Synthesis of new chiral bis-imidazolidin-4-ones: Comparison between the classic method and green chemistry conditions

Article abstract of DOI:10.24820/ark.5550190.p010.297

Novel bis-imidazolidin-4-ones were synthesized in moderate to good yields through the cyclocondensation of o-, m-and p-phthalaldehydes with various substituted phenylhydrazides. These nitrogenated cyclic compounds were prepared via green chemistry conditi

Full text of DOI:10.24820/ark.5550190.p010.297

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Arkivoc 2018, part iii, 229-239
Synthesis of new chiral bis-imidazolidin-4-ones: comparison between the classic
method and green chemistry conditions
a
a
b
a
a
Nadia Bouzayani, Wassima Talbi, Sylvain Marque, * Yakdhane Kacem, * and Béchir Ben Hassine
a
Laboratoire de Synthèse Asymétrique et Catalyse Homogène, Faculté des Sciences, Université de Monastir,
Avenue de l’Environnement, 5019 Monastir, Tunisie
Université de Versailles Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles (ILV), UMR CNRS 8180,
b
45 avenue des Etats-Unis, 78035 Versailles Cedex, France
Email: sylvain.marque@uvsq.fr, yakacem@yahoo.com
Received 08-06-2017
Accepted 12-29-2017
Published on line 03-15-2018
Abstract
Novel bis-imidazolidin-4-ones were synthesized in moderate to good yields through the cyclocondensation of
o-, m- and p-phthalaldehydes with various substituted phenylhydrazides. These nitrogenated cyclic
compounds were prepared via green chemistry conditions using microwave irradiation.
Keywords: Bis-imidazolidin-4-ones, cyclocondensation, phenylhydrazides
DOI: https://doi.org/10.24820/ark.5550190.p010.297
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Introduction
Nitrogen heterocycles are key building blocks for a large number of medicinally-relevant molecules. They
1
constitute an important core fragment in different natural products and pharmaceutical agents. The
chemistry of imidazolidinones has recently attracted more attention due to their reactivity and several
2
3
4
5
biological properties. They have been regarded as anthelmintic, analgesic, antibacterial, antifungal,
6
7
8
9
antiviral, antitubercular and anticancer effects, and also as a new chemical class of herbicide.
Imidazolidinones can be used as hydrolytically cleavable precursors for the controlled release of fragrant
9
aldehydes and ketones. Considerable efforts have recently been devoted to the development of more
efficient approaches for the preparation of imidazolidinone derivatives. They have generally been obtained by
10
condensation of α-aminoamides with carbonyl compounds (aldehyde or ketone). Among these preparations,
several studies concerning the synthesis of chiral imidazolidin-4-ones derivatives containing two stereogenic
centers using classical conditions have previously been described in papers by Milos.11-13
As part of our ongoing efforts directed toward the synthesis of heterocyclic compounds starting from α-
amino acids14-19 and our studies on the reactivity of α-amino acid phenylhydrazides,20,21 we describe herein a
practical and efficient synthetic pathway for the preparation of bis-imidazolidin-4-ones using a green
chemistry context (solvent free and without catalyst conditions). To the best of our knowledge, no synthesis of
bis-imidazolidin-4-ones have been reported with α-amino acid phenylhydrazide derivatives as starting
1
materials. On the other hand, green or sustainable chemistry has become, over time, a research concept for
the development of environmentally and eco-friendly chemistry using products, chemical processes and
synthetic pathways that decrease the production of hazardous substances. So, microwave irradiation (MW) is
one of the potential green chemistry techniques used during the recent years. The main benefits of
performing the reaction under microwave conditions are the higher product yields and the significant rate-
enhancements that can be observed. We have used, in this study, a new microwave synthesis system
(startSYNTH) that combines sophisticated design and high technology with ease of use and safety.
Results and Discussion
The starting L-α-amino acid phenylhydrazides 3a-e were prepared in a manner similar to the well-known
22
procedure described by Verardo et al. The commercially available L-α-amino acid ester hydrochlorides 1a-e
reacted with phenylhydrazine (2) under mild conditions affording the corresponding phenylhydrazides 3a-e in
good yields (Scheme 1, Table 1).
Scheme 1. Synthesis of substituted α-amino acid phenylhydrazides 3a-e.
For the investigation of optimal conditions of the coupling reactions, o-phthalaldehyde 4a and L-alanine
phenylhydrazide 3a were employed as reactants (Scheme 2). Two procedures were compared using the same
reacting mixtures: the conventional heating with a usual acidic catalyst and in a microwave-assisted approach.
First, the use of sulfuric acid or acetic acid as catalysts led to low yields (Table 2, entries 1-3). However, p-
toluenesulfonic acid brought about a double cyclization up to 94%, mainly due to the use of a higher
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temperature, allowing the water vaporization from the appropriate solvent (toluene) and favoring reduced
contact of water with the organic materials (entries 4-6). The role of the solvent is tricky to estimate, since it is
related to the nature of the catalyst. At first, reactants are not completely soluble in toluene at 70 °C and no
reaction was occurred with PTSA or sulfuric acid (results not depicted in table 2); a temperature of 100 °C
needed to perform reactions in this solvent. Regardless with the solvent, the reactions conducted with PTSA
are much cleaner by TLC compared to H
2
SO where a big spot was observed for this latter on the baseline,
4
added to numerous new spots. In fact, unidentified side products appeared with sulphuric acid and were
insoluble in the medium, likely due to opened forms of the condensation products. To further examine the
reactivity of the dialdehyde 4a, we tried the reaction in the absence of catalyst, but no formation of the
desired product was observed (entry 7).
Table 1. Synthesis of α-aminoacid phenylhydrazides 3a-e
Entry Product
R
[] a
+34.2
+22.8
+30.8
+39.4
+29.8
Yield (%) b
1
2
3
4
5
3a
3b
3c
3d
3e
Me
i-Pr
i-Bu
85
72
70
85
79
CH
(CH
2
Ph
2
)
2
SMe
a
b
Values were measured in MeOH (c 0.2). Isolated product yield.
Scheme 2. Condensation of o-phthalaldehyde 4a and L-alanine phenylhydrazide 3a.
The generalization of the double condensation was next examined with various α-amino acid-derived
phenylhydrazides 3a-e reacting with the 3 isomeric dialdehydes 4a-c (Scheme 3 and Table 3). The structure of
the resulting bis-imidazolidin-4-ones 5a-o was undoubtedly confirmed based on their analytical and spectral
data. The new compounds 5a-o were isolated as a mixture of two inseparable diastereoisomers (TLC showed
always a single spot whatever the eluents used); the duplication of signals on the 13C-NMR spectrum
corroborated the presence of two diastereoisomers. It is worth noting that among the three conceivable
diasteroisomers (see supporting information), only two were observed in a 1:1 ratio although the attribution
of the stereochemistries of the neo-formed stereocenters was not possible.
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Table 2. Optimization of reaction conditions for the coupling of o-phthalaldehyde 4a and L-alanine
phenylhydrazide 3a
Entry a Catalyst (mol %) Temp. ( C) Time (h) Solvent Yields (% in 5a)
o
1
2
3
4
5
6
7
AcOH (1)
70
70
24
24
24
10
24
24
24
EtOH
EtOH
Trace
<10
<10
<10
NR b
94a
H
2
SO
4
(1)
(1)
H
2
SO
4
100
70
Toluene
EtOH
PTSA (1)
PTSA (1)
PTSA (1)
-
85-90
100
100
Toluene
Toluene
Toluene
NR b
a
Conditions: L-alanine phenylhydrazide (2 mmol), o-phthalaldehyde (1 mmol) under argon. b No reaction
occurred.
Scheme 3. Synthesis of the bis-imidazolidin-4-ones 5a-o.
In conventional heating, the role of the solvent was crucial; thus, for the reaction performed with the o-
phthalaldehyde 4a or the m-phthalaldehyde 4b only a non-polar solvent (toluene) was employed, whereas
with the p-phthalaldehyde 4c, a mixture of toluene and ethanol was required due to the lesser solubility of
paraphthalaldehyde in toluene compare to the ortho isomer. Moreover, among the phenylhydrazide
derivatives 3a-e, the experiments conducted with L-valine phenylhydrazide 3b led to low yields (entries 2 , 7
and 12), where the two isopropyl moieties on the resulting products may cause steric hindrance,
thermodynamically disfavouring the formation of these corresponding bisimidazolidinones 5b, 5g, 5l. To avoid
these limitations, the development of an efficient alternative combining higher yields, shorter reaction times
and greener conditions (mild, practical, solvent free) was highly desirable. We had originally hoped that the o-,
m- and p-phthalaldehydes could be converted into the corresponding bis-imidazolidin-4-ones with a non
o
classical heating. Moving to a methodology using microwave irradiation at 100 C in both solvent- and catalyst
free conditions, reactions were completed in only 6 minutes affording the expected bis-imidazolidin-4-ones
5
a-o in higher yields. We were pleased to find that these conditions efficiently proceeded to afford the desired
products without any trace of the starting dialdehydes or the monocondensation product. The heterocycles
a-o are very silica gel sensitive compounds and numerous attempts failed to isolate them even though
basifying the silica gel with triethylamine, in all cases the corresponding starting dialdehydes 4a-c were
5
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Bouzayani, N. et al.
recovered. We succeeded in isolating a mixture of the two diastereoisomers by crystallization using
dichloromethane and diethyl ether (7:3). The workup was considerably simpler since a simple crystallization
from the crude rapidly gave the targeted heterocycles.
Table 3. Coupling of the phenylhydrazides 3a-e with the dialdehydes 4a-c
Entry Substrate Reactant Product Yields Δ (%) a Yields MW (%)b
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
5f
94
34
79
65
60
82
32
67
69
71
59
11
71
78
67
96
55
81
66
72
93
46
88
71
80
45
32
84
89
80
5g
5h
5i
1
0
1
2
3
4
5
5j
1
1
1
1
1
5k
5l
5m
5n
5o
a
Conventional heating (oil bath) in toluene (10 mL) for o-phthalaldehyde 4a or else in toluene/EtOH (10 mL)
b
o
for p-phthalaldehyde 4c. Conditions of activation: microwave irradiation (startSYNTH), 100 C, 6 min.
The conditions under which the reactions summarised in Table 2 were performed are as follows:
Entries 1-5: o-phthalaldehyde 4a (1.4 mmol), α-amino acid phenylhydrazide 3 (2.8 mmol), PTSA (10 % mol),
o
1
00 C, 24 h under argon.
Entries 6-10: m-phthalaldehyde 4b (1.4 mmol), α-amino acid phenylhydrazide (2.8 mmol), PTSA (10 % mol),
o
1
00 C, 24 h under argon.
Entries 11-15: p-phthalaldehyde 4c (1.4 mmol), α-amino acid phenylhydrazide 3a-e (2.8 mmol), PTSA (10 %
o
mol), 100 C, 24 h under argon.
Conclusions
In conclusion, we have developed a straightforward and efficient method for the synthesis of new bis-
imidazolidin-4-ones in moderate to good yields under catalytic conditions. The improvement in processing was
pursued up to an approach using the solvent free microwave irradiation in soft conditions (no metal and no
catalyst) leading to original nitrogenated compounds with respect to the green chemistry conditions and an
easy-to-operate procedure, including the purification by crystallization.
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Experimental Section
General. All reagents and chemicals were purchased from Sigma-Aldrich chemical company and Acros
Organics. Solvents used in reactions were dried and distilled before use. Toluene was distilled over sodium
metal, and EtOH was distilled over Mg/I . Nuclear magnetic resonance (NMR) was recorded on Bruker AC-300
2
1
13
spectrometers ( H at 300 MHz and C at 75 MHz) in deuterochloroform (CDCl
3
) as solvent. NMR chemical
1
13
shifts were calibrated on the solvent residual signal at 7.26 ppm for H and at 77.16 ppm for C. In most cases,
the C NMR spectra showed a duplication of the chemical shifts signals (presence of two diastereoisomers)
and are described herein in this sense, therefore with the twice carbon number vis-à-vis the formula weight.
Infrared spectra (IR) were obtained using a Perkin Elmer spectrometer in the range 4000-400 cm .
Electrospray ionisation (ESI) mass spectroscopy data of compounds 5a, 5c, 5d, 5e, 5k, 5m, 5n, 5o were
recorded on an UPLC Waters device (in positive mode); for the voltages of the mass spectroscopies, the
following abbreviations are used: C Capillary (kV), SC Sampling Cone, EC Extraction Cone. Calibration was
13
-
1
-
1
performed with sodium formate (range from 100 to 1000 g.mol ) and the lockspray (lockmass on the leucine
-1
encephaline 556.2771 g.mol ) was used without collision energy; the relative intensity of peaks is given in
brackets. Electrospray ionisation (ESI) mass spectroscopy data of compounds 5b, 5f, 5h, 5i and 5j were
recorded on a Q exactive hybrid quadrupole-orbitrap mass spectrometer coupled to a U3000 LC device; the
spray voltage was 3000 V. The positive ion calibration was performed with a commercially available mixture of
caffeine, MRFA, Ultramark1621 and n-butylamine in a acetonitrile /methanol/acetic acid solution.
Characterisation of the compounds 5a-o described herein is for thermal experiment; yields for conventional
heating and microwave activation are given in Table 3.
General procedure for the synthesis of bis-imidazolidin-4-ones 5
Catalytic conditions. To a stirred solution of the α-amino acid phenylhydrazide 3a-e (2.8 mmol, 2 eq) and the
o-phthalaldehyde 4a, m-phthalaldehyde 4b or the p-phthalaldehyde 4c (187.7 mg, 1.4 mmol, 1 eq) in dry
toluene (10 mL), was added PTSA (24.10 mg, 0.14 mmol, 10 % mol), and the mixture was heated for 24 h
under an inert atmosphere. After evaporating the solvent under reduced pressure, the residue was dissolved
in CH
mL, 65 mmol) for 30 min. The solution was dried over anhydrous Na
evaporated to obtain a pale-yellow solid, which was purified by precipitation from CH
2
Cl
2
(50 mL) and then the mixture was vigorously stirred with Na
2
CO
3
(0.24 g, 8.38 mmol) and H
SO and filtered. The solvent was
Cl /Et O 7:3 (10 mL)
2
O (1.17
2
4
2
2
2
then filtered to afford pure 5a-o. These products could not be purified by absorption chromatography since
they extensively decomposed upon contact on silica gel or alumina.
Solvent free microwave irradiation. A mixture of α-amino acid phenylhydrazide 3a-e (2.8 mmol, 2 eq) and the
o-phthalaldehyde 4a the m-phthalaldehyde 4b or the p-phthalaldehyde 4c (187.7 mg, 1.4 mmol, 1 eq) was
o
submitted to programmed microwave synthesis reactor (START SYNTH) at 100 C for 6 min. The crude product
o
was purified by precipitation in a mixture of CH
2
Cl
2
/Et
2
O 7:3 (10 mL) in a refrigerator at 3 C, then filtered to
afford pure 5a-o.
(
0
1
1,2-Phenylene)-2,2'-bis-[5-methyl-3-(phenylamino)imidazolidin-4-one] (5a). White solid, mp 115-117 °C. R
f
-1
1
.17 (EtOAc : c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3251, 2973, 1697, 1597, 1298. H NMR (300 MHz, CDCl
3
): δ
H
3
3
.47 (6H, d, JHH 6.6 Hz), 2.15 (2H, s, NH), 3.81 (2H, q, JHH 6.6 Hz), 5.57 and 5.59 (2 x 1H, 2s, CH), 5.76 and 5.78
(
2 x 1H, 2s, NHPh), 6.55-6.66 (4H, m, CH aromatic), 6.85-6.92 (2H, m, CH aromatic), 7.21-7.24 (4H, m, CH
13
aromatic), 7.37-7.42 (4H, m, CH aromatic). C NMR (75 MHz, CDCl
3
): δ
C
18.22 (2 x CH
3
), 18.49 (2 x CH ), 52.61
3
(2 x CH), 53.39 (2 x CH), 74.12 (2 x CH), 74.70 (2 x CH), 113.62 (4 x CH aromatic), 113.92 (4 x CH aromatic),
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Bouzayani, N. et al.
121.52 (2 x CH aromatic), 121.61 (2 x CH aromatic), 126.18 (2 x CH aromatic), 128.22 (2 x CH aromatic), 128.55
(2 x CH aromatic), 129.26 (4 x CH aromatic), 129.37 (4 x CH aromatic), 129.73 (2 x C aromatic), 138.83 (2 x C
aromatic), 139.46 (2 x C aromatic), 145.22 (2 x NHC aromatic), 145.25 (2 x NHC aromatic), 174.45 (2 x C=O),
+
1
74.71 (2 x C=O). ESI(+)-MS CH
3
CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 457 (100, M + H ), 386 (20, M-
+
+
+
CONHCHMe + H ), 315 (50), 295 (15); HRMS ES for C26
29
H N
6
O [M+H] Calc. 457.2352, found: 457.2349.
2
2
,2'-(1,2-Phenylene)bis-[5-isopropyl-3-(phenylamino)imidazolidin-4-one] (5b). White solid, mp 112-114 °C. R
f
-1
1
0.22 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3311, 1600, 1554, 1294. H NMR (300 MHz, CDCl
3
): δ
H
0.89
3
3
(12H, d, JHH 7,6 Hz), 2.02 (2H, s, NH), 2.14-2.17 (2H, m, CH(CH
)
3 2
), 3.56 (2H, d, JHH 6.2 Hz), 6.33 and 6.36 (2 x
3
1H, 2s, CH), 6.65 and 6.67 (2 x 1H, 2s, NHPh), 6.91-6.96 (4H, m, CH aromatic), 7.11 (2H aromatic, t, JHH 7.4 Hz),
3
3
13
7
.16 (4H aromatic, d, JHH 8.09 Hz), 7.18 (2H aromatic, d, JHH 8.09 Hz), 7.35-7.38 (2H, m, CH aromatic). C NMR
): δ 20.22 (2 x 2CH ), 32.13 (CH(CH ), 32.17 (CH(CH ), 74.09 (CH), 74.11 (CH), 80.70 (2 x
CHC=O), 80.73 (2 x CHC=O), 115.11 (2 x CH aromatic), 117.23 (2 x CH aromatic), 126.55 (2 x CH aromatic),
29.45 (2 x CH aromatic), 131.09 (2 x CH aromatic), 142.16 (2 x C aromatic), 155.01 (2 x NHC aromatic), 174.11
(75 MHz, CDCl
3
C
3
)
3 2
)
3 2
1
+
+
(2 x C=O), 174.14 (2 x C=O). HRMS ES (CH
3
CN) for C30
H
37
N
O
6 2
m/z: [M+H] Calc. 513.2911, found: 513.2914.
2
0
δ
,2'-(1,2-Phenylene)bis-[5-isobutyl-3-(phenylamino)imidazolidin-4-one] (5c). White solid, mp 118-120 °C. R
f
-1
1
.30 (EtOAc/c-C
6
3
H
12 1:1). IR (neat), νmax (cm ): 3280, 2955, 1700, 1601, 1496, 1246. H NMR (300 MHz, CDCl
3
):
3
H
0.98 (6H, d, JHH 6.3 Hz), 1.04 (6H, d, JHH 6.6 Hz), 1.47-1.51 (2H, m, CH(CH
3 2
)
), 1.75-1.92 (4H, m, CH ), 2.19
2
3
(2H, s, NH), 5.59 (2H, t, JHH 6.6 Hz), 6.53 and 6.56 (2 x 1H, 2s, CH), 6.59 and 6.62 (2 x 1H, 2s, NHPh), 6.63-6.69
3
(
4H, m, CH aromatic), 6.90 (2H, t, JHH 8.1 Hz), 7.12-7.24 (4H, m, CH aromatic), 7.37-7.46 (4H, m, CH aromatic).
13
C NMR (75 MHz, CDCl
CH), 55.35 (CH), 74.52 (2 x CH), 74.80 (2 x CH), 113.63 (2 x CH aromatic), 121.59 (2 x CH aromatic), 126.35 (2 x
CH aromatic), 127.14 (2 x CH aromatic), 129.53 (2 x CH aromatic), 138.56 (2 x C aromatic), 145.22 (2 x NHC
aromatic), 174.77 (2 x C=O), 174.84 (2 x C=O). ESI(+)-MS CH CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 541 (50,
): δ
3 C
21.45 (2 x CH
3
), 23.44 (2 x CH
3
2 2
), 29.71 (2 x CH), 41.81 (CH ), 41.90 (CH ), 55.27
(
3
+
+
+
+
M + H ), 428 (35, M-COCHiBuNH + H ), 315 (100), 149 (55). HRMS ES for C32
41
H N
6
O m/z: [M+H] Calc.
2
5
2
0
41.3291, found: 541.3296.
,2'-(1,2-Phenylene)bis-[5-benzyl-3-(phenylamino)imidazolidin-4-one] (5d). White solid, mp 124-126 °C. R
f
-1
1
.29 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3255, 1623, 1354, 1237. H NMR (300 MHz, CDCl
3
): δ
H
1.95 (2H,
3
3
3
3
3
s, NH), 3.22 (2H, dd, JHH 12.3, JHH 6.00 Hz), 3.41 (2H, dd, JHH 12.3, JHH 6.00 Hz), 4.00 (2H, t, JHH 6.00 Hz), 6.27
and 6.30 (2 x 1H, 2s, CH), 6.48 and 6.50 (2 x 1H, 2s, NHPh), 6.79-6.97 (4H, m, CH aromatic), 7.05-7.20 (4H, m,
13
CH aromatic), 7.23-7.29 (8H, m, 4CH aromatic), 7.37-7.39 (8H, m, 4CH aromatic). C NMR (75 MHz, CDCl
7.66 (CH ), 37.68 (CH ), 74.22 (2 x CHC=O), 74.25 (2 x CHC=O), 77.44 (2 x CH), 77.47 (2 x CH), 113.51 (2 x CH
3
): δ
C
3
2
2
aromatic), 113.57 (2 x CH aromatic), 114.04 (2 x CH aromatic), 121.51 (2 x CH aromatic), 125.42 (2 x CH
aromatic), 127.17 (2 x CH aromatic), 128.82 (CH aromatic), 128.88 (CH aromatic), 129.23 (2 x CH aromatic),
1
29.86 (2 x CH aromatic), 130.09 (2 x CH aromatic), 136.28 (2 x C aromatic), 139.83 (2 x C aromatic), 144.95 (2
+
x NHC aromatic), 172,69 (2 x C=O). ESI(+)-MS CH
3
CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 609 (100, M + H ),
+
+
+
4
6
2
1
62 (40, M-CONHCHBn + H ), 315 (40), 120 (60). HRMS ES for C38
09.2976.
,2'-(1,2-Phenylene)bis-[5-(2-methylthioethyl)-3-(phenylamino)imidazolidin-4-one] (5e). White solid, mp
37
H N
6
O m/z: [M+H] Calc. 609.2978, found:
2
-1
1
23-125 °C. R
f
0.45 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3275, 1690, 1367, 1278. H NMR (300 MHz,
CDCl
3
): δ 1.91-2.15 (2H, m, CH), 2.16 (6H, s, SCH
H
3
), 2.19-2.38 (2H, m, CH), 2.62 (2H, s, NH), 2.75-2.79 (4H, m,
CH
2
), 3.96-4.01 (2H, m, CHC=O), 5.56 and 5.60 (2 x 1H, 2s, CH), 5.63 and 5.83 (2 x 1H, 2s, NHPh), 6.57 (2H, d,
3
3
JHH 8.1 Hz), 6.65 (2H, d, JHH 7.8 Hz), 6.86-6.94 (2H, m, CH aromatic), 7.13-7.23 (4H, m, CH aromatic), 7.33-7.51
13
(4H, m, CH aromatic). C NMR (75 MHz, CDCl
3
): δ
C
15.31 (CH
2
), 15.37, (CH
2
), 30.35 (SCH
3
), 31.48 (CH ), 31.67
2
(
CH ), 55.65 (2 x CH), 56.13 (2 x CH), 74.38 (2 x CH), 74.82 (2 x CH), 113.69 (2 x CH aromatic), 113.84 (2 x CH
2
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aromatic), 121.62 (2 x CH aromatic), 122.28 (CH aromatic), 126.21 (CH aromatic), 129.27 (2 x CH aromatic),
1
39.12 (C aromatic), 145.25 (2 x NHC aromatic), 173.36 (2 x C=O), 173.73 (2 x C=O). ESI(+)-MS CH
3
CN [C = 0.5,
+
+
+
SC = 30, EC = 3] m/z (rel. int.): 577 (100, M + H ), 446 (5, M-CONHCH(CH
C
)
2 2
SMe + H ), 355 (10). HRMS ES for
+
30 37
H N
6 2
O S
2
m/z: [M+H] Calc. 577.2419, found: 577.2416.
2
0
δ
,2'-(1,3-Phenylene)bis-[5-methyl-3-(phenylamino)imidazolidin-4-one] (5f). White solid, mp 116-118 °C. R
f
-1
1
.18 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3253, 3024, 1707, 1694, 1600, 1495. H NMR (300 MHz, CDCl
3
):
3
3
H
1.52 and 1.54 (6H, 2d, JHH 6.6 Hz), 1.80 (2H, broad s, NH), 3.81 (2H, q, JHH 6.6 Hz), 5.55 and 5.58 (2 x 1H, 2s,
CH), 5.76 and 5.78 (2 x 1H, 2s, NHPh), 6.55-6.66 (4H, m, CH aromatic), 7.11-7.15 (2H, m, CH aromatic), 7.21-
13
7
.24 (4H, m, CH aromatic), 7.37-7.42 (4H, m, CH aromatic). C NMR (75 MHz, CDCl
3
): δ
C
18.29 (2 x CH ), 18.50
3
(
2 x CH ), 52.67 (2 x CH), 53.35 (2 x CH), 73.97 (2 x CH), 74.40 (2 x CH), 113.74 (4 x CH aromatic), 113.98 (4 x CH
3
aromatic), 121.61 (4 x CH aromatic), 121.75 (4 x CH aromatic), 127.57 (2 x CH aromatic), 128.41 (2 x CH
aromatic), 129.25 (4 x CH aromatic), 129.38 (4 x CH aromatic), 139.05 (2 x CH aromatic), 140.09 (2 x C
aromatic), 145.08 (2 x NHC aromatic), 145.24 (2 x NHC aromatic), 174.48 (2 x C=O), 174.55 (2 x C=O). ESI(+)-MS
+
+
+
+
CH
3
CN m/z (rel. int.): 530 (15), 495 (10, M + K ), 479 (60, M + Na ), 457 (100, M + H ). HRMS ES for C26
29
H N
O
6 2
+
m/z: [M+H] Calc. 457.2347, found: 457.2342.
2
,2'-(1,3-Phenylene)bis-[5-isopropyl-3-(phenylamino)imidazolidin-4-one] (5g). White solid, mp 111-113 °C. R
f
-1
1
0.21 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3300, 1620, 1543, 1290. H NMR (300 MHz, CDCl
3
): δ
H
0.91
3
3
(12H, d, JHH 7.4 Hz), 2.00 (2H, s, NH), 2.16-2.18 (2H, m, CH(CH
)
3 2
), 3.74 (2H, d, JHH 6.2 Hz), 6.31 and 6.33 (2 x
3
1H, 2s, CH), 6.55 and 6.57 (2 x 1H, 2s, NHPh), 6.87-6.90 (4H, m, CH aromatic), 7.09 (2H, t, JHH 7.9 Hz), 7.14 (4H,
3
3
13
d, JHH 8.1 Hz), 7.18 (2H, d, JHH 8.1 Hz), 7.32-7.36 (2H, m, CH aromatic). C NMR (75 MHz, CDCl
(CH ), 31.23 (CH), 31.25 (CH), 73.19 (CH), 73.21 (CH), 83.73 (2 x CH), 83.75 (2 x CH), 115.13 (2 x CH
3
): δ 20.44
C
(
)
3 2
aromatic), 116.25 (2 x CH aromatic), 126.45 (2 x CH aromatic), 128.62 (2 x CH aromatic), 130.15 (2 x CH
aromatic), 131.11 (2 x CH aromatic), 142.54 (2 x C aromatic), 156.41 (2 x NHC aromatic), 174.41 (2 x C=O),
1
2
0
74.43 (2 x C=O).
,2'-(1,3-Phenylene)bis-[5-isobutyl-3-(phenylamino)imidazolidin-4-one] (5h). White solid, mp 119-121 °C. R
f
-1
1
.28 (EtOAc/c-C
6
3
H
12 1:1). IR (neat), νmax (cm ): 3032, 2954, 2628, 1579, 1512, 1405. H-NMR (300 MHz, CDCl
3
):
3
δ = 1.00 (6H, d, JHH 5.7 Hz), 1.04 (6H, d, JHH 6.3 Hz), 1.56-1.62 (2H, m, CH(CH
3
)
2
), 1.88-1.90 (4H, m, CH ), 2.18
2
2H, s, NH), 3.85 (2H, dd, 3JHH 14.4, JHH 8.4 Hz), 5.61 and 5.63 (2 x 1H, 2s, CH), 5.69 and 5.71 (2 x 1H, 2s, NHPh),
3
(
6
.61-6.70 (4H, m, CH aromatic), 6.88-6.95 (2H, m, CH aromatic), 7.16-7.28 (4H, m, CH aromatic), 7.29-7.45 (4H,
13
m, CH aromatic). C NMR (75 MHz, CDCl
2.07 (2 x CH ), 55.29 (2 x CH), 55.91 (2 x CH), 74.21 (2 x CH), 74.58 (2 x CH), 113.75 (4 x CH aromatic), 114.00
4 x CH aromatic), 121.57 (4 x CH aromatic), 121.69 (4 x CH aromatic), 127.62 (2 x CH aromatic), 128.49 (2 x CH
aromatic), 129.23 (4 x CH aromatic), 129.36 (4 x CH aromatic), 140.22 (2 x C aromatic), 145.14 (2 x NHC
3
): δ
C
3
21.45 (4 x CH ), 21.47 (4 x CH
3
), 25.08 (2 x CH), 42.03 (2 x CH ),
2
4
(
2
aromatic), 145.26 (2 x NHC aromatic), 174.44 (2 x C=O), 174.68 (2 x C=O). ESI(+)-MS CH
3
CN m/z (rel. int.): 579
+
+
+
+
+
(
15, M + K ), 563 (100, M + Na ), 541 (75, M + H ), 464 (15, M-Ph + H ), 453 (55), 413 (10), 391 (15). HRMS ES
+
for C30H
41
N
O
6 2
m/z: [M+H] Calc. 541.3286, found: 541.3282.
2
,2'-(1,3-Phenylene)bis-[5-benzyl-3-(phenylamino)imidazolidin-4-one] (5i). White solid, mp 127-129 °C. R
f
-
1
1
0.29 (EtOAc/c-C
6
H12 1:1). IR (neat), νmax (cm ): 3294, 2920, 1699, 1601, 1495, 1453, 1090. H-NMR (300 MHz,
CDCl
3
): δ 1.14 (2H, s, NH), 3.10-3.30 (4H, m, CH
H
2
), 3.99-4.09 (2H, m, CH), 5.20 and 5.27 (2 x 1H, 2s, CH), 5.43
and 5.48 (2 x 1H, 2s, NHPh), 6.18-6.27 (2H, m, CH aromatic), 6.41-6.44 (2H, m, CH aromatic), 6.64-6.68 (2H, m,
CH aromatic), 6.78-6.80 (4H, m, CH aromatic); 7.00-7.07 (6H, m, CH aromatic), 7.19-7.29 (8H, m, CH aromatic).
1
3
C-NMR (75 MHz, CDCl
CH), 113.11 (2 x CH aromatic), 115.02 (2 x CH aromatic), 122.12 (2 x CH aromatic), 125.55 (2 x CH aromatic),
27.56 (2 x CH aromatic), 128.11 (2 x CH aromatic), 128.61 (2 x CH aromatic), 129.21 (2 x CH aromatic), 129.45
3
): δ
C
37.98 (CH
2
), 38.01 (CH ), 55.23 (2 x CH), 55.25 (2 x CH), 77.01 (2 x CH), 77.03 (2 x
2
1
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Bouzayani, N. et al.
(
CH aromatic), 131.13 (CH aromatic), 137.33 (2 x C aromatic), 139.23 (2 x C aromatic), 145.54 (2 x NHC
+
aromatic), 145.66 (2 x NHC aromatic), 171.34 (2 x C=O). ESI(+)-MS CH
3
CN m/z (rel. int.): 647 (20, M + K ), 631
+
+
+
(95, M + Na ), 609 (100, M + H ), 566 (15), 453 (30), 343 (10, M-imidazolidinone + H ), 294 (25), 272 (35).
+
+
HRMS ES for C38
37
H N
O
6 2
m/z: [M+H] Calc. 609.2973, found: 609.2966.
2
,2'-(1,3-Phenylene)bis-[5-(2-methylthioethyl)-3-(phenylamino)imidazolidin-4-one] (5j). White solid, mp 124-
-1
1
1
26 °C. R
f
0.46 (EtOAc/c-C
): δ 1.96-2.06 (2H, m, CH), 2.14 (6H, s, CH
.00-4.04 (2H, m, CH), 5.52 and 5.62 (2 x 1H, 2s, CH), 5.64 and 5.69 (2 x 1H, 2s, NHPh), 6.54-6.61 (4H, m, CH
aromatic), 6.65-6.71 (2H, m, CH aromatic), 7.15-7.20 (4H, m, CH aromatic), 7.33-7.37 (4H, m, CH aromatic),
6
H
12 1:1). IR (neat), νmax (cm ): 3278, 2913, 1695, 1601, 1495, 1445, 1092. H NMR
(300 MHz, CDCl
3
H
3
), 2.31-2.62 (2H, m, CH), 2.74-2.96 (4H, m, CH ),
2
4
13
7.42-7.47 (2H, m, CH aromatic). C NMR (75 MHz, CDCl
3
): δ
C
15.27 (4 x CH
2
), 15.36 (4 x CH
2
), 30.34 (4 x SCH ),
3
3
1.51 (2 x CH ), 31.59 (2 x CH ), 74.40 (2 x CH), 74.44 (2 x CH), 77.43 (2 x CH), 77.50 (2 x CH), 113.72 (4 x CH
2
2
aromatic), 113.94 (4 x CH aromatic), 121.66 (2 x CH aromatic), 122.04 (2 x CH aromatic), 125.23 (4 x CH
aromatic), 128.78 (4 x CH aromatic), 129.38 (4 x CH aromatic), 134.13 (4 x C aromatic), 145.55 (4 x NHC
+
aromatic), 173.31 (2 x C=O), 173.35 (2 x C=O). ESI(+)-MS CH
3
CN m/z (rel. int.): 615 (10, M + K ), 599 (70, M +
+
+
+
+
Na ), 577 (100, M + H ), 453 (10). HRMS ES for C30
H
37
N
O
6 2
S
2
m/z: [M+H] Calc. 577.2414, found: 577.2408.
2
0
δ
6
,2'-(1,4-Phenylene)bis-[5-methyl-3-(phenylamino)imidazolidin-4-one] (5k). White solid, mp 117-119 °C. R
f
-1
1
.17 (EtOAc/c-C
6
3
H
12 1:1). IR (neat), νmax (cm ): 3254, 3022, 1708, 1600, 1495, 1392. H NMR (300 MHz, CDCl
3
):
3
H
1.44 (6H, d, JHH 6.9 Hz), 2.00 (2H, s, NH), 3.74 (2H, q, JHH 6.9 Hz), 6.00 and 6.02 (2 x 1H, 2s, CH), 6.70 and
3
3
.72 (2 x 1H, 2s, NHPh), 6.78 (4H, dd, JHH 7.2, JHH 6.9 Hz), 6.85-6.92 (2H, m, CH aromatic), 7.12-7.22 (4H, m,
13
CH aromatic), 7.34-7.48 (4H, m, CH aromatic). C NMR (75 MHz, CDCl
1.81 (2 x CH), 51.83 (2 x CH), 75.19 (2 x CH), 75.21 (2 x CH), 113.22 (4 x CH aromatic), 113.24 (4 x CH
): δ
3 C
23.70 (2 x CH
3
), 23.71 (2 x CH ),
3
5
aromatic), 122.82 (4 x CH aromatic), 125.39 (4 x CH aromatic), 125.41 (4 x CH aromatic), 129.26 (4 x CH
aromatic), 129.27 (4 x CH aromatic), 137.83 (2 x C aromatic), 137.86 (2 x C aromatic), 151.00 (2 x NHC
aromatic), 151.03 (2 x NHC aromatic), 173.41 (2 x C=O), 173.43 (2 x C=O). ESI(+)-MS CH CN [C = 0.5, SC = 30, EC
3
+
+
+
=
3] m/z (rel. int.): 935 (5, 2M + Na ), 457 (50, M + H ), 386 (40, M-COCHMeNH + H ), 315 (100), 242 (10).
+
+
HRMS ES for C26
29
H N
O
6 2
m/z: [M+H] Calc. 457.2352, found: 457.2346.
2
R
,2'-(1,4-Phenylene)bis-[5-isopropyl-3-(phenylamino)imidazolidin-4-one] (5l). Yellow liquid, mp 113-115 °C.
-
1
1
f
0.22 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3330, 1601, 1555, 1300. H NMR (300 MHz, CDCl
3
): δ 1.00
H
3
3
(12H, d, JHH 6.2 Hz), 1.92 (2H, s, NH), 2.28-2.31 (2H, m, CH), 3.65 (2H, d, JHH 7.4 Hz), 6.00 and 6.02 (2 x 1H, 2s,
13
CH), 6.62 and 6.64 (2 x 1H, 2s, NHPh), 7.24-7.26 (4H, m, CH aromatic), 7.38-7.41 (10H, m, CH aromatic). C
NMR (75 MHz, CDCl ): δ 20.15 (2 x (CH ), 20.19 (2 x (CH ), 33.00 (CH), 33.04 (CH), 74.60 (CH), 74.66 (CH),
5.20 (2 x CH), 75.24 (2 x CH), 113.30 (2 x CH aromatic), 122.02 (CH aromatic), 126.00 (CH aromatic), 127.00 (2
x CH aromatic), 130.10 (2 x C aromatic), 151.30 (2 x NHC aromatic), 173.30 (2 x C=O), 173.32 (2 x C=O).
3
C
3
)
2
)
3 2
7
2
0
δ
,2'-(1,4-Phenylene)bis-[5-isobutyl-3-(phenylamino)imidazolidin-4-one] (5m). White solid, mp 120-122°C. R
f
-1
1
.33 (EtOAc/c-C
6
3
H
12 1:1). IR (neat), νmax (cm ): 3263, 2957, 1703, 1602, 1497, 1082. H NMR (300 MHz, CDCl
3
):
3
H
1.01 (6H, d, JHH 6.4 Hz), 1.05 (6H, d, JHH 6.7 Hz), 1.55-1.59 (2H, m, CH), 1.88-1.90 (4H, m, CH
2
), 3.82-3.85
3
(2H, m, CH), 5.59 (2H, s, CH), 5.61 (2H, s, NH), 6.87-6.92 (4H, m, CH aromatic), 7.05 (4H, d, JHH 8.7 Hz), 7.08-
13
7.11 (4H, m, CH aromatic), 7.33-7.37 (4H, m, CH aromatic). C NMR (75 MHz, CDCl
3
): δ
C
3
21.51 (CH ), 23.36
(CH
3
), 25.09 (2 x CH), 42.04 (CH ), 42.10 (CH ), 55.29 (CH), 55.92 (CH), 74.26 (CH), 74.65 (CH), 113.81 (2 x CH
2
2
aromatic), 121.59 (2 x CH aromatic), 121.70 (2 x CH aromatic), 127.59 (2 x CH aromatic), 127.68 (2 x CH
aromatic), 129.20 (2 x CH aromatic), 129.33 (2 x CH aromatic), 140.25 (2 x C aromatic), 145.20 (NHC aromatic),
1
45.32 (NHC aromatic), 174.39 (2 x C=O), 174.64 (2 x C=O). ESI(+)-MS CH
3
CN [C = 2, SC = 20, EC = 2] m/z (rel.
+
+
+
int.): 631 (15), 563 (100, M + Na ), 541 (90, M + H ), 428 (10, M-COCHiBuNH + H ), 301 (15), 242 (25). HRMS
ES for C32
+
+
H
41
N
O
6 2
m/z: [M+H] Calc. 541.3291, found: 541.3293.
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Arkivoc 2018, iii, 229-239
Bouzayani, N. et al.
2
0
1
,2'-(1,4-Phenylene)bis-[5-benzyl-3-(phenylamino)imidazolidin-4-one] (5n). White solid, mp 129-131°C. R
f
-
1
1
.28 (EtOAc/c-C
6
H
12 1:1). IR (neat), νmax (cm ): 3277, 3031, 1699, 1590, 1398. H-NMR (300 MHz, CDCl
3
): δ
H
.28 (2H, s, NH), 3.41 (2H, dd, JHH 12.3, 3JHH 6.0 Hz), 3.55 (2H, dd, JHH 12.3, JHH 6.0 Hz), 4.02 (2H, t, JHH 6.0
3
3
3
3
3
Hz), 4.09 (2H, t, JHH 6.0 Hz), 6.27 and 6.30 (2 x 1H, 2s, CH), 6.48 and 6.50 (2 x 1H, 2s, NHPh), 6.79-6.97 (8H, m,
CH aromatic), 7.05-7.20 (3H, m, CH aromatic), 7.23-7.29 (8H, m, CH aromatic), 7.37-7.39 (3H, m, CH aromatic).
1
3
C NMR (75 MHz, CDCl
aromatic), 114.07 (2 x CH aromatic), 121.51 (2 x CH aromatic), 125.42 (CH aromatic), 127.17 (2 x CH aromatic),
29.11 (4 x CH aromatic), 129.23 (4 x CH aromatic), 130.09 (2 x CH aromatic), 136.28 (2 x CH aromatic), 139.83
2 x C aromatic), 145.03 (2 x NHC aromatic), 145.12 (2 x NHC aromatic), 172,56 (2 x C=O). ESI(+)-MS CH CN [C =
.5, SC = 30, EC = 3] m/z (rel. int.): 609 (100, M + H ), 462 (50, M-CONHCHBn + H ), 315 (100), 120 (70). HRMS
3
): δ
C
36.84 (CH ), 57.74 (CH), 58.40 (CH), 73.88 (2 x CH), 74.83 (2 x CH), 113.66 (4 x CH
2
1
(
0
3
+
+
+
+
ES for C38
H
37
N
O
6 2
m/z: [M+H] Calc. 609.2978, found: 609.2975.
2
,2'-(1,4-Phenylene)bis-[5-(2-methylthioethyl)-3-(phenylamino)imidazolidin-4-one] (5o). Orange solid, mp
-1
1
125-127 °C. R
f
0.45 (EtOAc/c-C
6
H12 1:1). IR (neat), νmax (cm ): 3284, 2916, 1695, 1601, 1445, 1409, 1091. H
NMR (300 MHz, CDCl
3
): δ 2.00 (2H, s, NH), 2.00-2.04 (4H, m, CH
H
2
), 2.30 (6H, s, CH
3
), 2.62-2.64 (4H, m, CH ),
2
.74-3.77 (2H, m, CH)), 4.03 (2H, s, CH), 5.92 (2H, s, NHPh), 6.92 (2H, t, JHH 7.9 Hz), 7.12 (4H, d, 3JHH 8.7 Hz),
3
3
7
SCH
3
3
13
.24-7.27 (4H, m, CH aromatic), 7.40 (4H, dd, JHH 8.7, JHH 7.9 Hz). C NMR (75 MHz, CDCl
), 30.50 (CH ), 30.53 (CH ), 34.10 (2 x CH ), 34.14 (2 x CH ), 68.00 (2 x CH), 68.03 (2 x CH), 75.80 (2 x CH),
5.83 (2 x CH), 113.22 (2 x CH aromatic), 123.11 (2 x CH aromatic), 126.00 (CH aromatic), 130.40 (CH
aromatic), 136.50 (2 x C aromatic), 153.31 (2 x NHC aromatic), 173.20 (2 x C=O), 173.22 (2 x C=O). ESI(+)-MS
3
): δ
C
15.40 (2 x
3
2
2
2
2
7
+
+
CH
3
CN [C = 0.5, SC = 30, EC = 3] m/z (rel. int.): 577 (100, M + H ), 486 (10), 446 (5, M-COCH(CH ) SMeNH + H ),
2
2
+
+
355 (10). HRMS ES for C30
37
H N
6
O
2
S m/z: [M+H] Calc. 577.2419, found: 577.2418.
2
Acknowledgements
The authors thank the DGRSRT (Direction Générale de la Recherche Scientifique et de la Rénovation
Technologique) of the Tunisian Ministry of Higher Education and Scientific research for financial support.
Supplementary Material
1
13
Stereochemistry analysis, examples of H and C NMR spectra are available as supporting information.
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