NBS mediated one-pot regioselective synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines and their unambiguous characterization through 2D NMR and X-ray crystallography

Article abstract of DOI:10.1016/j.tet.2016.04.072

A simple and mild protocol towards the regioselective synthesis of 1-aryl/heteroaryl-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanones has been developed by one-pot condensation of 2-aminopyridine with 1,3-diketones involving the intermediacy of 2-bromo-1,

Full text of DOI:10.1016/j.tet.2016.04.072

Accepted Manuscript
NBS mediated one-pot regioselective synthesis of 2,3-disubstituted
imidazo[1,2-a]pyridines and their unambiguous characterization through 2D NMR and
X-ray crystallography
Ranjana Aggarwal, Gulshan Singh, Dionisia Sanz, Rosa M. Claramunt, M. Carmen
Torralba, M. Rosario Torres
PII:
S0040-4020(16)30349-0
10.1016/j.tet.2016.04.072
TET 27715
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 February 2016
Revised Date: 24 April 2016
Accepted Date: 26 April 2016
Please cite this article as: Aggarwal R, Singh G, Sanz D, Claramunt RM, Torralba MC, Torres MR,
NBS mediated one-pot regioselective synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines and their
unambiguous characterization through 2D NMR and X-ray crystallography, Tetrahedron (2016), doi:
10.1016/j.tet.2016.04.072.
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ACCEPTED MANUSCRIPT
Graphical abstract:
NBS mediated one-pot regioselective synthesis of 2,3-disubstituted imidazo[1,2-
a]pyridines and their unambiguous characterization through 2D NMR and X-ray
crystallography
Ranjana Aggarwala, Gulshan Singha, Dionisia Sanzb, Rosa M. Claramuntb, M. Carmen
Torralbac and M. Rosario Torresc
aDepartment of Chemistry, Kurukshetra University, Kurukshetra-136119, Haryana, India
ae-mail: ranjana67in@yahoo.com, ranjanaaggarwal67@gmail.com.
bDepartamento de Química Orgánica y Bio-orgánica, Facultad de Ciencias, UNED, Senda del
Rey 9, E-28040 Madrid, Spain
be-mail: dsanz@ccia.uned.es
cDepartamento de Química Inorgánica I and CAI de Difracción de Rayos-X, Facultad de
Ciencias Químicas, Universidad Complutense de Madrid (UCM), E-28040 Madrid, Spain
ce-mail: torralba@quim.ucm.es
NBS mediated one-pot regioselective synthesis of 2,3-disubstituted
imidazo[1,2-a]pyridines and their unambiguous characterization through 2D
NMR and X-ray crystallography
O
O
CH3
Ar
Ar
5
8
O
O
3
4
1)
2)
NBS, DCM, rt, 30 min
6
7
N
N
2
CH3 and/or
Ar
CH3
NH2
N
N
8a
1
1
DCM, rt, 4 hr
Not formed
N
2
7
Exclusive Product
e
p-ClPh
g
a
c
d
f
p-BrPh
b
1, 7
Ar
2-thienyl
Ph
p-FPh
p-CH3Ph p-OCH3Ph

ACCEPTED MANUSCRIPT
NBS mediated one-pot regioselective synthesis of 2,3-disubstituted imidazo[1,2-a]pyridines
and their unambiguous characterization through 2D NMR and X-ray crystallography
Ranjana Aggarwala, Gulshan Singha, Dionisia Sanzb, Rosa M. Claramuntb, M. Carmen Torralbac and M.
Rosario Torresc
aDepartment of Chemistry, Kurukshetra University, Kurukshetra-136119, Haryana, India
ae-mail: ranjana67in@yahoo.com, ranjanaaggarwal67@gmail.com.
bDepartamento de Química Orgánica y Bio-orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-
28040 Madrid, Spain
be-mail: dsanz@ccia.uned.es
cDepartamento de Química Inorgánica I and CAI de Difracción de Rayos-X, Facultad de Ciencias
Químicas, Universidad Complutense de Madrid (UCM), E-28040 Madrid, Spain
ce-mail: torralba@quim.ucm.es
Abstract:
A simple and mild protocol towards the regioselective synthesis of 1-aryl/heteroaryl-1-(2-
methylimidazo[1,2-a]pyridin-3-yl)methanones has been developed by one-pot condensation of 2-
aminopyridine with 1,3-diketones involving the intermediacy of 2-bromo-1,3-diketones formed in situ
from 1,3-diketones using N-bromosuccinimide (NBS) in DCM by stirring at room temperature. The
structure of the regioisomer has been confirmed unambiguously by the rigorous multinuclear NMR [(1H-
13C) HMBC, (1H-13C) HMQC, (1H-15N) HMBC] spectroscopy and X-ray crystallographic studies.
Keywords: 1-Aryl-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanones, regioselective synthesis, 2-
aminopyridine, 1,3-diketones, N-bromosuccinimide, 2D-NMR spectroscopy, X-ray crystallography.
Introduction:
Heterocycles are ubiquitous scaffolds in pharmaceuticals and biologically active compounds1. Thus
development of new and simple methodologies to prepare these useful heterocyclic frameworks has
attracted great attention from organic chemists. In recent years, in situ generation of one of the reactants,
from the simple precursors to condense with another reactant within the reaction vessel in one-pot
reaction is a popular synthetic strategy. One-pot method is more economic and convenient in terms of
avoidance of intermediates isolation, separation of side products at each step (if not interfering) and
higher reaction yields.
Among the fused bicyclic heterocyclic compounds with a heteroatom at the bridgehead position,
imidazo[1,2-a]pyridine ring system in particular constitutes a privileged substructure and is present in a
large number of compounds with remarkable biological activities. Imidazo[1,2-a]pyridines have been
1

ACCEPTED MANUSCRIPT
reported as anticancer agents by acting as a potent and selective class of cyclin-dependent kinase
inhibitors2, anticoccidial agents3, benzodiazepine receptors ligands4, antiviral agents5, antiprotozoal6,
antiherpes7 and antitubercular agents8. Moreover, imidazo[1,2-a]pyridine derivatives have been found in
many clinically accepted drugs like Zolpidem (I)9, Alpidem (II)10, Olprinone (III)11 etc (Figure-1).
H3C
CH3
C3H7
C3H7
N
N
H
O
N
CH3
O
O
H3C
Cl
N
N
NC
N
CH3
Cl
N
N
Alpidem (II)
N
Zolpidem (I)
Olprinone (III)
Figure-1 Clinically accepted derivatives of imidazo[1,2-a]pyridine
There are several reports cited in the literature for the synthesis of 3-substituted imidazo[1,2-a]pyridines
dealing with the cyclocondensation of binucleophilic 2-aminopyridine with α-functionalized carbonyl
compounds e.g. α-halo or α-tosyloxyketones functioning as bielectrophile12. In contrast, there are only a
few reports that describe the reaction of 2-aminopyridine with a potential trielectrophile i.e. 2-
functionalized diketones despite of the clear opportunity to introduce an acyl group on the imidazo[1,2-
a]pyridine ring which will act as an additional handle for chemical diversity. Moreover, a reaction of a
binucleophile (2) with a trielectrophilic entity (1), in principle, may produce positional isomers viz two (3
& 4) in case of symmetrical 1,3-diketones and four (3, 4, 5 & 6) in non-symmetrical 1,3-diketones, that
are difficult to differentiate (Scheme-1).
O
O
N
+
R
R'
NH2
X
1
2
O
O
R'
R'
R
R
R
R'
O
N
N
N
N
+
+
+
R
R'
N
O
N
N
N
3
5
4
6
Ref- 13a & 13b
Ref- 14
R= R' = CH3
R= CH3 R' =Ph
X= Cl , Br
X= H
3 (exclusive product)
3 (26%) 5 (48%)
Scheme-1 Possible positional isomers
In 2003 and 2004, Anderson group13a and Byth et al13b both reported, separately the synthesis of 3-acetyl-
2-methylimidazo[1,2-a]pyridine (3) starting from 3-bromo/3-chloropentane-2,4-dione as a symmetrical
trielectrophile. In 2011, Wang et al reported the formation of two regioisomers, 1-methyl-1-(2-
phenylimidazo[1,2-a]pyridin-3-yl)methanone isomer 3 (26%) and 1-phenyl-1-(2-methylimidazo[1,2-
a]pyridin-3-yl)methanone 5 (48%) by the reaction of 1-phenylbutane-1,3-dione (1a) with 2-
2

ACCEPTED MANUSCRIPT
aminopyridine (2) in presence of diacetoxyiodobenzene and boron trifluoride etherate at 7oC on overnight
stirring14. Neither of the reports considered the possibility of formation of other possible regioisomers (4
and 6), also no specific data for structure assignment was supplied in the support of the proposed
regioisomer(s).
In view of these observations and in continuation of our ongoing interest in 2D NMR spectroscopy for
characterization of regioisomers15, we report here an efficient regioselective method for the synthesis of
2,3-differently substituted imidazo[1,2-a]pyridines by in situ functionalization of non-symmetrical 1,3-
diketones by N-bromosuccinimide (NBS) and their subsequent condensation with 2-aminopyridine and
characterize the regioisomer(s) on the basis of 2D NMR spectroscopy and X-ray crystallography.
Results and Discussion:
We initially investigated the reaction system with 2-aminopyridine (2), 1-phenylbutane-1,3-dione (1a)
and NBS in DCM at room temperature to determine the optimum conditions for regioselective
cyclocondensation (Scheme-2). NBS was chosen as in situ brominating agent over other reagents e.g.
molecular bromine and its complexes16, tetraalkylammonium tribromide17and HBr-H2O218 due to ease of
application, less hazardous nature, better selectivity and low price.
O
O
Ar
CH3
DCM,
4-5h, rt
Br
1' b
NBS
2
DCM,
1h, rt
O
Ar
5
6
3
O
O
4
N
1) NBS, DCM, rt, 30 min
2
CH3
Ar
CH3
N
7
8
2) 2, DCM, rt, 4 hr
8a
1
1
7
e
g
a
c
d
f
b
1, 7
Ar
2-thienyl
Ph
p-FPh
p-ClPh
p-CH3Ph p-OCH3Ph
p-BrPh
Scheme-2 Regioselective synthesis of title compound
TLC of the reaction mixture was carried out at regular intervals which indicated that the reaction was
complete within 4 hr. resulting in the formation of a single regioisomer, one out of four possible isomers
3, 4, 5 & 6 (Scheme-1). Moreover, LCMS data of crude sample also ascertained the formation of single
isomer. The mass spectrum of the reaction product showed a molecular ion peak m/z 237(100%). The 1H
NMR spectrum of 7a revealed a sharp singlet at δ 2.51 ppm integrating for the three protons assigned to
methyl group and peculiar pattern of pyrimidine and the phenyl protons. 13C NMR spectrum also showed
the required number of signals thus confirming the successful condensation of two reactants.
3

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Intermediacy of 2-bromo-1,3-diketone has been established by isolation and characterization of them
1
through H NMR in one case 2-bromo-1-(4-methylphenyl)butane-1,3-dione (1'b). Subsequent reaction
of 1'b with 2 afforded again the same single isomer but the reaction took longer reaction time and yield
was much lower as compared to one-pot method.
With the optimized condition in hand, the scope of the methodology was investigated in the reaction with
2-aminopyridine (2) and various 1-aryl-1,3-diketones (1b-f) and 1-(2-thienyl)-1,3-diketone (1g) under
similar conditions. A range of electron donating & electron withdrawing substituents at the aryl ring of
1,3-diketones provided reaction products in high yields and excellent regioselectivity even when the
reaction was extended to gram scale.
After accomplishing the regioselective synthesis of imidazo[1,2-a]pyridines, the next challenge was to
assign correct regioisomeric structure to the reaction product out of four. Wang et al. reported formation
of two regioisomers 1-methyl-1-(2-phenylimidazo[1,2-a]pyridin-3-yl)methanone (3) and 1-phenyl-1-(2-
methylimidazo[1,2-a]pyridin-3-yl)methanone (5) on the basis of 1H and 13C NMR spectroscopy14. In the
compounds 3 and 5 the methyl protons have been reported as singlet at δ 2.19 and 2.13 ppm, respectively
1
13
in H NMR. These values are very close and may be interchangeable. In C NMR, methyl group has
been reported at δ 29.8 and δ17.4 and carbonyl carbon at δ189.1 and 186.8 ppm in the compounds 3 and
5, respectively. These values can also be attributed to the methyl group and carbonyl carbon in other
positional isomers 4 and 6 as well (Scheme-1).
So, it seems to be unreasonable to draw a conclusion about the structure on the basis of this elementary
data. Moreover, in the present study, we observed the signals for methyl protons resonating at δ 2.51 and
carbonyl at δ 186.1 ppm which did not match with any of the reported compounds. Therefore, it was
1
envisaged to carry out unambiguous assignments of all H, 13C and 15N NMR by 2D NMR [(1H-13C)
HMBC, (1H-13C) HMQC, (1H-15N) HMBC] experiments to provide a concluding evidence to support the
structure of the reaction product as 1-aryl-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanones (7).
The 2D NMR correlation results has been obtained for compounds 7c, 7f and 7g and their 1H, 13C and 15N
chemical shifts has been shown in Figure-2.
4

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3J = 3.9 Hz
7.13
114.3
7.85
131.9
163.7O
O
O
O
130.1
3.88
55.7
9.21
183.9
-182.8
7.13
114.3
129.2
7.58
120.7 7.85
4
N
3
117.7
131.9
2.29
13.4
3JCH3 = 4.0 Hz
N
2
CH3
141.0
8.05
112.4
N1
N
140.4
8.05
134.7
-209.6
2JCH3 = 6.9 Hz
7c
7c
7.81
132.0
7.75
131.0
7.74
133.86
7.25
Br
O
128.1
137.2
184.6
O
127.1
143.4
9.33
9.07
8.05
134.9
129.2
177.4
120.7
7.81
132.0
7.58
117.6
127.8
-182.1
120.5 7.75
131.0
S
-178.2
N
7.13
N
114.2
2.21
14.1
2.35
17.1
143.9
8.03
150.8
134.5
N
141.3
7.55
129.2
N
8.03
113.0
146.5
-198.08
7.68
-130.5
116.3
7g
7f
1
13
Figure-2 H (in red), C (in black) and 15N (in green) chemical shifts of compound 7c, 7f and 7g and
correlation depiction
The (1H-13C) HMBC of compound 1-(4-methoxyphenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-
2
yl)methanone 7c in Figure-2 showed cross peaks of methyl protons (δ 2.29) with C-2 (δ 141.0, JCH3
=
3
6.9 Hz) and C-3 (δ 120.7, JCH3 = 4.0 Hz). Further, (1H-15N) HMBC of compound 7c also showed cross
peak of methyl protons (δ 2.29) with N-1 (δ -209.6) thus confirmed the presence of methyl substituent at
position-2 of imidazo[1,2-a]pyridyl nucleus. Similarly (1H-13C) HMBC of carbonyl carbon at δ183.9
3
showed cross peak with 2'-H proton (δ 7.85, J = 3.9 Hz) of aryl part indicated the presence of carbonyl
carbon with aryl/heteroaryl ring. Had the structure of the isolated compound been corresponding to the
other positional isomers 4, 5 and 6, then the correlation between methyl protons with N-1 and cross peak
of carbonyl carbon with 2'-H proton of aryl part would have been absent. Similar correlation results of
(1H-13C) HMBC and (1H-15N) HMBC were observed for the compounds 7f and 7g as shown in Figure-2.
It is interesting to note that in case of 7c and 7f, N-1 was protonated as the value appeared highly
upfield19 at δ -209.6 & δ -198.8 while in case of 7g it was non-protonated, the signal appeared at δ -
1
130.5. Protonation of 7c and 7f is also observed in the J (1H-13C) coupling constant values of C5, C6,
C7, C8 when compared with those of 7g.
Final confirmation of the structure as 1-aryl-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanones isomer 7
was done by X-ray crystallography. Compound 7f crystallizes in the orthorhombic Pbca space group.
The asymmetric unit contains two crystallographically different and independent molecules (Figure-3),
5

ACCEPTED MANUSCRIPT
due to the diverse interactions that each type of them presents. The molecules, named type A and B, are
not planar with dihedral angles between the aromatic rings of 60.9(1)º for A molecules, and 55.6(1)º for
B molecules.
Figure-3 ORTEP plot (20% probability) showing the labeling scheme for compound 7f
Type A molecules are connected to each other through the bromide ion Br1A that forms a hydrogen bond
with the N1AH1A group (Table-1) of a molecule, and a Br···Br interaction with the bromine atom of
another adjacent molecule (Br1A···Br2A distance of 3.541(2)Å), giving rise to the formation of chains
along the a axis (Figure-4). On the other hand, type B molecules interact not only with the bromide ions
Br1B but also with a molecule of water. Thus, being focused on a water molecule, it forms three
hydrogen bonds with two different bromide ions Br1B and another one with a N1BH1B group of a type
B molecule (Table-1), so the bromide ions Br1B interact with two different water molecules, achieving
double chains along b axis. Besides, contacts between the parallel chains are observed due to additional
interactions between the bromide ions Br1B with the Br2B of the neighboring B molecule (distance of
3.584(2) Å) and with the H12B of a phenyl ring (distance of 3.009(1) Å) of a different one, spreading out
the dimensionality of the interactions in the ab plane (Figure 3b). By the way, there are no significant
interactions between type A and B molecules to be noted.
Table-1 Hydrogen bonds for 7f, C30H26Br4N4O3 (Å and °)
D-H...A
d(D-H)
d(H...A)
d(D...A)
<(DHA)
O(2B)-H(2)...Br(1B)
O(2B)-H(2')...Br(1B)a
N(1A)-H(1A)...Br(1A)
N(1B)-H(1B)...O(2B)
0.95
0.95
0.86
0.86
2.27
2.34
2.41
1.87
3.179(9)
3.225(9)
3.226(9)
2.712(12)
159.9
154.4
157.9
167.7
a Symmetry transformations used to generate equivalent atoms: -x+3/2, y+1/2, z
a)
6

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b)
Figure-4 (a) View of the chains formed by A type molecules in 7f; (b) View along c axis showing the 2D
interactions that B type molecules, Br1B ions and the water molecules are involved
Mechanism Involved:
The plausible mechanism for this regioselective synthesis of imidazo[1,2-a]pyridines 7(a-g) is outlined in
Scheme-3. It seems that, the reaction by endo nitrogen (ring N) of 2-aminopyridine 2 and 2-bromo
dicarbonyl compound 1'a undergoes initially through the nucleophilic displacement of bromine followed
by the nucleophilic addition of imine nitrogen at either of the carbonyl carbon leading to the formation of
2-alkyl/arylimidazo[1,2-a]pyridine (Route-A).
7

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O
CH3
Ar
N
b
Path-b
O
O
O
O
N
Route-A
N
3
Ar
CH3
NH
+
Ar
CH3
H
a
O
-HBr
N
N
Br
Ar
H
2
1'a
N
N
Path-a
CH3
CH3
N
7a
Ar = Phenyl
O
O
Ar
CH3
N
Route-B
Ar
O
+
N
Ar
CH3
NH2
and/or
Br
N
O
N
6
5
1'a
2
Scheme-3 Plausible mechanism for regioselective synthesis of imidazo[1,2-a]pyridines
In case of non-symmetrical 2-bromo-1,3-diketones after nucleophilic displacement of halogen residue,
there remains two electrophilic carbonyl site for nucleophilic addition elimination reaction by the imine
nitrogen. Thus there lies the possibility of formation of following two regioisomers. But due to lesser
steric crowding around the carbonyl group adjacent to methyl and more electrophilic nature of carbonyl
carbon adjacent to methyl group makes it more reactive than carbonyl carbon next to aryl part thus
rendering the regioselectivity in the reaction accomplishing 7(a-g) as the only product. This observation
is in consonance with our earlier observation12g. Whereas in Route-B, nucleophilic displacement of
bromine by nitrogen of amino group followed by the nucleophilic addition of endo nitrogen at either of
the carbonyl carbon might have led to the formation of 3-alkyl/arylimidazo[1,2-a]pyridine whose
formation is not observed in our case.
Conclusion:
In the present report, we describe a regioselective synthesis of 1-aryl/heteroaryl-1-(2-methylimidazo[1,2-
a]pyridin-3-yl)methanones following a simple and mild method. Synthesis involves one-pot condensation
of 2-aminopyridine with 1,3-diketones in presence of N-bromosuccinimide (NBS) in DCM by stirring at
room temperature. Reaction is found to involve the intermediacy of 2-bromo-1,3-diketones formed from
1,3-diketones on reaction with NBS and has been supported by isolation of intermediate in one case. The
structure of the regioisomer has been confirmed unambiguously by the rigorous multinuclear NMR [(1H-
13C) HMBC, (1H-13C) HMQC, (1H-15N) HMBC] spectroscopy and X-ray crystallographic studies.
Experimental:
General
1
Melting points were determined in open capillaries and are uncorrected. H and 13C NMR spectra for
analytical purpose were recorded in CDCl3 on a Bruker instrument at 300 MHz and 75 MHz,
8

ACCEPTED MANUSCRIPT
respectively, and chemical shifts were recorded in ppm (δ) downfield from internal standard
tetramethylsilane (δ 0.00). Mass spectra were measured in EI mode on a Kratos MS-50 spectrometer at
MS Facilities at SAIF, Panjab University, Chandigarh, India. Elemental analyses were also performed at
SAIF, Panjab University, Chandigarh, India. All the compounds gave C, H and N analysis within + 0.5 of
the theoretical values analyzed on Thermoscientfic (FLASH-2000).
2D correlation spectra, (1H-13C) gs-HMQC, (1H–13C) and (1H–15N) gs- HMBC, of compounds 7c, 7f and
7g, were acquired on a Bruker DRX 400 (9.4 Tesla, 400.13 MHz for 1H, 100.62 MHz for 13C and 40.56
15
for N) spectrometer with a 5-mm inverse-detection H–X probe equipped with a z-gradient coil, at 300
K and processed using standard Bruker NMR software and in non-phase-sensitive mode. Gradient
selection was achieved through a 5% sine truncated shaped pulse gradient of 1 ms. Selected parameters
for (1H–13C) gs-HMQC and gs-HMBC spectra were spectral width 3500 Hz for 1H and 20.5 kHz for 13C,
1024 x 256 data set, number of scans 2 (gs-HMQC) or 4 (gs-HMBC) and relaxation delay 1 s. The FIDs
were processed using zero filling in the F1 domain and a sine-bell window function in both dimensions
was applied prior to Fourier transformation. In the gs- HMQC experiments GARP modulation of 13C was
used for decoupling. Selected parameters for (1H-15N) gs-HMBC spectra were spectral width 3500 Hz
1
15
for H and 12.5 kHz for N, 1024 x 512 data set, number of scans 8, relaxation delay 1s, 60-100 ms
delay for the evolution of the 15N-1H long-range coupling. The FIDs were processed using zero filling in
the F1 domain and a sine-bell window function in both dimensions was applied prior to Fourier
transformation.
Synthesis
1,3-Diketones20 1a-g were prepared according to literature procedure and 2-aminopyridine (2) was
available commercially.
General procedure for one-pot synthesis of 1-aryl-1-(2-methylimidazo[1,2-a]pyridin-3-
yl)methanones (7 a-g) :
To a solution of 1,3-diketones 1a-g (1.0 mmol) in DCM (10 mL) was added NBS (0.177g, 1.0 mmol) and
mixture was allowed to stir at rt for 30 min. Subsequently, 2-aminopyridine 2 (0.094g, 1.0 mmol) was
added and reaction mixture was maintained at rt with stirring. The reaction was monitored with TLC. On
completion of reaction (4 hr), excess DCM was distilled off in vacuo and the residue was washed with
aq. NaHCO3 and extracted with DCM. Organic layers were combined, dried over anhyd. Na2SO4 and
excess solvent was distilled off. The residual mass was recrystallized from ethanol and 7a-g was obtained
in 71 to 81% yield.
1-Phenyl-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7a)
Creamy white solid.
Mp 62-64ºC, Lit. Mp 82-84ºC14.
9

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Yield: 75%.
1H NMR (300 MHz, CDCl3): δ = 9.51(d, 1H, J = 6.6 Hz, 5-H), 8.48 (d, 1H, J = 8.7 Hz, 8-H), 7.98-
8.03(m, 1H, 7-H), 7.73-7.77(m, 3H, Ph 2,4,6-H), 7.59-7.64 (m, 2H, Ph 3,5-H), 7.52-7.57 (m, 1H, 6-H),
2.51 (s, 3H, 2-CH3).
13C NMR (75 MHz, CDCl3): 14.12, 113.15, 118.40, 121.12, 129.41, 129.82, 133.80, 135.57, 138.55,
141.29, 143.35, 186.12.
MS (EI): 237 [M+H]+.
Anal. Calcd. for C15H12N2O: C, 76.25; H, 5.12; N, 11.86 % Found: C, 75.86; H, 4.92; N, 11.52 %.
1-(4-Methylphenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7b)
Creamy white solid.
Mp 116-118ºC.
Yield: 76%.
1H NMR (300 MHz, CDCl3): δ = 9.45 (d, 1H, J = 6.9 Hz, 5-H), 7.68 (d, 1H, J = 8.7 Hz, 8-H), 7.61 (d,
2H, J = 7.8 Hz, 4-CH3Ph 2,6-H), 7.45-7.51 (m, 1H 7-H), 7.32 (d, 2H, J = 7.8 Hz, 4-CH3Ph 3,5-H), 7.02-
7.07 (m, 1H, 6-H), 2.47 (s, 3H, 2-CH3), 2.23 (s, 3H, 4-CH3Ph).
13C NMR (75 MHz, CDCl3): 17.41, 21.64, 114.18, 116.52, 121.54, 128.44, 128.67, 129.03, 129.13,
129.26, 129.72, 137.52, 142.55, 147.34, 152.85, 186.89.
MS (EI): 251 [M+H]+.
Anal. Calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19 % Found: C, 76.43; H, 5.22; N,75.71 %.
1-(4-Methoxyphenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7c)
Creamy white solid.
Mp 56-58ºC.
Yield: 78%.
3
1H NMR (400 MHz, DMSO): δ = 9.21 (ddd, 1H, J = 6.9 Hz, 4J = 5J = 1.0 Hz, 5-H), 8.05 (m, 2H, 7, 8-
H), 7.85 (m, 2H, 4-OCH3Ph 2,6-H), 7.58 (ddd, 1H, 3J = 6.9 Hz, 3J = 6.1 Hz, 4J = 2.2 Hz, 6-H), 7.13 (m,
2H, 4-OCH3, Ph 3,5-H), 3.88 (s, 3H, 4-OCH3Ph), 2.29 (s, 3H, 2-CH3).
13C NMR (100 MHz, DMSO): 13.4, 55.7, 112.4, 114.3, 117.7, 120.7, 129.2, 130.1, 131.9, 134.7, 140.4,
141.0, 163.7, 183.9.
MS (EI): 267 [M+H]+.
Anal. Calcd. for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52 % Found: C, 71.94; H, 5.11; N, 10.30 %.
1-(4-Fluorophenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7d)
Light yellow solid.
Mp 108-110ºC.
Yield: 80%.
10

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1H NMR (300 MHz, DMSO): δ = 9.33 (d, 1H, J = 7.2 Hz, 5-H), 7.93-7.94 (m, 2H, 7,8-H), 7.85-7.87 (m,
2H, 4-FPh 2,6-H), 7.41-7.51(m, 3H, 6-H, 4-FPh 3,5-H), 2.18 (s, 3H, 2-CH3).
13C NMR (75 MHz, DMSO): 14.2, 113.2, 116.6 (2JF=21.9), 118.3, 121.1, 129.8, 132.6 (3JF=9.1), 135.1
(4JF=3.0), 135.3, 141.4, 143.3, 165.5 (1JF=252.1), 184.70.
MS (EI): 255 [M+H]+.
Anal. Calcd. for C15H11FN2O: C, 70.86; H, 4.36; N, 11.02 % Found: C, 70.23; H, 4.11; N, 10.92 %.
1-(4-Chlorophenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7e)
White solid.
Mp 142-144ºC.
Yield: 79%.
1H NMR (300 MHz, CDCl3): δ = 9.47 (d, 1H, J = 6.9 Hz, 5-H), 8.41 (d, 1H, J = 8.7 Hz, 8-H), 7.94-7.99
(m, 1H, 7-H), 7.72 (d, 2H, J = 8.7 Hz, 4-ClPh 2,6-H), 7.59 (d, 2H, J = 8.7 Hz, 4-ClPh 3,5-H), 7.48-7.53
(m, 1H, 6-H), 2.52 (s, 3H, 2-CH3).
13C NMR (75 MHz, CDCl3): 14.68, 113.66, 118.01, 121.01, 129.53, 129.69, 131.33, 134.77, 137.47,
138.43, 144.82, 184.94.
MS (EI): 271 [M+H]+, 273 [M+H+2]+ (3:1).
Anal. Calcd. for C15H11ClN2O: C, 66.55; H, 4.10; N, 10.35 % Found: C, 66.42; H, 3.95; N, 10.21 %.
1-(4-Bromophenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7f)
White solid.
Mp 136-138ºC.
Yield: 77%.
3
1H NMR (400 MHz, DMSO): δ = 9.33 (ddd, 1H, J = 6.9 Hz, 4J = 5J = 1.1 Hz, 5-H), 8.03 (m, 2H, 7, 8-
H), 7.81 (d, 2H, 4-BrPh 3,5-H), 7.75 (m, 2H, 4-BrPh 2,6-H), 7.58 (d, 1H, 3J = 6.9 Hz, 3J = 6.1 Hz, 4J =
2.3 Hz 6-H), 2.21 (s, 3H, 2-CH3).
13C NMR (100 MHz, DMSO): 14.1, 113.0, 117.6, 120.5, 127.1, 129.2, 131.0, 132.0, 134.5, 137.2, 141.3,
143.9, 184.6.
MS (EI): 315 [M+H]+, 317 [M+H+2]+ (1:1).
Anal. Calcd for C15H11BrN2O: C, 57.16; H, 3.52; N, 8.89 % Found: C, 56.98; H, 3.47; N, 8.75 %.
1-(Thien-2-yl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7g)
Light brown solid.
Mp 114-116ºC.
Yield: 71%.
11

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1H NMR (400 MHz, DMSO): δ = 9.07 (ddd, 1H, 3J = 6.9 Hz, 4J = 5J = 1.2 Hz, 5-H), 8.05 (m, 1H, thienyl
5-H), 7.74 (m, 1H, thienyl 3-H),7.68 (m, 1H, 8-H), 7.55 (m, 1H, 7-H), 7.25 (m, 1H, thienyl 4-H), 7.13
(ddd, 1H, 3J =, 3J = 6.9 Hz, 4J = 1.3 Hz, 6-H), 2.35 (s, 3H, 2-CH3).
13C NMR (100 MHz, DMSO): 17.1, 114.2, 116.3, 120.7, 127.8, 128.1, 129.2, 133.86, 134.09, 143.4,
146.5, 150.8, 177.4.
MS (EI): 243 [M+H]+.
Anal. Calcd. for C13H10N2OS: C, 64.44; H, 4.16; N, 11.56 % Found: C, 64.40; H, 4.06; N, 11.49s %.
General procedure for the step-wise synthesis of 1-aryl-1-(2-methylimidazo[1,2-a]pyridin-3-
yl)methanones (7b) :
2-bromo-1-(4-methylphenyl)butane-1,3-dione (1'b) :
A solution of 1-(4-methylphenyl)butane-1,3-dione 1b (0.176g, 1.0 mmol) and NBS (0.177g, 1.0 mmol)
was stirred in DCM at room temperature (rt) and the reaction was monitored with TLC at regular
intervals. On completion of reaction (1 hr), the reaction mixture was washed with water and extracted
with DCM. Organic extracts were combined, dried over anhyd. Na2SO4 and concentrated in vacuo to a
minimum and 1'b was obtained.
Pale Orange solid.
Mp 50-52ºC21.
Yield: 60%.
1H NMR (300 MHz, CDCl3): δ = 7.81-7.91 (d, 2H, J = 8.4 Hz, Ph 3,5-H), 7.30-7.33 (d, 2H, J = 8.1 Hz,
Ph 2,4-H), 5.61 (s, 1H, CHBr), 2.46 (s, 3H, Ph-CH3), 2.45 (s, 3H, COCH3).
1-(4-Methylphenyl)-1-(2-methylimidazo[1,2-a]pyridin-3-yl)methanone (7b) :
2-Aminopyridine 2 (0.094g, 1.0 mmol) was added to a solution of 2-bromo-1-(4-methylphenyl)butane-
1,3-dione (1'b) (0.255g, 1.0 mmol) in DCM and mixture was allowed to stir at rt. The reaction was
monitored with TLC. On completion of reaction (4 hr), excess DCM was removed in vacuo and the
residue was washed with aq. NaHCO3 and extracted with DCM. Organic layers were combined, dried
over anhyd. Na2SO4 and excess solvent was distilled off. The residual mass was recrystallized from
ethanol and 7b was obtained.
Creamy white solid.
Yield: 45% ; Overall Yield: 27%.
12

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X-Ray data collection and structure refinement
Suitable crystals for X-ray determination of compound 7f have been obtained from ethanol. Data
collection was carried out at room temperature on a Bruker Smart CCD diffractometer using graphite-
monochromated Mo-Kα radiation (λ= 0.71073 Å) operating at 50 kV and 20 mA. The data were
collected over a hemisphere of the reciprocal space by combination of three exposure sets. Each exposure
of 10s covered 0.3 in ω. The cell parameters were determined and refined by a least-squares fit of all
reflections. The first 100 frames were recollected at the end of the data collection to monitor crystal
decay, and no appreciable decay was observed. A summary of the fundamental crystal and refinement
data is given in Table 2. The structure was solved by direct methods and refined by full-matrix least-
square procedures on F2 (SHELXL-97)22.
Table-2 Crystal data and structure refinement for C30H26Br4N4O3 (7f)
CCDC-code
991345
Empirical formula
[C30H26Br4N4O3]
Formula weight
810.19
Crystal system
Orthorhombic
Space group
Pbca
Space group number
61
a / Å
25.378(2)
b / Å
8.0199(8)
c / Å
30.457(3)
α (º)
90.0
β (º)
90.0
γ (º)
V / Å3
90.0
6198.9(10)
Z
8
3184
F(000)
ρc / g cm-3
1.736
ꢀ / mm-1
5.232
Data collected
(−20, −9, −36) to (30, 9, 32)
1.34 to 25.00
45293
θ range (º)
Reflections collected
Independent reflections
Completeness to maximum θ (%)
Data / restrainsts / parameters
Observed reflections [I> 2σ(I)]
Ra
5470 (Rint = 0.2053)
100.0%
5470 / 0 / 372
1881
0.0567
b
RwF
0.1641
2
2 2
aΣ[|Fo| −|Fc|] / Σ[|Fo|. b {Σ[w(Fo −Fc2)2] / Σ[w(Fo ) ]}1/2
13

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All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were included in their
calculated positions and refined riding on the respective carbon atoms. Further crystallographic details for
the structure reported in this paper may be obtained from the Cambridge Crystallographic Data Center,
on quoting the depository number CCDC- 991345.
Acknowledgements:
We are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing
financial assistance (JRF) to Gulshan Singh. Thanks are also given to the Ministerio de Ciencia y
Tecnología of Spain (project CTQ2010-16122).
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16