Facile three-component domino reactions for the synthesis of 2-arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2013.04.126

The three-component domino reactions of pyridine/isoquinoline, phenacyl bromide, and substituted (E)-N-hydroxyarylimidoyl chloride in the presence of triethylamine afforded a series of 2-arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines. This one pot three-component transformation presumably proceeds via ylide generation/annulation/fragmentation/dehydration domino sequence of reactions.

Full text of DOI:10.1016/j.tetlet.2013.04.126

Accepted Manuscript
Facile three-component domino reactions for the synthesis of 2-arylimida‐
zo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines
Pitchaimani Prasanna, Sundaravel Vivek Kumar, Pethaiah Gunasekaran, Subbu
Perumal
PII:
S0040-4039(13)00742-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.04.126
TETL 42894
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Prasanna, P., Kumar, S.V., Gunasekaran, P., Perumal, S., Facile three-component domino
reactions for the synthesis of 2-arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.04.126
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Facile three-component domino reactions for the synthesis of
2-arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines
Pitchaimani Prasanna, Sundaravel Vivek Kumar, Pethaiah Gunasekaran and Subbu Perumal
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai – 625021, Tamil Nadu, India
Abstract: The three-component domino reactions of pyridine/isoquinoline, phenacyl
bromide and substituted (E)-N-hydroxyarylimidoyl chloride in the presence of triethylamine
afforded a series of 2-arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines.
This one pot three-component transformation presumably proceeds via ylide
generation/annulation/fragmentation/dehydration domino sequence of reactions.
Keywords: multi-component; domino; pyridine/isoquinoline; phenacyl bromide; (E)-N-
hydroxyarylimidoyl chloride; 2-arylimidazo[1,2-a]pyridines; 2-arylimidazo[2,1-a]isoquinolines.
Corresponding author: Tel./Fax:+91-452-2459845; e-mail: subbu.perum@gmail.com

Imidazo[1,2-a]pyridines are biologically and pharmaceutically active heterocycles, which
have received considerable attention in the field of pharmaceutical industry owing to their
broad range of useful activities such as antibacterial,1 antifungal,2 antiviral,3 antiulcer,4 and
anti-inflammatory.5 They have also been characterized as selective cyclin-dependent kinase
inhibitors,6 calcium channel blockers,7 β-amyloid formation inhibitors,8 and benzodiazepine
receptor agonists.9 They also act as orally active nonpeptide bradykinin B2 receptor
antagonists,10 besides being prevalent as the core structure of several drug formulations such
as alpidem, zolpidem, olprinone, zolimidine and minodronic acid, which are available
currently in the market (Figure 1).
Imidazo[1,2-a]pyridines have been synthesized by the two-component reactions of: (i)
2-aminopyridines with α-haloketones,11 α-diazoketones,12 1-phenylethanol,13 alkynyl-
(phenyl)iodonium salts,14 γ-bromodypnone,15 2-chloroacetaldehyde16 and acetophenones17
and (ii) 2-amino-1-[R-benzotriazol-1-ylmethyl]pyridinium chlorides with aldehydes in the
presence of DBU in dimethylformamide.18 Most of the three-component syntheses of these
compounds include the reaction of 2-aminopyridines with (i) benzyl halides and isocyanides
in the presence of potassium carbonate in dimethyl sulfoxide,19 (ii) aldehydes and isocyanides
in the presence of ZnCl2 in dioxane under thermal or microwave irradiation20 and (iii)
aldehydes and phenylacetylene in the presence of p-TSA with CuSO4 in toluene.21 Other
approaches involve the reactions of (i) N-fluoropyridinium triflate, isonitriles and nitrile in
the presence of NaBH(OAc)322 and (ii) pyridines, phenacyl bromides and thiocyanates in the
presence of potassium carbonate in toluene.23 This class of compounds has also been
prepared in three steps.24
These methods often involve harsh reaction conditions, inconsistent yields and long
reaction time. Under this context, we report a simple method that has emerged
serendipitously, for the preparation of these compounds. For some time, we have been
interested in the synthesis of novel heterocycles employing (i) the reaction of pyridinium
ylides and (ii) 1,3-dipolar cycloaddition reactions of 1,3-dipoles such as nitrile
oxides/azomethine ylides with -unsaturated carbonyl systems. In this context, we were
prompted to investigate whether the pyridinium ylides and nitrile oxides, both being 1,3-
dipoles, could react among themselves to furnish novel hybrid heterocycles, viz.
functionalized dihydropyrido[1,2-e][1,2,5]oxadiazines (Scheme 1) by forming bonds between
oppositely charged nuclei. Interestingly, the reaction (E)-N-hydroxyarylimidoyl chloride,
2

phenacyl bromide and pyridine/isoquinoline in the presence of triethylamine in acetonitrile
afforded imidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines through three-
component domino reactions in a one pot operation.
We started our study with the optimization of the model three-component reaction
between pyridine (1 mmol), phenacyl bromide (1 mmol) and (E)-4-chloro-N-
hydroxybenzimidoyl chloride (1 mmol) in the presence of potassium carbonate (1 mmol) in
acetonitrile at 80 °C for 4 h, which afforded 3-(4-chlorophenyl)imidazo[1,2-a]pyridine 5b in
83% yield (Table 1, entry 8). When triethylamine was used instead of potassium carbonate in
this reaction in acetonitrile at 80 °C for 3 h, an excellent yield of 96% of 5b was obtained
(Table 1, entry 1). As the selection of an appropriate reaction medium is crucial for the
success of reactions, the three-component reaction under heating was examined in N,N-
dimethylformamide, methanol, ethanol, dioxane, water and solvent-free condition (entries 2–
7). From the data listed in Table 1, acetonitrile has emerged as the solvent of choice
furnishing the highest yield of the product.
The model reaction was also investigated employing different bases, viz. sodium acetate,
1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane and -proline (entries 9–
L
12, Table 1). The reaction in presence of KOH or NaOH failed to afford any characterizable
product. Presumably, the nitrile oxides, generated initially from the reaction of (E)-4-chloro-
N-hydroxybenzimidoyl chloride by dehydrohalogenation, underwent decomposition in
presence of these bases. From the above results, triethylamine-acetonitrile pair is discerned as
the ideal choice of base and solvent for the synthesis of 5b in excellent yield. After
identifying these optimal conditions, the scope of this transformation was examined further
(Scheme 2 and Table 2) employing pyridine/isoquinoline (1 mmol), phenacyl bromide (1
mmol) and a series of substituted (E)-N-hydroxyarylimidoyl chlorides (1 mmol) in the
presence of triethylamine in acetonitrile at 80 °C for 3-4 h. After completion of the reaction,
the solvent was removed and the residue purified by column chromatography to obtain a
series of novel 2-arylimidazo[1,2-a]pyridines 5 and 2-arylimidazo[2,1-a]isoquinolines 6 in
85-96% yields25 (Table 2). It is pertinent to note that this transformation occurred
successfully in the presence of both strongly electron-releasing (4-MeO) as well as electron-
withdrawing substituents (4-CF3 and 4-NO2) in the aryl ring of (E)-N-hydroxyarylimidoyl
chlorides.
3

The structure of the products 5 and 6 was deduced from one- and two-dimensional
1
NMR spectroscopic data as detailed for 5b as a representative example (Figure 2). In the H
NMR spectrum of 5b, H-3 of imidazole ring appears as a singlet at 7.85 ppm, which shows
HMBCs with C-2 and C-8a at 144.8 and 145.8 ppm respectively. The H-5 appears as a
doublet of triplets at 8.13 ppm (J = 6.9 and 1.2 Hz), which shows HMBCs with C-3, C-6 and
C-8a at 108.1, 112.5 and 145.8 ppm respectively. Similarly, the H-6 gives a triplet of
doublets at 6.80 ppm (J = 6.3 and 1.2 Hz), which shows HMBCs with C-8 at 117.6 ppm. The
J value of 1.2 Hz found for H-3 and H-6 presumably arises from long range W-coupling. The
H-7 gives a triplet of doublets at 7.19 ppm (J = 7.8 and 1.2 Hz) and shows HMBCs with C-8a
and C-5 at 145.8 and 125.6 ppm respectively, while H-8 appearing as a multiplet at 7.61-7.64
ppm shows HMBC with C-6 at 112.5 ppm. Finally, the X-ray crystallographic study26 of a
single crystal of 6d confirmed the structure of 6 (Figure 3).
A plausible mechanism for the formation of 2-arylimidazo[1,2-a]pyridines 5 and
isoquinolines 6 is depicted in Scheme 3. Presumably, this transformation is triggered by the
formation of pyridinium salt 7 from the reaction of pyridine 1 and phenacyl bromide 3, which
reacts with base to furnish ylide 8. This ylide intermediate 8 then reacts with nitrile oxide 9
(generated in situ from the dehydrochlorination of 4 upon reaction with triethylamine) to
afford the intermediate 10, which subsequently undergoes annulation giving intermediate 11.
Then intermediate 11 undergoes base-catalyzed fragmentation with concomitant protonation
leading to the intermediate 12, which finally affords the product 5/6 via dehydration. To our
knowledge, this synthesis of 2-arylimidazo[1,2-a]pyridines 5 and 2-arylimidazo[2,1-
a]isoquinolines 6 through the three-component protocol is reported for the first time.
In conclusion, we have described a facile three-component synthesis of novel 2-
arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines via domino sequence of
reactions from simple, readily available starting materials in a one pot operation.
Acknowledgements
SP thanks the Department of Science and Technology, New Delhi for a major research
project (SR/S1/OC-50/2011) and for funds under IRHPA program for the purchase of a high
resolution NMR spectrometer. PG thanks the Council of Scientific and Industrial Research,
New Delhi for the award of Senior Research Fellowship.
4

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25. General procedure for the synthesis of 2-arylimidazo[1,2-a]pyridines 5 and 2-
arylimidazo[2,1-a]isoquinolines 6: A mixture of pyridine/isoquinoline (1 mmol), phenacyl
bromide (1 mmol) and (E)-N-hydroxyarylimidoyl chloride (1 mmol) in CH3CN (10 ml) in the
presence of triethylamine (1 mmol) was heated at 80 °C for 3-4 h. The reaction progress was
monitored by thin layer chromatography. After completion of the reaction, the solvent was
removed and the product was purified by flash column using petroleum ether–ethyl acetate
mixture (4:1 v/v) as eluent to afford pure 2-arylimidazo[1,2-a]pyridines 5 and 2-
arylimidazo[2,1-a]isoquinolines 6. Characterization data for representative compounds 5b
and 6h are given below.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine 5b: Isolated as white solid. Yield: 96%; mp =
208‒ 209 °C; 1H NMR (300 MHz, CDCl3) δH: 6.80 (td, J = 6.3, 1.2 Hz, 1H), 7.19 (td, J = 7.8,
1.2 Hz, 1H), 7.40-7.42 (m, 2H), 7.61‒ 7.64 (m, 1H), 7.85 (s, 1H), 7.88‒ 7.91 (m, 2H), 8.13
13
(dt, J = 6.9, 1.2 Hz, 1H); C NMR (75 MHz, CDCl3) δc: 108.1, 112.5, 117.6, 124.8, 125.6,
127.3, 128.9, 132.4, 133.7, 144.8, 145.8; Anal. Calcd for C13H9ClN2: C, 68.28; H, 3.97; N,
12.25 %. Found C, 68.37; H, 3.89; N, 12.36 %.
2-p-Tolylimidazo[2,1-a]isoquinoline 6h: Isolated as white solid. Yield: 89%; mp = 153‒ 154
1
°C; H NMR (300 MHz, CDCl3) δH: 2.39 (s, 3H), 6.98 (d, J = 7.2 Hz, 1H), 7.24‒ 7.23 (m,
2H), 7.52‒ 7.57 (m, 1H), 7.60‒ 7.68 (m, 2H), 7.75 (s, 1H), 7.85 (d, J = 7.2 Hz, 1H), 7.89 (d, J
= 8.1 Hz, 2H), 8.71‒ 8.73 (m, 1H); 13C NMR (75 MHz, CDCl3) δc: 21.1, 109.4, 112.6, 122.7,
6

123.2, 123.5, 125.6, 126.7, 127.8, 129.2, 131.1, 137.0, 142.9, 143.8; Anal. Calcd for
C18H14N2: C, 83.69; H, 5.46; N, 10.84 %. Found C, 83.78; H, 5.57; N, 10.73 %.
26. Crystallographic data (excluding structure factors) for compound 6d in this letter have
been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 930324. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223-336033
or e-mail:deposit@ccdc.cam.ac.uk].
N
N
Cl
N
N
Cl
O
O
Alpidem
Zolpidem
N
N
N
N
O
N
S
HN
N
O
Olprinone
Zolimidine
O
CN
N
O
OH
N
P
OH
O
HO
P
HO
OH
Minodronic acid
Figure 1. Structures of some imidazo[1,2-a]pyridine drug molecules.
7

Scheme 1. Retrosynthesis of dihydropyrido[1,2-e][1,2,5]oxadiazines
8

O
Cl
Ar
Br
CH3CN, Et3N
80 0C, 3-4 h
or
N
OH
N
or
N
+
+
N
N
N
N
1
2
3
4
5
6
Ar
Ar
Scheme 2. Three-component synthesis of 2-arylimidazo[1,2-a]pyridines 5
and 2-arylimidazo[2,1-a]isoquinolines 6.
9

Table 1. Solvent- and base-screen for the synthesis of 5b
Yield of 5ba
Reaction
time (h)
Entry
Base
Solvent
(%)
96
1
2
Et3N
Et3N
CH3CN
DMF
3
7
61
3
Et3N
MeOH
EtOH
5
69
4
Et3N
5
77
5
Et3N
Dioxane
Water
5
81
b
6
Et3N
6
-
7
Et3N
None
3
45
83
71
67
61
8
K2CO3
NaOAc
DBU
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
MeOH
4
9
5
10
11
12
13
\14
7
DABCO
L-Proline
NaOH
KOH
7
b
7
-
b
10
10
-
b
-
aIsolated yield after purification by column chromatography.
bNo reaction occurred.
10

Table 2. Synthesis of 2-arylimidazo[1,2-a]pyridines 5 and
2-arylimidazo[2,1-a]isoquinolines 6
Entry
Comp.
Ar
Time
(h)
Yield of
5/6 (%)a
1
2
C6H5
3
3
4
3
3
3
3
3
4
4
3
3
4
4
4
3
91
96
88
90
92
94
93
95
90
91
95
93
89
87
85
92
5a
5b
5c
6a
6b
6c
6d
6e
6f
4-ClC6H4
4-MeOC6H4
C6H5
3
4
5
2-ClC6H4
4-ClC6H4
3-FC6H4
6
7
8
4-FC6H4
9
3-BrC6H4
4-BrC6H4
4-NO2C6H4
4-CF3C6H4
4-H3CC6H4
4-MeOC6H4
4-PriC6H4
2,4-Cl2C6H3
10
11
12
13
14
15
16
6g
6h
6i
6j
6k
6l
6m
aIsolated yield after purification by column chromatography.
11

Figure 2. Selected 1H and 13C chemical shifts and HMB correlations of 5b.
12

Figure 3. ORTEP diagram for 6d.
13

Scheme 3. Probable domino sequence leading to the formation of 5 and 6.
14

Graphical Abstract
Facile three-component domino reactions for the synthesis of 2-
arylimidazo[1,2-a]pyridines and 2-arylimidazo[2,1-a]isoquinolines
Pitchaimani Prasanna, Sundaravel Vivek Kumar, Pethaiah Gunasekaran and Subbu Perumal
15