An easy one-step synthesis of imidazolin-2-ones from phthalic anhydrides and their antioxidant evaluation

Article abstract of DOI:10.1016/j.mencom.2016.01.027

Treatment of phthalic anhydride derivatives with trimethylsilyl azide affords benzimidazolin-2-ones in 45-91% yield, which is the result of two consecutive Curtius reactions. Within the series obtained, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one showed highest antioxidant activity.

Full text of DOI:10.1016/j.mencom.2016.01.027

Mendeleev
Communications
Mendeleev Commun., 2016, 26, 69–71
An easy one-step synthesis of imidazolin-2-ones
from phthalic anhydrides and their antioxidant evaluation
Héctor S. López,a José E. Enciso,a Adrián Ochoa-Terán,b Juan I. Velazquezc and Juan I. Sarmiento*c
a Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Sinaloa, 80040 Culiacán, Sinaloa,
México
b Centro de Graduados e Investigación en Química, Instituto Tecnológico de Tijuana, 22510 Tijuana, B.C.,
México
c Facultad de Ingeniería Culiacán, Universidad Autónoma de Sinaloa, 80040 Culiacán, Sinaloa, México.
Fax: +52 667 713 4043; e-mail: jsarmiento@uas.edu.mx
DOI: 10.1016/j.mencom.2016.01.027
Treatment of phthalic anhydride derivatives with trimethylsilyl azide affords benzimidazolin-2-ones in 45–91% yield, which is the
result of two consecutive Curtius reactions. Within the series obtained, 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one showed highest
antioxidant activity.
Imidazolidinones are commonly synthesized by cyclization of
1,2-diamines with phosgene or 1,1'-carbonyldiimidazole.1 For the
synthesis of imidazolidinones several routes have been reported,2
but probably the most commonly used methodology involves
the use of isocyanates, i.e., the reaction with amino alcohols,3
amines,4 a-imino ketones,5 vinylaziridines6 and allylamines.7
Imidazolidinones are found in several natural compounds, e.g.,
Biotin (vitamin B) which was isolated from yolk, and is a co-
enzyme in the carboxylation reaction in the biosynthesis of
the fatty acids.8 Imidazolidinones have been reported against
b-secretase (BACE1) inhibitors in Alzheimer’s disease,9 avb3-
antagonist in the prevention and treatment of Osteoporosis,10
against Schistosoma mansoni,11 selective Human Enterovirus 71
inhibitors,12 muscarinic M3 selective antagonists.13 They possess
anticancer (A549, COLO205, KATO III, K562),13(c) antibacterial
and antifungal,14 and antileishmanial15 activities.
O
O
Me3SiN3
N3
R
R
R
O
OH
O
O
1
N2
NCO
O
O
R
OH
N
H
O
O
2
Me3SiN3
CO2
O
Recently, we have reported the synthesis of small heterocyclic
compounds and their antioxidant evaluation.16 Currently, our
research is focused on the development of a simple one-pot syn-
thesis of small heterocyclic compounds with potential biological
activities. In this paper, an easy one-step synthesis of benzimid-
azolin-2-ones from phthalic anhydride derivatives with trimethyl-
silyl azide (TMSA) and their antioxidant evaluation are reported.
On the treatment of phthalic anhydrides 1 with TMSA the
Curtius rearrangement leads to benzoxazine-2,4-dione inter-
mediates 2, followed by the second Curtius rearrangement and
final intramolecular cyclization to provide imidazolin-2-ones 3
(Scheme 1). We started with the optimization of reaction condi-
tions using phthalic anhydride 1a as a model. First, a comparison
between the reaction efficiencies of TMSA generated in situ and
commercial reagent was made with TLC monitoring until the
reaction of the phthalic anhydride was complete. The reactions
of TMSA generated in situ (from trimethylsilyl chloride with
sodium azide) and commercial reagent in THF for 30 h at reflux
provided compound 3a in 20 and 51% isolated yields, respec-
tively. Subsequently, different solvents [DMSO, benzene, aceto-
nitrile and benzene–acetonitrile (3:1 v/v)] were tested under
optimal reaction conditions. When DMSO was used as a solvent,
product 3a was not formed and some non-identified by-products
were obtained. Probably this reaction follows a mechanism similar
to that proposed by Snyder17 for the synthesis of alkyl chloride
from TMSCl. In contrast, the employment of other above solvents
N=C=O
NH2
N3
NH2
R
R
R
N2
H
N
O
N
H
3
Scheme 1
favored the expected product but gave a lower yield than THF.
Note that the matched conditions do not require any sophistication
and can be readily accomplished. The solvent was evaporated
in vacuo and the product precipitated with diethyl ether, to provide
the corresponding imidazolin-2-ones in moderate to good yields.
The highest yield in THF could be associated with the solubility
of reagents and intermediates in this solvent. The yields of imid-
azolin-2-ones 3a–g synthesized using this methodology (Table 1)†
were 45–91% depending on the structure of the starting mate-
rial. The structures of the imidazolin-2-ones were confirmed by
NMR, IR spectra, and GC-MS. Jones and Schofield18 reported
the synthesis of imidazolin-2-one by a four-step method from
1,2,3,6-tetrahydrophthalic anhydride with TMSA in 72 h to give
a 19% of overall yield but obtained a mixture of imidazolin-
© 2016 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2016, 26, 69–71
Table 1 Yield and antioxidant activity of imidazolin-2-ones obtained.
In a comparative evaluation of antioxidant properties of new
molecules gallic acid, ascorbic acid and BHT are commonly used as
reference standards.21 Thus, compounds 3a–g were estimated up
to 100 mg ml–1 (for details, see Online Supplementary Materials) and
exhibited less activity than the reference standards. They revealed
an IC50 > 100 mg ml–1 being inactive as compared with gallic
acid (IC50 = 10.40 mg ml–1) and vitamin C (IC50 = 10.21 mg ml–1).
Compound 3e showed the highest IC50 of 315 mg ml–1.
In summary, in this work an easy one-step synthesis of imid-
azolin-2-ones from phthalic anhydride derivatives and TMSA in
good yields has been developed. From a combinatorial chemistry
viewpoint, this methodology could allow preparing a mini library
of analogues that exhibit the potential of being versatile synthons
in the synthesis of wide variety of heterocyclic compounds with
expected biological activity.
Entry
Compound
Yield (%)
IC50 (mg ml–1)
H
N
3a
O
51
2898
N
H
H
N
But
Me
F
3b
O
O
O
52
497
N
H
H
N
3c
3d
3e
3f
77
50
660
595
N
H
H
N
This work was supported by Consejo Nacional de Ciencia y
Tecnología (SEP-CONACyT, grant no. CB-2012-178266-Q).
N
H
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2016.01.027.
H
N
91
45
49
315
384
918
O
O
O
N
N
H
H
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†
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