Ammonium chloride catalyzed one-pot synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1007/s00706-008-0872-x

Ammonium chloride as a very inexpensive and readily available reagent efficiently catalyzes one-pot, three-component Groebke condensation reactions of aldehydes, isocyanides, and 2-aminopyridines or 2-aminopyrimidines in methanol to afford the corresponding imidazo[1,2-a]pyridines in high yields at room temperature.

Full text of DOI:10.1007/s00706-008-0872-x

Monatsh Chem 139, 931–933 (2008)
DOI 10.1007/s00706-008-0872-x
Printed in The Netherlands
Ammonium chloride catalyzed one-pot synthesis of imidazo[1,2-a]pyridines
Ahmad Shaabani, Fahimeh Rezazadeh, Ebrahim Soleimani
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Received 6 December 2007; Accepted 12 December 2007; Published online 26 June 2008
#
Springer-Verlag 2008
Abstract Ammonium chloride as a very inexpensive
and readily available reagent efficiently catalyzes one-
pot, three-component Groebke condensation reactions
of aldehydes, isocyanides, and 2-aminopyridines or
tions have been reported including classical condi-
tions, with microwave irradiation and by using Lewis
acids as well as protic liquid and solid acids pro-
moters such as: scandium triflate [12], ZnBr [13],
2
2-aminopyrimidines in methanol to afford the corre-
sponding imidazo[1,2-a]pyridines in high yields at
room temperature.
ZnCl [14], TsOH [15], HClO [16], HOAc [17],
2
4
montmorillonite K10 [18], cellulose sulfuric acid
[19], and ionic liquid [20].
However, in spite of potential utility of aforemen-
tioned routes for the synthesis of imidazo[1,2-a]pyri-
dine derivatives, many of these methods involve
expensive reagents, strong acidic conditions, long re-
action times, low yields, use of excess of reagents=
catalysts, and use of toxic organic solvents. For ex-
Keywords Imidazo[1,2-a]pyridine; Ammonium chloride;
Three-component reaction; Isocyanide.
Introduction
Imidazo[1,2-a]pyridines show anticytomegalo-zoster
and antivaricella-zoster virus [1a–e], antibacterial
ample, in the case of Sc(OTf) , the reaction mixture
3
was agitated for 72 h at ambient temperature, then
it was allowed slowly to adsorb onto Dowex 50WX
[
1, 2] antiinflammatory, analgesic, antipyretic [3a–
c], hypnoselective, and anxioselective activities [4].
They are ꢀ-amyloid formation inhibitors [5] and
constitute a novel class of orally active nonpeptide
bradykinin B2 receptor antagonists [6]. Several imi-
dazo[1,2-a]pyridines already on the market include
zolimidine (an antiulcer drug) [3c], zolpidem (ahyp-
notic drug), and alpidem (a nonsedative anxiolytic)
2-200 strongly acidic cation exchange resin. The res-
in was washed with MeOH, CH Cl , and MeOH
2
2
and finally the product was eluted using 2 M NH3
in MeOH and the solvent evaporated.
Ammonium chloride as an inexpensive and readi-
ly available reagent has been used in various reac-
tions. It effectively promotes the Ugi reaction [21],
Biginelli reaction [22], Claisen rearrangement [23],
isocyanide-based MCRs for the synthesis of 4-imi-
no-4H-3,1-benzoxazines [24], tetrahydrofuro[2,3-
c]pyridines [25], pyrrolo[3,4-b]pyridine-5-one [26],
and diindolylmethanes [27]. So, it is used as promot-
er in the oxidation [28] or reduction of organic com-
pounds [29].
[
7]. Imidazo[1,2-a]pyrimidine structural moieties are
also important as benzodiazepine receptor agonists
8], antiviral agents [1a], antibacterials [9], antifun-
[
gal agents [10], and calcium channel blockers [11].
Recently, several synthesis methods for preparing
these compounds based on multi-component reac-
Correspondence: Ahmad Shaabani, Department of Chemistry,
Shahid Beheshti University, PO Box 19396-4716, Tehran,
Iran. E-mail: a-shaabani@cc.sbu.ac.ir
The synthesis of imidazo[1,2-a]pyridine has also
been reported in the presence of NH Cl under reflux
4

9
32
A. Shaabani et al.
Scheme 1
conditions in toluene as a nonpolar aprotic solvent
corresponding N-alkyl- or aryl-aminoimidazo[1,2-
a]pyridine 4 under neutral conditions in good yields
after 3 h.
[
(
30]. However, this required long reaction times
30 h) and gave unsatisfactory yields (49–66%) un-
der reflux conditions.
In order to optimize the reaction conditions, we
conducted this reaction with various solvents and
under solvent-free conditions. The results showed
that the efficiency and the yield of the reaction in
MeOH was higher than those obtained in other sol-
vents like EtOH, H O, and CH CN and under sol-
A change of solvent can have drastic impact on
kinetics or thermodynamic of a chemical reaction
due to different stabilization of reagent, transition
state or product by the solvent molecules. In some
9
cases rate accelerations by a factor of up to 1ꢀ10
2
3
can be achieved solely by a solvent change [31].
Therefore, it is very important to select a suitable
solvent in chemical synthesis.
vent-free conditions.
To illustrate the need of NH Cl for these reactions,
4
an experiment was conducted in which the reaction
of 4-methylbenzaldehyde and 2-amino-5-methylpyri-
dine with cyclohexyl isocyanide was studied in the
In connection with our previous work on multi-
component reactions [32] and using ammonium
chloride as a catalyst and co-reactant [28], we wish
to report the results obtained from a study of the
preparation imidazo[1,2-a]pyridine [19, 20] in the
absence of NH Cl. The yield of product was only
4
10% at room temperature after 3 h. Obviously, the
NH Cl is an important component of the reaction.
4
presence of NH Cl as a very inexpensive and easily
4
In conclusions, we developed the synthesis of
3-aminoimidazo[1,2-a]pyridines and 3-aminoimi-
dazo[1,2-a]pyrazines via the condensation of an
aldehyde, 2-amino-5-methylpyridine or 2-amino-5-
bromopyridine or 2-aminopyrazine, and alkyl or aryl
available catalyst under neutral conditions in metha-
nol within 3 h at room temperature (Scheme 1).
Results and discussion
isocyanide in the presence of NH Cl as an inexpe-
4
As can be seen from Table 1, 2-aminopyridine or 2-
aminopyrazine (1), and isocyanides 2 with various
aromatic aldehydes 3, carrying either electron-donat-
ing or electron-withdrawing substituents, gave the
sive catalyst in methanol.
Experimental
Melting points were measured with an Electrothermal 9100
apparatus and are corrected. IR spectra were recorded with a
Shimadzu IR-470 spectrometer. Mass spectra were recorded
on a FINNIGAN-MAT 8430 mass spectrometer operating at
Table 1 Condensation reaction of 2-aminopyridine or 2-
aminopyrazine with aldehydes and isocyanides at room
temperature
1
13
an ionization potential of 70eV. H and C NMR spectra
were recorded with a BRUKER DRX-300 AVANCE spec-
trometer at 300.13 and 75.47MHz. NMR spectra were ob-
tained on solution in CDCl3.
1
Entry X
Y
R
Z
Product Yield=%
1
2
3
4
5
6
7
8
9
1
1
1
CH CH3 cyclohexyl H
4a
4b
4a
4d
4e
4f
73
72
86
67
60
73
85
87
96
80
63
58
CH CH3 cyclohexyl 4-CH3
CH CH3 cyclohexyl 4-Cl
CH CH3 cyclohexyl 3-NO2
CH CH3 t-but
CH CH3 t-but
All the products (except 4h and 4i) are known compounds
19, 20, 32d], which were characterized by melting point, IR,
[
1
13
H, and C NMR spectral data and mass spectroscopy.
H
CH3
General procedure
To a solution of 0.052g ammonium chloride (1mmol) in
CH Br
CH Br
CH Br
CH Br
N
N
cyclohexyl H
cyclohexyl 4-CH3
cyclohexyl 4-Cl
t-but
cyclohexyl 4-OCH3
t-but 4-OCH3
4g
4h
4i
3
cm methanol was added 1.2mmol isocyanide, 1.1mmol
4
aldehyde, and 1 mmol 2-aminoazine. The mixture was stirred
for 3 h at room temperature. After completion of the reaction,
as indicated by TLC (ethyl acetate:hexane, 2:1), the reaction
0
1
2
H
4j
4k
4l
H
H
3
mixture was diluted with 30cm water to afford the product as

One-pot synthesis of imidazo[1,2-a]pyridines
933
a precipitate. The solid residue was filtered and crystallized
from ethyl acetate to give products.
5. Fuchs K, Romig M, Mendla K, Briem H, Fechteler K
(2002) WO: 14313; (2002) Chem Abstr 136:183824r
6
. Abe Y, Kayakiri H, Satoh S, Inoue T, Sawada Y, Imai K,
Inamura N, Asano M, Hatori C, Katayama A, Oku T,
Tanaka H (1998) J Med Chem 41:564
N-Cyclohexyl-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-
amine (4h, C H N )
2
1 25 3
ꢁ
7. Langer SZ, Arbilla S, Benavides J, Scatton B (1990) Adv
Biochem Psychopharmacol 46:61
8. Tully WR, Gardner CR, Gillespie RJ, Westwood R (1991)
J Med Chem 34:2060
White powder (0.333 g, 87%); mp 210–212 C; IR (KBr):
ꢂ1
ꢁ
ꢀ¼ 3442 (NH), 3285, 2924, 1507cm ; MS: m=z (%) ¼ 385
þ
þ
(
M þ 2, 60), 383 (M , 55), 302 (55), 300 (55), 275 (96), 273
1
100), 158 (45), 156 (45); H NMR (300 MHz, CDCl ):
(
3
9
. Rival Y, Grassy G, Michel G (1992) Chem Pharm Bull
0:1170
ꢂ ¼ 1.18–1.78 (m, 5CH of cyclohexyl), 2.41 (s, CH ), 2.96
2
3
3
m, CH–N of cyclohexyl), 3.16 (bs, NH), 7.18 (d, J
4
(
¼
HH
3
1
1
1
0. Rival Y, Grassy G, Taudou A, Ecalle R (1991) Eur J Med
Chem 26:13
1. Sanfilippo PJ, Urbanski M, Press JB, Dubinsky B, Moore
JB Jr (1988) J Med Chem 31:2221
2. a) Blackburn C, Guan B, Fleming P, Shiosaki K, Tsai S
9
.4 Hz, H–Ar), 7.26 (d, JHH ¼ 7.8 Hz, H–Ar), 7.44 (d,
3
3
JHH ¼ 9.4 Hz, H–Ar), 7.90 (d, J ¼ 7.7 Hz, H–Ar), 8.23
HH
1
3
(
s, H–Ar) ppm; C NMR (75 MHz, CDCl ): ꢂ ¼ 21.34,
3
2
1
4.77, 25.67, 34.10, 56.83, 106.53, 117.81, 122.90, 124.88,
26.87, 127.27, 129.35, 130.85, 137.47, 139.69 ppm.
(
(
1998) Tetrahedron Lett 39:3635; b) Blackburn C
1998) Tetrahedron Lett 39:5469; c) Ireland SM, Tye H,
5
-Bromo-N-cyclohexyl-2-(4-chlorophenyl)-imidazo[1,2-
Whittaker M (2003) Tetrahedron Lett 44:4369
a]pyridin-3-amine (4i, C H BrClN )
3
1
9
19
ꢁ
13. Katrritzky AR, Xu YJ, Tu H (2003) J Org Chem 68:4935
14. Rousseau AL, Matlaba P, Parkinson CJ (2007) Tetrahe-
dron Lett 48:4079
15. Chen JJ, Golebiowski A, MeClenaghan J, Klopfenstein
SR, West L (2001) Tetrahedron Lett 42:2269
6. Bienayme H, Bouzid K (1998) Angew Chem Int Ed
37:2234
7. Groebke K, Weber L, Mehlin F (1998) Synlett:661
8. Varma RS, Kumar D (1999) Tetrahedron Lett 40:7665
9. Shaabani A, Maleki A, Moghimi-Rad J, Soleimani E
White powder (0.387 g, 96%); mp 213–214 C; IR (KBr):
ꢂ1
ꢁ
ꢀ¼ 3256 (NH), 2925, 2850, 1508cm ; MS: m=z (%) ¼ 405
þ
þ
(
2
M þ 2, 90), 403 (M , 80), 322 (90), 321 (80), 295 (100),
1
93 (78), 158 (45), 156 (45); H NMR (300 MHz, CDCl ):
3
ꢂ ¼ 1.18–1.81 (m, 5CH of cyclohexyl), 2.93 (m, CH–N of
2
1
cyclohexyl), 3.14 (bs, NH), 7.19–4.45 (m, H–A), 7.97–8.22
13
(
2
1
m, H–A) ppm; C NMR (75 MHz, CDCl ): ꢂ ¼ 24.76,
3
1
1
1
5.61, 34.14, 56.83, 106.95, 117.90, 122.91, 125.12, 127.87,
28.25, 128.78, 132.16, 133.49, 139.77 ppm.
(2007) Chem Pharm Bull 55:957
Acknowledgement
20. Shaabani A, Soleimani E, Maleki A (2006) Tetrahedron
Lett 47:3031
We gratefully acknowledge the financial support from the
Research Council of Shahid Beheshti University.
2
2
1. Bonne D, Dekhane M, Zhu J (2004) Org Lett 6:4771
2. Shaabani A, Bazgir A, Teimouri F (2003) Tetrahedron
Lett 44:857
2
3. Ralls JW, Lundin RE, Bailey GF (1963) J Org Chem
2
References
8:3521
24. Bonne D, Dekhane M, Zhu J (2005) Org Lett 7:5285
25. Fayol A, Zhu J (2004) Org Lett 6:115
26. Janvier P, Sun X, Bienayme H, Zhu J (2002) J Am Chem
Soc 124:2560
1
. a) Gueiffier A, Lhassani M, Elhakmaoui A, Snoeck R,
Andrei G, Chavignon O, Teulade JC, Kerbal A, Essassi
EM, Debouzy JC, Witvrouw M, Blache Y, Balzarini J,
De Clercq E, Chapat JP (1996) J Med Chem 39:2856;
b) Gueiffier A, Mavel S, Lhassani M, Elhakmaoui A,
Snoeck R, Andrei G, Chavignon O, Teulade JC, Witvrouw
M, Balzarini J, De Clercq E, Chapat JP (1998) J Med Chem
27. Azizian J, Teimouri F, Mohammadizadeh MR (2007) Cat
Commun 8:1117
28. Shaabani A, Ameri M (1998) J Chem Res (S):100
29. a) Sridhara MB, Srinivasa GR, Gowda DC (2004) J Chem
Res (S):74; b) Basu MK, Becker FF, Banik BK (2000)
Tetrahedron Lett 41:5603; c) Sridhara MB, Srinivasa GR,
Gowda DC (2004) Synth Commun 34:144
30. Parchinsky VZ, Koleda VV, Shuvalova O, Kravchenko
DV, Krasavin M (2006) Tetrahedron Lett 47:947
31. Reichardt C (1988) Solvent and Solvent Effects in
Organic Chemistry. VCH, Weinheim
32. a) Shaabani A, Soleimani E, Rezayan AH (2007)
Tetrahedron Lett 48:2185; b) Shaabani A, Soleimani E,
Khavasi HR (2007) Tetrahedron Lett 48:4743; c)
Shaabani A, Soleimani E, Khavasi HR, Hoffmann RD,
Rodewald UC, Po a¨ ttgen R (2006) Tetrahedron Lett
47:5493; d) Shaabani A, Soleimani E, Maleki A (2007)
Monatsh Chem 138:73; e) Shaabani A, Soleimani E,
Darvishi M (2007) Monatsh Chem 138:43
41:5108;c)ElhakmaouiA,GueiffierA, MilhavetJC, Blache
Y, Chapat JP, Chavignon O, Teulade JC, Snoeck R, Andrei
G, De Clercq E (1994) Bioorg Med Chem Lett 4:1937; d)
MavelS,RenouJL,GaltierC,SnoeckR,AndreiG,Balzarini
J, De Clercq E, Gueiffier A (2001) Arzneim Forsch 51:304
. Teulade JC, Grassy G, Girard JP, Chapat JP, deBuochberg
MMS (1978) Eur J Med Chem 13:271
. a) Abignente E (1991) Actual Chim Ther 18:193; b)
Abignente E, Arena F, Luraschi E, Saturnino C, Rossi
F, Lampa E, Cazzola M, Brandinelli E, Marrazzo R,
Marmo E (1985) Rend Atti Accad Sci Med Chir
2
3
1
39:313; c) Almirante L, Polo L, Mugnaini A, Provinciali
E, Rugarli P, Biancotti A, Gamba A, Murmann W (1965)
J Med Chem 8:305
4
. Bartholini G (1993) L E R S Monogr Ser 8:1; (1996)
Chem Abstr 124:164079n