Green synthesis of new chiral 1-(arylamino)imidazo-[2,1-a]isoindole-2,5-diones from the corresponding α-amino acid arylhydrazides in aqueous medium

Article abstract of DOI:10.3762/bjoc.14.271

New chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-dione derivatives were obtained in good to excellent yields via the cyclocondensation of 2-formylbenzoic acid and various α-amino acid arylhydrazides using water as the solvent in the presence of sodium

Full text of DOI:10.3762/bjoc.14.271

Green synthesis of new chiral 1-(arylamino)imidazo-
2,1-a]isoindole-2,5-diones from the corresponding
[
α-amino acid arylhydrazides in aqueous medium
Nadia Bouzayani1, Jamil Kraїem*2, Sylvain Marque*3, Yakdhane Kacem*1,
Abel Carlin-Sinclair4, Jérôme Marrot3 and Béchir Ben Hassine1
Full Research Paper
Open Access
Address:
Laboratoire de Synthèse Organique Asymétrique et Catalyse
Beilstein J. Org. Chem. 2018, 14, 2923–2930.
1
doi:10.3762/bjoc.14.271
Homogène, (UR 11ES56) Université de Monastir, Faculté des
Sciences de Monastir, avenue de l’environnement, 5000 Monastir,
Tunisie. Fax: (+216) 73 500 278; Tel: (+216) 73, 2Laboratoire de
Développement Chimique, Galénique et Pharmacologique des
Médicaments, Faculté de Pharmacie de Monastir, Université de
Monastir, Rue Avicenne, 5000 Monastir, Tunisie, 3Université de
Versailles Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles
Received: 11 August 2018
Accepted: 05 November 2018
Published: 26 November 2018
Associate Editor: L. Vaccaro
(
ILV), UMR CNRS 8180, 45 avenue des Etats-Unis, 78 035 Versailles
© 2018 Bouzayani et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Cedex, France and 4Université de Versailles
Saint-Quentin-en-Yvelines, Département de chimie, 45 avenue des
Etats-Unis, 78 035 Versailles Cedex, France
Email:
Jamil Kraїem* - jamil.kraiem.1@ulaval.ca; Sylvain Marque* -
sylvain.marque@uvsq.fr; Yakdhane Kacem* -
kacem.yakdhane@fphm.rnu.tn
*
Corresponding author
Keywords:
sodium dodecyl sulfate; totally diastereoselective;
trans-stereochemistry
Abstract
New chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-dione derivatives were obtained in good to excellent yields via the cyclocon-
densation of 2-formylbenzoic acid and various α-amino acid arylhydrazides using water as the solvent in the presence of sodium
dodecyl sulfate as the surfactant and under simple and minimum manipulation, without purification. The reaction is totally dia-
stereoselective and gives access to the nitrogenated tricyclic core with a relative trans stereochemistry.
Introduction
Tricyclic compounds, such as imidazo[2,1-a]isoindol-5-ones, tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones I which are
are widely distributed in nature and possess several biological recognized as anti-inflammatory and analgesic agents [1]. Other
activities. In 1967, Geigy described the preparation of 1,2,3,9b- compounds, such as 1H-imidazo[2,1-a]isoindole-2,5-diones II
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have been known as an important herbicides for bud growth ongoing efforts directed toward the development of environ-
inhibition [2-6] and plant growth regulation [7-11]. Several mentally safe conditions for the synthesis of heterocyclic com-
research groups have turned to the synthesis of these structural pounds starting from natural (L)-α-amino acids [19-23] and the
analogues (Figure 1) [12]. For example, the stereoselective syn- reactivity of α-amino acid phenylhydrazides [24,25], we now
thesis of chiral 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones report a green and eco-friendly procedure for the synthesis
[
[
6] and 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones of new chiral 1-(arylamino)-1H-imidazo[2,1-a]isoindole-
13] has been described by Katritzky et al. using α-amino- 2,5(3H,9bH)-diones (Scheme 1).
amides and diamines, respectively.
Scheme 1: Strategy for the formation of 1-(arylamino)-1H-imidazo[2,1-
a]isoindole-2,5(3H,9bH)-diones.
Results and Discussion
Synthesis
The starting (L)-α-amino acid arylhydrazides 3 were prepared
in a manner similar to the well-known procedures [26-28], im-
proving the amount of the added arylhydrazine 2 down to
Figure 1: Chemical structures of analogues.
Also, the imidazo[2,1-a]isoindole-2,5-dione derivatives of 2.5 equiv (Scheme 2, Table 1) in a sealed tube in the presence
primaquin have been synthesized from α-amino acids [14]. of Et3N and under solvent-free conditions. From green chem-
Focusing on the 1H-imidazo[2,1-a]isoindolone skeleton, istry point of view, this enhanced procedure appears to be a
Hosseini-Zare et al. reported the synthesis of new 2,3-diaryl- good alternative of the precedents for the synthesis of
5
1
H-imidazo[2,1-a]isoindol-5-ones via the one pot reaction of hydrazides 3a–m [26-29]. Moreover, the phenylglycine phenyl-
,2-diketones, 2-formylbenzoic acid and ammonium acetate hydrazide (3d), (L)-cysteine phenylhydrazide (3g), (L)-tyrosine
[
15]. These methodologies usually use toxic solvents such as phenylhydrazide (3j), (L)-alanine 4-chlorophenylhydrazide
benzene [16], dichloromethane and some catalyst such as para- (3k), (L)-phenylglycine 4-chlorophenylhydrazide (3l) and
toluenesulfonic acid [17]. Furthermore, most of them induce to (L)-phenylalanine 4-chlorophenylhydrazide (3m) were synthe-
manage undesirable waste produced in stoichiometric amounts. sized for the first time in this work.
Recently, such synthetic methods utilizing hazardous solvents
and reagents and generating toxic waste have become discour- Verardo et al. [29] have shown that refluxing α-amino acid
aged and there have been many efforts to develop safer and en- phenylhydrazides with levulinic acid in toluene led to the corre-
vironmentally benign alternatives. The green chemistry concept sponding dihydro-1H-pyrrolo[1,2-a]imidazole-2,5-diones.
emerged in 1990 [18] with the aim at developing cleaner ap- These authors explained clearly the behavior of the solvent and
proaches through the simplification of chemical processing its influence in the reaction. In addition, substituted 1-hydroxy-
along with the decreases of waste and cost. As a part of our 1H-imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones have been
Scheme 2: Synthesis of the starting (L)-α-amino acid phenylhydrazides and 4-chlorophenylhydrazides 3a–m under solvent-free conditions.
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Table 1: Synthesis of the α-amino acid arylhydrazides 3a–m.
entry
product (mol %)
R
R’
yielda [%]
mp [°C]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3db
3e
3f
Me
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
87
80
70
83
93
81
71
71
80
77
69
70
74
122–124
138–140
152–154
138–140
142–144
128–130
98–100
iPr
iBu
Ph
Bn
(CH2)2SMe
CH2SH
CH2OH
3-CH2-1H-indole
CH2C6H4OH
Me
3g
3h
3i
163–165
168–170
134–136
128–130
135–137
140–142
10
11
12
13
3j
3k
3l
Ph
3m
Bn
aYield of the isolated product. bThe compound 3d was obtained as a racemic mixture.
synthesized by the condensation of (L)-α-aminohydroxamic tally benign solvent and interest has increasingly turned to it as
acids and 2-formylbenzoic acid under the same conditions [30]. the greenest solvent of chemical reactions [34]. In order to find
Thus, they choose toluene as the best solvent for this reaction. the best reaction conditions, a model reaction was chosen using
To prepare the new chiral 1-(arylamino)imidazo[2,1-a]isoin- (L)-alanine phenylhydrazide (3a, Scheme 3), and the results of
dole-2,5-diones 5a–m under greener conditions, we investigat- these optimized studies were summarized in Table 2.
ed the reaction in nontoxic solvents such as water and dimethyl
carbonate (DMC). Indeed, DMC is well-known as safe reagent The best result was obtained when a mixture of hydrazide 3a
and solvent that has been used for many green applications and formylbenzoic acid 4 was heated at 120 °C (oil bath) using
[
31-33]. On the other hand, water is a simply and environmen- water as the solvent in the presence of SDS (10%) as the surfac-
Scheme 3: Cyclocondensation of 2-formylbenzoic acid (4) with (L)-alanine phenylhydrazide (3a).
Table 2: Optimization of the reaction conditions for the cyclocondensation of 2-formylbenzoic acid (4) with (L)-alanine phenylhydrazide (3a).a
entry
additive [mol %]
time [h]
conditionsa
yields [%]
1
2
3
4
5
6
–
4
DMCb
H2O
82
72
77
90
89
88
–
10
10
10
10
4
SDS [5]
H2O
SDS [10]
H2Oc
–
–
neatd
toluenee
aGeneral conditions for all the six entries: (L)-alanine phenylhydrazide (0.66 mmol), 2-formylbenzoic acid (0.66 mmol), 120 °C. bConditions: DMC
1.5 mL) in sealed tube. cConditions: water (1.5 mL) and sodium dodecyl sulfate (SDS) in sealed tube. dConditions: in sealed tube. eConditions:
toluene (3 mL), under argon.
(
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tant for 10 h leading to a 90% yield in 5a. To demonstrate the acid residue is. A weak acidic function was well-tolerated
generality of this method, we next investigated the scope of this yielding 5j with 66%. Bulky groups did not roughly affect the
reaction under the optimized conditions. A variety of the efficiency of the reactivity (5b, 5c).
1
-(arylamino)imidazo[2,1-a]isoindole-2,5-diones 5b–m were
prepared and the obtained results are summarized in Scheme 4. The new approach described in this work for the preparation of
The mild conditions of the reaction gave access to the tricyclic compounds 5a–m has the following advantages: (i) notably,
compounds 5a–m providing similar yields, regardless the amino under the reaction conditions described above, we have never
Scheme 4: Synthesis of the nitrogenated tricyclic compounds 5a–m. Diastereoisomeric (dr) and enantiomeric (er) ratio were determined by chiral
HPLC (see Supporting Information File 3).
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observed the formation of degradation products. (ii) The reac-
tion was performed in water, in the presence of SDS (sodium
dodecyl sulfate) as the surfactant. Based on previous studies
[
35], the most effective method for ensuring the solubility of
reactants in water is the use of surfactants that can form
micelles with a hydrophobic core and a hydrophilic corona.
(
iii) This clean method afforded compounds 5a–m without the
need of additional purification such as column chromatography
or recrystallization. (iv) The use of a sealed tube [36-43] obeys
to four out of the twelve green chemistry principles: a cleaner
and eco-friendly reaction profile with minimum of waste, sol-
vent without negative environmental impact, shorter reaction
time and safely work with a pressure tube canning prevent fires
and emissions of hazardous compounds and toxic gas. (v) The
reaction described in this work occurred with high atom effi-
ciency (atom economy of 90%) and produced only stoichio-
metric H2O as waste (E-factor of 0.1).
Stereochemistry and mechanism
The stereochemistries of 5a–m were ascribed by NOE NMR
experiments. By example using 5a depicted in Figure 2, the
1
H NMR spectrum showed that H(1) appears at 5.95 ppm as a
singlet and H(4) at 4.72 ppm as a quadruplet. No distinct NOE
effect was observed between H(1) and H(4), when either H(1)
or H(4) was irradiated. A significant positive NOE effect was
observed between H(1) and H(20). Thus, NOE analysis
assumed that H(1) is in a trans-orientation with H(4).
Figure 3: X-ray crystal structure of 5f shown at the 30% probability
level.
C(3)–O(1) with similar distances of 1.222 and 1.218 Å, respec-
tively. The intramolecular hydrogen bond O(1)–H(13) remains
strong in the nitrogenated tricycle (2.579 Å) vis-à-vis of the
starting hydrazide.
Analyzing the mechanism of the reaction between the 2-formyl-
benzoic acid 4 and α-amino acid arylhydrazides 3, we assumed
that the first steps lead to the formation of the imine intermedi-
ate A, which is the result of the nucleophile addition of the
α-amino group on the most electrophilic center in 4. This imino-
carboxylic acid form likely evolves to its iminium-carboxylate
form B [50]. This last intermediate involves the existence of
two possible transition states for the cyclization of the imidazo-
Figure 2: NOEs correlation showing the stereochemistry of the com-
pound 5a.
In addition, various crystallization tests were carried out in lidinone core of which one of them is favored by an intramolec-
order to confirm the absolute stereochemistry by X-ray diffrac- ular hydrogen bond (Scheme 5). This control is the main differ-
tion. The chiral 3-(2-(methylthio)ethyl)-1-(phenylamino)-1H- ence with the known reaction [51] between the hydrazides 3 and
imidazo[2,1-a]isoindole-2,5(3H,9bH)dione (5f) crystallized the phthalaldehydes in which two diasteroisomers have been
[
44-49] using a mixture of CH2Cl2/diethyl ether (3:1) as a observed. If the amino acid residue (R on the Scheme 5) enough
single diastereoisomer with the (3S,9R) configuration (Figure 3) implicates steric hindrance with the carboxyaromatic part of B,
showing clearly the trans relative stereochemistry.
the pathway with disfavored transition state becomes unlikely
and then the selectivity is important. Our model is in agreement
The dihedral angle value of −163.1° for H(1)–C(1)–C(4)–H(4) with the diasteroisomeric ratio results. In fact, a total diastereo-
close to the anti-planarity corroborates the expected non corre- selectivity was observed, including 5d (R = Ph) since an epi-
lation between H(1) and H(4) in the NOE experiment. The merization of the initial asymmetric center was observed, there-
structure contains two carbonyl moieties C(6)–O(2) and fore racemic trans-isomers were obtained in this case. Interest-
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Beilstein J. Org. Chem. 2018, 14, 2923–2930.
Scheme 5: Proposed partial mechanism with a selectivity model.
ingly, acidic (phenolic 5j) and basic moieties (as indolyl 5i) on
Supporting Information
the amino acid residue did not affect the selectivity.
Supporting Information File 1
Conclusion
Experimental procedures, spectroscopic and analytical data
and copies of spectra of the products.
In summary, we have developed environmentally safe condi-
tions for the synthesis of new chiral 1-(arylamino)-1H-
imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones in good yields
using water as the solvent in sealed tube. The aspects of green-
ness and good results make this methodology a practical and
atom economical alternative in the whole of the processing
since the syntheses of the α-amino acid arylhydrazide precur-
sors behave this greener aspect. Once more, the processing
includes this eco-friendly way up to have the compounds in
hand since simple precipitation allows to isolate the nitro-
genated tricyclic compounds; no purification is needed. The
model for the key step of the cyclization clearly explains the
stereochemistries, which are observed with a total trans-dia-
stereoselectivity controlled by intramolecular hydrogen bonds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-271-S1.pdf]
Supporting Information File 2
Crystallographic information for compound 5f.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-271-S2.pdf]
Supporting Information File 3
HPLC analysis of the products.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-271-S3.pdf]
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2
2
2
2
2
2
1.Tka, N.; Kraïem, J.; Kacem, Y.; Hajri, A.; Ben Hassine, B. C. R. Chim.
Acknowledgements
2009, 12, 1066–1071. doi:10.1016/j.crci.2008.09.004
The authors thank the DGRST (Direction Générale de la
Recherche Scientifique et Technologique) of the Tunisian
Ministry of Higher Education and Scientific research and Tech-
nology for financial support of this research.
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1
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