Microwave-assisted three-component reaction in conventional solvents and ionic liquids for the synthesis of amino-substituted imidazo[1,2-a]pyridines

Article abstract of DOI:10.3998/ark.5550190.0013.318

3-Amino-substituted imidazo[1,2-a]pyridines can be prepared with yields up to 98% within a few minutes by microwave-assisted three-component reaction between 2-aminopyridines, aldehydes and isocyanides using montmorillonite as the catalyst and toluene as the solvent. The organic solvent can be replaced by ionic liquids. With guanidinium salts the microwave-assisted reaction can be performed in the absence of any further catalyst. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.0013.318

Issue in Honor of Prof. Rainer Beckert
ARKIVOC 2012 (iii) 243-256
Microwave-assisted three-component reaction in conventional
solvents and ionic liquids for the synthesis of amino-substituted
imidazo[1,2-a]pyridines
Fadime Mert-Balci, Jürgen Conrad, and Uwe Beifuss*
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstr. 30, 70599
Stuttgart, Germany
E-mail: ubeifuss@uni-hohenheim.de
Dedicated to Professor Rainer Beckert on the occasion of his 60th birthday
Abstract
3-Amino-substituted imidazo[1,2-a]pyridines can be prepared with yields up to 98% within a
few minutes by microwave-assisted three-component reaction between 2-aminopyridines,
aldehydes and isocyanides using montmorillonite as the catalyst and toluene as the solvent. The
organic solvent can be replaced by ionic liquids. With guanidinium salts the microwave-assisted
reaction can be performed in the absence of any further catalyst.
Keywords: Multicomponent reactions, imidazo[1,2-a]pyridines, microwaves, ionic liquids,
imidazolium salts, guanidinium salts
Introduction
Recently, the application of microwaves in organic synthesis has become very popular.
Microwave-assisted syntheses are a particularly attractive alternative to syntheses under thermal
conditions since they often proceed much faster and deliver products with higher yields and
higher purity.1 Upon conventional heating using an external heat source like an oil bath the
energy transfer depends on the thermal conductivity of the sample to be penetrated, which is
relatively slow and inefficient. In contrast, the energy of the microwaves is directly transferred to
the molecules of the reaction mixture via dielectric heating. The heating is largely caused by
dipolar polarization and ionic conduction.
Currently, the use of ionic liquids (ILs) as solvents and catalysts in organic transformations
is receiving a great deal of interest.2 ILs have an ionic structure and they consist of an organic
cation and an inorganic or organic anion. They have nearly no vapor pressure, are thermally and
chemically robust, are non explosive, are convenient to use and can be recycled. Therefore, ILs
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can offer a more sustainable alternative to traditional organic solvents. In a number of reactions
performed in ILs both a greatly increased reaction rate and a change in selectivities has been
observed. These effects are probably due to polar interactions between the ILs and the substrates.
Meanwhile, numerous organic transformations have been performed in ILs,2 and many of them
from the field of heterocyclic chemistry.3 The significance which ILs have gained in organic
synthesis is not only due to their solvent properties but to their catalytic effects as well.4 Due to
their high polarity and high dielectricity constant ILs can be efficiently heated up by microwave
irradiation.5 This is why reactions in ILs can benefit tremendously from microwave conditions.
The best known ILs are the imidazolium salts which have been successfully used as solvents
and/or catalysts in numerous chemical transformations. In addition, there is a large number of
other ILs including pyridinium, phosphonium, ammonium and guanidinium salts.
Guanidinium salts, which are easily available by a number of methods, so far have been
used in a small number of organic reactions,6 including aldol reactions,6a,c Heck reactions,6b and
the oxidation of benzylic alcohols.6e Also, guanidinium salts have several properties predisposing
them for applications as potential electrolytes in electrochemical devices such as lithium
batteries, super capacitors, fuel cells and dye-sensitized solar cells.7
Multicomponent reactions are of great importance for the efficient assembly of compound
libraries.8 The Groebke reaction is a particularly valuable three component reaction as it allows
the synthesis of a number of relevant heterocyclic systems. It makes use of the reaction of 2-
aminoazines, aldehydes and isocyanides for the preparation of fused 3-aminoimidazoles,
including imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines and imidazo[1,2-a]pyrazines. Due
to the marked biological activity of many compounds with an imidazo[1,2-a]pyridine skeleton9 a
number of different protocols for the Groebke reaction have been developed.10 The synthesis of
imidazo[1,2-a]pyridines has been achieved in the presence of Brønsted acids 10h,i as well as with
Lewis acids.10b,d,g The reaction can also be performed in the absence of any catalyst.10a The
synthesis has also been performed under microwave conditions in the presence of
10f
montmorillonite
or ZnCl2.10b There is also a report on the use of [bmim]Br at room
temperature to bring about the synthesis of imidazo[1,2-a]pyridines.10c However, many of these
methods suffer from different drawbacks such as long reaction times and/or the application of
expensive catalysts. In order to establish a quick and efficient approach to this class of
compounds we decided to study the influence of solvents on the microwave-assisted reaction
between 2-aminopyridines, aldehydes and isocyanides in the presence of montmorillonite as the
catalyst. It was planned to perform a model reaction in the absence and presence of solvents,
including traditional organic solvents as well as ILs. Of particular interest was the use of
guanidinium salts as reaction medium.
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Results and Discussion
Here we present our results on the microwave-assisted three-component synthesis of 3-amino
substituted imidazo[1,2-a]pyridines 4 with montmorillonite as the catalyst under a variety of
reaction conditions. The reaction between 2-aminopyridine (1a), benzaldehyde (2a) and
benzylisocyanide (3a) was used as a model reaction. After some preliminary experiments it was
found that the reaction could be run in the absence of any solvent when equimolar amounts of
1a, 2a and 3a were reacted in the presence of montmorillonite in a sealed vial under microwave
conditions using a focused single mode microwave reactor for 5 min at 140°C. Under these
conditions N-benzyl-2-phenylimidazo[1,2-a]pyridin-3-amine (4a) could be isolated in 74% yield
(Scheme 1).
NH2
montmorillonite (50 mg)
+
MW (300 W), 5 min, 140°C
N
N
OHC
N
Bn NC
1a
(1 mmol)
2a
(1 mmol)
74 %
NH
Bn
3a
(1 mmol)
4a
Scheme 1. Microwave-assisted synthesis of 4a under solvent-free conditions.
Further experiments demonstrated that the yield of 4a could be improved markedly when the
reaction was run in an organic solvent (Table 1). Optimizing the reaction conditions with regard
to the amounts of substrates, reaction time and temperature, solvent and the amount of
montmorillonite revealed that 4a could be isolated in 92% yield when 1 mmol 1a, 1.09 mmol of
2a and 1.25 mmol of 3a were reacted with 76 mg montmorillonite in 2 mL toluene at 160 °C for
7 min (Entry 7). When the reaction was run in a sealed vial under thermal conditions (oil bath)
the yield of 4a dropped to 75%.
The microwave-assisted synthesis of 4a was also studied in different ILs in the presence of
montmorillonite. First, the reaction was performed with different imidazolium salts (Table 2). It
was found that at higher reaction temperatures mainly decomposition occurs (Entries 3,5). But
even at 90°C the formation of 4a was accompanied with the formation of a side product of
unknown structure (Entries 1,2,6). The only IL allowing for the clean formation of 4a was
[bmim]BF4 at 90°C (Entry 4). Under these conditions 4a could be isolated with 70% yield.
However, in no case did the yield of 4a exceed that obtained under the conditions given in Table
1, Entry 7.
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Table 1. Optimization of the reaction conditions for the synthesis of 4a in organic solvents
montmorillonite
organic solvent
MW
1a
+
2a
+
3a
4a
67 - 92 %
Entry
1a
2a
3a
t
T
Solvent
(2 mL)
Clay
(mg)
59
Yield
4a (%)
(mmol) (mmol) (mmol) (min) (°C)
1
2
3
4
5
6
7
1
1.02
1.01
1.25
1.30
1.22
1.20
1.25
1.25
5
7
5
7
5
7
7
140 o-dichlorobenzene
71
1
1
140
140
140
140
140
160
methanol
toluene
toluene
toluene
toluene
toluene
79
66
76
76
76
76
67
68
79
84
89
92
1.03
1
1
1.04
1.07
1.09
1.09
1
1
1
Table 2. The use of imidazolium salts as reaction medium in the synthesis of 4a
montmorillonite (76 mg)
MW
+
+
1a
(1 mmol)
2a
3a
4a
ionic liquid (2 mL)
(1.09 mmol) (1.25 mmol)
Entry
Ionic liquid
[bmim]Cl
[bmim]Br
[bmim]Br
[bmim]BF4
Power (W)
t (min)
T (°C)
90
yield 4a (%)
1
2
3
4
5
6
10
10
30
10
30
30
10
30
7
661
90
391
Decomposition
70
160
90
[bmim]MeSO4
[bmim]PF6
20
20
140
140
Decomposition
391
7
1 In addition, a side product of unknown structure was observed.
Furthermore, it was studied whether the imidazolium salts can be replaced by guanidinium
salts. When the microwave-assisted reaction between 1a, 2a and 3a was run in guanidinium salt
5a as ionic liquid in the presence of montmorillonite 43% of 4a could be isolated (Table 3, Entry
1). In a final set of experiments the reaction was studied in the absence of montmorillonite. For
this purpose 1 eq 1a, 1.09 eq 2a and 1.25 eq 3a were reacted under microwave conditions in 1 eq
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of different guanidinium salts 5a-d (Table 3, Structure Block 1). The product was formed in each
of the ionic liquids employed, but the outcome strongly depends on the structure of the
guanidinium salts employed. The highest yield (68%) was obtained with 5c (Entry 4). However,
in no case did the yield of 4a exceed that obtained under the conditions given in Table 1, Entry 7.
The results clearly demonstrate that the three component reaction can be performed in
guanidinium salts acting both as solvent and as catalyst. Further studies will be needed to study
the influence of the structure of the guanidinium salts.
Table 3. The use of guanidinium salts for the synthesis of 4a
ionic liquid (1 eq)
MW
+
+
1a
2a
3a
4a
(1 mmol)
(1.09 mmol)
(1.25 mmol)
27 - 68 %
Entry Ionic liquid montmorillonite Power (W)
t (min)
T (°C)
yield 4a (%)
1
2
3
4
5
6
5a1
5a
5a
5b
5c
76 mg
10
20
10
10
10
10
30
7
90
160
90
43
482
29
27
68
40
-
-
-
-
-
90
90
90
90
90
90
5d
90
1
The reaction was performed in 2 mL of 5a. 2 In addition, a side product of unknown structure
was observed.
O
5
5
N
5
N
N
N
5
O
I
Br
I
Br
N
N
N
N
N
N
N
N
5b
5c
5a
5d
Structure Block 1. Structures of guanidinium salts 5a-d.
It turned out that the highest yield of 4a could be obtained when the microwave-assisted
reaction between 1a, 2a and 3a using montmorillonite as a catalyst was run in toluene as the
solvent. Therefore, the scope of the three-component reaction was studied under these reaction
conditions. It was found that 2-aminopyridines 1a,b can be successfully reacted with different
aldehydes 2a-f and isocyanides 3a-c to produce a number of imidazo[1,2-a]pyridines 4a-j with
yields ranging from 16% to 98% in analytically pure form (Table 4, Structure Block 2).
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Table 4. Synthesis of imidazo[1,2-a]pyridines 4a-j from different 2-aminopyridines 1, aldehydes
2 and isocyanides 3
R2
CHO
montmorillonite (76 mg)
toluene
MW (300 W), 7 min, 160°C
NH2
R1
+
N
N
R2
2
R1
(1.09 mmol)
1
N
16 - 98 %
R3 NC
NHR3
(1 mmol)
3 (1.25 mmol)
4
Entry
1
1
R1
H
2
R2
3
R3
Product
Yield (%)
92
1a
2a
3a
4a
2
3
4
5
1a
1a
1a
1a
H
H
H
H
2b
2c
2d
2e
3a
3a
3a
3a
4b
4c
4d
4e
70
80
77
60
Cl
Br
NC
MeO
MeO
OMe
NO2
6
7
1a
1a
1b
1b
1a
H
H
2f
2a
2a
2g
2b
3a
3b
3a
3a
3c
4f
4g
4h
4i
53
94
72
16
98
O
O
tBu
8
5-Br
5-Br
H
OEt
O
9
10
4j
Cl
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Cl
Br
CN
N
N
N
N
N
N
N
N
NH
Bn
NH
Bn
NH
Bn
NH
Bn
4a
4b
4c
4d
OMe
OMe
OMe
N
N
N
NO2
N
N
N
NH
NH
Bn
NH
Bn
O
tBu
4e
4f
4g
O
Cl
OEt
O
N
N
N
N
N
N
Br
Br
NH
Bn
NH
Bn
NH
Cy
4j
4i
4h
Structure Block 2. Structures of imidazo[1,2-a]pyridines 4a-j.
The structures of all imidazo[1,2-a]pyridines 4a-j described here have been elucidated by
1
13
means of mass, H, C, COSY, HSQC and HMBC spectroscopic methods. The assignment of
the quaternary carbons relies on long-range correlations in the HMBC spectra.
Conclusions
In summary, the microwave-assisted three-component reaction between 2-aminopyridines,
aldehydes and isocyanides with montmorillonite as the catalyst and in toluene as the solvent
delivers 3-amino-substituted imidazo[1,2-a]pyridines with yields up to 98% within a few
minutes. The organic solvent can be replaced by ILs like imidazolium or guanidinium salts. With
guanidinium salts the reaction can be performed in the absence of any further catalyst.
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Experimental Section
General. Starting materials were purchased from chemical companies and used without
purification. Toluene was distilled from sodium. All microwave-assisted reactions were
performed using a DiscoverTM single mode cavity microwave synthesizer (CEM Corp.)
producing continuous microwave irradiation at 2450 MHz. All experiments were conducted
under argon. Thin-layer chromatography (TLC) was performed on TLC aluminum roll silica gel
60 F254 (Merck). Compounds were visualized with UV light (λ = 254 nm) and/or immersion in
KMnO4 solution followed by heating. Column chromatography was performed on silica gel MN
60, 0.063 mm-0.200 mm. Melting points were determined on a Kofler melting point apparatus
(Reichert, Austria) and are uncorrected. IR (ATR) spectra were taken on a Spectrum One FT-IR
spectrometer (Perkin Elmer). UV spectra were measured using a CARY 4E spectrophotometer
(Varian). NMR spectra were recorded on a Varian UnityINOVA spectrometer (300/75 MHz) in
1
13
CDCl3 ; the H and C chemical shifts were referenced to residual solvent signals at δH = 7.26
and δC = 77.0 relative to TMS. Mass spectra were recorded on a MAT 90 with 70 eV ionization
energy (Finnigan MAT). Elemental analyses were carried out by F. Hambloch, Institute of
Organic and Biomolecular Chemistry, University of Göttingen.
General procedure A for the reaction of 1, 2 and 3 under microwave conditions in toluene
1 (1 mmol), 2 (1.09 mmol) and 3 (1.25 mmol) were suspended in toluene (2 mL) and placed in a
10 mL reaction vial heated and cooled under Ar. After addition of montmorillonite (76 mg) the
vial was sealed with a septum and irradiated with microwaves (300W) for 7 min at 160°C. The
reaction mixture was allowed to cool to r.t. and was then diluted with CH2Cl2 (10 mL) and
filtered. The residue obtained after concentration in vacuo was purified by column
chromatography on silica gel to yield 4.
General procedure B for the reaction of 1a, 2a and 3a under microwave conditions in
imidazolium salts
1a (1 mmol), 2a (1.09 mmol), 3a (1.25 mmol) and montmorillonite (76 mg) were placed in a 10
mL reaction vial that had been heated and cooled under Ar. After addition of the imidazolium
salt (2 mL) the vial was sealed with a septum and irradiated with microwaves. After completion
of the reaction, the mixture was allowed to cool to r.t. and washed with EE or TBME (5 × 5 mL).
The combined organic extracts were concentrated in vacuo and the residue was purified by
column chromatography on silica gel to yield 4a.
General procedure C for the reaction of 1a, 2a and 3a under microwave conditions in
guanidinium salts
1a (1 mmol), 2a (1.09 mmol), 3a (1.25 mmol) and the guanidinium salt 5 (1 mmol) were placed
in a 10 mL reaction vial that had been heated and cooled under argon. The vial was sealed with a
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septum and irradiated with microwaves. After completion of the reaction, the mixture was
allowed to cool to r.t. and then purified by column chromatography on silica gel to yield 4a.
N-Benzyl-2-phenylimidazo[1,2-a]pyridin-3-amine (4a).10f According to general procedure A
94 mg (1 mmol) 1a, 116 mg (1.09 mmol) 2a and 146 mg (1.25 mmol) 3a were reacted with 76
mg montmorillonite in 2 mL toluene. After work up and column chromatography (TBME/PE =
10/2) 274 mg (0.92 mmol) 4a (92 %) were isolated as a yellow solid.
~
mp 122-123°C (Lit.10f mp 112-113°C). IR (ATR):
= 3256, 3057, 3020, 1564, 1491, 1472,
ν
1444, 1386, 1348, 1334, 1228, 1192, 1077, 1026, 907, 752, 735, 706, 694. 1H NMR (300 MHz,
CDCl3): δ = 3.53 (1H, t, J = 6.2 Hz, NH), 4.20 (2H, d, J = 6.3 Hz, 7‘‘-CH2), 6.74 (1H, ddd, J =
0.9 Hz, J = 6.8 Hz, J = 6.8 Hz, 5-H), 7.13 (1H, ddd, J = 1.3 Hz, J = 6.7 Hz, J = 9.2 Hz, 6-H),
7.27-7.38 (6H, m, 4‘-H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H), 7.45 (2H, t, J = 7.6 Hz, 3‘-H, 5‘-H),
7.56 (1H, bd, J = 9.1 Hz, 7-H), 7.90-8.05 (3H, m, 2‘-H, 6‘-H, 4-H). 13C-NMR (75 MHz, CDCl3):
δ = 52.40 (7‘‘-CH2), 111.79 (5-C), 117.31 (7-C), 122.35 (4-C), 124.20 (6-C), 125.62 (3-C),
127.01 (2‘-C, 6‘-C), 127.49 (4‘-C), 127.65 (4‘‘-C), 128.13 (2‘‘-C, 6‘‘-C), 128.67 (3‘-C, 5‘-C,
3‘‘-C, 5‘‘-C), 133.90 (1‘-C), 135.81 (2-C), 138.90 (1‘‘-C), 141.36 (7a-C). MS (70 eV, EI): m/z
(%) = 299 (45) [M+], 208 (100), 181 (97), 91 (13), 78 (87), 51 (11).
2-(4-Chlorophenyl)-N-benzylimidazo[1,2-a]pyridin-3-amine (4b). According to the general
procedure A 94 mg (1 mmol) 1a, 153 mg (1.09 mmol) 2b and 146 mg (1.25 mmol) 3a were
reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column chromatography
(TBME/PE = 5/3) 233mg (0.7 mmol) 4b (70 %) were isolated as a yellow solid.
~
ν
mp 166-167 °C. IR (ATR):
= 3249, 3018, 2919, 1558, 1488, 1454, 1384, 1350, 1332, 1242,
1188, 1090, 1076, 1010, 911, 835, 750, 732, 698. UV (CH3CN): λmax (lg ε) = 339 nm (3.89), 253
1
(4.58). H-NMR (300 MHz, CDCl3): δ = 3.42 (1H, t, J = 5.9 Hz, NH), 4.17 (2H, d, J = 5.9 Hz,
7‘‘-CH2), 6.74 (1H, ddd, J = 1.1 Hz, J = 6.7 Hz, J = 6.7 Hz, 5-H), 7.13 (1H, ddd, J = 1.3 Hz, J =
6.6 Hz, J = 9.1 Hz, 6-H), 7.28-7.35 (5H, m, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H), 7.37-7.41 (2H, m,
3‘-H, 5‘-H), 7.53 (1H, dt, J = 1.1 Hz, J = 9.1 Hz, 7-H), 7.96 (2H, m, 2‘-H, 6‘-H), 7.98 (1H, dt, J
= 1.4 Hz, J = 6.7 Hz, 4-H). 13C-NMR (75 MHz, CDCl3): δ = 52.39 (7‘‘-CH2), 111.85 (5-C),
117.48 (7-C), 122.27 (4-C), 124.28 (6-C), 125.52 (3-C), 127.74 (4‘‘-C), 128.15 (2‘-C, 6‘-C),
128.20 and 128.74 (2’’-C and 6’’-C or 3’’-C and 5’’-C), 128.76 (3’-C, 5’-C), 132.68 (1’-C),
133.17 (4’-C), 135.15 (2-C), 138.78 (1’’-C), 141.60 (7a-C). MS (70 eV, EI): m/z (%) = 333 (16)
[M+], 242 (100), 215 (71), 78 (40). Anal. Calcd. for C20H16ClN3: C, 71.96; H, 4.83; Cl, 10.62; N,
12.59. Found: C, 71.82; H, 4.74; N, 12.80.
N-Benzyl-2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-amine (4c). According to the general
procedure A 94 mg (1 mmol) 1a, 202 mg (1.09 mmol) 2c and 146 mg (1.25 mmol) 3a were
reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column chromatography
(TBME/PE = 5/2) 304 mg (0.8 mmol) 4c (80 %) were isolated as a pale yellow solid.
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~
ν
mp 165-166°C. IR (ATR):
= 3242, 1557, 1488, 1443, 1384, 1346, 1331, 1226, 1193, 1070,
1008, 829, 752, 733, 695. UV (CH3CN): λmax (lg ε) = 340 nm (3.93), 255 (4.59). 1H-NMR (300
MHz, CDCl3): δ = 3.42 (1H, t, J = 6.0 Hz, NH), 4.17 (2H, d, J = 6.2 Hz, 7‘‘-CH2), 6.75 (1H, ddd,
J = 1.1 Hz, J = 6.8 Hz, J = 6.8 Hz, 5-H), 7.14 (1H, ddd, J = 1.3 Hz, J = 6.7 Hz, J = 9.0 Hz, 6-H),
7.27-7.35 (5H, m, 2’’-H, 3’’-H, 4’’-H, 5’’-H, 6’’-H), 7.54 (3H, overlapped, 3’-H, 5’-H, 7-H),
13
7.87 (2H, d, J = 8.5 Hz, 2’-H, 6’-H), 7.95 (1H, dt, J = 1.2 Hz, J = 6.9 Hz, 4-H). C-NMR (75
MHz, CDCl3): δ = 52.32 (7‘‘-CH2), 112.05 (5-C), 117.28 (7-C), 121.51 (4’-C), 122.35 (4-C),
124.64 (6-C), 125.61 (3-C), 127.76 (4’’-C), 128.15 and 128.48 and 128.74 (2’-C and 6’-C or 2’’-
C and 6’’-C or 3’’-C and 5’’-C), 131.71 (3’-C, 5’-C), 132.76 (1’-C), 134.79 (2-C), 138.73 (1’’-
C), 141.39 (7a-C). MS (70 eV, EI): m/z (%) = 377 (26) [M+], 286 (100), 259 (64), 180 (9), 91
(19), 78 (80). Anal. Calcd. for C20H16BrN3: C, 63.50; H, 4.26; Br, 21.12; N, 11.11. Found: C,
63.55; H, 4.19; N, 11.02.
N-Benzyl-2-(4-cyanphenyl)imidazo[1,2-a]pyridin-3-amine (4d). According to the general
procedure A 94 mg (1 mmol) 1a, 143 mg (1.09 mmol) 2d and 146 mg (1.25 mmol) 3a were
reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column chromatography
(TBME/PE = 10/3) 249 mg (0.77 mmol) 4d (77 %) were isolated as a yellow solid.
~
ν
mp 190-191°C. IR (ATR):
= 3244, 2225, 1605, 1574, 1454, 1348, 1190, 851, 760, 748, 729,
1
701. UV (CH3CN): λmax (lg ε) = 350 nm (4.00), 265 (4.53). H-NMR (300 MHz, CDCl3): δ =
3.54 (1H, t, J = 6.0 Hz, NH), 4.18 (2H, d, J = 6.1 Hz, 7’’-CH2 ), 6.77 (1H, ddd, J = 1.1 Hz, J =
6.8 Hz, J = 6.8 Hz, 5-H), 7.18 (1H, ddd, J = 1.3 Hz, J = 6.6 Hz, J = 9.0 Hz, 6-H), 7.27-7.31 (5H,
m, 2’’-H, 3’’-H, 4’’-H, 5’’-H, 6’’-H), 7.54 (1H, dt, J = 1,1 Hz, J = 8.9 Hz, 7-H), 7.65 (2H, d, J =
8.4 Hz, 3’-H, 5’-H), 7.93 (1H, dt, J = 1.2 Hz, J = 6.8 Hz, 4-H), 8.12 (2H, d, J = 8.4 Hz, 2’-H, 6’-
H). 13C-NMR (75 MHz, CDCl3): δ = 52.40 (7’’-CH2), 110.43 (4’-C), 112.35 (5-C), 117.62 (7-C),
119.08 (1’-C), 122.36 (4-C), 125.09 (6-C), 126.70 (3-C), 127.11 (2’-C, 6’-C), 127.89 (4’’-C),
128.13 (2’’-C, 6’’-C), 128.80 (3’’-C, 5’’-C), 132.29 (3’-C, 5’-C), 133.90 (2-C), 138.47 (1’’-C),
141.74 (7a-C). MS (70 eV, EI): m/z (%) = 324 (45) [M+], 233 (100), 206 (85), 91 (12), 78 (76).
HRMS (70 eV, EI) for C21H16N4: Calcd.: 324.1375; Found: 324.1397.
N-Benzyl-2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridin-3-amine (4e). According to the
general procedure A 94 mg (1 mmol) 1a, 214 mg (1.09 mmol) 2e and 146 mg (1.25 mmol) 3a
were reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column
chromatography (EE/PE = 5/2) 232 mg (0.6 mmol) 4e (60 %) were isolated as a pale yellow
solid.
mp 131-132°C. IR (ATR):
~
ν
= 3189, 2829, 1587, 1495, 1446, 1412, 1391, 1357, 1231, 1120,
1000, 759, 723, 694. UV (CH3CN): λmax (lg ε) = 339 nm (3.89), 261 (4.43), 223 (4.59). 1H-NMR
(300 MHz, CDCl3): δ = 3.46 (1H, bs, NH), 3.90 (9H, s, 3‘-OCH3, 4‘-OCH3, 5‘-OCH3), 4.23 (2H,
d, J = 5.6 Hz, 7‘‘-CH2), 6.75 (1H, ddd, J = 1.1 Hz, J = 6.7 Hz, J = 6.7 Hz, 5-H), 7.13 (1H, ddd, J
= 1.3 Hz, J = 6.6 Hz, J = 9.0 Hz, 6-H), 7.27-7.35 (7H, m, 2‘-H, 6‘-H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H,
6‘‘-H), 7.55 (1H, dt, J = 1.1 Hz, J = 9.1 Hz, 7-H), 7.95 (1H, dt, J = 1.2 Hz, J = 6.8 Hz, 4-H). 13C-
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NMR (75 MHz, CDCl3): δ = 52.40 (7‘‘-CH2), 56.22 (3‘-OCH3, 5‘-OCH3), 60.91 (4‘-OCH3),
104.26 (2‘-C, 6‘-C), 111.89 (5-C), 117.23 (7-C), 122.20 (4-C), 124.26 (6-C), 125.28 (3-C),
127.73 (4‘‘-C), 128.02 (2‘‘-C, 6‘‘-C), 128.73 (3‘‘-C, 5‘‘-C), 129.57 (1‘-C), 135.67 (2-C), 137.67
(4‘-C), 138.88 (1‘‘-C), 141.22 (7a-C), 153.40 (3‘-C, 5‘-C). MS (70 eV, EI): m/z (%) = 389 (25)
[M+], 298 (100), 271 (72), 78 (16). HRMS (70 eV, EI) for C23H23N3O3: Calcd.: 389.1700;
Found: 389.1747.
N-Benzyl-2-(2-nitrophenylethenyl)imidazo[1,2-a]pyridin-3-amine (4f). According to the
general procedure A 94 mg (1 mmol) 1a, 193 mg (1.09 mmol) 2f and 146 mg (1.25 mmol) 3a
were reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column
chromatography (EE/PE = 5/3) 195 mg (0.53 mmol) 4f (53 %) were isolated as an orange solid.
~
ν
mp 152-154°C. IR (ATR):
= 3351, 2929, 1514, 1348, 1276, 958, 755, 740, 703. UV
(CH3CN): λmax (lg ε) = 375 nm (4.07), 317 (4.14), 261 (4.44). 1H-NMR (300 MHz, CDCl3): δ =
3.48 (1H, t, J = 6.8 Hz, NH), 4.22 (2H, d, J = 6.0 Hz, 7‘‘-CH2), 6.74 (1H, td, J = 1.1 Hz, J = 6.8
Hz, 5-H), 6.87 (1H, d, J = 15.8 Hz, 1‘-H), 7.14 (1H, ddd, J = 1.3 Hz, J = 6.7 Hz, J = 9.2 Hz, 6-
H), 7.28-7.32 (5H, m, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H), 7.33-7.39 (1H, m, 6‘-H), 7.51 (1H, dt, J
= 1.1 Hz, J = 9.1 Hz, 7-H), 7.53 (2H, overlapped, 7‘-H, 8‘-H), 7.85 (1H, d, J = 15.8 Hz, 2‘-H),
7.90 (1H, dt, J = 0.9 Hz, J = 8.3 Hz, 5‘-H), 7.93 (1H, dt, J = 1.1 Hz, J = 7.0 Hz, 4-H). 13C-NMR
(75 MHz, CDCl3): δ = 53.08 (7‘‘-CH2), 111.75 (5-C), 117.46 (7-C), 122.21 (4-C), 123.93 (2‘-C),
124.11 (1‘-C), 124.60 (5‘-C), 124.70 (6-C), 127.57 (6‘-C), 127.69 (4‘‘-C), 127.84 (3-C), 128.00
(8‘-C), 128.39 (3‘‘-C, 5‘‘-C), 128.72 (2‘‘-C, 6‘‘-C), 132.67 (7‘-C), 133.11 (3‘-C), 134.71 (2-C),
139.18 (1‘‘-C), 142.22 (7a-C), 148.01 (4’-C). MS (70 eV, EI): m/z (%) = 370 (42) [M+], 279
(100), 252 (46), 234 (16), 205 (10), 145 (7), 128 (6), 91 (7), 78 (41). HRMS (70 eV, EI) for
C22H18N4O2: Calcd.: 370.1430; Found: 370.1426.
N-(2-(2,2-Dimethyl-1-oxopropoxy)phenyl)-2-phenylimidazo[1,2-a]pyridin-3-amine (4g).
According to the general procedure A 94 mg (1 mmol) 1a, 116 mg (1.09 mmol) 2a and 254 mg
(1.25 mmol) 3b were reacted with 76 mg montmorillonite in 2 mL toluene. After work up and
column chromatography (TBME/PE = 4/3) 362 mg (0.94 mmol) 4g (94 %) were isolated as a
pale gray solid.
~
ν
mp 216-217°C. IR (ATR):
= 2970, 1743, 1519, 1492, 1447, 1391, 1343, 1254, 1172, 1106,
756, 741, 699. UV (CH3CN): λmax (lg ε) = 330 nm (3.83), 245 (4.60), 202 (4.60). 1H-NMR (300
MHz, CDCl3): δ = 1.43 (9H, s, 2‘‘‘-(CH3)3), 5.63 (1H, s, NH), 6.32 (1H, dd, J = 1.3 Hz, J = 7.9
Hz, 5’’-H), 6.80 (1H, t, J = 6.8 Hz, 5-H), 6.88 (1H, td, J = 1.4 Hz, J = 7.6 Hz, 3‘‘-H), 6.98 (1H,
td, J = 1.2 Hz, J = 7.8 Hz, 4‘‘-H), 7.11 (1H, dd, J = 1.3 Hz, J = 7.9 Hz, 2‘‘-H), 7.20-7.32 (2H, m,
4‘-H, 6-H), 7.38 (2H, t, J = 7.4 Hz, 3‘-H, 5‘-H), 7.66 (1H, d, J = 9.1 Hz, 7-H), 7.87 (1H, d, J =
6.9 Hz, 4-H), 8.02 (2H, d, J = 7.4 Hz, 2‘-H, 6‘-H). 13C-NMR (75 MHz, CDCl3): δ = 27.31 (2‘‘‘-
(CH3)3), 39.44 (2‘‘‘-C), 112.45 (5-C), 113.79 (5‘‘-C), 116.97 (3-C), 117.65 (7-C), 120.14 (3‘‘-
C), 122.67 (2‘‘-C), 122.84 (4-C), 125.18 (6-C), 126.88 (2‘-C, 6‘-C), 127.09 (4‘‘-C), 127.95 (4‘-
C), 128.67 (3‘-C, 5‘-C), 133.15 (1‘-C), 136.53 (6‘‘-C), 138.66 (1‘‘-C), 139.46 (2-C), 142.84 (7a-
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C), 176.77 (1’’’-C). MS (70 eV, EI): m/z (%) = 385 (100) [M+], 300 (49), 181 (77), 78 (31), 57
(20). Anal. Calcd. for C24H23N3O2: C, 74.78; H, 6.01; N, 10.90; O, 8.30. Found: C, 74.81; H,
5.87; N, 10.73.
N-Benzyl-5-bromo-2-phenylimidazo[1,2-a]pyridin-3-amine (4h). According to the general
procedure A 173 mg (1 mmol) 1b, 116 mg (1.09 mmol) 2a and 146 mg (1.25 mmol) 3a were
reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column chromatography
(CH2Cl2/EE = 12/1) 270 mg (0.72 mmol) 4h (72 %) were isolated as a white solid.
~
ν
mp 173-174°C. IR (ATR):
= 3241, 1474, 1445, 1404, 1323, 1215, 1054, 914, 805, 767, 752,
702, 693. UV (CH3CN): λmax (lg ε) = 347 nm (3.82), 251 (4.56). 1H-NMR (300 MHz, CDCl3): δ
= 3.54 (1H, t, J = 5.7 Hz, NH), 4.18 (2H, d, J = 5.9 Hz, 7‘‘-CH2), 7.16 (1H, dd, J = 1.8 Hz, J =
9.5 Hz, 6-H), 7.28-7.37 (6H, m, 4‘-H, 2‘‘-H, 3‘‘-H, 4‘‘-H, 5‘‘-H, 6‘‘-H), 7.40-7.48 (3H,
overlapped, 3‘-H, 5‘-H, 7-H), 7.95 (2H, d, J = 7.3 Hz, 2‘-H, 6‘-H), 8.03 (1H, dd, J = 0.8 Hz, J =
1.9 Hz, 4-H). 13C-NMR (75 MHz, CDCl3): δ = 52.49 (7‘‘-CH2), 106.67 (5-C), 117.96 (7-C),
122.66 (4-C), 125.84 (3-C), 126.99 (2‘-C, 6‘-C), 127.50 (6-C), 127.80 (4‘-C), 127.86 (4‘‘-C),
128.23 (2‘‘-C, 6‘‘-C), 128.74 (3‘-C, 5‘-C, 3‘‘-C, 5‘‘-C), 133.50 (1‘-C), 136.99 (2-C), 138.60
(1‘‘-C), 159.75 (7a-C). MS (70 eV, EI): m/z (%) = 377 (26) [M+], 286 (99), 259 (100), 180 (9),
156 (33), 103 (9), 91 (22), 76 (12). Anal. Calcd. for C20H16BrN3: C, 63.50; H, 4.26; Br, 21.12; N,
11.11. Found: C, 63.49; H, 4.06; N, 10.95.
N-Benzyl-5-bromo-2-(3-ethoxy-1-methyl-3-oxo-1-propen-1-yl)imidazo[1,2-a]pyridin-3-
amine (4i).
According to the general procedure A 173 mg (1 mmol) 1b, 155 mg (1.09 mmol) 2g and 146 mg
(1.25 mmol) 3a were reacted with 76 mg montmorillonite in 2 mL toluene. After work up and
column chromatography (CH2Cl2/TBME = 15/1) 67 mg (0.16 mmol) 4i (16 %) were isolated as
a yellow solid.
~
ν
mp 185-186°C. IR (ATR):
= 3303, 1687, 1614, 1451, 1331, 1311, 1197, 1169, 1105, 1048,
1
881, 812, 698. UV (CH3CN): λmax (lg ε) = 357 nm (3.84), 261 (4.49). H-NMR (300 MHz,
CDCl3): δ = 1.32 (3H, t, J = 7.1 Hz, 1‘‘-CH3), 2.65 (3H, s, 1‘-CH3), 3.53 (1H, t, J = 6.1 Hz, NH),
4.15 (2H, d, J = 6.1 Hz, 7’’’-CH2), 4.22 (2H, q, J = 7.1 Hz, 1’’-CH2), 6.53 (1H, s, 2’-H), 7.17
(1H, dd, J = 1.7 Hz, J = 9.5 Hz, 6-H), 7.29-7.35 (5H, m, 2’’’-H, 3’’’-H, 4’’’-H, 5’’’-H, 6’’’-H),
13
7.39 (1H, d, J = 9.5 Hz, 7-H), 8.02 (1H, s, 4-H). C-NMR (75 MHz, CDCl3): δ = 14.34 (1‘‘-
CH3), 16.86 (1’-CH3), 52.55 (7’’’-CH2), 59.81 (1’’-CH2), 107.16 (5-C), 117.47 (2’-C), 118.36
(7-C), 122.68 (4-C), 127.54 (3-C), 128.01 (6-C or 4’’’-C), 128.12 (6-C or 4’’’-C), 128.32 (2’’’-
C, 6’’’-C), 128.81 (3’’’-C, 5’’’-C), 137.53 (2-C), 138.12 (1’’’-C), 139.35 (7a-C), 148.45 (1’-C),
166.89 (3’-C). MS (70 eV, EI): m/z (%) = 413 (41) [M+], 322 (100), 295 (39), 278 (32), 156 (24),
91 (38). Anal. Calcd. for C20H20BrN3O2: C, 57.98; H, 4.87; Br, 19.29; N, 10.14; O, 7.72. Found:
C, 57.85; H, 4.58; N, 9.88.
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2-(4-Chlorophenyl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine (4j).10a According to the
general procedure A 94 mg (1 mmol) 1a, 153 mg (1.09 mmol) 2b and 136 mg (1.25 mmol) 3c
were reacted with 76 mg montmorillonite in 2 mL toluene. After work up and column
chromatography (CH2Cl2/TBME = 15/1) 320 mg (0.98 mmol) 4j (98 %) were isolated as a pale
gray solid.
1
mp 191-192°C (Lit.10a mp 179-181°C). H-NMR (300 MHz, CDCl3): δ = 1.19 (3H, overlapped,
4’’-Ha, 3’’-Ha, 5’’-Ha), 1.29 (2H, bt, J = 11.5 Hz, 2’’-Ha, 6’’-Ha), 1.61 (1H, bs, 4’’-Hb), 1.72
(2H, m, 3’’-Hb, 5’’-Hb), 1.83 (2H, m, 2’’-Hb, 6’’-Hb), 2.93- 2.95 (1H, m, 1’’-H), 3.05 (1H, d, J
= 4.5 Hz, NH), 6.79 (1H, ddd, J = 1.1 Hz, J = 6.8 Hz, J = 6.8 Hz, 5-H), 7.14 (1H, ddd, J = 1.2
Hz, J = 6.8 Hz, J = 8.9 Hz, 6-H), 7.40 (2H, m, 3’-H, 5’-H), 7.53 (1H, dt, J = 0.9 Hz, J = 9.0 Hz,
7-H), 8.02 (2H, m, 2’-H, 6’-H), 8.07 (1H, dt, J = 1.1 Hz, J = 6.8 Hz, 4-H). 13C-NMR (75 MHz,
CDCl3): δ = 24.77 (3’’-C, 5’’-C), 25.65 (4’’-C), 34.17 (2’’-C, 6’’-C), 56.82 (1’’-C), 111.98 (5-
C), 117.12 (7-C), 122.74 (4-C), 124.61 (6-C), 124.91 (3-C), 128.25 (2’-C, 6’-C), 128.65 (3’-C,
5’-C), 132.44 (1’-C), 133.13 (2-C), 135.06 (4’-C), 141.29 (7a-C). MS (70 eV, EI): m/z (%) = 325
(62) [M+], 242 (100), 215 (58), 78 (25). HRMS (70 eV, EI) for C19H20ClN3: Calcd.: 325.1300;
Found: 325.1354.
Acknowledgements
We thank Dr. A. Job, Lanxess for guanidinium salts and Ms. S. Mika for recording NMR
spectra. Financial support by the BMBF (01R105181) is greatly acknowledged.
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