Cellulose sulfuric acid catalyzed one-pot three-component synthesis of imidazoazines

Article abstract of DOI:10.1248/cpb.55.957

Imidazoazines have been synthesized by a one-pot three-component condensation reaction of an aldehyde, a 2-aminoazine and an isocyanide in the presence of the cellulose sulfuric acid, as an effective bio-supported catalyst in excellent yields. The reaction work-up is simple and the catalyst can be easily separated from the product and reused in several times.

Full text of DOI:10.1248/cpb.55.957

June 2007
Communications to the Editor
Chem. Pharm. Bull. 55(6) 957—958 (2007)
957
an Elementar Analysensysteme GmbH VarioEL. Mass spectra were recorded
on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization
potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470 spec-
trometer. 1H- and 13C-NMR spectra were recorded on a BRUKER DRX-300
AVANCE spectrometer at 300.13 and 75.47 MHz, respectively. All the prod-
ucts (except 4g) are known compounds, which were identified by IR and 1H-
NMR spectral data and comparing their melting points with literature re-
ports.
Preparation of Cellulose Sulfuric Acid To a magnetically stirred mix-
ture of 5.00 g of cellulose (DEAE for column chromatography, Merck) in
20 ml of n-hexane, 1.00 g of chlorosulfonic acid (9 mmol) was added drop-
wise at 0 °C during 2 h. HCl gas was removed from the reaction vessel im-
mediately. After the addition was complete, the mixture was stirred for 2 h.
Then, the mixture was filtered and washed with 30 ml of acetonitrile and
dried at room temperature to obtain 5.47 g cellulose sulfuric acid as white
powder. This white homogeneous solid acid is very stable and is not affected
by air, water and light. Sulfur content of sample obtained by conventional el-
emental analysis, was 0.68 mmol/g. The number of Hꢀ site of cellulose–
SO3H determined by acid-base titration was 0.65 meq/g. This value corre-
sponds to about 0.96% of the sulfur content, indicating that most of the sul-
fur species on the sample are in the form sulfonic acid groups.
Cellulose Sulfuric Acid Catalyzed One-
Pot Three-Component Synthesis of
Imidazoazines
Ahmad SHAABANI,* Ali MALEKI, Jafar MOGHIMI RAD,
and Ebrahim SOLEIMANI
Department of Chemistry, Shahid Beheshti University; P. O. Box
19396–4716, Tehran, Iran.
Received December 9, 2006; accepted March 16, 2007
Imidazoazines have been synthesized by a one-pot three-com-
ponent condensation reaction of an aldehyde, a 2-aminoazine
and an isocyanide in the presence of the cellulose sulfuric acid,
as an effective bio-supported catalyst in excellent yields. The re-
action work-up is simple and the catalyst can be easily sepa-
rated from the product and reused in several times.
Key words cellulose sulfuric acid; bio-supported catalyst; imidazo[1,2-
a]pyridine; isocyanide; multi-component reaction
Synthesis of Imidazoazines (4a—j) To a solution of 2-aminoazine
(1 mmol), aldehyde (1.2 mmol) and isocyanide (1.1 mmol), in 3 ml of
MeOH, was added cellulose sulfuric acid (0.05 g). The resulting mixture was
stirred for 2 h at room temperature. After completion of the reaction, as indi-
cated by TLC (ethyl acetate/n-hexane, 3/1), the reaction mixture was filtered
and washed with CH2Cl2 (10 ml) to separate the catalyst. Then the filtrate’s
solvent was evaporated under reduced pressure and followed by crystalliza-
Imidazo[1,2-a]pyridines, as an important class of versatile
pharmaceutically and biologically active compounds span-
ning applications in anti-inflammatory1,2) and antibacterial
agents,3) inhibitors of gastric acids secretion,4) calcium chan- tion from ethyl acetate to give the imidazoazines as pure product.
nel blockers,5) and antiulcer based therapies.6) As a result, nu-
Characterization of N-Cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-
1
amine (4g, C19H21N3) Yellow solid (0.274 g, 94%); mp 200—202 °C. H-
merous two- and three-component approaches for their syn-
NMR (CDCl3) d: 1.15—1.97 (10H, m), 2.94 (1H, m), 3.76 (1H, br), 7.06—
thesis have been reported.7—14)
8.15 (9H, m). 13C-NMR (CDCl3) d: 24.73, 25.61, 34.10, 56.82, 107.87,
Biopolymers, especially cellulose and its derivatives,15)
117.75, 123.02, 125.23, 127.03, 127.72, 128.62, 128.64, 133.36, 135.89,
137.53. IR (KBr) cmꢁ1: 3250, 2920, 1602. MS m/z: 291 (Mꢀ), 259, 158, 76.
have some unique properties, which make them attractive al-
ternatives for conventional organic or inorganic supports for
catalytic applications. Among others, they are extremely Results and Discussion
inert, inexpensive, biodegradable and environmentally be-
Cellulose sulfuric acid is readily prepared by the dropwise
nign allowing various reaction conditions to be employed. addition of chlorosulfonic acid to n-hexane mixture of cellu-
Cellulose is the most abundant natural material in the world lose at 0 °C. It is important to note that, this reaction is easy
and it has been widely studied during the past decades be- and clean without any work-up procedure due to HCl gas is
cause it is a biodegradable material and a renewable re- evolved from the reaction vessel immediately. This white ho-
source.
mogeneous, nonhygroscopic solid acid is very stable under
In recent years, the emphasis of science and technology is reaction conditions.
shifting more towards environmentally friendly and sustain-
In order to optimize the reaction conditions, we conducted
able resources and processes; in this regard, biopolymers are the condensation of benzaldehyde (1.2 mmol), 2-amino-5-
attractive candidates to explore for supported catalysis.16,17)
methylpyridine (1 mmol) and cyclohexyl isocyanide (1.1
Several interesting biopolymers for example alginate,18) mmol) with stirring at room temperature in various solvents
gelatin,19,20) starch21) and chistosan22) derivatives have been and solvent free conditions. The results showed that the effi-
utilized as a support for catalytic applications.
ciency and the yield of the reaction in MeOH was higher
During the course of our studies on the development of than those obtained in other solvents, such as H2O, EtOH,
new routes for the synthesis of organic compounds using CH2Cl2, toluene and CH3CN and or under solvent-free condi-
solid acid catalysts in organic transformations23—27) and our tions.
interest in isocyanide-based MCRs,28—31) we developed the
As shown in Table 1, the reaction of benzaldehyde, 2-
synthesis of imidazoazines 4a—j via the three-component amino-5-bromopyridine and cyclohexyl isocyanide was also
condensation of an aldehyde 1, a 2-aminoazine 2 and an iso- carried out in the presence of various protic solid acids (Am-
cyanide 3 in the presence of catalytic amount of cellulose berlyst-21, Montmorillonite-K10 and cellulose sulfuric acid),
sulfuric acid at room temperature (Chart 1).
liquid acids (HCl, H2SO4 and HOAc) and Lewis acid (AlCl3).
The best yield was obtained with cellulose sulfuric acid.
To illustrate the need of the cellulose sulfuric acid for
these reactions an experiment was conducted in the absence
of cellulose sulfuric acid. The yield in this case was trace
after 3 h (Table 1, Entry 1). Obviously, the cellulose sulfuric
acid is an important component of the reaction.
Experimental
Apparatus Melting points were measured on an Electrothermal 9100
apparatus and are uncorrected. The elemental analyses were performed with
As indicated in Table 2, the reaction of aldehydes with 2-
aminoazines and isocyanides afforded imidazoazines in the
presence of cellulose sulfuric acid as a promoter in very high
Chart 1. Synthesis of 3-Aminoimidazo[1,2-a]pyridines
∗ To whom correspondence should be addressed. e-mail: a-shaabani@cc.sbu.ac.ir
© 2007 Pharmaceutical Society of Japan

958
Vol. 55, No. 6
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One of the advantages of solid acid catalysts is their ability
to perform as a recyclable reaction media. We were able to
separate cellulose sulfuric acid from the reaction medium
easily by washing with CH2Cl2. After drying it was reused
for subsequent reactions (Table 2, Entry 1). Thus, this
process could be also interesting for large-scale synthesis.
Conclusions
In summary, cellulose sulfuric acid as an efficient and en-
vironmentally friendly bio-supported proton source catalyst
was prepared and employed for the synthesis of imidazoazines
via the condensation of an aldehyde, a 2-aminoazine and an
isocyanide in the presence of cellulose sulfuric acid in excel-
lent yields with relatively short reaction times at room tem-
perature. To the best our knowledge this is the first report on
the synthesis of imidazoazines in a bio-supported catalyst
and these new reaction conditions would be a superior proton
source comparing to reported inorganic supported solid acids
and acidic resins.
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Acknowledgements We gratefully acknowledge financial support from
the Research Council of Shahid Beheshti University.
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Table 1. Effect of Catalyst for the Synthesis of 4a in CH3OH at Room
Temperature
Entry
Catalyst
—
Amberlyst-21
Montmorillonite-K10
AlCl3
Time (h)
Yield (%)a)
1b)
2
3
3
24
12
6
Trace
72
57
4
68
5
6
7
8
CH3COOH
HCl
H2SO4
H2SO4/SiO2
Cellulose sulfuric acid
5
36
30
10
55
24
24
3
9
3
98
a) Isolated yield. b) In the absence of the catalyst.
Table 2. Synthesis of Imidazoazines 4a—j in the Presence of Cellulose Sulfuric Acid
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Br
Me
Me
Me
Me
Me
H
Me
Me
Br
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Butyl
4a
4b
4c
4d
4e
4f
4g
4h
4i
(98, 95, 92, 94, 85)a)
89
92
90
96
93
94
90
87
98
4-CH3C6H4
4-ClC6H4
3-O2NC6H4
4-Pyridyl
Ph
Ph
4-CH3C6H4
Ph
tert-Butyl
tert-Butyl
10
4j
a) The same catalyst was used for each of the five runs.