Metal-free construction of tricyclic or tetracyclic compounds - Acid-promoted synthesis of benzo[4,5]imidazo[2,1-a]isoindole and 1,2-dialkyl-2,3-dihydrobenzimidazoles

Article abstract of DOI:10.1016/j.tet.2012.10.030

An environmental friendly, efficient, and easy to operate strategy for synthesizing of benzo[4,5]imidazo[2,1-a]isoindole and 1,2-dialkyl-2,3- dihydrobenzimidazoles via acid-promoted coupling of dialdehyde and o-diaminobenzene under metal-free conditions is described. A series of products were generated in good yields under mild conditions.

Full text of DOI:10.1016/j.tet.2012.10.030

Tetrahedron 69 (2013) 316e319
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Metal-free construction of tricyclic or tetracyclic compoundsdacid-
promoted synthesis of benzo[4,5]imidazo[2,1-a]isoindole and
1,2-dialkyl-2,3-dihydrobenzimidazoles
,
,
,
,
,
,b,
*
Jinying Chen a b, Jinpeng Qu a b, Yuanqing Zhang a b, Yongxin Chen a b, Na Liu a b, Baohua Chen a
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu, Lanzhou 730000, PR China
b Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2012
Received in revised form 21 September 2012
Accepted 9 October 2012
Available online 16 October 2012
An environmental friendly, efficient, and easy to operate strategy for synthesizing of benzo[4,5]imidazo
[2,1-a]isoindole and 1,2-dialkyl-2,3-dihydrobenzimidazoles via acid-promoted coupling of dialdehyde
and o-diaminobenzene under metal-free conditions is described. A series of products were generated in
good yields under mild conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Environment friendly
Acid-promote
Dialdehyde
o-Diaminobenzene
Metal-free
1. Introduction
benzoic acid and o-diaminobenzene. Nevertheless it should be
pointed out that few of the methods for the formation of com-
Imidazo[2,1-a]isoindole and 1,2-dialkyl-2,3-dihydrobenzimida-
zoles compounds containing the skeleton of azoles have received
tremendous attention in recent years due to azoles displaying many
interesting properties, such as electrostatographic toners, organic
electronics.1 Moreover, the azoles, which contain C]N bond have
received epochal attention because of azoles’ potential application as
ligands.2,3
During the past decades, several transition-metal-catalyzed
methods for synthesis of a variety of N-heterocyclic compounds
have been emerged.4 For example, Y. Takegami,5 Pan,6 Fu7 groups
have already made many useful and extensively applicable
methods for the condensation of carbonyl group compounds and
amines, respectively. However, their corresponding catalytic sys-
tems have some drawbacks: they were complicated, the crude
materials and catalysts were obtained difficultly. In contrast, Foley8
group employed an efficient and easy to operate acid-promoted
method to form the skeleton of RN]CR0CR]NR with dialdehyde
and amine, and Daïch9 group made further study on 2-formyl-
pounds, which contain C]N and CeN.
In this paper, our group has developed an environmental friendly
and efficient method to prepare a series of benzo[4,5]imidazo[2,1-a]
isoindoles and 1,2-dialkyl-2,3-dihydrobenzimidazoles via acid-
promoted coupling of corresponding dialdehydes and o-dia-
minobenzenes under metal-free conditions. In our original as-
sumption, octatomic ring would be generated as same as the results
obtained by the Foley8 group. To our surprise, the results showed
that the interesting and useful tricyclic and tetracyclic N-heterocy-
cles were produced.
2. Results and discussion
In order to identify the optimal reaction conditions, o-phtha-
laldehyde (1a) and o-diaminobenzene (2a) were chosen as the test
substrates. When the reaction was carried out with 0.2 mL HCOOH
as the promoter, 2 mL MeOH as solvent at room temperature for
12 h under nitrogen atmosphere, and the product 3aa was obtained
in 60% (Table 1, entry 1). The result encouraged us to keep opti-
mizing the conditions of the reaction.
The use of 0.5 mL promoter HCOOH proved essential (Table 1,
entries 2, 3). The screening experiments also indicated that
* Corresponding author. E-mail address: truecwl123@126.com (B. Chen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.030

J. Chen et al. / Tetrahedron 69 (2013) 316e319
317
Table 1
Table 2
Study of the reactiona
o-Phthalaldehyde (1a) reacted with various o-diaminobenzenea
N
N
R
N
N
N
N
NH2
NH2
CHO
CHO
NH
CHO
2
2
HCOOH,MeOH
0oC,2h
HCOOH,MeOH
R
o
0 C,2h
R
NH
CHO
1a
2(a-h)
3
4
1a
3aa
2a
Entry
1
Amine
Product
Yieldb(%)
82
Entry
Pro. (mL)
Solvent (mL)
T/ꢀC
Yieldb (%)
1
2
3
4
5
6
7
8
9
HCOOH (0.2)
HCOOH (0.5)
HCOOH (0.5)
HCOOH (0.5)
HCOOH (0.5)
HCOOH (2)
AcOH (2)
MeOH (2)
MeOH (2)
MeOH (2)
EtOH (2)
EtOH (2)
HCOOH
AcOH
MeOH (2)
EtOH (2)
rt
0
0
0
90
90
90
90
90
60c
82
74d
72
68
54
53
56
65
N
N
3aa
N
N
AcOH (0.5)
AcOH (0.5)
NH2
NH2
2
98
3ab
N
a
3ab:4ab¼1.7:1
The reaction was carried out using 0.5 mmol of 1a,1 mmol of 2a, 0.5 mL of
catalyst, 2 mL solvent at 0 ꢀC for 2 h.
2b
2c
2d
2e
b
N
Isolated yields.
Under nitrogen atmosphere.
The reaction time is 4 h.
c
4ab
d
OCH
OCH
3
N
N
NH2
NH2
prolonged reaction time (4 h) would reduce the yield. After that,
we decided to perform further optimizations with a variety of
solvents. To our delight, MeOH was the best choice while EtOH
was less effective (Table 1, entries 3, 4). By improving the tem-
perature of reactions, the desirable yields were not obtained
(Table 1, entry 5). With promoters as the solvents, the yields were
failed to improve (Table 1, entries 6, 7). If we employed others as
the solvents, AcOH as the promoter would reduce the yields
(Table 1, entries 6e8). Therefore, the optimal metal-free system
for this reaction involves formic acid (0.5 mL), methanol (2 mL),
3
92
3ac
N
3ac:4ac¼1.4:1
H3CO
N
3
4ac
Cl
N
N
NH2
4
86
3ad
N
0
ꢀC, and 2 h. Considering to develop an environmental friendly
and easy to operate reaction, these metal-free conditions were
clearly the best.
3ad:4ad¼1.1:1
Cl
NH2
N
Cl
Br
Encouraged by the efficiency of the reaction protocol above,
the scope of the reaction was examined. Firstly, various o-dia-
minobenzenes were investigated to be reacted with o-phtha-
laldehyde under metal-free conditions at proper temperature
4ad
N
N
0
ꢀC. When o-diaminobenzene without functional groups was
NH2
NH2
employed, an acceptable yield was obtained (Table 2, entry 1).
Generally, good to all excellent yields were obtained for
electron-donating or with-drawing groups (Table 2, entries 2e5)
except nitro group (Table 2, entry 6). Notably, regioselectivities
were discovered when o-diaminobenzenes with Me, MeO, Cl,
and Br groups were investigated. The products of substrates
substituted by Me and MeO groups were distinguished well, but
Cl and Br groups offered a mixture of regioisomers. Affirmed by
1H NMR, 13C NMR, and the published literature,10 3 was the fa-
vorable isomer. However, when o-diaminobenzenes bearing
double electron-withdrawing groups were used, the yield de-
creased sharply (Table 2, entry 7). And no desired product was
detected when annular alkyldiamine 2h reacted with 1a (Table
2, entry 8).
Subsequently, we studied the reaction scope of glutaralde-
hyde (1b). However, at 0 ꢀC, all yields were lower than 120 ꢀC. It
was found that the reaction proceeded successfully when o-
diaminobenzene without functional group was used, affording
the corresponding product in excellent yield (Table 3, 3ba).
Substrate with electron-withdrawing functional groups formed
better yields (Table 3, 3bd, 3bf, 3bg) than electron-donating ones
(Table 3, 3bb, 3bc).Apart from this, 3be and 4be were formed
smoothly but produced in lower yields. Consistent with the
reaction between o-phthalaldehyde (1a) and kinds of o-
5
6
83
3ae
N
3ae:4ae¼1.5:1
Br
N
Br
4ae
NO2
NH2
NH2
N
Tracec
N
O2N
2f
3af
Cl
Cl
NH2
NH2
7
8
Tracec
N.D.d
2g
N
NH
2
2
N
NH
2h
3ah
a
The reaction was carried out using 0.5 mmol of 1a, 1.0 mmol of 2a, 0.5 mL of
HCOOH, then 2 mL MeOH was added to the mixture at 0 ꢀC for 2 h.
b
Isolated yields.
At 120 ꢀC.
No desired product was detected.
c
d

318
J. Chen et al. / Tetrahedron 69 (2013) 316e319
Table 3
synthesis of benzo[4,5]imidazo[2,1-a]isoindole and 1,2-dialkyl-
Glutaraldehydea (1b) reacted with various o-diaminobenzeneb,c
2,3-dihydrobenzimidazoles under metal-free conditions. The
easy to operate method could be effectively employed to com-
pose some compounds, which contain C]N and CeN in one-pot.
Simple available substrates, mild reaction conditions and de-
tailed investigation on the two further capable mechanisms all
showed the superiority of the reaction, which would be widely
employed.
N
NH
2
N
O
O
HCOOH,MeOH
N
N
3
o
120 C,2h
H
H
R
NH
2
R
R
2(a-g)
4
1b
N
N
N
N
N
N
OCH3
73%, 3ba
54%, 3bb
61%, 3bc
4. Experimental
4.1. General
N
N
N
N
N
N
Cl
NO2
All substrates are easily available. 1H NMR spectra were recor-
ded on 300 or 400 MHz in CDCl3 and 13C NMR spectra were
recorded on 75 or 100 MHz in CDCl3 using TMS as internal stan-
dard. Melting points were determined on a microscopic apparatus.
All experiments were carried out under air. Flash chromatography
was carried out with Merck silica gel 60 (63e200 mesh). Analyt-
ical TLC was performed with Merck silica gel 60 F254 plates, and
the products were visualized by UV detection. Copies of all desired
products 1H NMR and 13C NMR spectra are provided. Commer-
cially available reagents and solvents were used without further
purification.
Cl
4bd
3bd
80%, 3bd:4bd=1.7:1
71%, 3bf
N
N
N
N
N
N
Cl
Br
Br
3be,
4be
Cl
44%, 3be:4be=4.7:1
62%, 3bg
a Contents 50%.
b The reaction was carried out using 1.0 mmol of 1b, 1.0 mmol of 2(a-g), 0.5
mL of catalyst, then 2 mL solvent was added to the mixture at 120 °C for 2 h.
c Isolated yields.
4.2. General procedure for the synthesis of 11H-benzo[4,5]-
imidazo[2,1-a]isoindole 3aa (Table 2, entry 1)
The reaction was performed on a 0.50 mmol scale relative to o-
phthalaldehyde (1a), o-diaminobenzene (2a) (1.0 mmol), 0.5 mL
formic acid, and 2 mL methanol were taken in a round bottom flask
equipped with stirrer. The reaction mixture was agitated at 0 ꢀC for
diaminobenzenes, regioselectivities were also observed on Cl, Br
functional groups with o-diaminobenzene, which formed a mix-
ture of regioisomers. Similarly, 3 was the favorable isomer. 3bb,
3bc, 3bf have the high regioselectivities that we didn’t observe
isomers.
2
h. Afterward, the reaction was extracted with methanol
(3ꢁ10 mL) and concentrated in vacuo. The residue was subjected to
flash column chromatography with petroleum/EtOAc (2/1) as elu-
ent to obtain the desired product 3aa as yellow solid (84.4 mg,
0.41 mmol, yield: 82%), mp 190e191 ꢀC. The remaining products
were prepared in the similar manner except the temperature and
the scale of petroleum/EtOAc. 1H NMR (300 MHz, CDCl3)
On the basis of currently available publications,6,11 we initi-
ated our studies by choosing o-phthalaldehyde (1a) as a model
substrate, we had developed a further capable path to explain
the reaction. Intermediates
5 played a crucial role in the
mechanism. The proposed initiated complex 5 would lose one
H2O moiety to compose 6. Across the electron transfer, 7 would
be produced. Then 7 lost H2O to compose the goal compound.
Due to the position of functional group R, 3 was the main
product (Scheme 1).
d
7.92e7.94 (d, J¼8.4 Hz, 1H), 7.78e7.76 (d, J¼8.1 Hz, 1H), 7.42e7.32
(m, 3H), 7.27e7.11 (m, 3H), 4.73 (s, 2H); 13C NMR (75 MHz, CDCl3)
158.1, 148.0, 143.3, 132.3, 129.2, 128.9, 128.3, 123.6, 122.4, 121.8,
d
121.6, 120.1, 109.1, 46.8.
OH
N
OH
N
O
R
NH2
NH2
NH2
N
N
CHO
N
O
CHO
NH2
R
R
R
-H2O
OH
OH
-H2O
H
OH
N
N
NH2
R
NH2
R
NH2
R
N
N
R
N
NH2
OH
8
7
5
6
Scheme 1. A plausible mechanism.
3. Conclusion
Acknowledgements
In summary, we have successfully presented an environ-
mental friendly and economical acid-promoted method for
We are thankful for support of the Project of National Science
Foundation of P.R. China (No. J1103307).

J. Chen et al. / Tetrahedron 69 (2013) 316e319
319
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