Silica-sulfuric acid: a highly efficient catalyst for the synthesis of imidazo[1,2-a]pyridines using trimethysilyl cyanide or cyanohydrins

Article abstract of DOI:10.1016/j.tetlet.2009.05.080

This Letter describes a novel synthetic approach towards imidazo[1,2-a]pyridines via a three-component condensation using trimethylsilyl cyanide (TMSCN) or cyanohydrins as the source of CN^- ions and silica-sulfuric acid as the catalyst.

Full text of DOI:10.1016/j.tetlet.2009.05.080

Tetrahedron Letters 50 (2009) 4389–4393
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silica-sulfuric acid: a highly efficient catalyst for the synthesis
of imidazo[1,2-a]pyridines using trimethysilyl cyanide or cyanohydrins
Anatoliy I. Polyakov a, Vera A. Eryomina a, Lidiya A. Medvedeva a, Nadezhda I. Tihonova a,
b,
Anna V. Listratova b, Leonid G. Voskressensky
*
a New Chemistry Horizons Laboratories Ltd, PO Box 130, Moscow 115522, Russia
b Organic Chemistry Department of Russian Peoples’ Friendship University, 6, Miklukho-Maklaya St., Moscow 117198, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes a novel synthetic approach towards imidazo[1,2-a]pyridines via a three-component
condensation using trimethylsilyl cyanide (TMSCN) or cyanohydrins as the source of CNÀ ions and silica-
sulfuric acid as the catalyst.
Received 14 March 2009
Revised 12 May 2009
Accepted 22 May 2009
Available online 27 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent condensation
Cyanohydrins
Imidazopyridines
Catalyst
Cyanides
Imidazo[1,2-a] annulated nitrogen heterocycles containing pyr-
idine, pyrazine or pyrimidine fragments constitute a class of bio-
logically active compounds that are potent antibacterial agents,1
inhibitors of gastric acid secretion,2 calcium channel blockers3
and which also exhibit cytoprotective properties.4 The isocya-
nide-based multi-component condensation (MCC) reported simul-
taneously by Blackburn,5 Bienayme and Bouzid6 and Groebke
et al.7 represents an effective synthetic pathway towards these
compounds. Since, several groups have reported modifications of
the protocol, including the use of Montmorillonite K-10 clay as a
catalyst8 and microwave acceleration.9 However, the main disad-
vantage of this approach is the use of pungent isonitriles. A more
recent Letter10 describes the discovery of a unique application of
TMSCN as a non-classic isonitrile equivalent; however, microwave
irradiation was required. An attractive protocol has recently been
reported11 which uses an ionic liquid as a promoter for the one-
pot, three-component condensation of 2-aminoazines, aldehydes
and TMSCN. However, all our attempts to reproduce this process
were unsuccessful. In our hands, the yields of the target products
did not exceed 12%, while isolation required column chromatogra-
phy. This communication details the application of TMSCN or ace-
tone–cyanohydrin as functional isonitrile equivalents in the MCR
catalyzed by silica-sulfuric acid,12 leading to the target imi-
dazo[1,2-a]pyridines. The current study was aimed at elaborating
a synthetic protocol towards imidazo[1,2-a](di)azines avoiding
the use of (i) isonitriles as starting materials; (ii) costly catalysts,
for example, scandium triflate; (iii) special instrumentation, for
example, microwave reactors; and (iv) column chromatography.
The method should be applicable to routine parallel solution-
phase synthesis followed by a simple isolation procedure. Thus,
we turned our attention to the use of the H2SO4/SiO2 catalytic sys-
tem (silica-sulfuric acid).13 TMSCN or the cyanohydrin of acetone
or acetaldehyde was used instead of isonitriles.
Aminoimidazo(di)azines 1–10 were synthesized from the
appropriate aminoazines, aldehydes and cyano-substituted com-
pounds, via condensation catalyzed by silica-sulfuric acid.
We presume that the reaction starts with the formation of cyano-
hydrins from the aldehydes and TMSCN or 2-hydroxy-2-methylpro-
panenitrile, followed by Strecker reaction with the corresponding 2-
aminoazine to form the intermediate aminonitrile A. Acid-catalyzed
cyclization of A, followed by a [1,3] proton-shift in intermediate B
yields the amino imidazo(di)azines 1a, 2a, 3 and 4. (Scheme 1, Table
1). In some cases (Table 1, entries 1, 2 and 5) further modification of
the primary amino group occurred and the corresponding Schiff
bases were also isolated. The 3-aminoimidazopyridines and the cor-
responding Schiff bases could be separated easily due to their differ-
ent solubilities in hexane. The structure of compound 1b was
additionally confirmed by the alternative ‘classical’ synthesis of its
reduced derivative 14.14 (Scheme 2).
In the case of 2-hydroxypropanenitrile (Scheme 3) Strecker
reaction leads to 3-amino-2-methylimidazopyridines, which can
* Corresponding author. Tel.: +7 495 955 0757; fax: +7 495 955 0779.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.080

4390
A. I. Polyakov et al. / Tetrahedron Letters 50 (2009) 4389–4393
O
H
O
C
Si(CH3)3
X
N
X
N
+
TMSCN
R
R
R'
R'
NH2
H
NH
N
O
OH
C
CH3OH
+
(CH3)2C(OH)CN
R
R
C
R
N
H
A
N
X
X
O
H
X
X
R'
R
R'
R'
N
N
R
H
N
[1,3]-shift
N
N
R
N
N
N
N
-
H
N
R
H2N
1a, 2a, 3, 4
R
N
H
R
B
H
H
1b, 2b, 5, 6, 8-10
Scheme 1. Three-component condensation via Strecker reaction.
Table 1
Products of condensation and yields via method A using TMSCN
Entry
1b
Amidine
Aldehyde
Product
Yielda (%)
Mp (°C)
N
Ph
N
O
55
15
190
N
NH2
NH2
1a
N
Ph
N
110
187
N
Ph
1b
N
N
O
2
49
21
N
NH2
NH2
2a
N
N
N
135
2b
N
Ph
O
N
3
38
53
184
N
NH2
NH2
N
3
S
N
N
N
O
415
130–132
N
S
NH2
4
NH2
N
N
N
OH
O
5c
47
210–211
OH
N
NH2
HO
5
a
Isolated yield.
b
c
Compound 1a was isolated and described previously;11 however, the data given therein differ from ours.
When a 2:1 ratio of salicylic aldehyde 2-amino-4-picoline was used, the yield of product was 83%.

A. I. Polyakov et al. / Tetrahedron Letters 50 (2009) 4389–4393
4391
O
C
H
N
N
N
N
N
N
+
+
CH3OH
AcOH
NaBH4
CH3OH
N
NH2
N
1b
14
Scheme 2. ’Classical’ synthesis of 14.
H
N
H
N
OH
C
CH3
CH3
+
H3C
N
R
N
C
N
R
N
NH2
NH2
R
N
N
CH3
CN
CH3CH(OH)CN
N
N
R
H
CH3
7, 11-13
Scheme 3. Condensation with 2-hydroxypropanenitrile.
Table 2
Products of condensation and yields via method B using (CH3)2C(OH)CN
Entry
Amidine
Aldehyde
Product
Yielda (%)
70
Mp (°C)
N
Ph
HO
CN
O
*
116
65
N
Ph
N
NH2
NH2
N
6
Ph
N
HO
CN
*
2
3
4
CH3CHO
16
67
61
Oil
N
N
HN
7
CN
HO
Ph
N
N
*
O
O
CN
80–82
135
Ph
Ph
N
N
NH2
8
N
Ph
N
N
N
NH2
NH2
Ph
9
O
N
N
O
5
74
175
O
N
N
10
O
a
Isolated yield.
react with the excess of 2-hydroxypropanenitrile giving substi-
tuted imidazopyridines 7 and 11–13.
further derivatization of the NH2 group, yielding the corresponding
Schiff bases (6, 8, 9 and 10) or aminonitrile 7, in the case of acetal-
dehyde (Table 2, entry 2). In some cases (Table 2, entries 1–3), the
target products were isolated as Schiff base complexes with cyano-
hydrins (ratio, 1:1, according to 1H NMR analysis). After treatment
of the complexes with aqueous ammonia, the free Schiff bases
were isolated. The low yield (16%) of 7 encouraged us to explore
the use of acetaldehyde cyanohydrin as the CN-source (Scheme
3) in the condensation reaction. The reactions proceeded smoothly,
The use of TMSCN seems to be more appropriate in order to syn-
thesize primary amines, that is, 1a, 2a, 3 and 4 (Table 1). At the
same time, 2-hydroxy-2-methylpropanenitrile can be used if fur-
ther modifications of the NH2 group are required. The use of 2-hy-
droxy-2-methylpropanenitrile as the CN source via formation of
the aldehyde cyanohydrin (Scheme 1) required a fivefold molar ex-
cess of the aldehyde in order to proceed effectively. This caused

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A. I. Polyakov et al. / Tetrahedron Letters 50 (2009) 4389–4393
Table 3
Products of condensation and yields via method C using CH3CH(OH)CN
Entry
1
Amidine
Product
Yielda (%)
48
Mp (°C)
N
HO
CN
*
N
Oil
HN
N
NH2
NH2
CN
7
N
2b,17
80
135
N
N
H
N
CN
11
N
N
3
46
51
137
120
N
H
CN
N
NH2
12
N
N
4
HN
13
N
NH2
CN
a
Isolated yield.
Yield after treatment of complex 11 with aqueous NH3.
b
In conclusion, we have reported a method for the synthesis of 3-
aminoimidazoles using silica-sulfuric acid as a catalyst for the con-
densation of aminoazines and cyano-substituted compounds, via
the Strecker reaction. Further experiments aimed at exploring the
scope and limitations of this procedure and its optimization are
underway and will be reported in due course.
General procedure. Method A. To a stirred mixture of aminoazine
(3 mmol) in methanol (5 mL), aldehyde (3 mmol), TMSCN
(3.3 mmol) and silica-sulfuric acid (0.4 g) were added. Stirring
was continued for 3–5 d at room temperature (TLC monitoring).
The catalyst was filtered off and the filtrate was evaporated under
reduced pressure. The remaining residue was diluted with CH2Cl2,
washed with aqueous NaHCO3 (10%), dried and evaporated. The
Schiff base was extracted with hot hexane. The obtained residue
was recrystallized from hexane to give the 3-aminoimidazole.
Method B. Aminoazine (3 mmol) was added to a stirred mixture
of aldehyde (15 mmol), 2-hydroxy-2-methylpropanenitrile (15
mmol) and silica-sulfuric acid (0.4 g). Stirring was continued for
2–3 d at room temperature (TLC monitoring). The catalyst was re-
moved by filtration, the filtrate was diluted with isopropanol and
left at 0 °C to give a complex of the cyanohydrin with imidazo[1,2-
a]pyridine. Treatment of the complex with aqueous NH3 (5%) pro-
duced the free Schiff base.
Figure 1. X-ray structure of complex 6.
Method C. Aminoazine (3 mmol) was added to a stirred mixture
of 2-hydroxypropanenitrile (30 mmol) and silica-sulfuric acid
(0.4 g). Stirring was continued at room temperature for 2–3 d
(TLC monitoring). The catalyst was removed by filtration and
washed with CH2Cl2 (30 mL). The filtrate was washed with brine
(3 Â 50 mL), followed by aqueous NH3 (5%, 50 mL) and dried over
Na2SO4. The solvent was evaporated under reduced pressure and
the residue was triturated in isopropanol/hexane mixture.
providing the target aminonitriles 7, 11, 12 and 13 in good pre-
parative yields (Table 3).
To determine whether this approach can be applied to other 2-
aminoazines, we studied the condensation of 2-aminopyrazine,
thiophene-2-carboxaldehyde and trimethylsilyl cyanide. The cor-
responding imidazo[1,2-a]pyrazine 4 was obtained in 53% yield,
(Table 1, entry 4).
Deep-red crystals of the complex of mandelic acid nitrile and N-
benzylidene-6-methyl-2-phenylimidazo[1,2-a]pyridine-3-amine 6
were used for X-ray analysis (Fig. 1). A suitable monocrystal of
compound 6 was obtained by recrystallization from methanol by
slow evaporation at room temperature.18 The benzylideneamino
and imidazolopyridine fragments are located in the same plane
while the C7-phenyl ring is partially withdrawn from conjugation
forming a torsion angle of 42.6°.
References and notes
1. Rival, Y.; Grassy, G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170.
2. Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B. M. J. Med. Chem. 1991, 34,
533.
3. Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.; Moore, J. B. J. Med. Chem.
1988, 31, 2221.
4. Starrett, J. E.; Montzka, T. A.; Crosswell, A. R.; Cavanagh, R. L. J. Med. Chem. 1998,
32, 2204.

A. I. Polyakov et al. / Tetrahedron Letters 50 (2009) 4389–4393
4393
5. Blackburn, C. Tetrahedron Lett. 1998, 39, 5469.
(32), 91 (100), 77 (6), 65 (93), 51 (22), 39 (45). Calcd for C21H19N3 (313.41): C,
80.40; H, 6.06; N, 13.40. Found: C, 80.48; H, 5.97; N, 13.32.
6. Bienayme, H.; Bouzid, K. Angew. Chem., Int. Ed. 1998, 37, 2234.
7. Groebke, K.; Weber, L.; Fridolin, M. Synlett 1998, 661.
8. Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665.
9. Ireland, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369.
10. Schwerkoske, J.; Masquelin, T.; Perun, T.; Hulme, C. Tetrahedron Lett. 2005, 46,
8355.
11. Shaabani, A.; Maleki, A. Monatsh. Chem. 2007, 138, 51.
12. Chaves, F.; Suares, S.; Diaz, V. A. Synth. Commun. 1994, 24, 2325.
13. For a recent paper on a-aminonitrile synthesis using the H2SO4/SiO2 catalytic
15. 2-(2-Thienyl)imidazo[1,2-a]pyrazin-3-amine (4) was obtained by method A.
Yellow solid, mp 130–132 °C (methanol). 1H NMR (300 MHz, DMSO-d6):
d = 6.73 (br s, 2H, NH2), 7.22 (dd, 1H, J = 4.6 Hz, J = 5.3 Hz, 4-H-thienyl), 7.54 (d,
1H, J = 4.6 Hz, 3-H-thienyl), 7.75 (m, 2H, CH-Ar), 8.30 (d, 1H, J = 5.3 Hz, 5-H-
thienyl), 8.92 (s, 1H, CH-Ar) ppm. 13C NMR (50 MHz, DMSO-d6): d = 115.1,
122.5, 125.0, 127.0, 128.5, 129.8, 131.3, 132.5, 135.7, 136.2 ppm. EI MS: m/z
(%) = 216 (100) [M+], 188 (27), 137 (6), 122 (12), 110 (30), 95 (5), 84 (23), 80
(53), 69 (5), 64 (29), 58 (5), 52 (36), 48 (9), 44 (21), 39 (17). Calcd for C10H8N4S
(216.05): C, 55.55; H, 3.70; N, 25.92. Found: C, 55.30; H, 3.76; N, 25.67.
16. (E)-3-(Benzylideneamino)-6-methyl-2-phenylimidazo[1,2-a]pyridin-1-ium
cyano(phenyl) methanolate (6) was obtained by method B. Deep-red crystals,
mp 65 °C (methanol). 1H NMR (300 MHz, DMSO-d6): d = 2.34 (s, 3H, CH3), 3.35
(br s, 3H, CH3), 5.72 (d, 1H, J = 7.3 Hz, CH–OH), 7.02 (br d, 1H, J = 7.3 Hz, CH–
OH), 7.18 (d, 1H, J = 10.1 Hz, CH-Ar), 7.30–7.55 (m, 10H, CH-Ar), 7.87–7.97 (m,
3H, CH-Ar), 8.39 (s, 1H, CH-Ar), 8.87 (s, 1H, CH@N) ppm. Calcd for C29H24N4O
(444.20): C, 78.36; H, 5.44; N, 12.60. Found: C, 78.42; H, 5.76; N, 12.31.
17. 2-[(2,6-Dimethylimidazo[1,2-a]pyridine-3-yl)amino]propanenitrile (11) was
obtained by method C. White solid, mp 135 °C (methanol). 1H NMR
(300 MHz, DMSO-d6): d = 1.52 (d, 3H, J = 7.2 Hz, CH–CH3), 2.27 (s, 3H, CH3),
2.32 (s, 3H, CH3), 4.17 (q, 1H, J = 7.2 Hz, CH–CH3), 5.56 (d, 1H, J = 8.5 Hz, NH),
6.98 (d, 1H, J = 9.2 Hz, CH-Ar), 7.27 (d, 1H, J = 9.2 Hz, CH-Ar), 7.93 (s, 1H, CH-Ar)
ppm. 13C NMR (50 MHz, DMSO-d6): d = 13.0, 17.7, 19.3, 44.4, 115.5, 120.3,
120.4, 122.2, 123.1, 126.3, 135.1, 139.6 ppm. ESI MS m/z 215 (M++1). Calcd for
C12H14N4 (214.11): C, 67.28; H, 6.54; N, 26.16. Found: C, 67.12; H, 6.42; N,
25.89.
system, see: Oskooie, H. A.; Heravi, M. M.; Sadnia, A.; Jannati, F.; Benhbahani, F.
K. Monatsh. Chem. 2008, 139, 27.
14. N-Benzyl-6-methyl-2-phenylimidazo[1,2-a]pyridine-3-amine (14): Method A.
To a stirred mixture of 1b (0.1 g, 0.33 mmol) in ethanol (5 mL) at 40 °C was
added NaBH4 (0.015 g, 0.4 mmol). Stirring was continued (TLC monitoring).
The solvent was evaporated under reduced pressure and CH2Cl2 (15 mL) was
added. The resulting solution was washed with H2O and dried over Na2SO4.
The solvent was evaporated under reduced pressure to give 14 (0.07 g, 70%).
Method B. Benzyl isocyanide (0.35 g, 3 mmol) was added to a stirred mixture
of 2-amino-5-methylpyridine (0.31 g, 3 mmol), benzaldehyde (0.32 g,
3 mmol) and acetic acid (0.18 g, 3 mmol) in methanol (10 mL). Stirring was
continued (TLC monitoring). The product 14 (0.71 g, 78%) precipitated from
the reaction.
The samples of 14, obtained by both methods after recrystallization from
ethanol were identical and gave no melting point depression.
Compound 14: White solid, mp 165–167 °C (ethanol). 1H NMR (300 MHz,
DMSO-d6): d = 2.23 (s, 3H, CH3), 4.12 (d, 2H, J = 4.4 Hz, CH2–NH), 5.18 (t, 1H,
J = 4.4 Hz, NH), 6.98 (d, 1H, J = 8.8 Hz, CH-Ar), 7.18–7.48 (m, 9H, CH-Ar), 7.94
(s, 1H, CH-Ar), 8.12 (d, 2H, J = 7.3 Hz, CH-Ar) ppm. 13C NMR (50 MHz, DMSO-
d6): d = 17.7, 51.3, 116.1, 120.2, 120.5, 126.3, 126.4, 126.7, 126.9, 128.1, 128.2,
128.3, 134.7, 139.5, 139.8 ppm. EI MS: m/z (%) = 313 (3) [M+], 222 (23), 195
18. Crystallographic data (excluding structure factors) for compound 6 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 712214. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html.