Chiral arylideneaminoimidazolidin-4-ones: Green synthesis and isomerisation mechanism in solution

Article abstract of DOI:10.1039/c9nj00022d

A green and eco-friendly synthetic approach of pure 2,5-disubstituted 3-arylideneaminoimidazolidin-4-ones is developed using water as the solvent. These new chiral arylideneaminoimidazolidin-4-one derivatives were obtained diastereoselectively in high ove

Full text of DOI:10.1039/c9nj00022d

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Chiral arylideneaminoimidazolidin-4-ones:
green synthesis and isomerisation mechanism
Cite this:DOI: 10.1039/c9nj00022d
in solution†
Nadia Bouzayani,a Sylvain Marque, *b Yakdhane Kacem,*a Jamil Kraıem,c
¨
Flavien Bourdreux,b Jerome Marrotb and Bechir Ben Hassinea
´ ˆ
´
A green and eco-friendly synthetic approach of pure 2,5-disubstituted 3-arylideneaminoimidazolidin-4-ones is
developed using water as the solvent. These new chiral arylideneaminoimidazolidin-4-one derivatives were
obtained diastereoselectively in high overall yields and with high atom economy via the cyclocondensation
of various aromatic aldehydes and a-amino acid hydrazides. Solid state studies were complemented by
the behavior in solution investigated by NMR experiments and DFT quantum chemical calculations. The
transformation from the kinetic arylideneaminoimidazolidin-4-one to the thermodynamic form is explained by
a ring opening mechanism and by kinetic observations highlighting the important role played by the electronic
richness of the substituents.
Received 2nd January 2019,
Accepted 19th February 2019
DOI: 10.1039/c9nj00022d
rsc.li/njc
Introduction
One of the main objectives of organic and medicinal chemistry is
the synthesis and production of compounds having value as
human therapeutic targets. Heterocyclic structures have attracted
the attention of many scientists in recent decades, as an important
class of compounds with proven utility in medicinal chemistry.1
Particularly, nitrogenated compounds with five membered
rings containing two heteroatoms (e.g. imidazolidinone) are
an important scaffold known to be associated with various
biological activities. Cyclocondensation is a simple and efficient
Fig. 1 Bioactive molecules containing an alkyl-arylideneaminoimidazolidin-
4-one.
reaction leading to a nitrogenated core associated with various potent antibiotic, which is a famous example derived from the
biological activities of drugs, pharmaceutical intermediates and family of aminohydantoins (Fig. 1).9 Among bioactive molecules,
agrochemicals.2–4 N-Aminoimidazolidin-4-one derivatives5 belong Azimilide II is an antiarrhythmic drug that has been developed
to the family of heterocyclic compounds, which exhibit a wide to treat supraventricular and ventricular tachyarrhythmias.10
range of biological properties such as antibacterial,6 antifungal7 The synthesis of N-aminoimidazolidin-4-ones can be generally
and anticonvulsant activities.8 For example, Nitrofurantoin I is a prepared through the cyclocondensation of amino amides with
carbonyl compounds.11 The traditional protocol for these com-
pounds requires the use of solvents, catalysts and heating.12
a
`
´
`
Laboratoire de Synthese Organique Asymetrique et Catalyse Homogene, (UR
´
´
11ES56) Universite de Monastir, Faculte des Sciences de Monastir, avenue de
l’environnement, Monastir 5000, Tunisia. E-mail: kacem.yakdhane@fphm.rnu.tn;
Fax: +216 73 500 278; Tel: +216 73 500 275
According to solvent selection guides described by chemical
companies,13 the major drawback of such reactions in terms of
green chemistry is the use of toxic or non-ecofriendly solvents.
However, most of these protocols generate undesirable waste in
stoichiometric amounts. The search for simple chemical processes
as well as the decrease of waste and the use of non-toxic solvents is a
primary goal for human development.14 As a continuation of our
studies on the development of environmentally-safe conditions,15–17
we describe herein a green and eco-friendly route to reach new
analogues of chiral arylideneaminoimidazolidin-4-ones using
water as the solvent (Scheme 1). Moreover, the objective is to get
b
c
´
Universite de Versailles, Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles
(ILV), UMR CNRS 8180, 45 avenue des Etats-Unis, 78035 Versailles Cedex, France.
E-mail: sylvain.marque@uvsq.fr
´
´
Laboratoire de Developpement Chimique, Galenique et Pharmacologique des
´
´
´
Medicaments, Faculte de Pharmacie de Monastir, Universite de Monastir, Rue
Avicenne, 5000 Monastir, Tunisia
† Electronic supplementary information (ESI) available: Crystallographic data,
cartesian coordinates and energies of species 5b and 5f, 1D & 2D NMR spectra of
5a–m and dynamic behaviors from NMR spectra. CCDC 1829442. See DOI:
10.1039/c9nj00022d
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Table 2 Optimization of the reaction conditions in ethanola
Scheme 1 Objectives of this work.
Entry
Temp. (1C)
Time (h)
Yieldsb (%)
control of the stereochemistry and to investigate its potential
change.
1
2
3
55
55
rt
12
24
20
40
23
84
a
Conditions: 4-methoxybenzaldehyde 4 (20 mmol, 2 eq.), (L)-methio-
Results and discussion
Green synthesis
b
nine hydrazide 3d (10 mmol, 1 eq.), ethanol (5 mL). Yield of the
isolated product.
The chiral (L)-a-amino acid hydrazides 3a–e were used as the starting
materials. These compounds were prepared from commercially
available (L)-a-amino acid ester hydrochlorides 1a–e and hydrazine
monohydrate 2, under solvent-free conditions,18,19 to afford the
corresponding hydrazides in good to excellent yields (Table 1).
Following our investigations on developing synthetically
useful cyclocondensation reactions with a-amino acid derivatives
as chiral pool substrates,20–25 a novel series of chiral arylidene-
aminoimidazolidin-4-ones have been synthesized using green
conditions. At first, the reaction was screened with EtOH as the
solvent under different temperatures and reaction times (Table 2).
An investigation of the optimum reaction conditions for the
synthesis of compounds 5a–m was undertaken. A model reaction
was chosen using (L)-methionine hydrazide 3d with 4-methoxy-
benzaldehyde 4c. When the reaction was run in EtOH by heating
at 55 1C (entries 1 and 2), low yields were obtained and again the
yield was much less with the increase of the reaction time. This
may be due to the instability of the targeted compounds. Indeed,
we tried the reaction at room temperature (entry 3) and the
reaction led to the formation of solid arylideneaminoimidazoli-
din-4-ones in good yields, which were isolated by simple filtration,
with complete consumption of the starting materials in a reason-
able time (20 h). As mentioned before, one of the principles of
green chemistry to develop safer and environmentally-benign
alternatives is the choice of green and non-toxic solvents such
as water. Furthermore, water is considered to be the greenest
solvent despite its high boiling temperature. It is non-hazardous
to health and a non-flammable solvent. The efficient conversion
of reagents into arylideneaminoimidazolidin-4-ones described
above inspired us to explore the possibility of the coupling of
(L)-a-amino acid hydrazides with different aldehydes ‘‘in water’’.
Generally, very low amounts of by-products (mainly the
reaction intermediates) were observed in water compared with
the same reaction performed in organic solvents.
In order to find the optimized conditions for the synthesis of the
chiral arylideneaminomidazolidin-4-ones starting from (L)-a-amino
acid hydrazides, the same model reaction (Table 2) was chosen for
our continuing studies. Firstly, the reaction was screened in water at
room temperature without any catalyst (Table 3, entries 1–3). On the
other hand, the reaction was performed under the same conditions
using SDS (sodium dodecyl sulfate), with different proportions
(Table 3, entries 4–9), as a surfactant to ensure the solubility of the
starting materials in water. This choice is based on the fact that most
organic compounds have poor solubility in water. However, the
optimization studies revealed that the reaction works well without
using SDS. In the absence of SDS, the reaction medium is homo-
genous with the naked eye in water at rt, in any event, with the
stoichiometric ratio and the concentrations used. Considering this
and the organic–water interface, the observed reaction would
be more an ‘‘in water’’ than an ‘‘on water’’ process.26 When the
amount of SDS was increased (5%, 10%, and 15%), the reaction was
Table 1 Synthesis of a-amino acid hydrazides 3a–e
Table 3 Optimization of the reaction conditions in watera
Entry
Additive (mol%)
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
9
—
—
—
SDS (5)
SDS (5)
SDS (10)
SDS (10)
SDS (15)
SDS (15)
3
5
11
5
11
5
11
5
11
54
60
86
48
76
42
71
39
65
Entry
Product
R
Yielda (%)
mp (1C)
1
2
3
4
5
3a
3b
3c
3d
3e
i-Bu
Ph
Bn
92
88
85
90
83
59–61
81–83
85–87
55–57
77–79
(CH2)2SMe
a
Trpb
Conditions: 4-methoxybenzaldehyde 4c (20 mmol, 2 eq.), (L)-methionine
hydrazide 3d (10 mmol, 1 eq.), water (5 mL), rt. b Yield of the isolated
Yield of the isolated product. b Trp: tryptophan(1H-indol-3-yl)methyl moiety. product.
a
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Table 4 Products of the coupling of the aldehydes 4 and a-amino acid
hydrazides 3a–ea
Entry
Product
Yield in EtOHb (%)
Yield in H2Oc (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
78
75
71
78
80
79
84
80
87
81
76
75
77
82
81
81
80
88
86
86
83
90
84
88
81
80
9
10
11
12
13
5j
5k
5l
5m
a
General conditions: aldehyde (20 mmol, 2 eq.), a-amino acid hydrazide
(10 mmol, 1 eq.), ethanol (5 mL), 20 h. b Yield of the isolated product: in
ethanol (5 mL), 20 h. c Yield of the isolated product: in water (5 mL), 11 h.
accompanied by a development of yellow coloration with a yield
reduction of the product 5. On the other hand, the starting
hydrazides as well as the aldehydes are soluble in water, therefore
we continued to work in water without SDS. We kept working at
room temperature, increasing the reaction time to total conversion
into the desired product, which was obtained after 11 h of stirring
(entry 3).
This clean method produced quantitatively pure arylidenea-
minomidazolidin-4-ones 5 (Table 4) by simple filtration and wash-
ing with water without the need for supplementary purification
(neither column chromatography nor recrystallization). It is inter-
esting to note that the reaction occurred in ethanol with a slightly
prolonged reaction time (20 h). The synthesis of arylideneamino-
midazolidin-4-ones in water was extended using various aldehydes
such as 4-methoxybenzaldehyde, thiophene-2-carbaldehyde and
furan-2-carbaldehyde (Scheme 2).
In order to demonstrate the applicability of our green method
(water as the solvent), we have synthesized a novel series of chiral
arylideneaminomidazolidin-4-ones 5a–m in good to excellent
yields by comparing it with the classical method (EtOH as the
solvent); these results are summarized in Table 4. From an
ecological point of view, new indicators of the efficiency of green
processes have been introduced, such as the atom economy and
environmental factor. The atom economy27 (AE) is the quantity
defined as the weighted ratio of the molar mass of the desired
product to the sum of the molar masses of the reactants:
Scheme 2 Synthesis of the chiral arylideneaminoimidazolidin-4-ones 5a–m.
MðproductÞ
P
AE ¼
ꢀ 100
MðreactantiÞ
i
as low as possible, tending towards zero. As a conclusion, the closer
the atomic use is to 100% and the E-factor to zero, the more
efficient the method is in obtaining the desired product. In our
case, the green method (water as the solvent) is very profitable with
a very high atom economy (91.7%) and an excellent E-factor (0.09),
since only water is left as waste, which is already green.
We define, also, the environmental factor (E-factor) intro-
duced by Roger Sheldon.28 It is the ratio of the total mass of
waste to the mass of product:
P
MðwastejÞ
j
E ¼
MðproductÞ
Stereochemistry and mechanism
The environmental factor E highlights the importance of the The arylideneaminoimidazolidin-4-ones present several sources
mass of waste generated during a synthesis. Its ideal value must be of stereochemistry (Fig. 2): three asymmetric centers of which
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stereorelationship exists between H(2) and H(5), the interatomic
distance of 3.671 Å is important and NOE interactions remain
difficult to see by NMR experiments.
Method of calculations and basis sets. The restraint free
geometry optimization of species was performed using the
Gaussian 09 software30 with standard parameters and tight criteria
of convergence. The determination of structures in benzene
solution was carried out using the self-consistent reaction field
(SCRF) method. Calculations were performed at the BMK31
/
6-31++G(df,pd)32 level using the conductor-polarizable continuum
model (CPCM)33 with the Universal Force Field (UFF). Final
predicted energies included the zero-point vibrational and
thermal energy corrections at 298.15 K (see the ESI†), giving
the Gibbs free energy in solution for minima of the electrostatic
potential surface. NMR shielding tensors were computed with
the Gauge-Independent Atomic Orbital method (GIAO).34
Dynamic behavior and mechanism. The molecule 5b has
been chosen as a model. The stereochemistry of C(5) was fixed
as a (S) absolute configuration and then all combinations of
absolute configurations of N(1) and C(2) atoms and the relative
configuration of the C(6)–N(3) bond were tested (Table 5).
Several singular conformations of the nitrogenated pendant
arms were obtained revealing, vis-a-vis the imidazolidin-4-one
core, coplanar positions (in or out) on the one hand and
perpendicular positions on the other hand. The chemical shift
of the carbon 6 allows us to clearly differentiate the conforma-
tions of the nitrogenated pendant arm. This is an expected
result since the chemical environment around this carbon
(oxygen of the carbonyl) strongly impacts its magnetic environ-
ment. In fact, the C(6) signal for the calculated out conforma-
tions is between 148.3 and 149.3 ppm, for in it is between 156.0
and 159.0 ppm and for the others (i.e. perpendicular) it is
between 161.3 and 164.4 ppm (Table 5). The change of the
experimental spectrum shows that the clean initial signal at
Fig. 2 Notation of configurations and conformations of the arylidene
group.
one is nitrogen, a NQC double bond and the possibility to take
into account a rotation of the N–N bond (or an inversion of the
doublet of the nitrogen), defining two particular conformations
`
in and out according to the position of the hydrogen vis-a-vis that
of the carbonyl as depicted in Fig. 2. Data of the NMR spectro-
scopies, X-ray diffraction and theoretical values found by quantum
chemical calculations were compared to have a better under-
standing of the structures and their behaviors.
Static approach. All products 5a–m were obtained in the form of a
white solid. We have noticed that they are stable in the solid state,
but reactivity in solution was observed, inducing a development,
often a partial isomerization and in rare cases a very limited amount
of hydrolysis, of the arylidene moiety, leading to the heterocycle with
a primary hydrazide function 3 and the remarkable starting aldehyde
4. The structures of 5a–m were elucidated by IR, NMR spectroscopies
in benzene-d6 (1H, 13C, 1H–13C HSQC and HMBC, COSY and NOESY)
and mass spectrometric methods. Each proton and carbon could be
assigned. The structures of the arylideneaminomidazolidin-4-ones
were confirmed by HMBC 1H–15N analysis. The crystallographic
analysis of the monocrystal25 of the stereoisomer 5f (Fig. 3), obtained
after filtration with ethanol and drying in the open air, makes it
possible to establish the absolute configuration of the asymmetric
centers (1RN,2SC,5SC). It is worth noting that the carbon 5 retains the
configuration S of the starting amino acid since it has been worked
under mild conditions (rt); this is already proved in the course of
our work in the literature.24,29 The first observation is that the
hydrazide function is coplanar with the nitrogenated cycle with
values of dihedral angles of ꢁ4.51 for N(6)–N(3)–C(4)–O and +1.31
for C(2)–N(3)–C(4)–C(5). So, there is very little possibility for
conformational flexibility of the central cycle. Although the cis
Table 5 Privileged stereoisomers of 5b at BMK/6-31++G(df,pd) in ben-
zene CPCM–UFFa
Entry Configuration H(6) positionb dc (ppm) Grel (kJ molꢁ1
)
d
1
2
3
4
5
6
7
8
1RNꢂ2RCꢂE
1RNꢂ2RCꢂE
1RNꢂ2RCꢂZ
1RNꢂ2SCꢂE
1RNꢂ2SCꢂZ
1RNꢂ2SCꢂZ
1SNꢂ2RCꢂE
1SNꢂ2RCꢂE
1SNꢂ2RCꢂZ
1SNꢂ2SCꢂE
1SNꢂ2SCꢂZ
1SNꢂ2SCꢂZ
Out
In
—
Out
—
—
Out
In
—
Out
—
—
149.66
159.05
163.04
149.37
162.79
163.99
148.32
156.02
161.31
149.26
164.40
162.17
ꢁ28.97
ꢁ33.77
ꢁ12.25
ꢁ32.46
ꢁ5.33
ꢁ5.77
ꢁ25.22
ꢁ28.34
ꢁ9.68
ꢁ18.03
0
9
10
11
12
ꢁ19.60
a
Experimental NMR result gives the iminic carbon C(6) signal of 5b at
149.62 ppm in benzene-d6 at rt, referenced to the TMS signal at 0 ppm.
b
If nothing is specified H(6) and arylidene moieties are in a conforma-
tion perpendicular to the medium plane defined by the imidazolidin-4-
c
one cycle (see pictures in the ESI). The chemical shift is given by
the difference: calculated nuclear isotropic magnetic shielding of the
carbon C(6) – calculated nuclear isotropic magnetic shielding of the
carbon in TMS. Relative Gibbs free energy compared to entry 11 at
d
Fig. 3 Structure of the 5f stereoisomer by X-ray diffraction at a 30%
probability level.
T = 298.15 K and P = 1 atm.
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a
Table 7 Kinetic behavior of 5a–m in C6D6
149.62 ppm of C(6) decreases for the benefit to the emergence
of a second signal at 156.0 ppm involving 5b is evolving from an
out conformation to an in one. This result is surprising with the
absence of the N–N bond rotation, which is expected since this
has been estimated about 117 kJ molꢁ1 in a similar system.35 It
suggests that the development of 5b does not simply involve the
sole rotation of the N–N bond, but is also concomitant with
another phenomenon, maybe a ring opening. Moreover, slight
but clear correlations for 5b between H(2) and H(5) and then
Entry
Product
R from 3
Ar from 4
Stabilityb
Ratio
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
Ph
Fur
Th
Th
Th
Th
PMP
PMP
PMP
Ph
24 h
48 h
88 : 12
(CH2)2SMe
i-Bu
Bn
i-Bu
(CH2)2SMe
Ph
E16 h
E16 h
E16 h
448 h
448 h
448 h
E16 h
E16 h
E16 h
6 h
1
9
Ph
H(1) and H(5) are shown by the H–1H NOESY NMR spectrum
10
11
12
13
5j
5k
5l
5m
Bn
Bn
Bn
Trp
PMP
Ph
Fur
Fur
and these interactions are absent in the newly isomerized
product, confirming that the change concerns a different
stereochemistry problem, attributed to an epimerization of
the C(2) or N(1) atoms.
The interpretation of all of the data allows us to ascribe the
stereochemistry: the compound 5b very slowly evolves from the
1 : 1
+4 in 18 h
4 hc
a
All spectra were initially recorded with all products freshly placed in
solution to check the isomeric purity and showed the obtaining of a
pure isomer form. The given stability indicates the time to get the
b
corresponding ratio; if no ratio is reported, it gives an idea of time up to
isomer 1RN,2SC,E-out (entry 4) to 1RN,2RC,E-in (entry 2) in the NMR recording at which it is possible to get a clean spectrum.
c
Time in neat C6D6; if some drops of CD3CN were added due to the
benzene-d6. It is interesting to note that the final isomer is
poor solubility of 5m in C6D6, the time was less than 1 h.
the more stable (Table 5, entry 2), involving a thermodynamic
behavior for the transformation, with a low gap of 1.2 kJ molꢁ1
between both isomers. The compounds 5a–m showed the same has poor influence (entries 2–11) on the stability, but a significant
stereochemistry links, with an S absolute configuration for C(2) effect when Ar = Fur (entries 1, 12 and 13). In these last cases, the
of the isolated products. This is in agreement with the crystal- steric hindrance of the amino acid residue goes hand-in-hand with
lographic data of 5f. The behavior of 5f was also investigated in the isomerization. It is worth noting that this observation is in
benzene-d6, where a weak interaction between H(2) and H(5) in agreement with a development process by a ring opening, other-
the NOESY spectrum was observed; on the contrary the inter- wise the epimerization would not proceed with similar rates for all
action is absent in the newly formed product. Once more, it is amino acid residues with Ar = Th (entries 2–5) or else with Ar = PMP
likely due to the epimerization of C(2), from the (1RN,2SC,E) (entries 7, 8 and 10). Moreover, arylideneaminoimidazolidin-4-ones
kinetic product (Table 6, entry 2) to the (1RN,2RC,E) thermo- from valine (R = i-Pr) presented very low solubility (results not
dynamic one (entry 1). The relative Gibbs energies are in reported here) suggesting that carbonyl and amine moieties require
concordance with the adequate route for the isomerization a close environment with non bulky groups for solvation. This
with a gap of about 11.5 kJ molꢁ1 between both isomers.
The partial transformation of 5a–m can be very fast (less function (Scheme 3).
explanation is coherent with the ionic writing of the hydrazide
than 1 min) or slower (1 h) in CDCl3 or in dichloromethane, but
The fine stereochemistry determination, the kinetic change,
significantly slowed down in benzene-d6 to between 1 h and the quantum chemical calculations results, and the relationship
more than 48 h (see Table 7 and the ESI† for details).
between the structure and the behavior allow us to present a detailed
Table 7 shows that the more pronounced the electron donor and proved mechanism for the development of the arylideneamino-
character (Fur o Ph E Th o PMP) for the Ar group (Fig. 2), the imidazolidin-4-ones (Scheme 3). The 5a–m compounds are isolated
more the kinetic form is stable and the thermodynamic trans- with total diastereoselectivity for the (1RN,2SC,E) configuration in the
formation is slowed down. In a more nuanced way, the influence solid state. In solution, whatever the solvent is, compounds evolve to
of the amino acid residue (R) is less. Thus, with a well-marked acyclic forms having an iminium function, where C–N and N–N
aromatic character (Ar = Ph, Th, PMP), the amino acid residue bond rotations can take place. In benzene this change is sufficiently
slowed down to be followed by NMR spectroscopy. In agreement
with the electronic effects, an electron donor moiety on the C(2)
position decreases the ring opening rate and allows a longer half-life
time of the kinetic product.
Table 6 Privileged stereoisomers of 5f at BMK/6-31++G(df,pd) in ben-
zene CPCM–UFFa
With a prolonged analysis time, the equilibrium is governed
by thermodynamic control: the trend of the pseudo axial Ar
group to situate in the equatorial position leads to the
(1RN,2RC,E) configuration with the aim of avoiding electrostatic
repulsion with the anionic oxygen. However in the thermo-
dynamic transition state there may exist also interactions
db (ppm)
Grel (kJ molꢁ1
)
c
Entry
Configuration
H(6) position
1
2
3
4
1RNꢂ2RCꢂE
1RNꢂ2SCꢂE
1SNꢂ2RCꢂE
1SNꢂ2SCꢂE
Out
Out
Out
Out
153.50
153.52
153.32
153.97
ꢁ11.53
0
ꢁ7.14
ꢁ8.50
a
Experimental NMR result gives the iminic carbon C(6) signal of 5f at
151.94 ppm in benzene-d6 at rt, referenced to the TMS signal at 0 ppm. between both Ar groups, according to the conformations of
b
The chemical shift is given by the difference: calculated nuclear
the aminoarylidene pendant arm, which is why the transforma-
tion is not complete and the compounds 5a–m evolve to reach
isotropic magnetic shielding of the carbon C(6) – nuclear isotropic
magnetic shielding of the carbon in TMS. Relative Gibbs free energy
c
compared to entry 2 at T = 298.15 K and P = 1 atm.
their corresponding thermodynamic ratios.
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Scheme 3 Proposed mechanism for the development of the arylideneaminoimidazolidin-4-ones.
Conclusions
without collision energy; the relative intensity of peaks is given in
brackets. Optical rotations were measured by using a PerkinElmer
Polarimeter (Model 341) using a mercury lamp (578 nm) at ambient
temperature.
In summary, the efficient and eco-friendly process described in
this paper has enabled us to prepare a new series of chiral
arylideneaminomidazolidin-4-ones from the chiral pool using
water as the solvent with a high atom economy (AE = 91.7%) and
an excellent E-factor (0.09). NMR spectroscopies and crystallo-
graphic data have undoubtedly established the unique configu-
ration of the asymmetric centers (1RN,2SC,5SC), which shows the
total diastereoselectivity of the reaction. Further experimental
investigations in solution aided by DFT calculations at the
BMK/6-311++G(df,pd) level of theory have allowed us to explain
the change of the stereochemistry. This is under thermodynamic
control; the transformation is rapid in chloroform and very
slowed down in benzene. An electron donor group on the C(2)
position allows the kinetic isomer to be preserved longer in an
apolar solvent. All of these data are in full concordance with a
ring opening mechanism leading to the isomerization of the
heterocycles in solution.
General procedures
General procedure for the synthesis of (L)-a-amino acid
hydrazides 3a–j. Monohydrate hydrazine (30 mmol, 3 eq.) and
(L)-a-amino acid methyl ester hydrochloride (10 mmol, 1 eq.)
were mixed in a flask fitted with a condenser and a magnetic
stirring bar. The mixture was stirred at 60 1C for 10 h under an
inert atmosphere. It was allowed to cool to room temperature.
Then, 100 mL of EtOAc, 6 g of Na2CO3 and 3 mL of H2O were
added. The mixture was vigorously stirred for 3 h. After filtra-
tion, the solvent was concentrated in vacuo to obtain the
corresponding pure L-a-amino acid hydrazides.
Synthesis of arylideneaminomidazolidin-4-ones in ethanol.
A mixture of the corresponding aldehyde (20 mmol, 2 eq.) and
a-amino acid hydrazide (10 mmol, 1 eq.) in ethanol (5 mL) was
stirred at room temperature for 20 h. The white colored precipitate
was filtered, washed with ethanol and dried in air to obtain the
corresponding arylideneaminoimidazolidin-4-one.
Experimental
General comments
Synthesis of arylideneaminomidazolidin-4-ones in water.
A mixture of the corresponding aldehyde (20 mmol, 2 eq.)
and a-amino acid hydrazide (10 mmol, 1 eq.) in water (5 mL)
was stirred at room temperature for 11 h. The white colored
precipitate was filtered, washed with water and dried in air to
obtain the corresponding arylideneaminoimidazolidin-4-one.
All reactions are carried out under an argon atmosphere in
round-bottomed flasks equipped with magnetic stirring. The
cyclizations to get 5a–m compounds were performed under
argon or under air; no difference was observed. All solvents
were freshly distilled before use. Melting points were deter-
mined on a Buchi 510 capillary apparatus. NMR spectra were
recorded on Bruker Avance 1 300 MHz and Bruker Avance 1
400 MHz spectrometers [300 MHz (1H), 400 MHz (1H), and
Characterization of organic compounds
(L)-Leucine hydrazide (3a). Yield 92%. White solid; mp 59–
75 MHz (13C)] using CDCl3 and C6D6 as solvents. Signals due to 61 1C; [a]578 = +24 ꢃ 1 (MeOH, C = 0.768 ꢃ 0.004) (lit. 36: [a]D
=
the solvent served as the internal standard (CHCl3: d 7.26 for +29.5 (MeOH, C = 1)). FT-IR (neat, cmꢁ1): 3294, 3240, 3208,
1H, d 77.16 for 13C; C6D6: d 7.16 for H, d 128.38 for 13C). IR 3028, 2954, 1617, 1521; 1H-NMR (300 MHz, CDCl3): d = 1.37
1
spectra were recorded on a Nicolet 6700 FT-IR, ATR, with an (d, 3H, J = 6.24 Hz), 1.40 (d, 3H, J = 6.6 Hz), 1.60 (br s, 2H),
accuracy of 1 cmꢁ1 (Diamond support). Electrospray ionisation 1.77–1.86 (m, 1H), 2.07–2.22 (m, 2H), 3.15 (br s, 2H), 3.87
(ESI) mass spectroscopy data of compounds 5a–m were (dd, 1H, 1J = 9.7 Hz, 2J = 4.3 Hz), 9.01 (br s, 1H); 13C-NMR
recorded on an UPLC Waters device (in positive mode); for (75 MHz, CDCl3): d = 21.31, 23.32, 24.68, 44.03, 52.68, 175.89;
the voltages of the mass spectroscopies, the following abbrevia- ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 168
tions are used: C Capillary (kV), SC Sampling Cone, EC Extrac- (100, [M + Na]+), HRMS ES+ for C6H15N3ONa m/z: [M + Na]+ calc.
tion Cone. Calibration was performed with sodium formate 168.1113, found: 168.1118.
(in the range from 100 to 1000 g molꢁ1) and the lockspray
(L)-Phenylglycine hydrazide (3b). Yield 88%. White solid; mp
(lock mass leucine enkephalin 556.2771 g molꢁ1) was used 81–83 1C; [a]578 = +79 ꢃ 3 (MeOH, C = 1.280 ꢃ 0.037). FT-IR
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(neat, cmꢁ1): 3301, 3215, 3147, 3059, 3024, 1664, 1493; 1H-NMR 141–143 1C; Rf 0.62 (EtOAc/c-C6H12 = 40/60); [a]578 = ꢁ6 ꢃ 2
(300 MHz, CDCl3): d = 1.89 (br s, 2H), 3.88 (br s, 2H), 4.59 (C6H6, C = 0.126 ꢃ 0.004) FT-IR (neat, cmꢁ1): 3104, 3077, 3026,
(s, 1H), 7.30–7.48 (m, 5H), 8.17 (br s, 1H); 13C-NMR (75 MHz, 1719, 1588; 1H-NMR (300 MHz, benzene-d6): d = 1.93 (s, 1H),
CDCl3): d = 59.03, 126.59, 128.19, 128.96, 140.48, 173.38; ESI(+)- 4.18 (s, 1H), 5.61 (s, 1H), 6.46–6.49 (m, 1H), 6.63–6.65 (m, 1H),
MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 188 6.70–6.75 (m, 2H), 6.89–6.91 (m, 1H), 7.09–7.14 (m, 1H),
(100, [M + Na]+), HRMS ES+ for C8H11N3ONa m/z: [M + Na]+ 7.16–7.28 (m, 3H), 7.67 (d, 1H, J = 7.5 Hz), 9.43 (s, 1H);
calc. 188.0800, found: 188.0796.
13C-NMR (75 MHz, benzene-d6): d = 62.57, 72.77, 126.58, 127.00,
(L)-Phenylalanine hydrazide (3c). Yield 85%. White solid; mp 127.54, 128.14, 128.37, 128.61, 128.73, 131.35, 138.83, 140.29,
85–87 1C; (lit. 18: mp 85–87 1C); [a]578 = +49 ꢃ 1 (MeOH, 145.09, 149.62, 168.58; DEPT 135 (75 MHz, benzene-d6): d = 62.57
C = 0.800 ꢃ 0.004) (lit. 18: [a]D = +33 ꢃ 1 (MeOH, C = 1)). FT-IR (up), 72.77 (up), 126.58 (up), 127.00 (up), 127.54 (up), 128.14 (up),
1
(neat, cmꢁ1): 3347, 3175, 2947, 2925, 1662; H-NMR (300 MHz, 128.37 (up), 128.61 (up), 128.73 (up), 131.35 (up), 149.62 (up);
CDCl3): d = 2.39 (br s, 2H), 2.74 (dd, 1H, 1J = 13.5 Hz, 2J = 9.2 Hz), ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 354
1
2
1
3.28 (dd, 1H, J = 13.5 Hz, J = 3.9 Hz), 3.67 (dd, 1H, J = 9.2 Hz, (100, [M + H]+), HRMS ES+ for C18H16N3OS2 m/z: [M + H]+ calc.
2J = 3.9 Hz), 7.22–7.37 (m, 5H), 8.32 (br s, 1H); 13C-NMR (75 MHz, 354.0735, found: 354.0742.
CDCl3): d = 41.10, 55.90, 126.84, 128.78, 129.16, 137.58, 174.38;
(2S,3E,5S)-5-((2-(Methylthio)ethyl)-2-(thiophen-2-yl)-3-(thiophen-
ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 180 (100, 2-yl)methylene)aminoimidazolidin-4-one (5c). Yield 81%. White
[M + H]+), HRMS ES+ for C9H14N3O m/z: [M + H]+ calc. 180.1137, solid; mp 123–125 1C; Rf 0.84 (EtOAc/c-C6H12 = 40/60); [a]578
=
found: 180.1136.
ꢁ51 ꢃ 3 (C6H6, C = 0.108 ꢃ 0.004). FT-IR (neat, cmꢁ1): 3272, 3085,
1
(L)-Methionine hydrazide (3d). Yield 90%. White solid; mp 2902, 1696, 1594; H-NMR (400 MHz, benzene-d6): d = 1.58–1.62
55–57 1C; [a]578 = ꢁ37 ꢃ 2 (MeOH, C = 0.140 ꢃ 0.004). FT-IR (m, 1H), 1.74 (s, 3H), 1.77 (s, 1H), 1.96–2.01 (m, 1H), 2.39–2.43 (m,
(neat, cmꢁ1): 3289, 3175, 3078, 2915, 2660, 1611; 1H-NMR 2H), 3.63 (q, 1H, J = 3.9 Hz), 5.81 (s, 1H), 6.63 (t, 1H, J = 4.2 Hz),
(300 MHz, CDCl3): d = 1.57–1.64 (m, 1H), 1.66–1.93 (m, 1H), 6.76–6.79 (m, 1H), 6.82 (d, 1H, J = 4.8 Hz), 6.87 (d, 1H, J = 3.3 Hz),
1.87 (s, 3H), 2.40–2.45 (m, 2H), 2.77 (br s, 2H), 3.32–3.37 6.94 (d, 1H, J = 4.8 Hz), 7.15 (d, 1H, J = 3.6 Hz), 9.88 (s, 1H);
(m, 1H), 8.61 (br s, 1H); 13C-NMR (75 MHz, CDCl3): d = 15.26, 13C-NMR (75 MHz, benzene-d6): d = 15.01, 30.45, 31.11, 57.57,
30.37, 34.12, 53.21, 175.00; ESI(+)-MS CH3CN [C = 0.5, SC = 30, 73.72, 126.09, 126.17, 127.22, 127.60, 128.38, 128.72, 131.20,
EC = 3] m/z (rel. int.): 164 (100, [M + H]+), HRMS ES+ for 140.49, 143.87, 147.85, 171.42; DEPT 135 (75 MHz, benzene-d6):
C5H14N3OS m/z: [M + H]+ calc. 164.0858, found: 164.0857.
d = 15.01 (up), 30.45 (down), 31.11 (down), 57.57 (up), 73.72 (up),
(L)-Tryptophane hydrazide (3e). Yield 83%. White solid; mp 126.09 (up), 126.17 (up), 127.22 (up), 127.60 (up), 128.38 (up),
77–79 1C; [a]578 = +46 ꢃ 2 (MeOH, C = 0.254 ꢃ 0.005). FT-IR 128.72 (up), 131.20 (up), 147.85 (up); ESI(+)-MS CH3CN [C = 0.5,
(neat, cmꢁ1): 3251, 3047, 2914, 1616; 1H-NMR (300 MHz, SC = 30, EC = 3] m/z (rel. int.): 352 (100, [M + H]+), HRMS ES+ for
CD3OD): d = 2.97 (dd, 1H, 1J = 14.1 Hz, 2J = 6.9 Hz), 3.15 C15H18N3OS3 m/z: [M + H]+ calc. 352.0612, found: 352.0603.
1
2
(dd, 1H, J = 14.1 Hz, J = 6.3 Hz), 3.54–3.58 (m, 1H), 7.00–7.13
(2S,3E,5S)-5-Isobutyl-2-(thiophen-2-yl)-3-(thiophen-2-yl)methyl-
(m, 3H), 7.35 (d, 1H, J = 7.8 Hz), 7.60 (d, 1H, J = 7.5 Hz); eneaminoimidazolidin-4-one (5d). Yield 80%. White solid; mp
13C-NMR (75 MHz, CD3OD): d = 32.37, 55.88, 111.28, 112.54, 134–136 1C; Rf 0.63 (EtOAc/c-C6H12 = 40/60); [a]578 = ꢁ114 ꢃ 4
119.48, 119.98, 122.96, 124.86, 128.86, 138.14, 176.27; ESI(+)-MS (C6H6, C = 0.740 ꢃ 0.027). FT-IR (neat), nmax (cmꢁ1): 3307, 3076,
CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 219 (100, [M + H]+), 2952, 2932, 1690, 1593; 1H-NMR (300 MHz, benzene-d6): d = 0.81
HRMS ES+ for C11H15N4O m/z: [M + H]+ calc. 219.1246, found: (d, 3H, J = 6.3 Hz), 0.86 (d, 3H, J = 6.3 Hz), 1.49–1.51 (m, 1H),
1
2
219.1237.
1.59 (br s, 1H), 1.69–1.90 (m, 2H), 3.21 (dd, 1H, J = 11.7 Hz, J =
1
2
(2S,3E,5S)-2-((Furan-2-yl)-3-(furan-2-yl)methyleneamino)-5- 3.3 Hz), 5.58 (s, 1H), 6.51 (dd, 2H, J = 4.8 Hz, J = 3.6 Hz), 6.69–
phenylimidazolidin-4-one (5a). Yield 82%. White solid; mp 6.77 (m, 3H), 6.86 (dd, 1H, 1J = 5.1 Hz, 2J = 0.09 Hz), 7.18 (d, 1H, J =
131–133 1C; Rf 0.60 (EtOAc/c-C6H12 = 40/60); [a]578 = ꢁ9 ꢃ 2 3.3 Hz), 9.73 (s, 1H); 13C-NMR (75 MHz, benzene-d6): d = 20.34,
(C6H6, C = 0.096 ꢃ 0.004). FT-IR (neat, cmꢁ1): 3313, 3129, 21.99, 23.18, 40.59, 56.29, 72.16, 124.85, 125.13, 125.63, 126.26,
3026, 1705, 1480; 1H-NMR (300 MHz, benzene-d6): d = 2.12 126.54, 127.05, 127.54, 128.35, 128.50, 131.09, 139.37, 143.40,
(s, 1H), 4.26 (s, 1H), 5.59 (s, 1H), 5.83–5.84 (m, 1H), 5.95–5.96 147.18, 170.57; DEPT 135 (75 MHz, benzene-d6): d = 15.01 (up),
(m, 1H), 6.24 (d, 2H, J = 2.7 Hz), 6.87 (d, 1H, J = 1.2 Hz), 6.98 20.34 (up), 21.99 (up), 23.18 (up), 40.59 (down), 56.29 (up), 72.16
(d, 1H, J = 0.9 Hz), 7.08–7.11 (m, 1H), 7.16–7.20 (m, 2H), 7.59 (up), 126.26 (up), 126.54 (up), 127.05 (up), 127.54 (up), 128.35 (up),
(d, 1H, J = 5.7 Hz), 9.39 (s, 1H); 13C-NMR (75 MHz, benzene-d6): d = 128.50 (up), 131.09 (up), 147.18 (up); ESI(+)-MS CH3CN [C = 0.5,
62.78, 71.69, 110.03, 110.65, 111.82, 114.02, 127.99, 128.29, 128.76, SC = 30, EC = 3] m/z (rel. int.): 356 (100, [M + Na]+), HRMS ES+ for
128.81, 138.63, 143.13, 143.60, 144.63, 150.51, 152.21, 169.59; DEPT C16H19N3OS2Na m/z: [M + Na]+ calc. 356.0867, found: 356.0867.
135 (75 MHz, benzene-d6): d = 62.78 (up), 71.69 (up), 110.03 (up),
(2S,3E,5S)-5-Benzyl-2-(thiophen-2-yl)-3-(thiophen-2-
110.65 (up), 111.82 (up), 114.02 (up), 127.99 (up), 128.29 (up), yl)methyleneaminoimidazolidin-4-one (5e). Yield 88%. White
128.76 (up), 143.13 (up), 143.60 (up), 144.63 (up); ESI(+)-MS CH3CN solid; mp 151–153 1C; Rf 0.66 (EtOAc/c-C6H12 = 40/60); [a]578
=
[C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 322 (100, [M + H]+), HRMS ꢁ381 ꢃ 3 (MeCN, C = 0.546 ꢃ 0.004). FT-IR (neat, cmꢁ1): 3319,
ES+ for C18H15N3O3 m/z: [M + H]+ calc. 322.1192, found: 322.1192. 3298, 3075, 3028, 2927, 1695, 1591; 1H-NMR (300 MHz,
(2S,3E,5S)-5-Phenyl-2-(thiophen-2-yl)-3-(thiophen-2-yl)methyl- benzene-d6): d = 1.75 (br s, 1H), 3.10 (dd, 1H, 1J = 12.9 Hz,
1
2
eneaminoimidazolidin-4-one (5b). Yield 81%. White solid; mp 2J = 8.1 Hz), 3.25 (dd, 1H, J = 13.8 Hz, J = 3.3 Hz), 3.51–3.56
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(m, 1H), 5.58 (s, 1H), 6.60 (dd, 1H, 1J = 4.8 Hz, 2J = 3.9 Hz), 6.76–6.81 62.98, 77.11, 114.34, 128.14, 128.25, 128.35, 128.80, 129.25, 129.46,
2
(m, 3H), 6.91 (dd, 1H, 1J = 4.8 Hz, J = 1.2 Hz), 7.17–7.25 (m, 3H), 132.41, 138.88, 154.07, 161.91, 169.88; DEPT 135 (75 MHz, benzene-
7.28–7.31 (m, 3H), 9.79 (s, 1H); 13C-NMR (75 MHz, benzene-d6): d6): d = 54.70 (up), 54.77 (up), 62.98 (up), 77.11 (up), 114.34 (up),
d = 38.55, 60.45, 73.31, 126.26, 126.48, 126.79, 126.96, 127.49, 128.14 (up), 128.25 (up), 128.35 (up), 128.80 (up), 129.25 (up),
128.36, 128.56, 128.85, 130.03, 131.16, 137.96, 140.43, 144.80, 129.46 (up), 154.07 (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC =
148.88, 170.11; DEPT 135 (75 MHz, benzene-d6): d = 38.55 (down), 3] m/z (rel. int.): 402 (100, [M + H]+), HRMS ES+ for C24H23N3O3 m/z:
60.45 (up), 73.31 (up), 126.48 (up), 126.79 (up), 126.96 (up), 127.49 [M + H]+ calc. 402.1818, found: 402.1809.
(up), 128.36 (up), 128.56 (up), 128.85 (up), 130.03 (up), 131.16 (up),
(2S,3E,5S)-3-(Benzylideneamino)-2,5-diphenylimidazolidin-4-
148.88 (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. one (5i). Yield 90%. White solid; mp 137–139 1C; Rf 0.64 (EtOAc/
int.): 368 (100, [M + H]+), HRMS ES+ for C19H18N3OS2 m/z: [M + H]+ c-C6H12 = 40/60); [a]578 = ꢁ4 ꢃ 2 (C6H6, C = 0.104 ꢃ 0.004). FT-IR
calc. 368.0891, found: 368.0895.
(neat, cmꢁ1): 3351, 3060, 3033, 2886, 1709, 1397; 1H-NMR
(2S,3E,5S)-5-Isobutyl-3-(4-methoxybenzylideneamino)-2-(4- (300 MHz, benzene-d6): d = 1.90 (s, 1H), 4.45 (s, 1H), 5.57
methoxyphenyl)imidazolidin-4-one (5f). Yield 86%. White (s, 1H), 7.03–7.05 (m, 3H), 7.18–7.24 (m, 3H), 7.30–7.35
solid; mp 136–138 1C; Rf 0.56 (EtOAc/c-C6H12 = 40/60); (m, 3H), 7.50 (d, 2H, J = 7.2 Hz), 7.58–7.61 (m, 2H), 7.70
[a]578 = ꢁ112 ꢃ 8 (C6H6, C = 0.290 ꢃ 0.021). FT-IR (neat), (d, 2H, J = 7.5 Hz), 9.47 (s, 1H); 13C-NMR (75 MHz, benzene-
1
nmax (cmꢁ1): 3310, 2950, 2865, 1700, 1606; H-NMR (300 MHz, d6): d = 62.91, 77.37, 127.81, 127.93, 128.07, 128.35, 128.75,
benzene-d6): d = 0.96 (d, 3H, J = 4.5 Hz), 0.98 (d, 3H, J = 5.1 Hz), 128.81, 128.88, 129.16, 130.45, 135.15, 138.51, 140.24, 154.00,
1.46–1.55 (m, 3H), 1.81–1.91 (m, 1H), 2.13–2.22 (m, 1H), 3.23 170.04; DEPT 135 (75 MHz, benzene-d6): d = 62.91 (up), 77.37
1
2
(s, 3H), 3.35 (s, 3H), 3.52 (dd, 1H, J = 9.6 Hz, J = 3.9 Hz), 5.64 (up), 127.81 (up), 127.93 (up), 128.07 (up), 128.35 (up), 128.75
(s, 1H), 6.69 (d, 2H, J = 8.7 Hz), 6.87 (d, 2H, J = 8.7 Hz), 7.43 (up), 128.81 (up), 128.88 (up), 129.16 (up), 130.45 (up), 154.00
(d, 2H, J = 8.7 Hz), 7.65 (d, 2H, J = 8.7 Hz), 9.61 (s, 1H); 13C-NMR (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.):
(75 MHz, benzene-d6): d = 21.74, 23.37, 25.53, 41.97, 54.65, 54.73, 342 (100, [M + H]+), HRMS ES+ for C22H20N3O m/z: [M + H]+ calc.
58.05, 77.79, 114.29, 114.37, 128.35, 128.86, 128.93, 129.34, 342.1606, found: 342.1614.
129.40, 132.31, 153.27, 160.53, 161.80, 173.08; DEPT 135
(2S,3E,5S)-5-Benzyl-3-(4-methoxybenzylideneamino)-2-(4-
(75 MHz, benzene-d6): d = 21.74 (up), 23.37 (up), 25.53 (up), methoxyphenyl)imidazolidin-4-one (5j). Yield 84%. White
41.97 (down), 54.65 (up), 54.73 (up), 58.05 (up), 77.79 (up), 114.29 solid; mp 132–134 1C; Rf 0.54 (EtOAc/c-C6H12 = 40/60);
(up), 114.37 (up), 128.35 (up), 128.93 (up), 129.40 (up), 153.27 [a]578 = ꢁ330 ꢃ 2 (C6H6, C = 0.620 ꢃ 0.041). FT-IR (neat,
1
(up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): cmꢁ1): 3307, 3080, 2837, 1712, 1513, 1250; H-NMR (300 MHz,
1
2
382 (100, [M + H]+), HRMS ES+ for C22H28N3O3 m/z: [M + H]+ calc. benzene-d6): d = 1.66 (br s, 1H), 3.05 (dd, 1H, J = 10.4 Hz, J =
382.2131, found: 382.2108.
3.2 Hz), 3.11 (s, 3H), 3.18 (s, 3H), 3.23 (dd, 1H, 1J = 10.4 Hz, 2J =
(2S,3E,5S)-3-(4-Methoxybenzylideneamino)-2-(4-methoxyphenyl)- 4.5 Hz), 3.63-3.70 (m, 1H), 5.44 (s, 1H), 6.53 (d, 2H, J = 6.6 Hz),
5-(2-(methylthio)ethyl)imidazolidin-4-one (5g). Yield 86%. White 6.65 (d, 2H, J = 6.6 Hz), 6.98 (d, 2H, J = 6.5 Hz), 7.03–7.20 (m, 5H),
solid; mp 140–142 1C; Rf 0.39 (EtOAc/c-C6H12 = 40/60); [a]578
=
7.48 (d, 2H, J = 6.5 Hz), 9.43 (s, 1H); 13C-NMR (75 MHz, benzene-
ꢁ55 ꢃ 1 (C6H6, C = 0.322 ꢃ 0.004). FT-IR (neat, cmꢁ1): 3312, 3300, d6): d = 37.38, 54.71, 60.47, 77.81, 114.30, 114.35, 127.02, 128.35,
2930, 2839, 1693, 1512; 1H-NMR (300 MHz, benzene-d6): d = 1.49– 128.92, 128.97, 129.41, 130.25, 132.32, 137.47, 153.41, 160.58,
1.63 (m, 1H), 1.78 (s, 3H), 1.81–1.89 (m, 1H), 2.18–2.34 (m, 1H), 161.87, 171.28; DEPT 135 (75 MHz, benzene-d6): d = 37.38
2.48–2.53 (m, 2H), 3.12 (s, 3H), 3.59 (s, 3H), 5.42 (s, 1H), 6.56 (d, 2H, (down), 54.71 (up), 60.47 (up), 77.81 (up), 114.30 (up), 114.35
J = 8.7 Hz), 6.77 (d, 2H, J = 8.7 Hz), 7.32 (d, 2H, J = 8.7 Hz), 7.51 (up), 127.02 (up), 128.35 (up), 128.92 (up), 128.97 (up), 129.41
(d, 2H, J = 8.7 Hz), 9.47 (s, 1H); 13C-NMR (75 MHz, benzene-d6): d = (up), 130.25 (up), 153.41 (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30,
15.03, 30.60, 31.93, 54.71, 54.79, 58.25, 77.45, 114.32, 114.34, EC = 3] m/z (rel. int.): 416 (100, [M + H]+), HRMS ES+ for
114.35, 128.27, 129.07, 129.31, 132.36, 153.28, 160.61, 161.89, C25H26N3O3 m/z: [M + H]+ calc. 416.1974, found: 416.1947.
171.75; DEPT 135 (75 MHz, benzene-d6): d = 15.03 (up), 30.60
(2S,3E,5S)-5-Benzyl-3-(benzylideneamino)-2-phenylimidazolidin-
(down), 25.53 (down), 31.93 (down), 54.79 (up), 58.25 (up), 77.45 4-one (5k). Yield 88%. White solid; mp 152–154 1C; Rf 0.61 (EtOAc/
(up), 114.25 (up), 128.27 (up), 129.07 (up), 129.31 (up), 153.28 (up); c-C6H12 = 40/60); [a]578 = ꢁ388 ꢃ 15 (C6H6, C = 0.108 ꢃ 0.004). FT-IR
ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 400 (100, (neat, cmꢁ1): 3309, 3058, 3024, 2936, 1713, 1393; 1H-NMR
[M + H]+), HRMS ES+ for C21H26N3O3S m/z: [M + H]+ calc. 400.1695, (300 MHz, benzene-d6): d = 3.13 (dd, 1H, 1J = 14.4 Hz, 2J =
1
2
found: 400.1689.
4.2 Hz), 3.27 (dd, 1H, J = 14.4 Hz, J = 6.3 Hz), 3.72 (t, 1H, J =
(2S,3E,5S)-3-(4-Methoxybenzylideneamino)-2-(4-methoxyphenyl)- 5.4 Hz), 5.47 (s, 1H), 7.01–7.04 (m, 3H), 7.12–7.18 (m, 8H), 7.23
5-phenylimidazolidin-4-one (5h). Yield 83%. White solid; mp (d, 2H, J = 1.5 Hz), 7.56–7.59 (m, 2H), 9.53 (s, 1H); 13C-NMR
129–131 1C; Rf 0.68 (EtOAc/c-C6H12 = 40/60); [a]578 = ꢁ156 ꢃ 5 (75 MHz, benzene-d6): d = 37.43, 60.47, 78.02, 127.03, 127.63,
(MeCN, C = 0.700 ꢃ 0.022). FT-IR (neat, cmꢁ1): 3311, 3062, 3030, 127.76, 128.35, 128.69, 128.87, 128.96, 129.11, 130.16, 130.37,
2834, 1696, 1512; 1H-NMR (300 MHz, benzene-d6): d = 1.82 135.18, 137.36, 140.16, 153.31, 171.41; DEPT 135 (75 MHz,
(s, 1H), 3.12 (s, 3H), 3.24 (s, 3H), 4.40 (s, 1H), 5.51 (s, 1H), 6.55 benzene-d6): d = 37.43 (down), 60.47 (up), 78.02 (up), 127.03
(d, 2H, J = 8.4 Hz), 6.76 (d, 2H, J = 8.4 Hz), 7.21–7.26 (m, 2H), 7.37 (up), 127.63 (up), 127.76 (up), 128.35 (up), 128.69 (up), 128.87
(d, 2H, J = 8.1 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.66 (d, 2H, J = 7.2 Hz), (up), 128.96 (up), 129.11 (up), 130.16 (up), 130.37 (up), 153.31
9.40 (s, 1H); 13C-NMR (75 MHz, benzene-d6): d = 54.70, 54.77, (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.):
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356 (100, [M + H]+), HRMS ES+ for C23H22N3O m/z: [M + H]+ calc.
356.1763, found: 356.1757.
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(2S,3E,5S)-5-Benzyl-2-(furan-2-yl)-3-(furan-2-yl)methylene-
aminoimidazolidin-4-one (5l). Yield 81%. White solid; mp
132–134 1C; Rf 0.59 (EtOAc/c-C6H12 = 40/60); [a]578 = ꢁ341 ꢃ 19
(C6H6, C = 0.070 ꢃ 0.004). FT-IR (neat, cmꢁ1): 3314, 3113, 3021, 1699,
1327; 1H-NMR (400 MHz, benzene-d6): d = 1.88 (s, 1H), 3.02 (dd, 1H,
1J = 14.4 Hz, 2J = 7.6 Hz), 3.12 (dd, 1H, 1J = 14.4 Hz, 2J = 4.0 Hz), 3.44–
3.49 (m, 1H), 5.45 (d, 1H, J = 8.0 Hz), 5.83 (dd, 1H, 1J = 3.2 Hz, 2J = 1.6
Hz), 5.91 (dd, 1H, 1J = 2.8 Hz, 2J = 1.6 Hz), 7.09 (d, 1H, J = 2.8 Hz), 7.26
(d, 1H, J = 3.2 Hz), 6.86 (s, 1H), 6.90 (s, 1H), 7.02–7.14 (m, 5H), 9.49 (s,
1H); 13C-NMR (75 MHz, benzene-d6): d = 36.54, 59.44, 70.67, 108.34,
109.28, 110.44, 112.41, 125.54, 126.32, 127.42, 128.52, 136.61, 141.70,
143.60, 149.54, 150.60, 169.47; DEPT 135 (75 MHz, benzene-d6): d =
36.54 (down), 59.44 (up), 70.67 (up), 109.28 (up), 110.44 (up), 112.41
(up), 125.54 (up), 126.32 (up), 127.42 (up), 128.52 (up), 129.94 (up),
143.60 (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.):
336 (100, [M + H]+), HRMS ES+ for C19H18N3O3 m/z: [M + H]+ calc.
336.1348, found: 336.1347.
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(2S,3E,5S)-5-((1H-Indol-3-yl)methyl)-2-(furan-2-yl)-3-(furan-2-
yl)methyleneaminoimidazolidin-4-one (5m). Yield 80%. White
10 J. Mao, Y. Wang, B. Wan, A. P. Kozikowski and S. G. Franzblau,
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solid; mp 135–137 1C; Rf 0.19 (EtOAc/c-C6H12 = 40/60); [a]578
=
ˇ
´
%
11 J. Dumciute, V. Martynaitis, W. Holzer, S. Mangelinckx, N. De
ꢁ268 ꢃ 4 (C6H6/MeCN (1 : 1), C = 0.290 ꢃ 0.004). FT-IR
(neat, cmꢁ1): 3329, 3319, 1698, 1625; 1H-NMR (400 MHz,
benzene-d6): d = 2.15 (s, 1H), 3.21 (dd, 1H, 1J = 14.8 Hz, 2J =
ˇ
ˇ
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4.4 Hz), 3.27 (dd, 1H, 1J = 14.8 Hz, J = 4.8 Hz), 3.95–3.99 (m, 1H),
5.00 (s, 1H), 5.84–5.86 (m, 2H), 5.96 (d, 2H, J = 3.2 Hz), 6.30 (d, 1H, J =
3.2 Hz), 6.74–6.77 (m, 1H), 6.86 (s, 1H), 7.00–7.03 (m, 1H), 7.17–7.21
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(75 MHz, benzene-d6 + CD3CN): d = 26.66, 59.15, 70.07, 108.95,
110.25, 110.62, 111.69, 112.14, 114.05, 114.89, 119.23, 119.60, 122.10,
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157.91, 177.70; DEPT 135 (75 MHz, benzene-d6): d = 36.54 (down),
59.44 (up), 70.67 (up), 108.95 (up), 110.25 (up), 110.62 (up), 111.69
(up), 112.14 (up), 114.05 (up), 114.89 (up), 119.23 (up), 119.60 (up),
122.10 (up), 124.21 (up), 128.34 (up), 139.61 (up) 142.45 (up), 143.11
(up), 144.93 (up); ESI(+)-MS CH3CN [C = 0.5, SC = 30, EC = 3] m/z (rel.
int.): 375 (100, [M + H]+), HRMS ES+ for C21H19N4O3 m/z: [M + H]+
calc. 375.1457, found: 375.1462.
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Conflicts of interest
¨
17 N. Bouzayani, J. Kraıem, S. Marque, Y. Kacem, A. Carlin-
Sinclair, J. Marrot and B. Ben Hassine, Beilstein J. Org.
Chem., 2018, 14, 2923–2930.
There are no conflicts to declare.
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21 A. O. Aliyenne, J. E. Khiari, J. Kraiem, Y. Kacem and B. Ben
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22 A. O. Aliyenne, J. Kraiem, Y. Kacem and B. Ben Hassine,
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Acknowledgements
´ ´
Authors thank the DGRST (Direction Generale de la Recherche
Scientifique et de la Technologie) of the Tunisian Ministry of
Higher Education and Scientific research and Technology for
financial support of this research.
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