Synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the one-pot reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate

Article abstract of DOI:10.1016/j.tetlet.2012.04.088

We describe a new one-pot synthesis of 2,3-diaryl-5H-imidazo[2,1-a] isoindol-5-ones via the reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate in acetic acid under reflux conditions and in the absence of a catalyst.

Full text of DOI:10.1016/j.tetlet.2012.04.088

Tetrahedron Letters 53 (2012) 3448–3451
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Synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the one-pot
reaction of 1,2-diketones, 2-formylbenzoic acids, and ammonium acetate
Maryam Sadat Hosseini-Zare a, Mohammad Mahdavi b, Mina Saeedi b, Mehdi Asadi b, Shahrzad Javanshir a,
Abbas Shafiee b, Alireza Foroumadi b,
⇑
a Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran
b Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences, Tehran 14176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe a new one-pot synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones via the reaction of
1,2-diketones, 2-formylbenzoic acids, and ammonium acetate in acetic acid under reflux conditions and
in the absence of a catalyst.
Received 3 March 2012
Revised 30 March 2012
Accepted 19 April 2012
Available online 26 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[2,1-a]isoindol-5-one
1,2-Diketones
Ammonium acetate
The synthesis of benzimidazole-based heterocycles has attracted
growing interest owing to their important biological activities.1–3 2-
Substituted 4,5-diaryl-1H-imidazoles have been identified as COX-2
inhibitors4 and as human cannabinoid-1 (CB1) receptor inverse ago-
nists.5 Moreover, fused imidazoles have exhibited interesting bio-
logical properties.6 5H-Imidazo[2,1-a]isoindol-5-one derivatives
have also been applied as biologically active agents. For example,
1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones (Fig. 1) pos-
sess anti-inflammatory, analgesic, antihypertensive, spasmolytic,
tranquilizing, and antitussive properties,7 and are also useful seda-
tive and hypotensive agents.8
Thus improvements in the synthesis of imidazoles, including the
preparation of new 5H-imidazo[2,1-a]isoindol-5-one derivatives
are very important in the context of medicinal chemistry. There
are a number of useful routes for the synthesis of imidazo[2,1-a]iso-
indol-5-one derivatives. Katritzky et al.9 reported the synthesis of
chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-
ones via condensation of 2-formylbenzoic acids or 2-acetylbenzoic
acid with chiral diamines. The synthesis of 5H-imidazo[2,1-a]
isoindol-5-ones by reaction of o-benzoylbenzoic acids and
ethylenediamine has also been reported.10,11 Focusing on the
imidazo[2,1-a]isoindolone skeleton, Gomes et al.12 synthesized
various 1H-imidazo[2,1-a]isoindol-2,5(3H,9bH)-diones by the reac-
tion of N-{4-[(6-methoxyquinolin-8-yl)amino]pentyl}-2-amin-
oalkylamide derivatives and formylbenzoic acid. Their products
were found to exhibit anti-malarial activity.
In continuation of our research on the synthesis of biologically
active heterocycles,13–16 and due to the fact that reports on the syn-
thesis of 5H-imidazo[2,1-a]isoindol-5-ones are infrequent, herein,
we present a new, reliable, and efficient synthetic route for the syn-
thesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-one derivatives 4
in the absence of a catalyst (Scheme 1). The products were obtained
by the condensation reaction between 1,2-diketones 1, 2-formyl-
benzoic acids 2, and ammonium acetate (NH4OAc) (3) in acetic acid
under reflux conditions.
It is worthwhile to mention that there are reports on the
synthesis of 2,4,5-triaryl-1H-imidazoles 6 using 1,2-diketones 1,
aromatic aldehydes 5, and ammonium acetate 3 under various
conditions (Scheme 2).17–20
Our results revealed that replacing the aldehyde with a 2-formyl-
benzoic acid can lead directly to the formation of the imidazo[2,1-a]
isoindol-5-one nucleus which undergoes further cyclization to give
2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-one derivatives 4.
O
R3
R2
N
R4
N
R1
Figure 1. 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-one derivatives.
⇑
Corresponding author. Tel.: +98 21 66954708; fax: +98 21 66461178.
E-mail address: aforoumadi@yahoo.com (A. Foroumadi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.088

M. S. Hosseini-Zare et al. / Tetrahedron Letters 53 (2012) 3448–3451
3449
N
N
Ar
CHO
O
AcOH, reflux
R
Ar
+
+
Ar
NH4OAc (excess)
R
Ar
CO2H
5 h
O
O
1
2
3
4
Scheme 1. Synthesis of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-one derivatives 4.
was obtained in good yield after reflux for five hours in acetic acid
in the presence of excess ammonium acetate.
O
O
N
Ar
Ar
different conditions
Ar1
Ar
Ar1
H
+
+
NH4OAc
Ar
The structure of product 4a was elucidated by spectroscopic
analysis. In the 1H NMR spectrum, signals for 14 aromatic protons
were observed around 7.30–7.91 ppm. The 13C NMR spectrum
showed 11 distinct signals in the aromatic region and a resonance
at d = 169.1 ppm for C@O group. The structure was also confirmed
by mass spectrometric fragmentation pattern analysis which dis-
played the molecular ion peak at 322 for C22H14N2O.
N
H
6
O
1
5
3
Scheme 2. Synthesis of 2,4,5-triaryl-1H-imidazole derivatives 6.
Our initial efforts to obtain compounds 4 involved the reaction
of stoichiometric amounts of benzil, 2-formylbenzoic acid, and
NH4OAc in solvents such as ethanol, dichloromethane, acetonitrile,
toluene, and acetic acid at various temperatures. There was no reac-
tion at room temperature and as expected, acetic acid proved to be
the best solvent under reflux conditions. The application of ammo-
nium acetate in acetic acid as a source of ammonia has been studied
widely in the synthesis of N-heterocycles.21 Also it was found that
excess ammonium acetate should be used to obtain the highest
yield of product. The corresponding product 4a (Table 1, entry 1)
To determine the most appropriate conditions, the reaction was
conducted under solvent-free conditions; however, the corre-
sponding product 4a was obtained in lower yield even after a long
reaction time. Also, using acetic acid allowed the reaction to
proceed using a wider range of substrates under the optimized
conditions (Table 1).22
The procedure was effective for both electron-donating and
electron-withdrawing substituents on the aromatic rings of the
1,2-diketone. The yield of the 2,3-diaryl-5H-imidazo[2,1-a]isoin-
Table 1
Synthesis of 5H-imidazo[2,1-a]isoindol-5-one derivatives 4
Entry
1,2-Diketone
2-Formylbenzoic acid
Product
Mp (°C)
Yield (%)
CHO
O
O
N
N
CO2H
1
293–294
85
O
4a
CHO
O
O
N
N
MeO
CO2H
OMe
2
3
4
5
180–181
273–274
234–236
219–220
90
80
80
OMe
O
OMe
4b
F
CHO
F
F
O
N
N
CO2H
O
F
O
4c
Cl
CHO
Cl
O
O
N
N
CO2H
Cl
Cl
Cl
O
4d
CHO
Cl
O
O
N
N
MeO
CO2H
OMe
85
OMe
Cl
Cl
O
OMe
4e
(continued on next page)

3450
M. S. Hosseini-Zare et al. / Tetrahedron Letters 53 (2012) 3448–3451
Table 1 (continued)
Entry
1,2-Diketone
2-Formylbenzoic acid
Product
Mp (°C)
Yield (%)
Br
CHO
Br
O
O
N
CO2H
6
7
301–302
80
Br
Br
O
4f
MeO
CHO
MeO
O
O
N
CO2H
N
218–219
70
MeO
OMe
MeO
OMe
O
4g
CHO
MeO
CO2H
O
O
N
OMe
N
8
213–215
70
OMe
O
OMe
OMe
Me
OMe
Me
4h
CHO
O
N
CO2H
N
9
O
265–266
206–207
75
70
Me
Me
O
4i
CHO
O
O
O
N
O
O
CO2H
N
O
10
O
4j
NH3
CHO
NH
CO2H
CO2H
Ar
Ar
N
O
2
7
+
HOAc
NH2 CO2H
Ar
NH
O
Ar
O
NH3
9
Ar
Ar
O
1
8
Ar
Ar
N
N
Ar
Ar
Ar
Ar
N
N
N
[1,5]-H shift
N
H
O
HO2C
HO2C
4
10
Scheme 3. A proposed mechanism for the formation of 2,3-diaryl-5H-imidazo[2,1-a]isoindol-5-ones 4.
dol-5-one product was moderate in the case of electron-donating
substituents. The proposed mechanism for this reaction is shown
in Scheme 3.
2-(4,5-diaryl-1H-imidazol-2-yl)benzoic acid 10. In the last step,
nucleophilic attack of the ring nitrogen on the carbonyl of the car-
boxylic acid leads to formation of products 4.
The first step is the formation of imine intermediate 7 and
-imino ketone 8 via nucleophilic attack of ammonia, derived from
NH4OAc, on the self-activated (by acetic acid) carbonyl groups.
Reaction of 7 and 8 leads to the formation of intermediate 9, which
undergoes cyclization, dehydration, and a [1,5]-H shift to give
In conclusion, a reliable, rapid, and high-yielding procedure for
the synthesis of potentially bioactive 2,3-diaryl-5H-imidazo[2,1-
a]isoindol-5-one derivatives 4 has been reported. The products
were obtained via the one-pot reaction of 1,2-diketones, 2-formyl-
benzoic acids, and ammonium acetate in acetic acid under reflux
a

M. S. Hosseini-Zare et al. / Tetrahedron Letters 53 (2012) 3448–3451
3451
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Acknowledgements
This research was supported by grants from the research coun-
cil of Tehran University of Medical Sciences and the Iran National
Science Foundation (INSF).
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Supplementary data
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S. Bull. Korean Chem. Soc. 2009, 30, 1057–1060.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
088. These data include MOL files and InChiKeys of the most
important compounds described in this article.
21. (a)Weiss, M. J. Am. Chem. Soc. 1952, 74, 200–202; (b)Davidson, D. J. Am. Chem. Soc.
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22. General procedure for the preparation of compounds 4: A mixture of 1,2-
diketone 1 (1 mmol), 2-formylbenzoic acid 2 (1 mmol), NH4OAc (3) (excess),
and AcOH (5 mL) was heated at reflux for 5 h. Upon completion of the reaction,
the mixture was cooled to room temperature and poured into cold H2O to
precipitate the crude product. Recrystallization from petroleum ether–EtOAc
gave the pure product 4. Compound 4a: Yield 85%, colorless crystals, mp 293–
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294 °C; IR (KBr): 3058, 2933, 1595 cmÀ1 1H NMR (DMSO-d6, 500 MHz):
;
dH = 7.30–7.33 (m, 2H), 7.37–7.40 (m, 4H), 7.50–7.53 (m, 5H), 7.62–7.65 (m,
1H), 7.83–7.85 (dd, J = 1.05, 1.1 Hz, 1H), 7.89–7.91 (d, J = 7.0 Hz, 1H); 13C NMR
(DMSO-d6, 125 MHz): dC = 169.1, 144.9, 132.7, 132.5, 132.0, 130.7, 130.1, 129.0,
128.8, 128.5, 127.6, 127.3; MS m/z (%) = 322 (M+, 23), 296 (82), 190 (30), 165
(100); Anal. Calcd for C22H14N2O: C, 81.97; H, 4.38; N, 8.69. Found: C, 82.10; H,
4.44; N, 8.75. Compound 4b: Yield 90%, colorless crystals, mp 180–181 °C; IR
(KBr): 3058, 2939, 1643 cmÀ1 1H NMR (DMSO-d6, 500 MHz): dH = 3.73 (s, 3H),
;
3.83 (s, 3H), 6.95–6.97 (d, J = 8.6 Hz, 1H), 7.23–7.47 (m, 10H), 7.71–7.73 (d,
J = 8.5 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz): dC = 171.5, 152.6, 146.3, 144.1,
137.2, 133.5, 128.6, 127.1, 126.9, 123.4, 118.4, 110.4, 60.5, 55.6; MS m/z
(%) = 382 (M+, 90), 342 (100), 299 (20), 165 (30); Anal. Calcd for C24H18N2O3: C,
75.38; H, 4.74; N, 7.33. Found: C, 75.45; H, 4.60; N, 7.25.