Ionic liquid promoted facile one-pot synthesis of 1-pyridylimidazo[1,5-a] pyridines from dipyridylketone and aryl aldehydes

Article abstract of DOI:10.1055/s-2006-942522

A highly efficient one-pot methodology has been developed to synthesize a class of substituted 1-pyridylimidazo[1,5-a]pyridines, using Bronsted acidic ionic liquid 1-butylimidazolium tetrafluoroborate, [Hbim]BF₄ in excellent isolated yields in

Full text of DOI:10.1055/s-2006-942522

PAPER
2849
Ionic Liquid Promoted Facile One-Pot Synthesis of 1-Pyridylimidazo[1,5-a]py-
ridines from Dipyridylketone and Aryl Aldehydes
O
S
ne-PotSynth
h
esisof 1-Pyr
a
idylimidaz
f
o[1,5-
a
]p
i
yridines from
A
Dipyridylketone
.
and
A
ryl
Al Sd ehydes iddiqui, Taterao M. Potewar, Rajgopal J. Lahoti, Kumar V. Srinivasan*
Division of Organic Chemistry Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune – 411 008, India
E-mail: kv.srinivasan@ncl.res.in
Received 6 February 2006; revised 24 May 2006
expensive acid catalysts. Moreover, the synthesis of these
Abstract: A highly efficient one-pot methodology has been devel-
heterocycles is usually carried out in polar solvents such
as methanol, acetic acid, THF, phosphorous oxychloride,
ridines, using Bronsted acidic ionic liquid 1-butylimidazolium
tetrafluoroborate, [Hbim]BF in excellent isolated yields in the ab- DMF, and toluene, leading to complex isolation and re-
oped to synthesize a class of substituted 1-pyridylimidazo[1,5-a]py-
4
sence of any catalyst. The methodology is characterized by simple covery procedures. These processes also generate waste
work-up procedures along with efficient recovery and recycling of
containing both catalyst and solvent, which have to be re-
the ionic liquid, which acts as a reaction medium as well as a pro-
covered, treated, and disposed of.
moter.
Organic solvents used in most of the synthetic processes
in the chemical industry evaporate into the atmosphere
with detrimental effects on the environment as well as hu-
man health. Most of the time, these volatile organic sol-
Key words: imidazo[1,5-a]pyridines, aldehyde, heterocycles, ionic
liquids, ammonium acetate
vents are expensive to purchase, difficult to recycle or
Fused imidazopyridine ring systems represent an impor-
reuse, and impractical to dispose of without incurring sub-
tant class of compounds not only for their theoretical in-
stantial costs and/or adversely affecting the environment
terest but also from a pharmacological point of view.
and/or personnel.
These heterocyclic structures form part of the skeleton of
1
2
3
Recently, room-temperature ionic liquids (RTILs) have
attracted much attention as promising alternative ‘green’
solvents to hazardous traditional organic solvents, due to
their properties such as non-flammability, negligible va-
por pressure, high thermal stability, solvating ability, and
natural alkaloids, act as neuromuscular blocking agents,
+
+
are reversible inhibitors of the H , K -ATPase enzyme
4
with a potent anti-secretory activity, and are known to be
5
sedative hypnotics of the nervous system. The imida-
zo[1,5-a]pyridine skeleton is a basic structure of synthetic
drugs such as Pirmogrel, with human clinical applications
as effective platelet aggregation and thromboxane syn-
1
7
easy recyclability. They have the potential to be highly
polar yet non-coordinating. In addition to the above-men-
tioned salient features of ionic liquids (ILs) as reaction
media, we have also recently shown that they can promote
and catalyze important organic transformations under am-
bient conditions without the need for any added catalyst or
ligand. The reactions investigated by us are Heck and
6
thase inhibitors. Moreover, N,N-bidentate ligands with
mixed five- and six-membered heterocycles are a desir-
able class of compounds in the pursuit of structural diver-
sity to enhance the physical and chemical properties. In
particular, 1-pyridylimidazo[1,5-a]pyridines possessing a
bidentate structural feature with a pyridyl unit adjacent to
a fused imidazole have emerged as a new class of
18
Suzuki reactions, as well as the Friedlander hetero-annu-
1
9
lation, which proceeded with significantly enhanced re-
action rates, high regioselectivity, and excellent isolated
yields.
7
,8
ligands. Syntheses of imidazo[1,5-a]pyridines are well
documented. Most routes involve reaction of a 2-amino-
methylpyridine with acylation followed by cyclization
As part of an ongoing project concerned with the develop-
ment of efficient protocols for the preparation of biologi-
cally active heterocycles from common intermediates
using RTILs, we herein report for the first time, a one-pot
condensation of 1,2-dipyridylketone, 2-benzoyl and 2-
acetyl pyridines, aromatic aldehydes, and ammonium ace-
tate in 1-butylimidazolium tetrafluoroborate ([Hbim]BF4),
which afforded a diverse array of 1-pyridylimidazo[1,5-
a]pyridines and substituted imidazo[1,5-a]pyridines in
excellent isolated yields in the absence of any added cata-
lyst (Scheme 1).
9
with phosphorus oxychloride or polyphosphoric acid or
thioacylation followed by ring closure using DCC or mer-
1
0
curic salts. Imidazo[1,5-a]pyridines were also obtained
from 2-cyanopyridine by the Vilsmeier reaction,11 or by
reaction with, or oxidization of, Schiff bases in the pres-
ence of molecular sieves or metal ions requiring two to
1
2–16
three steps from the dipyridyl ketone.
Many of the synthetic protocols for imidazo[1,5-a]py-
ridines reported so far suffer from one or more disadvan-
tages such as harsh reaction conditions, poor yields,
prolonged reaction times, or use of hazardous and often
ILs based on 1,3-dibutyl imidazolium salts [bbim]X and
N-butyl imidazolium salts [Hbim]X with anions of vary-
ing basicity were tested as solvents and promoters for the
typical reaction of 1,2-dipyridylketone (1b) with p-anisal-
dehyde in the absence of any added catalyst to afford 1-(2-
SYNTHESIS 2006, No. 17, pp 2849–2854
x
x.
x
x
.
2
0
0
6
Advanced online publication: 25.07.2006
DOI: 10.1055/s-2006-942522; Art ID: T02306SS
Georg Thieme Verlag Stuttgart · New York
©

2
850
S. A. Siddiqui et al.
PAPER
stituted imidazo[1,5-a]pyridines 3a–l by the reaction of
1
,2-dipyridylketone (1), 2-benzoyl and 2-acetyl pyridine
O
CHO
N
N
with aryl aldehydes 2 and ammonium acetate, respective-
ly, at 100 °C (Scheme 1).
NH4OAc
[Hbim]BF4
+
N
N
R'
100 °C
N
All the reactions proceeded to completion within the time
indicated in Table 2. The recovered IL could be reused
three times without loss of activity for the typical reaction
of 1 with p-anisaldehyde. The 1-pyridylimidazo[1,5-a]pyr-
idines have been obtained in excellent isolated yields in
relatively short reaction times. It can be observed that the
process tolerates both electron-donating and electron-
withdrawing substituents on the aldehyde.
R'
R' = H, 4-OMe, 2-Me, 2-OH, 4-OH, 3-OH, 2-Cl,
-OMe-4-OH, 3-NO2, 2,6-t-Bu-4-OH
3a–j
3
1
2
O
CHO
R'
N
R
NH4OAc
Hbim]BF4
00 °C
+
R
N
N
[
The efficacy of the ILs to promote these heterocyclization
reactions was correlated to the basicity of the anions of the
ILs as well as the polarity of the ILs. It was assumed that
the nature of the anion would govern the electrophilicity
of the imidazolium cation, which in turn has a bearing on
the acidity of the ILs. It was observed that with increasing
1
R'
R' = 2-NH2, 2-OH
k–l
R = Ph, Me
3
Scheme 1
basicity of the anion (increasing pK of the corresponding
a
acid), there is a progressive increase in yield (Table 1).
pyridyl)-3-(4-methoxyphenyl)imidazo[1,5-a]pyridines
This correlation was also evident when the yield of 3b was
(
1
3b). The reactions in the various ILs were carried out at compared with NH proton chemical shifts of the ILs in-
00 °C for 12 hours (Tables 1 and 2).
dicative of the Bronsted acidities of the [Hbim] ILs
Table 1). The yield of 3b increases progressively not
(
It was observed that for a typical reaction of 1 with p-anis-
only with increasing Bronsted acidity of the ILs, as indi-
cated by the increasing downfield shift of the NH proton,
but also with increasing polarity of these ILs as indicated
aldehyde at 90 °C, the conversion does not go beyond
4
5%; even after 24 hours at 130 °C the IL decomposed to
give a black charry material. Hence, a reaction tempera-
ture of 100 °C was found to be optimum.
by their E (30) values.
T
Thus, among the ILs screened, [Hbim]BF promoted this
4
It becomes evident from these results (Table 1) that
heterocyclization reaction by virtue of its inherent
Brønsted acidity conferred by the most acidic NH hydro-
gen (d = 14.6 ppm). The IL is capable of bonding with the
carbonyl oxygen, increasing the reactivity of the parent
carbonyl compounds without the need for the addition of
any acid catalyst.
[
Hbim]BF afforded the best results. Consequently, all
4
further studies were conducted using this IL as the reac-
tion medium and promoter to generate a variety of 1-sub-
Table 1 Synthesis of Imidazole 3b in [bbim]X and [Hbim]X
pK a
a
Yieldc
(%)
Furthermore, the versatility of the method was tested by
subjecting 2-benzoyl and 2-acetyl pyridine, respectively,
to the reaction protocol under identical conditions. The
corresponding 1-(2-phenyl)-3-(2-hydroxyphenyl)imida-
zo[1,5-a]pyridine (3k) was obtained in excellent isolated
yield (85%) requiring a reaction time of 2.3 hours
IL
NH proton ET (30)
–
1 b
(
d, ppm)
(kcal mol )
[
[
[
[
[
[
[
[
bbim]ClO4
–11
–9
–
76.34
38
53
55
55
69
76
82
93
bbim]Br
bbim]Cl
bbim]BF4
–
66.49
–7
–
68.89
(
Table 2, entry 11) whereas the 1-(2-methyl)-3-(2-ami-
nophenyl)imidazo[1,5-a]pyridine (3l) was obtained in rel-
atively lower yield (55%) after a much longer reaction
time (12 h, Table 2, entry 12).
0.5
–11
–9
–
75.73
Hbim]ClO4
11.83
12.17
12.22
14.59
63.82
Hbim]Br
73.68
It was experimentally established as shown in Table 3 that
the corresponding synthesis of 1-(2-pyridyl)-3-(4-meth-
oxyphenyl)imidazo[1,5-a]pyridine (3b) using molecular
solvents such as methanol, ethanol, toluene, acetic acid,
DMSO, and DMF afforded 3b in lower yields, ranging
from 17–70%, with longer reaction times of 12 hours, thus
highlighting the role of the Bronsted acidic IL as a reac-
tion medium as well as a promoter.
Hbim]Cl
–7
73.59
Hbim]BF4
0.5
74.35
a
b
c
20
The pK values of the parent acid of the anions.
Polarity determined by Reichardt’s dye.
Isolated yield after column chromatography.
a
21
Synthesis 2006, No. 17, 2849–2854 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 1-Pyridylimidazo[1,5-a]pyridines from Dipyridylketone and Aryl Aldehydes
2851
Table 2 Synthesis 1-Pyridylimidazo[1,5-a]pyridines 3a–l
a
Entry
1
Ketone
Aldehyde 2
3
3
Time (h)
Yield (%)
O
CHO
N
1
94
N
N
N
N
1
a
CHO
OMe
N
2
3
4
5
1
1
1
1
1
92
91
93
92
N
N
MeO
3
b
c
CHO
Me
N
1.1
1.2
2.3
N
N
Me
3
3
CHO
OH
N
N
OH
N
d
CHO
OH
N
N
N
HO
3
e
CHO
N
6
7
8
1
1
1
2
89
91
93
N
N
OH
OH
3
3
f
CHO
Cl
N
1.5
N
N
Cl
g
CHO
N
2
N
N
OMe
HO
OH
OMe
3
h
Synthesis 2006, No. 17, 2849–2854 © Thieme Stuttgart · New York

2
852
S. A. Siddiqui et al.
PAPER
Table 2 Synthesis 1-Pyridylimidazo[1,5-a]pyridines 3a–l (continued)
a
Entry
Ketone
Aldehyde 2
3
Time (h)
Yield (%)
CHO
N
9
1
2
87
N
N
NO2
NO2
3
i
CHO
OH
N
N
1
0
1
1.3
94
N
HO
3
j
O
CHO
N
1
1
2
NH2
2.3
85
55
N
N
NH2
3
3
k
O
CHO
N
OH
1
12
Me
Me
N
N
OH
l
a
Isolated yield after column chromatography.
In conclusion, we have developed a mild, convenient, and excluding those wherein microwave assisted synthesis
efficient protocol for the synthesis of 1-pyridylimida- was carried out. The versatility of the method was estab-
zo[1,5-a]pyridines via the condensation of 1,2-dipyr- lished by conducting the reaction successfully with 2-ben-
idylketone with aromatic aldehydes and ammonium zoyl and 2-acetyl pyridines under identical conditions to
acetate using a RTIL as a recyclable medium as well as a afford the corresponding substituted imidazo[1,5-a]pyr-
promoter. The process gave rise to excellent isolated idines in good to excellent isolated yields. Consequently,
yields of 1-pyridylimidazo[1,5-a]pyridines in short reac- this methodology becomes an efficient strategy for the
tion times (1–12 h). The reaction times achieved are short- rapid synthesis of highly substituted imidazo[1,5-a]pyr-
er than those hitherto reported under thermal conditions, idines libraries in a recyclable homogeneous medium in
the absence of a catalyst. The corresponding reaction in
Table 3 Synthesis of 3b in Molecular Solvents
molecular solvents under similar conditions in the ab-
sence of a catalyst are sluggish giving poor yields. The ex-
b
Solvents
MeOH
EtOH
Temp (°C)
65a
Time (h)
Yield (%)
perimental procedure, combining the features of simple
isolation procedure, efficient recovery and recycling of
IL, and the absence of a catalyst makes this an environ-
mentally benign methodology amenable for scale-up.
12
12
12
12
12
12
25
22
70
17
20
28
78a
AcOH
110
NMR spectra were recorded on a Bruker AC-200 spectrometer with
TMS as internal standard. IR spectra were recorded with an ATI
MATTSON RS-1 FTIR spectrometer. The polarity of ILs were re-
corded on a Lambda EZ 201, UV-VIS spectrophotometer using
Toluene
DMSO
110
110
2
1
DMF
110
Reichardt’s dye. Melting points were recorded in an open capil-
lary and were uncorrected. All solvents and chemicals were of re-
search grade and were used as obtained from Merck and Lancaster.
a
Reflux temperature.
Isolated yield of product after column chromatography.
b
Synthesis 2006, No. 17, 2849–2854 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 1-Pyridylimidazo[1,5-a]pyridines from Dipyridylketone and Aryl Aldehydes
2853
The pK values are those of the parent acid of the anions and are tak-
en from the literature.
The ILs were prepared as per the procedure reported by us earlier.19
Anal. Calcd for C H N (285.34): C, 79.98; H, 5.30; N, 14.73.
Found: C, 80.04; H, 5.29; N, 14.75.
a
19 15
3
2
0
1
-(2-Pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3d)
Pale yellow solid; mp 195–196 °C.
1
-Pyridylimidazo[1,5-a]pyridines; General Procedure
A mixture of 1,2-dipyridylketone 1 (4 mmol), substituted aldehyde
(6 mmol), ammonium acetate (16 mmol), and [Hbim]BF (8
1
H NMR (CDCl –DMSO-d , 200 MHz): d = 9.12 (d, J = 9.3 Hz, 1
3
6
2
H), 9.00 (d, J = 4.5 Hz, 1 H), 8.66 (d, J = 6.8 Hz, 1 H), 8.52 (d, J =
7. 8 Hz, 1 H), 8.16 (d, J = 7.9 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H),
7.54–7.34 (m, 4 H), 7.18 (t, J = 6.8 Hz, 1 H).
4
mmol) was heated at 100 °C with vigorous stirring for the appropri-
ate time (Table 2). The progress of the reaction was monitored by
TLC (EtOAc–PE, 7:13). After completion of the reaction, the reac-
13
C NMR (CDCl –DMSO-d , 50 MHz): d = 156.5, 153.3, 147.3,
3
6
tion mixture was diluted with H O (25 mL). The substituted imida-
zo[1,5-a]pyridines, which separated out as solids, were filtered,
washed with H O, and dried. The crude products, thus isolated,
were pure (single spot on TLC). They were subjected to further pu-
rification by column chromatography (silica gel; EtOAc–PE, 1:3) to
yield the desired substituted imidazo[1,5-a]pyridines in excellent
yields of 84–94%.
2
1
1
36.4, 134.8, 129.4, 128.6, 128.2, 120.6, 119.9, 118.9, 118.0, 117.3,
14.8, 113.8, 112.5.
2
LC-MS: m/z = 288 (M+).
Anal. Calcd for C H N O (287.32): C, 75.25; H, 4.56; N, 14.63.
1
8
13
3
Found: C, 74.71; H, 4.32; N, 14.48.
1
-(2-Pyridyl)-3-(4-hydroxyphenyl)imidazo[1,5-a] pyridine (3e)
The aqueous layer containing the IL was subjected to distillation
Yellow solid; mp 195–196 °C.
(
80 °C, 10 mmHg) for 4 h to remove H O, leaving behind the IL
2
[
Hbim]BF (recovery 98%), which was recycled.
1
4
H NMR (CDCl –DMSO-d , 200 MHz): d = 8.80 (d, J = 9.0 Hz, 1
3
6
H), 8.60 (d, J = 5.8 Hz, 1 H), 8.12 (dd, J = 8.0, 7.2 Hz, 2 H), 7.70–
The identical procedure was followed for the reactions with 2-ben-
zoyl and 2-acetyl pyridines.
7
6
.54 (m, 3 H), 7.31 (dd, J = 9.0, 6.4 Hz, 1 H), 6.83–7.05 (m, 3 H),
.62 (t, J = 7.0 Hz, 1 H).
1
-(2-Pyridyl)-3-phenylimidazo[1,5-a]pyridine (3a)
13
C NMR (CDCl –DMSO-d , 50 MHz): d = 157.6, 155.4, 149.4,
3
6
1
5
Yellow solid; mp 91–92 °C; (Lit. 92–93 °C).
1
47.3, 143.4, 136.4, 134.8, 129.4, 128.6, 128.2, 120.6, 119.9, 118.9,
1
118.0, 117.3, 114.8.
LC-MS: m/z = 288 (M +).
H NMR (CDCl , 200 MHz): d = 8.66 (d, J = 9.0 Hz, 1 H), 8.58 (d,
3
J = 4.5 Hz, 1 H), 8.21 (d, J = 7.5 Hz, 2 H), 7.80 (d, J = 7.5 Hz, 2
H), 7.67 (t, J = 7.5 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 2 H), 7.42 (t, J =
Anal. Calcd for C H N O (287.32): C, 75.25; H, 4.56; N, 14.63.
Found: C, 74.69; H, 4.42; N, 14.48.
1
8
13
3
7
.5 Hz, 1 H), 7.05 (t, J = 6.5 Hz, 1 H), 6.88 (dd, J = 9.0, 6.4 Hz, 1
H), 6.60 (t, J = 6.5 Hz, 1 H).
1
3
C NMR (CDCl , 50 MHz): d = 154.8, 148.8, 137.9, 136.1, 130.4,
3
1-(2-Pyridyl)-3-(3-hydroxyphenyl)imidazo[1,5-a]pyridine (3f)
Yellow solid; mp 200–201 °C.
1
1
30.1, 129.9, 128.9, 128.8, 128.2, 121.6, 121.5, 120.9, 120.3, 119.8,
13.8.
1
H NMR (CDCl –DMSO-d , 200 MHz): d = 8.65–8.60 (d, J = 9.3
3
6
LC-MS: m/z = 272 (M +).
Hz, 1 H), 8.58–8.55 (d, J = 5.6 Hz, 1 H), 8.40–8.37 (d, J = 7.1 Hz,
1
H), 8.15–8.11 (d, J = 8.1 Hz, 1 H), 7.79–7.70 (m, 1 H), 7.35–7.31
Anal. Calcd for C H N (271.11): C, 79.68; H, 4.83; N, 15.49.
Found: C, 79.55; H, 4.79; N, 15.41.
1
8
13
3
(
d, J = 8.0 Hz, 1 H), 7.15–7.09 (m, 1 H), 7.01–6.72 (m, 5 H).
1
3
C NMR (CDCl –DMSO-d , 50 MHz): d = 156.5, 153.3, 147.3,
3
6
1
-(2-Pyridyl)-3-(4-methoxyphenyl)imidazo[1,5-a]pyridine (3b)
1
1
36.4, 134.8, 129.4, 128.6, 128.2, 120.6, 119.9, 118.9, 118.0, 117.3,
14.8, 113.8, 112.5.
Yellow solid; mp 120–121 °C.
1
H NMR (CDCl , 200 MHz): d = 8.61 (d, J = 9.3 Hz, 1 H), 8.56 (d,
LC-MS: m/z = 306 (M+).
3
J = 5.9 Hz, 1 H), 8.17 (dd, J = 8.2, 7.0 Hz, 2 H), 7.69–7.59 (m, 3
H), 7.04–6.96 (m, 3 H), 6.85 (dd, J = 9.0, 6.4 Hz, 1 H), 6.57 (t, J =
Anal. Calcd for C H N O (287.32): C, 75.25; H, 4.56; N, 14.63.
Found: C, 74.82; H, 4.42; N, 14.68.
1
8
13
3
7
.7 Hz, 1 H), 3.80 (s, 3 H).
1
3
C NMR (CDCl , 50 MHz): d = 160.0, 154.9, 148.8, 138.0, 136.2,
3
1-(2-Pyridyl)-3-(2-chlorophenyl)imidazo[1,5-a]pyridine (3g)
Bright yellow solid; mp 178–179 °C.
1
1
30.0, 129.8, 129.7, 122.6, 122.4, 121.5, 120.8, 120.2, 119.8, 114.4,
13.6, 55.3.
1
H NMR (CDCl , 200 MHz): d = 8.74–8.69 (m, 1 H), 8.63–8.60 (m,
3
LC-MS: m/z = 302 (M+).
1
6
H), 8.24–8.19 (m, 1 H), 7.72–7.37 (m, 6 H), 7.10–7.16 (m, 1 H),
.98–6.90 (m, 1 H), 6.67–6.60 (m, 1 H).
Anal. Calcd for C H N O (301.34): C, 75.73; H, 5.02; N, 13.94.
Found: C, 75.66; H, 4.59; N, 13.72.
19
15
3
13
C NMR (CDCl , 50 MHz): d = 154.8, 148.9, 136.1, 135.5, 134.3,
3
1
1
33.2, 130.8, 129.8, 129.7, 129.1, 127.2, 122.2, 121.4, 121.1, 120.3,
19.7, 113.4.
1
-(2-Pyridyl)-3-(2-methylphenyl)imidazo[1,5-a]pyridine(3c)
1
5
Yellow solid; mp 114–115 °C (Lit. 112–113 °C).
LC-MS: m/z = 306 (M+).
1
H NMR (CDCl , 200 MHz): d = 8.66 (d, J = 9.0 Hz, 1 H), 8.58 (d,
3
Anal. Calcd for C H N Cl (305.76): C, 70.71; H, 3.96; N, 13.74;
1
8
12
3
J = 4.5 Hz, 1 H), 8.19 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 8.0 Hz, 1 H),
7
3
(
1
Cl, 11.6. Found: C, 70.59; H, 3.71; N, 13.59; Cl, 11.5.
.57 (d, J = 7.5 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 1 H), 7.38–7.21 (m,
H), 7.03 (t, J = 6.5 Hz, 1 H), 6.86 (dd, J = 9.0, 6.3 Hz, 1 H), 6.54
t, J = 6.5 Hz, 1 H), 2.21 (s, 3 H).
1
-(2-Pyridyl)-3-(3-methoxy-4-hydroxyphenyl)imidazo[1,5-
a]pyridine (3h)
Yellow solid; mp 132–133 °C.
3
C NMR (CDCl –DMSO-d , 50 MHz): d = 155.2, 149.0, 139.14,
3
6
1
1
38.6, 137.8, 136.3, 130.9, 130.6, 129.9, 129.7, 129.3, 126.2, 121.7,
21.6, 121.0, 120.4, 119.9, 113.6, 19.8.
1
H NMR (CDCl –DMSO-d , 200 MHz): d = 8.44–8.39 (d, J = 8.4
3
6
Hz, 2 H), 8.03–7.99 (d, J = 9.6 Hz, 2 H), 7.56–7.47 (m, 1 H), 7.14–
LC-MS: m/z = 285 (M+).
7
.12 (m, 1 H), 7.05–7.00 (m, 1 H), 6.92–6.81 (m, 2 H), 6.74–6.66
Synthesis 2006, No. 17, 2849–2854 © Thieme Stuttgart · New York

2
854
S. A. Siddiqui et al.
PAPER
(
3
m, 1 H), 6.47–6.41 (t, J = 9.1 Hz, 1 H), 5.12 (br s, 1 H), 3.71 (s, Acknowledgment
H).
S.A.S. and T.M.P. thank CSIR, New Delhi, for the award of
Research Fellowships. The authors also acknowledge financial as-
sistance from Department of Science and Technology (DST), New
Delhi, vide Project No. SR/S5/OC-23/2002).
1
3
C NMR (CDCl –DMSO-d , 50 MHz): d = 153.9, 147.9, 147.4,
3
6
1
1
46.8, 137.7, 135.7, 129.1, 128.6, 127.5, 121.8, 120.5, 120.4, 120.3,
20.2, 119.6, 199.0, 114.9, 113.1, 111.5, 55.2.
LC-MS: m/z = 318 (M+).
Anal. Calcd for C H N O (317.34): C, 71.91; H, 4.76; N, 13.24.
Found: C, 71.54; H, 4.38; N, 13.12.
19
15
3
2
References
(1) Biachi, G.; Rodriguez, A.; Yakurshigiu, K. J. Org. Chem.
1
-(2-Pyridyl)-3-(3-nitrophenyl)imidazo[1,5-a]pyridine(3i)
1989, 54, 4497.
1
5
Yellow solid; mp 188–187 °C (Lit. 185–186 °C).
(2) Bolger, L.; Brittain, R. J.; Jack, D.; Jackson, M. R.; Martin,
1
L. E.; Mills, J.; Poynter, D.; Tyers, M. B. Nature (London)
H NMR (CDCl –DMSO-d , 200 MHz): d = 8.60–8.57 (m, 4 H),
3
6
1972, 238, 354.
8
.34 (d, J = 8.0 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.10 (d, J = 8.0
(
(
3) Zito, S. W.; Martlnez, M. J. Biol. Chem. 1980, 255, 8645.
4) Jansonius, J. N.; Eichele, G.; Ford, G. C.; Picot, D.; Thaller,
C.; Vicent, M. G. In Transaminases; Christen, P.; Metzler,
D. E., Eds.; Wiley: New York, 1985, 110.
5) Arbilla, S.; Allen, J.; Wick, A.; Langer, S. Eur. J.
Pharmacol. 1986, 130, 257.
(6) Ford, N. F.; Browne, L. J.; Campbell, T.; Gemenden, C.;
Hz, 1 H), 7.80–7.79 (m, 1 H), 7.14 (t, J = 7.0 Hz, 1 H), 7.09 (t, J =
.0 Hz, 1 H), 6.81 (t, J = 7.0 Hz, 1 H).
7
1
3
C NMR (CDCl –DMSO-d , 50 MHz): d = 155.0, 149.5, 149.0,
3
6
1
1
38.1, 136.0, 134.1, 131.8, 131.3, 131.0, 130.7, 124.0, 123.7, 123.3,
23.2, 121.8, 121.5, 120.0, 115.8.
(
LC-MS: m/z = 317 (M+).
Goldstein, R.; Gude, C.; Wasley, J. N. F. J. Med. Chem.
Anal. Calcd for C H N O (316.31): C, 68.35; H, 3.82; N, 17.71.
Found: C, 68.32; H, 3.82; N 17.52.
18
12
4
2
1985, 28, 164.
(
(
(
7) Ligtenbarg, A. J.; Spek, A. L.; Hage, R.; Feringa, B. L. J.
Chem. Soc., Dalton Trans. 1999, 659.
8) Bluhm, M. E.; Ciesielski, M.; Gorls, H.; Walter, O.; Doring,
M. Inorg. Chem. 2003, 42, 8878.
9) (a) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2834.
(b) Winterfeld, K.; Franzke, H. Angew. Chem., Int. Ed. Engl.
1963, 75, 1101.
(10) (a) Bourdais, J.; Omar, A.-M. E. J. Heterocycl. Chem. 1980,
17, 555. (b) El Khadem, H. S.; Kawai, J.; Swartz, D. L.
Heterocycles 1989, 28, 239.
1
-(2-Pyridyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)imida-
zo[1,5-a]pyridine (3j)
Yellow solid; mp 212–213 °C.
1
H NMR (CDCl , 200 MHz): d = 8.71–8.60 (m, 2 H), 8.28–8.24 (d,
3
J = 8.5 Hz, 1 H), 8.16–8.12 (d, J = 7.3 Hz, 1 H), 7.74–7.66 (m, 1
H), 7.58 (s, 2 H), 7.10–7.03 (m, 1 H), 6.92–6.84 (m, 1 H), 5.45 (br
s, 1 H), 1.50 (s, 18 H).
1
3
C NMR (CDCl , 50 MHz): d = 136.2, 125.6, 121.7, 120.7, 120.2,
3
(
11) Sasaki, K.; Tsurumori, A.; Hirota, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3851.
12) Palacios, F.; Alonso, C.; Rubiales, G. Tetrahedron 1995, 51,
1
19.9, 113.5, 30.2.
LC-MS: m/z = 401 (M+).
(
Anal. Calcd for C H N O (399.53): C, 78.16; H, 7.32; N, 10.52.
3683.
26
29
3
Found: C, 78.04; H, 7.10; N, 10.20.
(13) Katritzky, A. R.; Qiu, G. J. Org. Chem. 2001, 66, 2862.
(
14) (a) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27,
3713. (b) Grigg, R.; Kennewell, P.; Savic, V.; Sridharan, V.
Tetrahedron 1992, 48, 10423.
1
-(2-Phenyl)-3-(2-aminophenyl)imidazo[1,5-a]pyridine (3k)
1
6
Yellow solid; mp 146–147 °C (Lit. 146 °C).
(15) Wang, J.; Dyers, L.; Mason, R. Jr.; Amoyaw, P. Jr.; Bu, X.
R. J. Org. Chem. 2005, 70, 2353.
1
H NMR (CDCl , 200 MHz): d = 8.02 (d, J = 8.0 Hz, 2 H), 7.48 (m,
3
1
H), 7.36–7.30 (m, 3 H), 7.16 (m, 1 H), 7.03 (m, 1 H), 6.59–6.43
(
16) Bluhm, M. E.; Ciesielski, M.; Gorls, H.; Walter, O.; Doring,
M. Angew. Chem. Int. Ed. 2002, 41, 2962.
(
m, 2 H), 6.12 (m, 1 H), 5.78 (m, 1 H), 4.20 (br s, 2 H).
1
3
C NMR (CDCl , 50 MHz): d = 145.0, 143.4, 133.5, 130.0, 129.1,
(17) (a) Welton, T. Chem. Rev. 1999, 99, 2071.
(b) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000,
39, 3772.
3
1
27.7, 122.0, 119.8, 116.3, 110.0.
LC-MS: m/z = 286 (M+).
(
18) (a) Deshmukh, R. R.; Rajagopal, R.; Srinivasan, K. V.
Chem. Commun. 2001, 1544. (b) Rajagopal, R.; Jarikote, D.
V.; Srinivasan, K. V. Chem. Commun. 2002, 616.
Anal. Calcd for C H N (285.34): C, 79.98; H, 5.30; N, 14.73:
19
15
3
Found: C, 79.82; H, 5.21; N, 14.61.
(
19) (a) Palimkar, S. S.; Siddiqui, S. A.; Thomas, D.; Lahoti, R.
1
-(2-Methyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3l)
J.; Srinivasan, K. V. J. Org. Chem. 2003, 68, 9371.
1
6
Yellow solid; mp 149–151 °C (Lit. 146 °C).
(
b) Siddiqui, S. A. Synlett 2006, 155.
1
H NMR (CDCl , 200 MHz): d = 7.89 (d, J = 8.5 Hz, 1 H), 7.42–
(20) Perrin, D. D. Ionization Constant of Inorganic Acids and
Bases in Aqueous Solution, 2nd ed.; Pergamon: Elmsford,
New York, 1982.
3
7
3
.38 (m, 2 H), 7.08 (m, 2 H), 6.81 (m, 2 H), 6.63 (m, 1 H), 2.29 (s,
H).
(21) Fletcher, K. A.; Storey, I. A.; Hendricks, A. E.; Pandey, S.;
1
3
C NMR (CDCl , 50 MHz): d = 155.0, 143.1, 136.0, 131.0, 129.2,
3
Pandey, S. Green Chem. 2001, 3, 210.
1
28.0, 126.2, 123.4, 122.0, 119.4, 116.0, 17.0.
LC-MS: m/z = 225 (M+)
Anal. Calcd for C H N O (224.26): C, 74.98; H, 5.39; N, 12.49:
1
4
12
2
Found: C, 74.84; H, 5.27; N, 12.38.
Synthesis 2006, No. 17, 2849–2854 © Thieme Stuttgart · New York