Mechanistic studies on a new catalyst system (CuI-NaHSO4· SiO2) leading to the one-pot synthesis of imidazo[1,2- a ]pyridines from reactions of 2-aminopyridines, aldehydes, and terminal alkynes

Article abstract of DOI:10.1055/s-0030-1260255

One-pot reactions of aldehydes, 2-aminopyridines, and terminal alkynes, in the presence of the copper(I) iodide-NaHSO₄·SiO₂ combination catalyst in refluxing toluene, generate the corresponding imidazo[1,2-a]pyridines in high to excellent yields; the mechanism has been studied. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260255

PAPER
3463
Mechanistic Studies on a New Catalyst System (CuI–NaHSO4·SiO2) Leading to
the One-Pot Synthesis of Imidazo[1,2-a]pyridines from Reactions of
2-Aminopyridines, Aldehydes, and Terminal Alkynes
O
ne-Pot Synth
a
esis of Imi
r
dazo[1,2
i
-
a
]pyr
i
t
dines a Mishra, Rina Ghosh*
Department of Chemistry, Jadavpur University, Kolkata 700032, India
Fax +91(33)24146266.; E-mail: ghoshrina@yahoo.com; E-mail: ghosh_rina@hotmail.com
Received 12 July 2011; revised 26 August 2011
efficient general one-pot cascade synthesis of clinically
Abstract: One-pot reactions of aldehydes, 2-aminopyridines, and
terminal alkynes, in the presence of the copper(I) iodide–
NaHSO4·SiO2 combination catalyst in refluxing toluene, generate
the corresponding imidazo[1,2-a]pyridines in high to excellent
yields; the mechanism has been studied.
potent compounds containing this backbone is highly de-
sirable. In continuation of our research on one-pot multi-
component reactions,7 we report herein, an efficient, and
versatile one-pot synthesis of imidazo[1,2-a]pyridine
scaffolds from cascade reactions of aldehydes, 2-ami-
nopyridines, and terminal alkynes in the presence of the
copper(I) iodide–NaHSO4·SiO2 combination catalyst
(Tables 1 and 2).
Key words: CuI–NaHSO4·SiO2, one-pot synthesis, imidazo[1,2-
a]pyridine, 2-aminopyridine, cascade reaction
Since copper,8 iron,9 and other metal salts10 are known to
form propargylamine in a one-pot reaction from an alde-
hyde, amine, and phenylacetylene, we initially screened
copper(I) iodide, copper(II) acetate, iron(III) chloride, and
ruthenium(III) chloride to check whether these also could
effect the in situ generation of a propargylamine in a mod-
el reaction using 2-aminopyridine (3a), benzaldehyde
(1a), and phenylacetylene (2a), with a view to cyclization
to give a heterocyclic system. Although, copper(I) iodide
(50 mol%) afforded the corresponding imidazo[1,2-a]py-
ridine 4a in 45% yield (Table 1, entry 2), the remaining
reagents did not generate 4a (entries 3–5). It may be men-
tioned here that two reports have been made very recently,
of the one-pot, three component synthesis of imidazo[1,2-
a]pyridines from cascade reactions of 2-aminopyridines,
aldehydes, and phenylacetylenes. A one-pot reaction was
Due to its advantages over multistep synthesis, one-pot
multicomponent synthesis has gained prime importance1
over the last decade in the synthesis of medicinally impor-
tant pharmacophores and also in drug development. The
pyridine ring is a common fragment among many natural-
ly occurring bioactive molecules,2 of these the imida-
zo[1,2-a]pyridine framework is present in established
drugs like Zolpidem,3a Necopidem,3b Saripidem,3c
Zolimidine,3d Olprinone,4 and Minodronic acid4
(Figure 1), and also in other biologically active com-
pounds.2,4 Reports have been made of several multistep
syntheses5 of the imidazo[1,2-a]pyridine fragment that
are not devoid of limitations. Although, various one-pot
multicomponent syntheses of imidazo[1,2-a]pyridines
have been reported, these are limited to the synthesis of 3-
aminoimidazo[1,2-a]pyridine derivatives only.6 Thus, an
N
N
O
OH
Cl
N
N
P
OH
N
NC
O
N
N
SO2Me
OH
OH
OH
N
N
O
P
Me
O
n-Pr
N
H
Saripidem
(anxiolytic agent)
Olprinone
(to treat acute
heart failure)
Minodronic acid
(to treat osteoporosis)
Zolimidine (antiulcer)
N
Et
N
N
N
N
Me
i-Bu
O
O
Necopidem
(anxiolytic agent)
N
Me
Me
Zolpidem
(hypnotic agent)
Figure 1 Drugs containing the imidazo[1,2-a]pyridine framework
SYNTHESIS 2011, No. 21, pp 3463–3470
x
x.
x
x
.
2
0
1
1
Advanced online publication: 06.10.2011
DOI: 10.1055/s-0030-1260255; Art ID: Z69211SS
© Georg Thieme Verlag Stuttgart · New York

3464
S. Mishra, R. Ghosh
PAPER
first developed by Gevorgyan’s group, who used the mmol with respect to NaHSO4) in refluxing toluene to fur-
11
CuCl–Cu(OTf)2 [Cu(I)–Cu(II)] co-catalyst system, this nish the corresponding imidazo[1,2-a]pyridine 4a in ex-
was followed by the report of a similar one-pot synthesis cellent yield (91%, Table 1, entry 12, Table 2, entry 1).
by Liu et al. based on the CuSO4–TsOH12 system.
To check the generality and scope of the present protocol
Recently silica-supported Brønsted acids13 have gained (Table 2), benzaldehyde (1a, entries 14–18) or a variety of
much interest in organic synthesis. The use of Brønsted aromatic aldehydes containing electron-donating (entries
acids such as HClO4·SiO2, H2SO4·SiO2, HBF4·SiO2, 2–7, 11–13, 19, and 20) or electron-withdrawing substitu-
NaHSO4·SiO2, or K-1014 or resins like Dowex 50W ents (entries 8–10, 21–23) were reacted under these con-
(H+)15a,b or Amberlite IR 120 (H+),15c (Table 1) together ditions with 2-aminopyridine or its derivatives 3 (4- or 5-
with copper(I) iodide (entries 6–16), copper sulfate (entry methyl or 5-bromo) and arylacetylene 2, which afforded
18), or copper(I) chloride (entry 19) in different solvents the corresponding imidazo[1,2-a]pyridine scaffolds with-
improved the yields of the corresponding imidazopyridine in 12–14 hours in generally high yields (70–91%). Thus,
4a to different extents. The best result was obtained using this one-pot synthesis is not affected by electronic factors
the copper(I) iodide (5 mol%)–NaHSO4·SiO2 combina- within these substrates. Even ortho-substituted aldehydes
tion catalyst system in refluxing toluene (entry 12). Thus, (entries 12 and 13) give good yields of the desired prod-
under optimized reaction conditions, 2-aminopyridine ucts. Unlike the reported CuSO4–TsOH-based reactions,12
(3a, 1.2 mmol), benzaldehyde (1a, 1 mmol), and pheny- where 4-(dimethylamino)benzaldehyde was found to in-
lacetylene (2a, 1.5 mmol) reacted in the presence of cop- tervene the reaction conditions, reaction of this substrate
16
per(I) iodide (0.05 mmol) and NaHSO4·SiO2 (0.27 with 2-aminopyridine and phenylacetylene following the
Table 1 Screening of Solvent and Catalyst for the Three-Component Coupling Reaction
catalyst
N
PhCHO
+
Ph
Ph
+
N
co-catalyst, N2
solvent, reflux
N
NH2
1a
1 mmol
2a
1.5 mmol
3a
1.2 mmol
Ph
4a
Entry
1
Catalyst (mol%)
CuI (10)
CuI (50)
FeCl3 (20)
Cu(OAc)2 (50)
RuCl3 (10)
CuI (5)
Co-catalysta
–
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Time (h)
24
Yield (%) of 4a
35
45
–
2
–
24
3
–
24
4
–
24
–
5
–
24
–
6
H2SO4·SiO2
HClO4·SiO2
HBF4·SiO2
Amberlite
Dowex-50
K-10
14
50
60
65
56
62
75
91
45
60
30
75
–
7
CuI (5)
14
8
CuI (5)
14
9
CuI (5)
16
10
11
12
13
14
15
16
17
18
19
CuI (5)
16
CuI (5)
14
CuI (5)
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
NaHSO4·SiO2
12
CuI (5)
18
CuI (5)
MeCN
DCE
18
CuI (5)
18
CuI (5)
xylene
toluene
toluene
toluene
10
–
16
CuSO4 (10)
CuCl (5)
16
65
70
16
a Catalytic load of each co-catalyst is 123 mg/mmol of aldehyde.
Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Imidazo[1,2-a]pyridines
3465
present methodology furnished the corresponding product analogue and phenylacetylene or its 4-methyl derivative
4k in 73% yield (entry 11), thus once more establishing under the standard protocol affording the corresponding
the generality of the present procedure. Heteroaromatic imidazopyridines 4x and 4y in high yields. An alkyl-sub-
aldehydes such as thiophene-2-carbaldehyde (entries 24 stituted acetylene, hex-1-yne, was also a good substrate
and 25) also reacted with 2-aminopyridine or its 5-methyl and reacted with benzaldehyde and 2-aminopyridine re-
Table 2 Synthesis of Imidazo[1,2-a]pyridines
CuI (5 mol%)
NaHSO4•SiO2
N
R1CHO
R2
+
R1
+
R3
R3
N
toluene, reflux
N
NH2
1
Entry
1
2
3
4
R2
R1
Ph
R2
R3
Time (h)
12
12
12
12
14
13
13
13
14
14
14
14
14
14
13
13
13
14
13
13
14
13
13
13
14
14
14
14
Product
4a11,12
4b12
4c12
4d
Yield (%)
91
Mp (°C)
121
Ph
H
2
4-MeC6H4
Ph
H
88
160
3
4-MeOC6H4
Ph
H
86
127
4
3,4-(MeO)2C6H3
4-ClC6H4
4-FC6H4
4-BrC6H4
4-NCC6H4
3-O2NC6H4
4-O2NC6H4
4-Me2NC6H4
2-MeC6H4
2-ClC6H4
Ph
Ph
H
89
124
5
Ph
H
4e12
4f11,12
4g11
4h11
4i12
4j
75
142
6
Ph
H
88
80
7
Ph
H
87
162 (dec)
132
8
Ph
H
84
9
Ph
H
71
165
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Ph
H
70
158
Ph
H
4k
73
255–256
semisolid
125–126
90
Ph
H
4l
80
Ph
H
4m12
4n12
4o12
4p11
4q
72
4-FC6H4
H
80
Ph
4-MeC6H4
H
72
syrup
146
Ph
Ph
4-Me
5-Br
5-Me
4-Me
5-Br
5-Br
5-Me
4-Me
H
72
Ph
Ph
82
209–210
80
Ph
Ph
4r12
4s11
4t
80
4-MeC6H4
4-MeC6H4
4-NCC6H4
4-NCC6H4
4-NCC6H4
2-thienyl
2-thienyl
Ph
4-MeC6H4
89
152
Ph
80
208–209
198
Ph
4u
81
Ph
4v
83
205–206
136
4-MeC6H4
4w11
4x
88
4-MeC6H4
70
126
Ph
Bu
Ph
Ph
5-Me
Ph
4y
76
185
4z11
4aa12
4ab11
60a
70
syrup
syrup
86
Cy
Ph
i-Pr
Ph
66b
a Hex-1-yne (2.5 mmol) was added in 2 portions (initially 1.5 mmol and then after 4 h, 1 mmol).
b i-PrCHO (1.5 mmol) was used.
Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York

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S. Mishra, R. Ghosh
PAPER
CuI
NaHSO4•SiO2
N
(1)
(2)
PhCHO
+
Ph
+
+
+
Ph
Ph
Ph
N
N
N
N
NH2
toluene, reflux
Ph
4a (91%)
N
CuI
+
PhCHO Ph
N
toluene, reflux
NH2
Ph
4a (45%)
NaHSO4•SiO2
N
(3)
(4)
+
PhCHO
PhCHO
Ph
X
N
toluene, reflux
NH2
Ph
Ph
4a
CN
H
CuI
NC
CN
Ph
N
Ph
NaHSO4•SiO2
+
+
Ph
N
toluene
reflux, 14 h
PhS
N
NH2
NC
5
SPh
Ph
6
Scheme 1 Examination of various factors in the one-pot reaction to give imidazo[1,2-a]pyridine
sulting in the desired product 4z in good yield. Aliphatic benzaldehyde, phenylacetylene, and a densely functional-
aldehydes such as cyclohexanecarbaldehyde and 3-meth- ized 2-aminopyridine 5 in the presence of copper(I) iodide
ylbutanal (entries 27 and 28) reacted under similar condi- and NaHSO4·SiO2 in toluene for 14 hours generated the
tions with 2-aminopyridine and phenylacetylene corresponding propargylamine 6 [Scheme 1, (4)]. Thus,
affording the corresponding products 4aa and 4ab in high propargylamines are intermediates for such one-pot reac-
yields.
tions. An attempt to isolate such an intermediate 9 from an
incomplete one-pot reaction, failed, indicating 9 to be
highly reactive under the reaction condition, and, thus, in-
stantaneously converted into the product 4a.
The mechanistic pathway for this one-pot synthesis was
established from various reactions (Schemes 1– 3). Imi-
dazopyridine 4a was synthesized from the one-pot reac-
tion
of
benzaldehyde,
2-aminopyridine,
and To establish the roles of copper(I) iodide and
phenylacetylene in the presence of a combination catalyst NaHSO4·SiO2 in this one-pot reaction, and also the reac-
copper(I) iodide and NaHSO4·SiO2 [Scheme 1, (1)]; the tion mechanism, two sets (Scheme 2, path A and path B)
reaction performed with copper(I) iodide alone also gives of multistep reactions were performed. In path A, benzal-
4a in moderate yield [Scheme 1, (2)], but NaHSO4·SiO2 dehyde was first reacted with 2-aminopyridine in the pres-
alone is unable to carry out this transformation [Scheme 1, ence of NaHSO4·SiO2, and the resulting product was
(3)]. It is interesting to note that refluxing a mixture of isolated and purified to give imine 7, which was then re-
Path A
N
Ph
NH2
N
N
imine
7
Ph
H
5-exo-dig
cyclization
Ph
Ph
N
N
N
Ph
PhCHO
NH
N
N
Ph
Ph
Ph
(not isolable)
Ph
NH2
OH
9'
9
10
isomerization
N
Ph
Ph
8
N
Ph
Ph
Path B
N
4a
Scheme 2 Multistep reactions to study the reaction mechanism for copper(I) iodide–NaHSO4·SiO2 catalyzed one-pot synthesis of imid-
azo[1,2-a]pyridine
Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Imidazo[1,2-a]pyridines
3467
CN
Ph
CN
Ph
PhS
Ph
Ph
H
OH
CuI
Ph
NC
CN
Ph
N
NC
CN
one pot
NaHSO4•SiO2
N
+
+
+
N
CN
toluene
reflux, 20 h
conditions
reflux, 20 h
NC
PhS
N
NH2
PhS
Ph
N
N
N
SPh
Ph
Ph
Ph
imine 11
Ph
6, major
8
5
Ph
12, minor
Scheme 3 Reaction of propargyl alcohol 8 with hindered 2-aminopyridine 5 under the one-pot reaction conditions
fluxed in toluene with phenylacetylene catalyzed by cop- All commercial reagents were used as obtained without further pu-
rification. All reactions were carried out under a N2 atmosphere and
monitored by TLC. Toluene was dried by a standard method prior
to use. TLC was performed on glass plates precoated with silica gel
or on Merck silica gel plates (60-F254). Column chromatography
per(I) iodide to generate imidazopyridine 4a via initial
formation of the propargylamine 9. Tautomerization of 9
to 9¢ followed by 5-exo-dig cyclization formed 10, which
finally isomerized to product 4a. In path B, the reaction of
was carried out on silica gel 60–120 mesh (SRL, India). Mixtures of
benzaldehyde and phenylacetylene catalyzed by copper(I)
iodide furnished propargyl alcohol 8. Isolated pure 8 was
then reacted with 2-aminopyridine in the presence of
NaHSO4·SiO2 to afford imidazopyridine 4a. It is notewor-
thy that the reaction of propargyl alcohol 8 with 2-ami-
nopyridine in the presence of copper(I) iodide–
NaHSO4·SiO2 (not shown) proceeds at a faster rate than
the above reaction.
EtOAc, petroleum ether (PE), and Et3N were used as eluents. Melt-
ing points were determined on a Toshniwal melting point apparatus
and are uncorrected. IR spectra were measured on a Perkin Elmer
1
spectrum BX-II FT-IR spectrophotometer. H NMR spectra were
recorded on a Bruker DPX-300 at r.t. in CDCl3 at 300 MHz. 13C
NMR spectra were recorded on a Bruker DPX-300 at r.t. in CDCl3
at 75 MHz. HRMS (ESI) measurements were made with a Q-tof-
Micro (YA-263) mass spectrometer.
All known compounds (see Table 2) had physical spectroscopic
1
To show whether both paths A and path B operate simul-
taneously, propargyl alcohol 8 was also reacted with the
hindered 2-aminopyridine 5 under the one-pot reaction
condition (Scheme 3), but for a prolonged time (20 h),
which generated the propargyl amine 6 as the major prod-
uct together with the corresponding imidazopyridine 12 as
a minor product. A similar product composition (of 6 and
12) was also obtained from the reaction of a mixture of
imine 11 with phenylacetylene under the above reaction
conditions. Thus, both path A and path B (Scheme 2) take
place simultaneously in the one-pot formation of imida-
zopyridine. From the foregoing experiments it is clear that
in the one-pot reaction, the presence of copper(I) iodide is
mandatory for the C–H activation steps (for the formation
of 9 from 7, and also 8 from benzaldehyde). Copper(I) io-
dide also catalyzes the isomerization of 9 to 9¢ as the final
cyclization step. NaHSO4·SiO2 enhances imine forma-
data (IR, H NMR) corresponding to the literature; all new com-
1
pounds were characterized by IR, H and 13C NMR spectroscopy,
and HRMS spectrometry.
Imidazo[1,2-a]pyridines 4a–ab; General Procedure
To a mixture of 2-aminopyridine 3 (1.2 mmol) and CuI (0.05 mmol)
in toluene (5 mL) under N2 atmosphere were added aldehyde 1 (1
mmol), NaHSO4·SiO2 (123 mg, 0.27 mmol with respect to
NaHSO4), and terminal alkyne 2 (1.5 mmol) successively. The re-
sulting mixture was stirred under reflux until completion of the re-
action (TLC monitoring, 12–14 h, Table 2). Then the mixture was
filtered through a short plug of alumina, and washed well with
CH2Cl2. The combined filtrate and washings were concentrated un-
der vacuum to give the crude product, which was purified by col-
umn chromatography (silica gel, EtOAc–PE–Et3N).
3-Benzyl-2-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine (4d)
White crystals (EtOAc–PE); yield: 0.305 g (89%); mp 124 °C.
IR (KBr): 3069, 3024, 2361, 1503, 1495, 1450, 1440, 1359, 1272,
tion; it protonates the propargyl alcohol 8 thus activating 1257 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.73 (s, 3 H), 3.77 (s, 3 H), 4.36
(s, 2 H), 6.57–6.61 (t, J = 6.0 Hz, 1 H), 6.77–6.79 (d, J = 6.0 Hz, 1
H), 7.00–7.26 (m, 8 H), 7.54–7.61 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 29.8, 55.75, 55.8, 111.1, 111.5,
112.1, 117.3, 120.2, 123.1, 124.0, 126.8, 127.6, 129.0, 136.9, 144.0,
144.7, 148.8, 149.1.
it to nucleophilic attack by 2-aminopyridine giving prop-
argylamine 9, and it also promotes nucleophilic attack by
the C–H activated phenylacetylene on the intermediate
imine 7. Cyclization of 9 to 4a is also catalyzed by
NaHSO4·SiO2 via protonation of the alkyne group in 9.
NaHSO4·SiO2 thus plays a synergistic rate enhancing role
in various steps except the C–H activation step. It also ap-
HRMS (ESI): m/z [M + H]+ calcd for C20H21N2O2: 345.1603; found:
pears that path A proceeds at a faster rate than path B, but 345.1606.
both are operating simultaneously.
3-Benzyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (4j)
Yellow crystals (EtOAc–PE); yield: 0.231 g (70%); mp 158 °C.
In conclusion, we have developed an efficient one-pot
method for the synthesis of diverse imidazo[1,2-a]py-
ridines through copper(I) iodide or NaHSO4·SiO2 combi-
nation catalyst based reactions of aldehydes, 2-
aminopyridines, and terminal alkynes in refluxing tolu-
ene, and also have established the corresponding mecha-
nistic pathways.
IR (KBr): 3079, 3052, 2352, 1519, 1492, 1350, 1280, 1250, 1091
cm–1.
1H NMR (300 MHz, CDCl3): d = 4.53 (s, 2 H), 6.77–6.81 (t, J = 6.6
Hz, 1 H), 7.13 (d, J = 6.7 Hz, 2 H), 7.23 (s, 1 H), 7.26–7.37 (m, 3
H), 7.71 (d, J = 9.1 Hz, 1 H), 7.76 (d, J = 6.9 Hz, 1 H), 7.96 (d,
J = 8.8 Hz, 2 H), 8.29 (d, J = 8.8 Hz, 2 H).
Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York

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S. Mishra, R. Ghosh
PAPER
3-Benzyl-6-bromo-2-(4-cyanophenyl)imidazo[1,2-a]pyridine
13C NMR (75 MHz, CDCl3): d = 30.0, 113.1, 118.0, 119.6, 123.7,
124.1, 125.3, 127.4, 127.7, 128.7, 128.9, 136.1, 141.2, 141.8, 145.4,
147.2.
(4u)
White crystals (EtOAc–PE); yield: 0.315 g (81%); mp 198 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H16N3O2: 330.1243; found:
330.1248.
IR (KBr): 3066, 2360, 2220, 1608, 1518, 1495, 1409, 1242, 1068
cm–1.
1H NMR (300 MHz, CDCl3): d = 4.48 (s, 2 H), 7.11 (d, J = 6.8 Hz,
2 H), 7.27 (d, J = 4.6 Hz, 1 H), 7.33–7.35 (m, 3 H), 7.59 (d, J = 9.5
Hz, 1 H), 7.71 (d, J = 8.2 Hz, 2 H), 7.86–7.88 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 29.8, 107.7, 111.4, 118.5, 118.9,
119.5, 123.5, 127.46, 127.50, 128.5, 129.4, 132.5, 135.5, 138.6,
142.8, 143.6, 152.0.
3-Benzyl-2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridine
(4k)
Pale-yellow crystals (EtOAc–PE); yield: 0.238 g (73%); mp 255–
256 °C.
IR (KBr): 2917, 2849, 1617, 1515, 1492, 1450, 1359, 1198, 1062
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.98 (s, 6 H), 4.48 (s, 2 H), 6.66
(t, J = 6.7 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 2 H), 7.11–7.17 (m, 3 H),
7.24–7.32 (m, 3 H), 7.68 (t, J = 8.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): d = 30.1, 40.6, 111.9, 112.6, 116.5,
117.2, 122.7, 123.2, 123.8, 126.9, 127.9, 129.1, 137.3, 144.7, 144.8,
150.2.
HRMS (ESI): m/z [M + H]+ calcd for C21H15BrN3: 388.0449; found:
388.0451.
3-Benzyl-6-methyl-2-(4-cyanophenyl)imidazo[1,2-a]pyridine
(4v)
White crystals (EtOAc–PE); yield: 0.268 g (83%); mp 205–206 °C.
IR (KBr): 3024, 2358, 2223, 1605, 1551, 1494, 1454, 1418, 1346,
1182 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C22H22N3: 328.1814; found:
328.1808.
1H NMR (300 MHz, CDCl3): d = 2.25 (s, 3 H), 4.46 (s, 2 H), 7.06–
7.12 (m, 3 H), 7.27–7.35 (m, 3 H), 7.51 (s, 1 H), 7.58 (d, J = 9.2 Hz,
1 H), 7.7 (d, J = 8.2 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 18.4, 29.8, 110.8, 117.1, 118.7,
119.1, 121.0, 122.6, 127.2, 127.6, 128.2, 128.3, 129.2, 132.4, 136.3,
139.4, 141.8, 144.3.
3-Benzyl-2-(2-methylphenyl)imidazo[1,2-a]pyridine (4l)
Semisolid; yield: 0.238 g (80%).
IR (KBr): 3021, 1643, 1602, 1505, 1491, 1449, 1358, 1258, 1172,
1028 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H), 4.30 (s, 2 H), 6.68
(t, J = 6.8 Hz, 1 H), 7.05 (d, J = 6.9 Hz, 2 H), 7.16–7.34 (m, 8 H),
7.64–7.69 (m, 2 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H18N3: 324.1501; found:
324.1504.
13C NMR (75 MHz, CDCl3): d = 20.4, 29.8, 112.0, 117.6, 118.9,
123.9, 125.5, 126.8, 127.9, 128.7, 130.5, 130.6, 133.9, 136.9, 138.6,
144.6, 145.0.
3-(4-Methylbenzyl)-2-(thiophen-2-yl)imidazo[1,2-a]pyridine
(4x)
White crystals (EtOAc–PE); yield: 0.214 g (70%); mp 126 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H19N2: 299.1548; found:
299.1551.
IR (KBr): 3104, 1573, 1538, 1492, 1382, 1338, 1271, 1192, 1178,
1032 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31 (s, 3 H), 4.50 (s, 2 H), 6.70
(t, J = 4.2 Hz, 4.5 Hz, 1 H), 7.04 (d, J = 4.8 Hz, 2 H), 7.08–7.10 (m,
3 H), 7.14–7.18 (m, 1 H), 7.34 (d, J = 3.0 Hz, 1 H), 7.41 (d, J = 2.7
Hz, 1 H), 7.65 (d, J = 5.4 Hz, 1 H), 7.73 (d, J = 4.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.1, 29.6, 112.4, 117.4, 117.7,
123.3, 124.5, 124.7, 125.6, 127.75, 127.8, 129.8, 133.3, 136.7,
137.7, 138.5, 144.8.
3-Benzyl-6-bromo-2-phenylimidazo[1,2-a]pyridine (4q)
White crystals (EtOAc–PE); yield: 0.298 g (82%);mp 209–210 °C.
IR (KBr): 3081, 2908, 2362, 1519, 1493, 1450, 1388, 1324, 1253,
1081 cm–1.
1 H NMR (300 MHz, CDCl3): d = 4.47 (s, 2 H), 7.14 (d, J = 7.1 Hz,
2 H), 7.23–7.46 (m, 7 H), 7.58 (d, J = 9.5 Hz, 1 H), 7.76 (d, J = 7.5
Hz, 2 H), 7.84 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 29.8, 107.0, 118.2, 118.3, 123.4,
127.2, 127.6, 128.0, 128.2, 128.7, 129.2, 134.0, 136.2, 143.3, 145.0.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S: 305.1112; found:
305.1107.
3-Benzyl-6-methyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine
(4y)
Pale-yellow crystals (EtOAc–PE); yield: 0.231 g (76%); mp 185 °C.
HRMS (ESI): m/z [M + H]+ calcd for C20H16BrN2: 363.0497; found:
363.0500.
3-Benzyl-6-bromo-2-(4-methylphenyl)imidazo[1,2-a]pyridine
(4t)
IR (KBr): 3104, 3065, 2920, 1573, 1538, 1492, 1430, 1382, 1338,
1271, 1192, 1032 cm–1.
White crystals (EtOAc–PE); yield: 0.303 g (80%); mp 208–209 °C.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 4.52 (s, 2 H), 7.01–
7.09 (m, 2 H), 7.15–7.18 (d, J = 7.3 Hz, 2 H), 7.24–7.36 (m, 5 H),
7.51–7.57 (m, 2 H).
IR (KBr): 3081, 2908, 2362, 1519, 1493, 1450, 1388, 1324, 1253,
1082 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.32 (s, 3 H), 4.40 (s, 2 H), 7.06
(d, J = 6.9 Hz, 2 H), 7.14–7.30 (m, 6 H), 7.50 (d, J = 9.3 Hz, 1 H),
7.59 (d, J = 7.8 Hz, 2 H), 7.75 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.1, 30.6, 111.9, 117.4, 117.9,
121.5, 122.9, 125.1, 126.1, 127.6, 128.46, 128.5, 128.9, 129.8,
130.9, 137.3, 138.3, 140.0, 144.5.
13C NMR (75 MHz, CDCl3): d = 21.3, 29.9, 106.8, 118.1, 123.3,
127.1, 127.4, 127.7, 128.0, 129.2, 129.5, 131.1, 136.3, 137.9, 143.3,
145.1, 162.3.
HRMS (ESI): m/z [M + H]+ calcd for C19H17N2S: 305.1112; found:
305.1116.
2-(1,3-Diphenylprop-2-ynylamino)-4-phenyl-6-(phenylthio)py-
ridine-3,5-dicarbonitrile (6)
White solid (EtOAc–PE); mp 183 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H18BrN2: 377.0653; found:
377.0657.
IR (KBr): 3390, 3227, 3223, 1649, 1544, 1421, 1263, 1022 cm–1.
Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Imidazo[1,2-a]pyridines
3469
1H NMR (300 MHz, CDCl3): d = 5.83 (d, J = 8.2 Hz, 1 H), 6.06 (d,
J = 8.1 Hz, 1 H), 7.16–7.19 (m, 2 H), 7.30–7.36 (m, 6 H), 7.45–7.47
(m, 5 H), 7.50–7.57 (m, 5 H), 7.64–7.67 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 47.2, 85.5, 86.3, 88.2, 95.4, 115.0,
115.2, 122.2, 127.2, 127.4, 128.5, 128.6, 128.9, 129.2, 129.4, 130.3,
131.1, 131.9, 133.4, 136.4, 138.0, 156.1, 158.5, 169.4.
Latrofa, A.; Trapani, G.; Sanna, E. J. Med. Chem. 2008, 51,
6876. (c) Laquintana, V.; Denora, N.; Lopedota, A.; Suzuki,
H.; Sawada, M.; Serra, M.; Biggio, G.; Latrofa, A.; Trapani,
G.; Liso, G. Bioconjugate Chem. 2007, 18, 1397.
(d) Trapani, G.; Laquintana, V.; Denora, N.; Trapani, A.;
Lopedota, A.; Latrofa, A.; Franco, M.; Serra, M.; Pisu, M.
G.; Floris, I.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem.
2005, 48, 292.
HRMS (ESI): m/z [M + H]+ calcd for C34H23N4S: 519.1643; found:
519.1645.
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Tetrahedron Lett. 2007, 48, 4079. (b) Adib, M.; Mahdavi,
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3-Benzyl-2,7-diphenyl-5-(phenylthio)imidazo[1,2-a]pyridine-
6,8-dicarbonitrile (12)
Yellow crystal (EtOAc–PE); mp 220–222 °C.
(7) (a) Ghosh, R.; Maiti, S.; Chakraborty, A.; Maiti, D. K.
J. Mol. Catal. A: Chem. 2004, 210, 53. (b) Ghosh, R.;
Maiti, S.; Chakraborty, A. J. Mol. Catal. A: Chem. 2004,
217, 47. (c) Ghosh, R.; Maiti, S.; Chakraborty, A. Synlett
2005, 115; erratum: Synlett 2005,1344. (d) Ghosh, R.;
Maiti, S.; Ghosh, S.; Mukherjee, A. K. Synthesis 2007, 190.
(e) Ghosh, R.; Maiti, S.; Chakraborty, A.; Chakraborty, S.;
Mukherjee, A. K. Tetrahedron 2006, 62, 4059. (f) Ghosh,
R.; Maity, S.; Maity, S.; Roy, S. Synth. Commun. 2008, 38,
1958. (g) Mishra, S.; Ghosh, R. Synth. Commun. 2011, in
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2857.
IR (KBr): 3480, 3323, 3157, 3028, 2903, 2368, 2208, 1607, 1498,
1363, 1260 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.58 (s, 1 H), 5.19 (s, 1 H), 7.01–
7.03 (m, 2 H), 7.12 (m, 2 H), 7.32–7.34 (m, 6 H), 7.41–7.43 (m, 4
H), 7.57–7.59 (m, 4 H), 7.65–7.66 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 30.9, 53.4, 59.6, 103.9, 114.3,
115.0, 122.0, 126.2, 126.9, 127.5, 128.66, 128.74, 128.9, 129.0,
129.4, 129.5, 129.6, 131.2, 131.6, 132.9, 133.2, 137.9, 141.1, 146.1,
153.2, 154.2.
HRMS (ESI): m/z [M + H]+ calcd for C34H23N4S: 519.1643; found:
519.1639.
(8) (a) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.
(b) Park, S. B.; Alper, H. Chem. Commun. 2005, 1315.
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Acad. Sci. U.S.A. 2004, 101, 5749. (f) Fodor, A.; Kiss, A.;
Debreczeni, N.; Hell, Z.; Gresits, I. Org. Biomol. Chem.
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2405. (h) Gommermann, N.; Koradin, C.; Polborn, K.;
Knochel, P. Angew. Chem. Int. Ed. 2003, 42, 5763.
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C.-A. Chem. Eur. J. 2009, 15, 6332. (b) Li, P.; Zhang, Y.;
Wang, L. Chem. Eur. J. 2009, 15, 2045. (c) Zhang, Y.; Li,
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(10) (a) Wei, C. M.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 9584.
(b) Lo, V. K. Y.; Liu, Y.; Wong, M. K.; Che, C. M. Org. Lett.
2006, 8, 1529. (c) Lo, V. K. Y.; Kung, K. K. Y.; Wong, M.
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Acknowledgement
S.M. thanks UGC, India for providing SRF. CAS – UGC and FIST
– DST, New Delhi, India are acknowledged for supporting research
facilities to the Department of Chemistry, Jadavpur University.
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Synthesis 2011, No. 21, 3463–3470 © Thieme Stuttgart · New York