A one-pot four-component synthesis of N-arylidene-2-aryl-imidazo[1,2-a] azin-3-amines

Article abstract of DOI:10.1016/j.tetlet.2014.03.098

N-Arylidene-2-aryl-imidazo[1,2-a]azin-3-amines were synthesized via a one-pot, four-component condensation reaction using a 2-aminoazine, toluene-4-sulfonylmethyl isocyanide (TsCH₂NC), and two equivalents of readily available aromatic aldehydes. The reaction was performed in diethyl ether as the solvent, with p-toluenesulfonic acid (p-TSA) as the catalyst at reflux temperature.

Full text of DOI:10.1016/j.tetlet.2014.03.098

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot four-component synthesis
of N-arylidene-2-aryl-imidazo[1,2-a]azin-3-amines
⇑
Abbas Rahmati , Ali Moazzam, Zahra Khalesi
Department of Chemistry, University of Isfahan, PO Box 81746-73441, Isfahan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Arylidene-2-aryl-imidazo[1,2-a]azin-3-amines were synthesized via a one-pot, four-component con-
densation reaction using a 2-aminoazine, toluene-4-sulfonylmethyl isocyanide (TsCH2NC), and two
equivalents of readily available aromatic aldehydes. The reaction was performed in diethyl ether as
the solvent, with p-toluenesulfonic acid (p-TSA) as the catalyst at reflux temperature.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 31 August 2013
Revised 8 February 2014
Accepted 20 March 2014
Available online xxxx
Keywords:
Multi-component reactions
Imidazo[1,2-a]pyrazines
Imidazo[1,2-a]pyridine
Imidazo[1,2-a]azines are an important class of fused
heterocyclic compounds which demonstrate a wide spectrum of
biological activities.1 Due to these useful properties, the syntheses
of these heterocyclic compounds have been studied extensively.
The classical synthetic method for the preparation of imidazo[1,2-
condensation utilizing toluene-4-sulfonylmethyl isocyanide (route
D, Scheme 1).
In a pilot experiment, 2-aminopyridine (1 equiv) and p-chloro-
benzaldehyde (1 equiv) were treated with TsCH2NC (1 equiv) in
acetonitrile (5 mL) in the presence of p-toluenesulfonic acid
(5 mol %) as catalyst under reflux conditions. After 48 h, monitor-
ing of the reaction showed the presence of a new product along
with unreacted starting materials (2-aminopyridine and TsCH2NC).
After separation of the reaction mixture, the spectroscopic data of
the product indicated that N-(4-chlorobenzylidene)-2-(4-chloro-
phenyl)imidazo[1,2-a]pyridin-3-amine (4a) had been obtained
via a four-component reaction. The results showed that two equiv-
alents of p-chlorobenzaldehyde had been incorporated into the
structure of the final product (route D, Scheme 1).
To optimize the conditions for this four-component reaction,
2 equiv of p-chlorobenzaldehyde with 2-aminopyridine (1 equiv)
and TsCH2NC (1 equiv) was used. First, different solvents in the
presence of p-TSA (5 mol %), at 15–20 °C and under reflux condi-
tions, were utilized for investigation of the solvent and tempera-
ture effects (Table 1). Among the different solvents, diethyl ether
was found to be the best solvent (Table 1). Also, between the var-
ious temperatures, reflux temperature was the best.
a]azines involves the condensation of a-haloketones with 2-amino-
azines.2 However, this reaction is not suited for the generation a
large number of compounds. Multi-component reactions (MCRs)
are widely used in synthetic and combinatorial chemistry to gener-
ate large libraries of compounds.3,4 For this reason, MCR approaches
have been used for the synthesis of imidazo[1,2-a]azines.5–8 One of
well-known methods is the Groebke-Blackburn–Bienayme three-
component reaction that was reported in 1998. In this reaction an
isocyanide, an aldehyde, and a 2-aminoazine and/or aminoazole
are reacted in the presence of an acid catalyst.8 In this context,
N-arylidene-2-aryl-imidazo[1,2-a]pyridin-3-amines have also been
produced by means of MCRs.9–11 Hulme et al. synthesized N-arylid-
ene-2-aryl-imidazo[1,2-a]pyridin-3-amines using a four-compo-
nent approach employing trimethylsilyl cyanide, two aldehyde
molecules, and 2-aminopyridine (route A, Scheme 1).9 In similar
routes, Voskressensky10 and Adib11 generated the same products
by using 2-hydroxypropanenitrile and imidazoline-2,4,5-trione
instead of trimethylsilyl cyanide (routes B and C, Scheme 1). In
continuation of this research, we have synthesized N-arylidene-2-
aryl-imidazo[1,2-a]pyridin-3-amines and N-arylidene-2-aryl-imi-
Next, in order to find the best catalyst, a number of Lewis and
Bronsted acids (5 mol %) were screened. The employed catalysts
are listed in Table 2. The experiments showed that the highest yield
was obtained using p-TSA as the catalyst. The optimum catalyst
loading was next investigated by studying the reaction with differ-
ent amounts of p-TSA under reflux conditions. The best results were
obtained in the presence of 5 mol % of p-TSA. The results showed
that reducing or increasing the amount of catalyst from 5 mol %,
dazo[1,2-a]pyrazin-3-amines via
a
one-pot, four-component
⇑
Corresponding author. Tel.: +98 311 7932730; fax: +98 311 6689732.
E-mail address: a.rahmati@sci.ui.ac.ir (A. Rahmati).
http://dx.doi.org/10.1016/j.tetlet.2014.03.098
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Rahmati, A.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.098

2
A. Rahmati et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Hulme in 2005 and 2006
Ar
Adib in 2008
Ar
Ar
O
O
N
N
N
C
N
NH
HN
Si
N
route C
route A
Ar
O
N
N
MW
200 °C
O
H
N
NH2
Ar
O
H
OH
CN
Ar
Ar
Ar
N
Ts
NC
N
N
N
route B
Ar
Voskressensky in 2009
route D
Ar
N
N
this work
Scheme 1. Methods for the synthesis of N-arylidene-2-aryl-imidazo[1,2-a]pyridin-3-amines.
Table 1
One-pot synthesis of N-(4-chlorobenzylidene)-2-(4-chlorophenyl)imidazo [1,2-a]pyridin-3-amine in different solvents and at different temperaturesa
Cl
O
H
O
O
N
NH2
N
p-TSA
S
NC
N
+
+
2
N
Cl
3
Cl
1
2
Entry
Solvent
Yieldb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Et2O
38c
25c
20c
30c
0c
48d
37d
34d
41d
0d
MeCN
EtOH
MeOH
1,4-Dioxane
DMF
CHCl3
H2O
[bmim]BF4
0c
22d
20d
0d
13c
0c
0c
12e
a
b
c
p-Chlorobenzaldehyde (2 mmol), TsCH2NC (1 mmol), 2-aminopyridine (1 mmol), in the presence of p-TSA (5 mol %), solvent (5 mL), 48 h.
Isolated yields.
Reactions run at 15–20 °C.
Reactions run under reflux conditions.
Reaction runs at 100 °C.
d
e
Table 2
Effects of various catalysts on the synthesis of N-(4-chlorobenzylidene)-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-aminea
Entry
Catalyst
Amount (%)
Time (h)
Temperature (°C)
Yieldb (%)
1
2
3
4
5
6
7
Nano-SiO2-CF3SO3H
SiO2–H2SO4
AcOH
InCl3
CF3SO3H
0.2 g
0.2 g
48
48
48
48
48
48
48
48
48
48
48
48
48
48
6
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
25
30
28
38
41
14
11
Trace
36
48
34
23
15
42
38
18
28
36
48
5 mol
5 mol
5 mol
5 mol
10 mol
7 mol
5 mol
2 mol
1 mol
0.5 mol
5 mol
5 mol
5 mol
5 mol
5 mol
5 mol
CCl3CO2H
p-TsOH
8
9
p-TsOH
p-TsOH
15
Reflux
Reflux
Reflux
Reflux
12
24
72
a
Benzaldehyde (2 mmol), TsCH2NC (1 mmol), 2-aminopyridine (1 mmol), Et2O (5 mL), reflux.
Isolated yields.
b
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A. Rahmati et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 3
Synthesis of N-arylidene-2-aryl-imidazo[1,2-a]pyridin-3-amines
R1
R1
R2
Y
O
H
O
O
N
X
NH2
N
p-TSA
S
NC
N
+
X
+
2
Et2O
Y
reflux, 48 h
N
R1
R2
3
Y
R2
1
2
Y= CH, N
X= CH, N
Entry
X
Y
R1
R2
Product
Yielda (%)
Mp (°C)Ref
1
2
3
4
5
6
7
8
9
10
11
12
13
CH
CH
CH
CH
CH
CH
CH
CH
N
N
N
N
N
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
4-Cl
4-F
H
H
H
H
H
H
4-Cl
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
48
57
79
82
77
65
69
63
80
67
73
71
67
163–164
150–15111a
284–286
312–313
289–291
248–250
191–193
223–2249b
270–272
225–226
226–228
207–209
213–215
4-CN
4-NO2
3-NO2
2-NO2
2-Cl
H
3-NO2
2-NO2
2-Cl
2-Cl
2-Cl
H
4j
4k
4l
4-Cl
6-Cl
6-F
4m
a
Isolated yield.
gave decreased yields. The reaction was then repeated at various
temperatures (Table 2, entry 8) in Et2O with the results showing
that the best yields were obtained under reflux conditions (Table 2,
entries 7 and 8).
To determine the scope and limitations of the reaction, we
investigated the use of various substituted benzaldehydes in the
presence of 3-aminopyridine or 3-aminopyrazine and toluene-4-
sulfonylmethyl isocyanide (Table 3).12 The reactions proceeded
only with aldehydes possessing electron-withdrawing substituents
at ortho, meta, and para positions. Benzaldehydes bearing electron-
donating substituents did not participate in the reaction under this
condition and other conditions attempted.
The structures of products 4a–m were determined from their
IR, 1H NMR, 13C NMR, and mass spectra and elemental analyses.13
All the products are new except for 4b11a and 4h.9b
A mechanistic rationalization for this reaction is provided in
Scheme 2. Initially, protonated Schiff base 5 is formed by the
addition of the aldehyde to the aminoazine solution in the presence
of p-toluenesulfonic acid. Next, compound 6 was produced by a non-
concerted [4+1] cycloaddition between protonated Schiff base 5 and
isocyanide 3, followed by tautomerization.8 Subsequently, elimina-
tion of p-toluenesulfonic acid from 6 and then hydrolysis gives 3-
amino-2-aryl-1H-imidazo[1,2-a]pyridine 7. Finally, the second
equivalent of benzaldehyde reacts with the amine group and gener-
ates the N-arylidene-2-aryl-imidazo[1,2-a]pyridin-3-amines 4.
In conclusion, a convenient and efficient one-pot, four-compo-
nent synthesis of N-arylidene-2-aryl-imidazo[1,2-a]pyridin-3-
amines is reported from readily available and inexpensive alde-
hydes, 3-aminopyridine, and tosmic isocyanide starting materials.
Also, N-arylidene-2-arylimidazo[1,2-a]pyrazin-3-amines are syn-
thesized via this approach. In addition, the proposed method is a
new alternative one that could be extended to the synthesis of
other types of these compounds. The method also could be consid-
ered as a protocol in biochemistry and medicinal discovery.
O
O
C
O
H
S
N
H
TsOH
-H2O
N
H
H2N
N
3
N
R
+
[1+4]
5
-
2
TsO
1
R
O
H
H
N
N
H2N
N
N
N
2H2O
N
-TsOH
-H2CO
NH
N
R
R
S
O
O
7
-H2O
-H
R
6
R
4
R
Scheme 2. A mechanistic rationalization.
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4
A. Rahmati et al. / Tetrahedron Letters xxx (2014) xxx–xxx
6. Veljkovic, I.; Zimmer, R.; Reissig, H.-U.; Brüdgam, I.; Hartl, H. Synthesis 2006,
Acknowledgement
2677–2684.
7. Adib, M.; Sheikhi, E.; Rezaei, N. Tetrahedron Lett. 2011, 52, 3191–3194.
8. (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661–664; (b) Blackburn, C.
Tetrahedron Lett. 1998, 39, 5469–5472; (c) Bienayme, H.; Bouzid, K. Angew.
Chem., Int. Ed. 1998, 37, 2234–2237.
We gratefully acknowledge financial support from the Research
Council of the University of Isfahan.
9. (a) Schwerkoske, J.; Masquelin, T.; Perun, T.; Hulme, C. Tetrahedron Lett. 2005,
46, 8355–8357; (b) Masquelin, T.; Bui, H.; Brickley, B.; Stephenson, G.;
Schwerkoske, J.; Hulme, C. Tetrahedron Lett. 2006, 47, 2989–2991.
10. Polyakov, A. I.; Eryomina, V. A.; Medvedeva, L.; Tihonova, N. I.; Listratova, A. V.;
Voskressensky, L. G. Tetrahedron Lett. 2009, 50, 4389–4393.
11. (a) Adib, M.; Sheibani, E.; Bijanzadeh, H. R.; Zhu, L.-G. Tetrahedron 2008, 64,
10681–10686; (b) Adib, M.; Sheibani, E.; Zhu, L.-G.; Mirzaei, P. Tetrahedron Lett.
2008, 49, 5108–5110.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.03.
098.
12. General procedure for the synthesis of N-arylidene-2-aryl-imidazo[1,2-a]pyridin-
References and notes
3-amines 4a–m:
A solution of an aldehyde (0.2 mmol), a 2-aminoazine
(0.1 mmol), and p-toluenesulfonic acid (0.5 mol%) in Et2O (5 ml) was
magnetically stirred for 12 h at room temperature. Next, TsCH2NC
(0.1 mmol) was added and the mixture was stirred for 36 h at reflux
temperature. After completion of the reaction (which was followed by TLC,
EtOAc–petroleum ether, 1:5), the solvent was evaporated, and the resulting
precipitate was washed with methanol. Finally, pure solid product was
obtained by column chromatography.
1. (a) Hieke, M.; Rödl, C. B.; Wisniewska, J. M.; la Buscató, E.; Stark, H.; Schubert-
Zsilavecz, M.; Steinhilber, D.; Hofmann, B.; Proschak, E. Bioorg. Med. Chem. Lett.
2012, 22, 1969–1975; (b) Hafmann, B.; Franke, L.; Proschak, E.; Tanrikulu, Y.;
Schneider, P.; Steinhilber, D.; Schneider, G. ChemMedChem 2008, 3, 1535–1538;
(c) Gueiffier, A.; Mavel, S.; Lhassni, M.; Elhakmaoui, A.; Snoeck, R.; Andrei, G.;
Chavignon, O.; Teulade, J. C.; Witvrouw, M.; Balzarini, J.; Clercq, E. D.; Chapat, J.
P. J. Med. Chem. 1998, 41, 5108–5112; (d) Starrett, J. E.; Montzka, T. A.;
Crosswell, A. R.; Cavanagh, R. L. J. Med. Chem. 1989, 32, 2204–2210.
2. (a) Adams, R.; Dix, J. S. J. Am. Chem. Soc. 1958, 80, 4618–4620; (b) Chichibabin,
A. E. Berichte 1926, 59, 2048–2055.
13. Characterization data: N-(4-Chlorobenzylidene)-2-(4-chlorophenyl)imidazo
[1,2-a]pyridin-3-amine (4a): Yellow powder (0.017 g). Yield: 48%. IR (KBr)
3050, 2941, 2548, 1590, 1488, 1463, 1404, 1347, 1230, 1182, 1087, 1010, 929,
825, 751 cmÀ1 1H NMR (400 MHz, CDCl3) d: 6.93 (dt, J = 6.8 Hz, J = 1.2 Hz, 1H,
t:
.
Harom), 7.28 (dt, J = 7.4 Hz, J = 1.2 Hz, 1H, Harom), 7.43–7.47 (m, 4H, Harom), 7.60
(d, J = 9.2 Hz, 1H, Harom), 7.79 (dt, J = 8 Hz, J = 0.8 Hz, 4H, Harom), 8.44 (d,
J = 6.8 Hz, 1H, Harom), 8.73 (s, 1H, Himine) ppm. 13C NMR (100 MHz, CDCl3) d:
112.7, 117.5, 123.3, 125.6, 129.1, 129.2, 129.5, 129.6, 133.0, 133.3, 133.9, 134.7,
137.5, 143.2, 155.8 ppm. MS (EI, 70 eV): m/z (%): 369 (M++4, 2), 367 (M++2, 25),
365 (M+, 49). Anal. Calcd for C20H13Cl2N3: C 65.59, H 3.58, N 11.47; Found: C
65.90, H 3.60, N 11.42.
3. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005; (b) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41, 3969–
4009.
4. (a) Terrett, N. K. Combinatorial Chemistry; Oxford University Press: New York,
1998; (b) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A. Angew. Chem., Int. Ed. 2011, 50,
6234–6246; (c) Ruijter, E.; Orru, R. V. A. Drug Discovery Today: Technol. 2013, 10,
e15–e20.
5. Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 4487–4490.
Please cite this article in press as: Rahmati, A.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.03.098