjugated-form 10 presents the systematic
1:1 (E/Z)-isomeric mixture arising from a racemic mixture of the
starting spiro bicyclic compounds 4aec [step (a), Scheme 5]. Sta-
tistically, the involvement of both E- and (Z)-configurations of 10 in
the reaction mechanism may, respectively, provide two pairs of
enantiomers (20R,5R and 20S,5S) and (20R,5S and 20S,5R) in a 1:1
ratio [step (b), Scheme 5]. Since the experimentally isolated com-
pounds 4aec are structured as a unique pair of the mentioned
enantiomers (20R,5S and 20S,5R), the opening of the racemic R/S
spiro bicyclic compounds 3aec is compulsory driven to the most
stable (Z)-isomer of the intermediate 10, assuming a greater pla-
narity and suitability for the ring-closure, while the (E)-isomer is
probably found destabilized by the internal electronic repulsion
between carbonyl groups C-20 and C-4. Based on these mechanistic
explanations, we have been convinced by further empirical studies:
the NOESY spectrum analysis of the isolated compound 8c (as
represented by the intermediate 10) show undoubtedly the (Z)-
configuration because no significant NOE effects are observed be-
tween the vinylic proton and tolyl protons so to evidence the E-
configuration.
oxobenzofuran-2(3H)-ylidene)imidazolidine-2,4-diones
5aec
have been selectively obtained as their (Z)-isomer (35e65%,
Scheme 6). A remarkable case in the dehydrogenation consists of
the parallel isolation of (E)-isomer (in low yield 21%) only when
dealing with the tolyl derivative 4c.
Scheme 6. Synthesis of 1,3-disubstituted 5-(3-oxobenzofuran-2(3H)-ylidene)imida-
zolidine-2,4-diones 5aec.
This final dehydrogenation step was firstly monitored by NMR
analysis. The 1H NMR spectra of the resulting compounds 5aec
show the clear disappearance of both H-20 and H-5 when compared
to those of the starting materials 4aec. A double bond bridging
both moieties of the benzofuran-3(2H)-one-hydantoin structure is
formed as determined by the high-resolution mass spectra show-
ing a loss of a hydrogen molecule in compounds 5aec. In such
circumstances, 2D NMR experiments were less informative for the
study of the stereochemical course of this transformation. The
determination of (E)- or (Z)-configuration in the resulting olefins
5aec is unsolvable using particularly the NOESY technique because
no characteristic protons exist around the C20]C5 double bond.
In short, the origin of the diastereoselective rearrangement of
the spiro bicyclic chromanoneehydantoin 3aec into the benzofu-
ran-3(2H)-one-hydantoin 4aec is based on the chromanone ring-
opening of 3aec (Scheme 5), which provides the conjugated in-
termediate 10 in its most stable (Z)-form. The oxygen nucleophilic
attack usually occurs on both sides of the C10dC5 sp2 plane of 10

O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
5417
This structural feature could only be unveiled by single-crystal X-
ray diffraction studies. The crystallization of the conjugated dyads
5aec was not a trivial task. As a matter of fact, compound 5a could
not be isolated as single-crystals with quality enough for a full
structural elucidation even after using a myriad of solvents and
crystallization conditions. Compound 5c was, however, successfully
crystallized as long fine needles using toluene solution at 6 ꢀC.
Several attempts for finding both isomers were considered, but
only crystals of the (Z)-enriched product (Z)-5c could be isolated
(Fig. 7).
Scheme 7. Proposed mechanism for the diastereoselective dehydrogenation of
compounds 5aec.
Fig. 7. Schematic representation of the asymmetric unit of compound C25H18N2O4 [(Z)-
5c], which comprises a whole molecular unit in the (Z)-configuration around the
double bond. Non-hydrogen atoms are represented as thermal ellipsoids drawn at the
50% probability level, while hydrogen atoms are represented as small spheres with
arbitrary radii.
3. Conclusion
The present study describes convenient synthetic approaches
leading to a facile bridging of two biologically active heterocycles.
Starting from the easily prepared spiro bicyclic chromano-
A piece of the utmost importance must be emphasized re-
garding the dehydrogenation process of the single bonded benzo-
furan-3(2H)-one-hydantoin 4aec. In the case of the tolyl derivative
4c, the dehydrogenation process allows the formation of a minor
amount of (E)-isomer of 5c, which is isolated by preparative TLC
along with (Z)-5c. We assume that this compound must feasibly be
the (E)-isomer because of its similar features of both the 1H NMR
and the high-resolution mass spectra relative to those of the (Z)-
isomer of 5c. Several crystallization attempts of (E)-5c were carried
out, but no valuable crystallographic data could be derived. Thus,
the structure of (E)-5c was elucidated on the basis of extensive
NMR data that clearly sort the great differences in terms of proton
and carbon chemical shifts to those of (Z)-5c. Despite of their
similar yellow physical appearance, the isomer (Z)-5c is a solid that
could be visually distinguished from the (E)-5c one. Additionally,
their melting points are largely different (see Experimental). As
a result, we have accomplished the isolation of two separable di-
astereomers of compound 5c (E/Z) obtained in a 1:3 ratio (calcu-
lated by NMR chemical shift integration and confirmed by HPLC
neehydantoin skeleton,
s single bonded and p double bonded
benzofuran-3-one-hydantoin dyads have been produced following
diastereoselective organic pathways. In-depth spectroscopic stud-
ies, single-crystal X-ray diffraction and NMR techniques, have
revealed various structural features regarding the stereochemical
course of the sequential transformations. Important diaster-
eoselective patterns, conformational and geometrical factors have
been underlined due to their influence on future chemical and bi-
ological applications.
4. Experimental section
4.1. General
Melting points were measured on a Buchi melting point B-545
apparatus and are uncorrected. NMR spectra were recorded on
a 300 Bruker Avance spectrometer operating at 300.13 for 1H and
75.47 MHz for 13C, with CDCl3 as solvent if not stated otherwise.
analysis). Therefore, we disclose
hydrogenation majorly yielding the (Z)-5aec isomers.
The last conversion can be mechanistically outlined by the
a
diastereoselective de-
Chemical shifts (d) are reported in parts per million and coupling
s
/p
constants (J) in Hertz. The internal standard was TMS. The signals
are described as s (singlet), d (doublet), dd (doublet of doublet), ddd
(double doublet of doublet), t (triplet), tt (triplet of triplets), q
(quartet), sept (septet) and m (multiplet). Unequivocal 13C assign-
ments were made with the aid of 2D HSQC and HMBC (delays for
one bond and long-range JC/H couplings were optimized for 145 and
7 Hz, respectively) experiments. Exact mass measurements were
recorded using a TOF-Q analyser and elemental analysis on Truspec
630-200-200 equipment.
formation of the benzofuran-3(2H)-ones enolic form 11, which
should take the stabilized rotamer 12 due to an intramolecular
hydrogen bond. It subsequently undergoes a sequence of a-iodin-
ation to give 13, and E2 elimination of hydroiodic acid to yield the
final (Z)-5aec. The formed hydroiodic acid follows its redox cycle
by reacting with DMSO to regenerate the catalyst molecular iodine
and producing the thioether, which smells during the course of the
reaction (Scheme 7). In these particular conjugated heterocyclic
hybrids, the (Z)-configuration is apparently the most stable due to
the quasi-planarity of the scaffold (Fig. 7). This geometrical feature
is not expected for the (E)-configured scaffold, which obviously
inflicts a very close proximity, and a consequent considerable steric
hindrance, between the benzofuran-3(2H)-one carbonyl group and
the neighbouring substituent. Thus, rotation over the central C-
20eC5 bond minimizes the internal structural interactions ulti-
mately promoting the appearance of the thermodynamic most
stable (Z)-product.
4.2. Synthesis of 10,30-disubstituted spiro[chroman-2,40-imi-
dazolidine]-20,4,50-triones 3aec
Chromone-2-carboxylic acid 1 (2 g, 10.52 mmol) was added to
a solution of the appropriate carbodiimides 2aec (10.52 mmol,
1 equiv) in dichloromethane (20 mL), followed by the addition of
a catalytic amount of 4-PPy (0.52 mmol, 0.08 g, 0.05 equiv).

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O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
The resulting mixture was allowed to stir overnight at room tem-
perature. After that period, the solvent was evaporated to dryness
and the resulting resinous solid was directly recrystallized from
ethanol to afford compounds 3aec.
8c was first eluted from the column chromatography, isolated and
recrystallized from ethanol.
4.3.1. (20R,5S)/(20S,5R)-1,3-Dicyclohexyl-5-(3-oxo-2,3-dihydrobenzo-
furan-2-yl)imidazolidine-2,4-dione 4a. C23H28N2O4 (white solid,
2.38 g, yield 57%, mp¼154e155 ꢀC). 1H NMR (300.13 MHz, CDCl3):
4.2.1. (R/S)-10,30-Dicyclohexylspiro[chroman-2,40-imidazolidine]-
20,4,50-trione 3a. C23H28N2O4 (white solid, 3.32 g, yield 80%;
mp¼189e190 ꢀC, lit. 188 ꢀC8b). 1H NMR (300.13 MHz, CDCl3):
d
¼1.23e2.03 (m, 20H, eCH2-cyclohexyl), 3.67 (tt, J¼12.0, 4.1 Hz, 1H,
H-100), 3.81 ppm (tt, J¼12.2, 3.8 Hz, 1H, H-1000), 4.56 (d, J¼2.0 Hz, 1H,
H-5), 4.90 (d, J¼2.0 Hz, 1H, H-20), 7.07 (d, J¼8.5 Hz, 1H, H-70),
7.11e7.17 (m, 1H, H-50), 7.61 (ddd, J¼8.5, 7.3, 1.5 Hz, 1H, H-60),
d
¼1.10e2.16 (m, 20H, eCH2ecyclohexyl), 2.89 (d, J¼16.7 Hz, 1H, H-
3), 3.30 (d, J¼16.7 Hz, 1H, H-3), 3.33 (tt, J¼12.2, 3.8 Hz, 1H, H-1000),
3.83 (tt, J¼12.2, 3.8 Hz, 1H, H-100), 6.96 (dd, J¼8.3, 0.8 Hz, 1H, H-8),
7.05e7.11 (m, 1H, H-6), 7.50 (ddd, J¼8.3, 7.2, 1.6 Hz, 1H, H-7), 7.88
7.69e7.74 (m, 1H, H-40). 13C NMR (75.47 MHz, CDCl3):
d
¼24.9, 25.4,
25.71, 25.74, 25.76, 25.82, 29.8, 29.2, 30.3 and 31.4 (-CH2-cyclo-
hexyl), 51.8 (C-1000), 54.1 (C-100), 60.1 (C-5), 82.3 (C-20), 112.9 (C-70),
121.7 (C-90), 122.7 (C-50), 124.3 (C-40), 138.0 (C-60þ), 156.2 (C-2), 168.1
(C-4), 172.5 (C-80), 196.9 (C-30). HRMS (ESI ), m/z calcd for
[C23H28N2O4þNa]þ: 419.1947; found: 419.1947.
(dd, J¼7.8, 1.6 Hz, 1H, H-5). 13C NMR (75.47 MHz, CDCl3):
¼24.9,
d
25.0, 25.68, 25.71, 26.15, 26.15, 29.29, 29.33, 30.8 and 31.0
(eCH2ecyclohexyl), 41.3 (C-3), 51.6 (C-100), 54.0 (C-1000), 88.5 (C-2),
117.6 (C-8), 119.8 (C-10), 122.3 (C-6), 126.2 (C-5), 136.3 (C-7), 153.8
(C-20), 158.4 (C-9), 168.7 (C-50), 188.7 (C-4). HRMS (ESIþ), m/z calcd
for [C23H28N2O4þNa]þ: 419.1947; found: 419.1939. Anal. Calcd for
C23H28N2O4: C 69.67, H 7.12, N 7.07. Found: C 69.36, H 7.10, N 7.11%.
4.3.2. (20R,5S)/(20S,5R)-1,3-Diisopropyl-5-(3-oxo-2,3-dihydrobenzo-
furan-2-yl)imidazolidine-2,4-dione 4b. C17H20N2O4 (white solid,
1.574 g, yield 47%, mp¼122 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼1.30,
d
4.2.2. (R/S)-10,30-Diisopropylspiro[chroman-2,40-imidazolidine]-
20,4,50-trione 3b. C17H20N2O4 (white solid, 2.20 g, yield 66%,
1.32 and 1.35 (d, J¼7.0 Hz, 12H, H-200 and H-2000), 4.10 ppm (sept,
J¼7.0 Hz, 1H, H-100), 4.22 ppm (sept, J¼7.0 Hz, 1H, H-1000), 4.55 (d,
J¼2.0 Hz, 1H, H-5), 4.89 ppm (d, J¼2.0 Hz, 1H, H-20), 7.08 (dd, J¼8.4,
0.7 Hz, 1H, H-70), 7.11e7.18 (m, 1H, H-50), 7.58e7.65 (m, 1H, H-60),
mp¼157e158 ꢀC). 1H NMR (300.13 MHz, CDCl3):
d
¼1.39 (d,
J¼6.9 Hz, 6H, H-200), 1.46 (d, J¼6.9 Hz, 3H, H-2000), 1.51 (d, J¼6.9 Hz,
3H, H-2000), 2.93 (d, J¼16.7 Hz, 1H, H-3), 3.27 (d, J¼16.7 Hz, 1H, H-3),
3.77 (sept, J¼6.9 Hz, 1H, H-1000), 4.26 (sept, J¼6.9 Hz, 1H, H-100), 6.97
(dd J¼8.3, 0.9 Hz, 1H, H-8), 7.04e7.12 (m, 1H, H-6), 7.51 (ddd, J¼8.3,
7.3, 1.8 Hz, 1H, H-7), 7.88 (dd, J¼7.8, 1.8 Hz, 1H, H-5). 13C NMR
7.70e7.74 (m,1H, H-40).13CNMR (75.47MHz,CDCl3):
d
¼19.2,19.5,19.9
and 21.1 (C-20 and C-2000), 44.2 (C-1000), 46.0 (C-100), 59.9 (C-5), 82.2 (C-
20),112.9(C-70),121.7(C-90),122.8(C-50),124.4(C-40),138.0(C-60),156.0
(C-2),168.0 (C-4),172.5 (C-80),196.8 (C-30). HRMS (ESIþ), m/z calcd for
[C17H20N2O4þNa]þ: 339.1324; found: 339.1318. Anal. Calcd for
C17H20N2O4: C 64.54, H 6.37, N 8.86. Found: C 64.49, H 6.38, N 8.91%.
(75.47 MHz, CDCl3):
d
¼19.57 and 19.63 (C-200), 20.96 and 21.03 (C-
2000), 41.0 (C-3), 43.9 (C-100), 45.9 (C-1000), 88.6 (C-2), 117.5 (C-8), 119.7
(C-10), 122.3 (C-6), 126.3 (C-5), 136.4 (C-7), 153.6 (C-20), 158.4 (C-9),
168.6 (C-50), 188.5 (C-4). HRMS (ESIþ), m/z calcd for
[C17H20N2O4þNa]þ: 339.1321; found: 339.1324. Anal. Calcd for
C17H20N2O4: C 64.54, H 6.37, N 8.86. Found: C 64.49, H 6.38, N 8.91%.
4.3.3. (20R,5S)/(20S,5R)-10,30-Ditolyl-5-(3-oxo-2,3-dihydrobenzofu-
ran-2-yl)imidazolidine-2,4-dione 4c. C25H20N2O4 (white solid,
2.74 g, yield 63%, mp¼181e183 ꢀC). 1H NMR (300.13 MHz, CDCl3):
d
¼2.34 and 2.36 (2s, 6H, 400-CH3, 4000-CH3), 4.93 (d, J¼1.9 Hz, 1H, H-
4.2.3. (R/S)-10,30-Ditolylspiro[chroman-2,40-imidazolidine]-20,4,50-tri-
20), 5.34 (d, J¼1.9 Hz, 1H, H-5), 7.00 (d, J¼8.5 Hz, 1H, H-70), 7.06e7.13
(m, 1H, H-50), 7.18e7.29 (2m, 6H, tolyl) and 7.36 (d, J¼8.4 Hz, 2H,
tolyl), 7.55 (ddd, J¼8.5, 7.3, 1.5 Hz, 1H, H-60), 7.69 (d, J¼7.7 Hz, 1H, H-
one 3c. C25H20N2O4 (pale yellow solid, 3.80 g, yield 88%,
mp¼182e183 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼2.33 and 2.35
d
(2s, 6H, 400-CH3 and 4000-CH3), 3.14 (3d, J¼16.9 Hz, 1H, H-3), 3.22 (d,
J¼16.9 Hz, 1H, H-3), 6.98e7.09 (m, 2H, H-6, H-8), 7.18 and 7.23 (2d,
J¼8.1 Hz, 4H, tolyl), 7.28 and 7.35 (2d, J¼8.4 Hz, 4H, tolyl), 7.44e7.53
(m, 1H, H-7), 7.76 (dd, J¼7.8, 1.7 Hz, 1H, H-5). 13C NMR (75.47 MHz,
40). 13C NMR (75.47 MHz, CDCl3):
d
¼20.92 and 21.15 (400-CH3, 4000-
CH3), 62.1 (C-5), 80.6 (C-20), 113.0 (C-70), 121.5 (C-90), 122.7 (C-50),
123.5 and 126.0 (C-200 and C-2000), 124.3 (C-40), 128.5 and 131.8 (C-100
and C-1000), 129.7 and 129.9 (C-300 and C-3000), 136.6 and 138.5 (C-400
and C-4000), 138.1 (C-60), 153.6 (C-2), 166.2 (C-4), 172.6 (C-80), 196.8
(C-30). HRMS (ESIþ), m/z calcd for [C25H20N2O4þNa]þ: 435.1321;
found: 435.1329.
CDCl3):
d
¼21.06 and 21.08 (400-CH3 and 4000-CH3), 41.1 (C-3), 89.2 (C-
2),117.4 (C-8), 119.8 (C-10),122.4 (C-6),125.5 and 128.4 (C-200 and C-
2000),126.2 (C-5),127.9 and 129.5 (C-100 and C-1000),129.6 and 130.1 (C-
300 and C-3000), 136.3 (C-7), 138.4 and 139.1 (C-400 andþC-4000), 153.1 (C-
20), 158.0 (C-9), 167.1 (C-50), 187.8 (C-4). HRMS (ESI ), m/z calcd for
[C25H20N2O4þNa]þ: 435.1321; found: 435.1309. Anal. Calcd for
C25H20N2O4: C 72.80, H 4.89, N 6.79. Found: C 72.75, H 5.05, N 6.89%.
4.3.4. (Z)-1,3-Ditolyl-5-[2-(2-hydroxyphenyl)-2-oxoethylidene] imi-
dazolidine-2,4-dione 8c. C25H20N2O4 (yellow solid, 0.22 g, yield 5%,
mp¼223e224 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼2.31 and 2.41
d
(2s, 6H, 40-CH3 and 400-CH3), 6.86e6.93 (m, 2H, H-30000, H-50000), 6.93 (s,
1H, H-1000), 7.01e7.07, 7.30e7.35 (2m, 4H, tolyl), 7.32 and 7.40 (2d,
J¼8.1 Hz, 4H, tolyl), 7.44e7.48 (m, 1H, H-40000), 7.71 (dd, J¼8.0, 1.6 Hz,
1H, H-60000), 11.31 (s, 1H, 20000-OH). 13C NMR (75.47 MHz, CDCl3):
4.3. Synthesis of 1,3-disubstituted 5-(3-oxo-2,3-
dihydrobenzofuran-2-yl)imidazolidine-2,4-diones 4aec
Sodium (10.52 mmol, 0.242 g) was added to ethanol (5 mL) and
the resulting solution was added dropwise (for 15 min) to a solution
of the appropriate 10,30-disubstituted spiro[chroman-2,40-imida-
zolidine]-20,4,50-trione 3aec (10.52 mmol) in ethanol (20 mL),
placed in an ice-water bath (0 ꢀC). The reaction was left for 1 h to
reach room temperature under constant stirring. After TLC moni-
toring, the ethanolic solution was poured in ice and water to be
neutralized to pH 7 with diluted hydrochloric acid. A yellowish
white precipitate appeared, which was then purified by silica gel
d
¼21.1 and 21.2 (40-CH3 and 400-CH3), 104.3 (C-1000), 118.2 (C-30000),
119.0 (C-50000), 120.2 (C-10000), 125.7 and 126.2 (C-20 and C-200), 128.2
(C-10 or C-100), 129.7 and 129.9 (C-30 and C-300), 131.0 (C-60000, C-100 or
C-10), 135.1 (C-5), 137.0 (C-40000), 138.8 (C-40 and Cþ-400),152.9 (C-2),
161.7 (C-4), 162.3 (C-20000), 194.5 (C-2000). HRMS (ESI ), m/z calcd for
[C25H20N2O4þNa]þ: 435.1321; found: 435.1329. Anal. Calcd for
C25H20N2O4: C 72.80, H 4.89, N, 6.79. Found: C 72.71, H 4.89, N 6.84%.
4.4. Synthesis of 1,3-disubstituted 5-[3-oxobenzofuran-2(3H)-
ylidene]imidazolidine-2,4-dione 5aec
column chromatography using
a (1:1) of light petroleum/
dichloromethane as eluent. The resulting pure compounds were
recrystallized from ethanol to afford compounds 4aec. In the case
of the reaction of compound 3c, the opened conjugated compound
Iodine (0.068 g dissolved in 1 mL of DMSO) was added to a -
solution of the appropriate 1,3-disubstituted 5-(3-oxo-2,3-

O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
5419
dihydrobenzofuran-2-yl)imidazolidine-2,4-dione 4aec (5.26 mmol)
in DMSO (3 mL) and the reaction mixture was refluxed under ni-
trogen flow and shielded from intense light for 30 min. After TLC
monitoring, the reaction solution was poured into ice (10 g) and
water (20 mL). An intense yellow precipitate appeared, which was
filtrated and washed with water. The obtained solid was taken in
dichloromethane (150 mL) and washed with a saturated solution of
sodium thiosulfate (2ꢁ150 mL). After solvent evaporation the resi-
due dissolved in dichloromethane was purified by silica gel column
chromatography using a (1:1) mixture of light petroleum and
dichloromethane as eluent. The resulting pure compound was
recrystallized from ethanol to give compounds (Z)-5aec. In the case
of 4c, two isomers (Z)-5c and (E)-5c were jointly obtained in a 3:1
ratio (evaluated by NMR proton integration and confirmed by HPLC
analysis: Gilson HPLC conditions: column: Silica gel, mobile phase:
hexane/THF (80:20), flow rate: 1 mL/min, UVevisible detection:
(2s, 6H, 400-CH3 and 4000-CH3), 7.15e7.21 (m, 1H, H-50), 7.28e7.35 and
7.37e7.42 (2m, 9H, H-70 and tolyl), 7.58e7.68 (m, 2H, H-60, H-40). 13C
NMR (75.47 MHz, CDCl3):
d
¼21.2 and 21.3 (400-CH3 and 4000-CH3),112.4
(C-70), 118.8 (C-5), 121.8 (C-90), 124.0 (C-50), 124.8 (C-40), 126.0 and
127.7 (C-200 and C-2000), 128.3 and 131.5 (C-100 and C-1000), 129.3 and
129.7 (C-300 and C-3000),136.5 (C-60),137.0 (C-20),138.6 and 139.0 (C-400
and C-4000), 152.9 (C-2), 164.0 (C-80), 180.6 (C-4), 191.3 (C-30). HRMS
(ESIþ), m/z calcd for [C25H18N2O4þNa]þ: 433.1164; found: 433.1171.
Acknowledgements
~
^
We would like to thank Fundac¸ ao para a Ciencia e a Tecnologia
(FCT, Portugal), the European Union, QREN, FEDER, COMPETE, for
funding the Organic Chemistry Research Unit (QOPNA) (project
ꢀ
PEst-C/QUI/UI0062/2011), Laboratorio Associado Centro de Inves-
~
^
ꢀ
tigac¸ ao em Materiais Ceramicos e Compositos e CICECO (project
PEst-C/CTM/LA0011/2011) and the Portuguese National NMR Net-
work (RNRMN). European Community’s Seventh Framework Pro-
gramme (FP7/2007-20139 under grant agreement nꢀ 215009) is
also acknowledged for financial support. We further wish to thank
FCT for the post-doctoral grant SFRH/BD/63736/2009 (to J.A.F.) and
for specific funding towards the purchase of the single-crystal X-ray
diffractometer.
l¼254; analysis: (E)-5c retention time¼10.4 min, (Z)-5c retention
time¼14.5 min). Subsequently, the two isomers were separated and
isolated by preparative TLC using dichloromethane as eluent, being
(E)-5c the first compound eluted and recrystallized from ethanol,
while (Z)-5c was recrystallized from toluene. Please note: it is
strongly recommended to work away from intense light since these
compounds are photosensitive.
4.4.1. (Z)-1,3-Dicyclohexyl-5-[3-oxobenzofuran-2(3H)-ylidene] imi-
Supplementary data
dazolidine-2,4-dione (Z)-5a. C23H26N2O4 (yellow solid, 1.36 g, yield
65%, mp¼203e204 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼1.26e2.31
d
Supplementary data associated with this article [spectroscopic
data for the all reported compounds; X-ray data (CIF files) and
additional crystallographic details for compounds 3a, 3c, 4a, 4c, and
(Z)-5c]. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.111.
(m, 20H, eCH2ecyclohexyl), 4.02 (tt, J¼12.3, 3.5 Hz, 1H, H-100), 4.63
(tt, J¼12.0, 3.6 Hz,1H, H-1000), 7.22e7.29 (m, 2H, H-50, H-70), 7.61e7.68
(m, 1H, H-60), 7.82e7.85 (m, 1H, H-40). 13C NMR (75.47 MHz, CDCl3):
d
¼25.0, 25.1, 25.82, 25.85, 26.0, 26.3, 29.24, 29.29, 30.5 and 30.6
(eCH2e, cyclohexyl), 52.2 (C-1000), 60.4 (C-100), 113.2 (C-70), 121.7 (C-
20), 123.5 (C-50), 124 (C-90), 124.3 (C-40), 136.2 (C-5), 137.0þ(C-60),
153.3 (C-2), 161.6 (C-4), 165.9 (C-80), 183.5 (C-30). HRMS (ESI ), m/z
calcd for [C23H26N2O4þNa]þ: 417.1790; found: 417.1792.
References and notes
1. (a) Palomo, C.; Oiarbide, M.; Landa, A.; Gonzalez-Rego, M. C.; Garcıa, J. M.;
Gonzalez, A.; Odriozola, J. M.; Martın-Pastor, M.; Linden, A. J. Am. Chem. Soc.
2002, 124, 8637e8643; (b) Toshima, K.; Kimura, T.; Takano, R.; Ozawa, T.; Ariga,
A.; Shima, Y.; Umezawa, K.; Matsumura., S. Tetrahedron 2003, 59, 7057e7066;
(c) Kamal, A.; Ramu, R.; Khanna, G. B. R.; Saxena, A. K.; Shanmugavel, M.;
Pandita, R. M. Arkivoc 2005, iii, 83e91; (d) Belluti, F.; Fontana, G.; Dal Bo, L.;
Carenini, N.; Giommarelli, C.; Zunino, F. Bioorg. Med. Chem. 2010, 18,
3543e3550; (e) Franke, K.; Porzel, A.; Schmidt, J. Phytochemistry 2002, 61,
873e878; (f) Belovodskii, A. V.; Shults, E. E.; Shakirov, M. M.; Romanov, V. E.;
Elmuradov, B. Z.; Shakhidoyatov, K. M.; Tolstikov, G. A. Chem. Nat. Compd. 2011,
46, 880e885; (g) Romanov, V. E.; Shults, E. E.; Shakirov, M. M.; Tolstikov, G. A.
Doklady Chem. 2010, 430, 27e31; (h) Ohshita, K.; Ishiyama, H.; Oyanagi, K.;
Nakata, H.; Kobayashi, J. Bioorg. Med. Chem. 2007, 15, 3235e3240.
2. (a) Sim, H. M.; Loh, K. Y.; Yeo, W. K.; Lee, C. Y.; Go, M. L. ChemMedChem 2011, 6,
713e724; (b) Heidari, M. R.; Foroumadi, A.; Noroozi, H.; Samzadeh-Kermani, A.;
Azimzadeh, B. S. Pak. J. Pharm. Sci. 2009, 22, 395e401; (c) McAlpine, J. B.; Chu,
W. A.; Ratnayake, S.; Jiang, J. B.; Stafford, A. M.; Jackson, C. U.S. Patent 768,320,
1996. (d) Bursavich, M. G.; Brooijmans, N.; Feldberg, L.; Hollander, I.; Kim, S.;
Lombardi, S.; Kaapjoo, P.; Mallon, R.; Gilbert, A. M. Bioorg. Med. Chem. Lett. 2010,
20, 2586e2590.
4.4.2. (Z)-1,3-Diisopropyl-5-[3-oxobenzofuran-2(3H)-ylidene]
imidazolidine-2,4-dione (Z)-5b. C17H18N2O4 (yellow solid, 0.58 g,
yield 35%, mp¼135e137 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼1.45
d
and 1.58 (d, J¼6.9 Hz, 12H, H-200 and H-2000), 4.44 ppm (sept,
J¼6.9 Hz, 1H, H-1000), 4.22 ppm (sept, J¼6.9 Hz, 1H, H-100), 7.23e7.29
(m, 2H, H-70, H-50), 7.62e7.68 (m, 1H, H-60), 7.82e7.86 (m, 1H, H-40).
13C NMR (75.47 MHz, CDCl3):
d
¼19.6 and 21.8 (C-20 and C-2000), 44.8
(C-1000), 48.3 (C-100), 112.3 (C-70), 121.7 (C-5), 122.3 (C-90), 124.0 (C-
50), 125.0 (C-40), 135.0 (C-20), 136.3 (C-60), 153.7 (C-2), 159.6 (C-4),
163.5 (C-80), 180.5 (C-30). HRMS (ESIþ), m/z calcd for
[C17H18N2O4þNa]þ: 337.1164; found: 337.1156.
4.4.3. (Z)-1,3-Ditolyl-5-[3-oxobenzofuran-2(3H)-ylidene]imidazoli-
dine-2,4-dione (Z)-5c. C25H18N2O4 (yellow solid, 1.35 g, yield 62%,
mp¼232 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼2.39 and 2.46 (2s, 6H,
d
3. Ware, E. Chem. Rev. 1950, 46, 403e470.
4. (a) Close, W. J. U.S. Patent 2,793,157, 1946. (b) Hense, H. R. U.S. Patent 2,409,754,
1946. (c) Shorvon, S. D.; Fish, D. R.; Perucca, E.; Dodson, W. E. The Treatment of
Epilepsy; Blackwell: Victoria, Australia, 2004; (d) Johnson, J.; Wrenn, K. Am. J.
Emerg. Med. 2001, 19, 293e294.
5. Jeffrey, J. S.; Donald, F. W. J. Chem. Inf. Comput. Sci. 2003, 43, 1028e1036.
6. (a) Snyder, H. R.; Davis, C. S.; Bickerton, R. K.; Halliday, R. P. J. Med. Chem. 1967,
10, 807e810; (b) Ellis, K. O.; Castellion, A. W.; Honkomp, L. J.; Wessels, F. L.;
Carpenter, J. F.; Halliday, R. P. J. Pharm. Sci. 1973, 62, 948e951.
7. (a) Pulina, N. A.; Zalesov, V. V. Chem. Heterocycl. Compd. 2007, 43, 685e689; (b)
Watanabe, M.; Kawada, M.; Takamoto, M.; Imada, I.; Noguchi, S. Chem. Pharm.
Bull. 1984, 32, 3373e3377; (c) Filloux, C. M.; Lathrop, S. P.; Rovis, T. Proc. Natl.
Acad. Sci. U.S.A. 2010, 107, 20666e20671; (d) Muccioli, G. G.; Wouters, J.;
Charlier, C.; Scriba, G. K. E.; Pizza, T.; Di Pace, P.; De Martino, P.; Poppitz, W.;
Poupaert, J. H.; Lambert, D. M. J. Med. Chem. 2006, 49, 872e882; (e) Londhe, A.;
Gupta, B.; Khatri, P.; Pardasani, P.; Pardasani, R. T. Indian J. Heterocycl. Chem.
2005, 15, 137e140; (f) Yao-Zhi, W.; Chun-Chang, W.; Hong-Wei, Z.; Ai-Xi, H.
Hecheng Huaxue 2001, 9, 267e268; (g) Trisovic, N.; Valentic, N.; Erovic, M.;
Dakovic-Sekulic, T.; Uscumlic, G.; Juranic, I. Monatsh. Chem. 2011, 142,
1227e1234; (h) Wei, H.; Ming-Zhen, L.; Yan, L.; Ying, T.; Guang-Fu, Y. Bioorg.
Med. Chem. 2007, 15, 5191e5197.
H-400-CH3 and 4000-CH3), 6.74 (dd, J¼8.9, 0.6 Hz, 1H, H-70), 7.13e7.20
(m, 1H, H-50), 7.24e7.29 (2m, 6H, tolyl) and 7.40 (d, J¼8.4 Hz, 2H,
tolyl), 7.46e7.54 (m, 1H, H-60), 7.74e7.77 (m, 1H, H-40). 13C NMR
(75.47 MHz, CDCl3):
d
¼21.1 and 21.2 (400-CH3 and 4000-CH3), 112.4 (C-
70), 119.7 (C-5), 121.7 (C-90), 123.9 (C-50), 124.7 (C-40), 125.9 and
127.6 (C-200 and C-2000), 128.3 and 131.4 (C-100 and C-1000), 129.3 and
129.7 (C-300 and C-3000), 136.40 (C-20), 136.43 (C-60), 138.5 and 138.9
(C-400 and C-4000),152.8 (C-2), 158.3 (C-4), 163.9 (C-80), 180.5 (C-30).
HRMS (ESIþ), m/z calcd for [C25H18N2O4þNa]þ: 433.1164; found:
433.1171. Anal. Calcd for C25H18N2O4: C 73.16, H 4.42, N 6.83. Found:
C 73.23, H 4.52, N 6.70%.
4.4.4. (E)-1,3-Ditolyl-5-[3-oxobenzofuran-2(3H)-ylidene]imidazoli-
dine -2,4-dione (E)-3c. C25H18N2O4 (yellow solid, 0.46 g, yield 21%,
mp¼208e210 ꢀC). 1H NMR (300.13 MHz, CDCl3):
¼2.42 and 2.45
d

5420
O. Talhi et al. / Tetrahedron 69 (2013) 5413e5420
8. (a) Olimpieri, F.; Bellucci, M. C.; Marcelli, T.; Volonterio, A. Org. Biomol. Chem.
2012, 10, 9538e9555; (b) Filliatre, C.; Servens, C. J. Heterocycl. Chem. 1985, 22,
1009e1010; (c) Marcelli, T.; Olimpieri, F.; Volonterio, A. Org. Biomol. Chem. 2011,
9, 5156e5161.
9. Singh, P.; Kaur, M.; Holzer, W. Eur. J. Med. Chem. 2010, 45, 4968e4982.
10. (a) Hoessel, R.; Leclerc, S.; Endicott, J. A.; Nobel, M. E. M.; Lawrie, A.; Tunnah, P.;
Leost, M.; Damiens, E.; Marie, D.; Marko, D.; Niederberger, E.; Tang, W.;
Eisenbrand, G.; Meijer, L. Nat. Cell Biol.1999,1, 60e67; (b) Riepl, H. M.; Urmann, C.
Helv. Chim. Acta 2012, 95, 1461e1477; (c) Moon, M. J.; Lee, S. K.; Lee, J.-W.; Song,
W. K.; Kim, S. W.; Kim, J. I.; Cho, C.; Choi, S. J.; Kim, Y.-C. Bioorg. Med. Chem. 2006,
14, 237e246; (d) Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.; Myr-
ianthopoulos, V.; Mikros, E.; Tarricone, A.; Musacchio, A.; Roe, S. M.; Pearl, L.;
Leost, M.; Greengard, P.; Meijer, L. J. Med. Chem. 2004, 47, 935e946; (e) Zhang, A.;
Yu, M.; Lan, T.; Liu, Z.; Mao, Z. Synth. Commun. 2010, 40, 3125e3134.