Imidazo[1,2-a]pyridines susceptible to excited state intramolecular proton transfer: One-pot synthesis via an Ortoleva-King reaction

Article abstract of DOI:10.1021/jo300643w

A short and efficient route to a broad range of imidazo[1,2-a]pyridines from 2-aminopyridines and acetophenones is achieved by a tandem, one-pot process starting with an Ortoleva-King reaction. Optimal conditions for the first step were established after

Full text of DOI:10.1021/jo300643w

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Article
Imidazo[1,2-a]pyridines susceptible to excited state intramolecular
proton transfer: one-pot synthesis via an Ortoleva-King reaction
Anton J Stasyuk, Marzena Banasiewicz, Michal Ksawery Cyranski, and Daniel Tomasz Gryko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300643w • Publication Date (Web): 04 Jun 2012
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Imidazo[1,2-a]pyridines susceptible to excited state
intramolecular proton transfer: one-pot synthesis via an
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Ortoleva-King reaction
Anton J. Stasyuk,a,b Marzena Banasiewicz,c Michał K. Cyrańskib* and Daniel T. Grykoa,*
a Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland.
b Warsaw University, Chemistry Department, Pasteura 1, 01-173 Warsaw, Poland
c Institute of Physics of the Polish Academy of Sciences, Al. Lotników 32/46, 02-668 Warsaw, Poland
dtgryko@icho.edu.pl
chamis@chem.uw.edu.pl
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT A short and efficient route to a broad range of imidazo[1,2-a]pyridines from 2-
aminopyridines and acetophenones is achieved by a tandem, one-pot process starting with an Ortoleva-
King reaction. Optimal conditions for the first step were established after examining various reaction
parameters (solvent, reagent ratios, and temperature). The conditions identified (1st step: neat, 2.3 equiv.
of 2-aminopyridine, 1.20 equiv of I2, 4 h, 110 °C; 2nd step: NaOHaq, 1 h, 100 °C) resulted in the
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formation of imidazo[1,2-a]pyridines in 40-60% yields. The synthesis is compatible with various
functionalities (OH, NMe2, Br, OMe). Products containing a 2-(2’-hydroxyphenyl) substituent undergo
excited state intramolecular proton transfer (ESIPT) in non-polar and polar-aprotic solvents. Although
ESIPT-type emission in non-polar solvents is weak the Stokes shifts are very high (11000 cm-1). The
comparison of the properties of six ESIPT-capable imidazo[1,2-a]pyridines shows the influence of
various substituents on emission characteristics. All of them also display strong, solid-state emission in
blue-green-yellow region. 2-Aryl-imidazo[1,2-a]pyridines not capable of ESIPT emit in the blue region,
displaying high fluorescence quantum yield.
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Introduction: The chemistry of imidazo[1,2-a]pyridines has been intensively investigated since
the beginning of the last century.1 This area is still of great interest, mainly due to important biological
activity of these molecules. Imidazo[1,2-a]pyridines have significant importance in the pharmaceutical
industry owing to their interesting biological activity displayed over a broad range of therapeutic
classes; these molecules exhibit antiviral (anticytomegalo-zoster and antivaricella-zoster virus),2 anti-
inflammatory,3 analgesic, antipyretic,4 antiulcer,5 and antibacterial6 properties. They are also β-amyloid
formation inhibitors,7 GABA and benzodiazepine receptor agonists,8 and cardiotonic agents.9 Drug
formulations containing imidazo[1,2-a]pyridine which are currently available on the market include
alpidem (anxiolytic),10 zolpidem (hypnotic),11 and olprinone (PDE-3 inhibitor).12
Acuña and co-workers were the first to report that imidazo[1,2-a]pyridines possessing a 2-
hydroxyphenyl substituent at position 2 display excited-state intramolecular proton transfer (ESIPT).13
More recently, the photophysics of these compounds was studied by Araki and co-workers, who
discovered their strong solid-state emission.14 The design and characterization of compounds which
undergo ESIPT continues to engage the interest of scientists throughout the world15 because of the wide
applications of this phenomenon to such systems as laser dyes,16 fluorescence sensors17 and molecular
switches.18
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A variety of synthetic methods have been reported for the preparation of substituted
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imidazo[1,2-a]pyridines. The most important approaches embrace: (i) condensation of 2-aminopyridine
with α-halocarbonyl compounds,19 (ii) one-pot condensations of aldehydes, isonitriles, and 2-
aminopyridines,20 and (iii) copper catalyzed three-component reactions of 2-aminopyridines, aldehydes
and alkynes.21 Other methods have also been developed within the last three decades.22-26 Although new
methods are continuously published,27 the reaction of 2-aminopyridines with α-halogenoketones and α-
halogenoaldehydes is still the most popular. There are however two intrinsic limitations to this
methodology, namely the small variety of commercially available α-halogenocarbonyl compounds, and
their lachrymatory properties.
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Herein we describe a new approach to the synthesis of substituted imidazo[1,2-a]pyridines,
based on the condensation of 2-aminopyridine with various aromatic ketones under Ortoleva-King
reaction conditions, followed by cyclization under the influence of base.
Results and discussion
We have observed that the structure of the intermediate product in the synthesis of imidazo[1,2-
a]pyridines from 2-aminopyridine and α-halocarbonyl compounds (i.e. the corresponding pyridinium
salt with a halogen counterion) represents the same type of compound as is formed in the Ortoleva-King
reaction. First Ortoleva,28 and then King29 demonstrated that pyridinium salts can often be conveniently
prepared in a direct synthesis by heating active methyl and methylene compounds with iodine in
pyridine. The yields of this elegant method are usually very good,30 and a variety of heterocyclic bases
may be used instead of pyridine, including quinolines,31 isoquinolines, picolines32 and nicotinamide.33
The reaction has been extended to include a variety other compounds containing active methyl and
methylene groups.
We envisioned that if 2-aminopyridine (1) could be used as a component in an Ortoleva-King
reaction with methylketones, the initially formed pyridinium salts would bear suitable functional groups
to form 2-substituted imidazo[1,2-a]pyridines in the second step. Needless to say, one must take into
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consideration the numerous side reactions which may occur, including iodination of 2-aminopyridine.34
Careful analysis of published data showed that the yields in Ortoleva-King reaction are usually very
good, but that separation of the iodide byproducts is sometimes accompanied by considerable losses.
These difficulties can be circumvented by precipitating the product from aqueous solution with sodium
perchlorate.35 However, this route appeared unproductive to us, because it required additional time and
led to inevitable losses of the intermediate product.
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It has been shown by Pearson36 that the Ortoleva-King reaction can be represented as stepwise
mechanism. In this representation, the first step is α-proton detachment from the ketone with pyridine
serving as a base. This forms the corresponding conjugate base of the ketone, with is able to interact
with iodine giving α-iodomethylketone. The latter can react relatively easily with another molecule of
pyridine. Pearson has also shown that the rate of formation of β-ketoalkyl pyridinium iodides is much
faster than both the rate of reaction between ketone and heterocyclic amine base, and the rate of reaction
of the conjugate base with iodine. The limiting step of the whole process is the interaction of ketone
with amine. Therefore, we reasoned that when carrying out the reaction in excess of 2-aminopyridine it
might be possible to obtain reaction kinetics that were first order with respect to ketone and apparent-
zero-order with respect to 2-aminopyridine. An another mechanistic possibility which has to be taken
into consideration, is initial formation enamine intermediates in reaction of 2-aminopyridine with
acetophenone followed by iodination and subsequent cyclization to provide imidazo[1,2-a]pyridines.
Since our aim was to develop a methodology with the widest possible scope, as a model, we
chose the reaction between 2-aminopyridine (1) and 2-hydroxyacetophenone (2a) (the presence of a
phenolic hydroxyl group makes ketone 2a prone to iodination under the reaction conditions) (Scheme
1). An additional reason for the choice of substrates was that the prospective product of this reaction (2-
(imidazo[1,2-a]pyridin-2-yl)phenol (3a) had been shown to display ESIPT,13,14 which was of interest to
us. Initially, we performed the model reaction using acetonitrile as a solvent, which led to the formation
of desired product 3a, but in only 10 % yield. Since reactions in other solvents did not bring any
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appreciable change (Table 1), we attempted to perform the first step in the neat, which improved the
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yield of product 3a considerably (Table 2, entry 1).
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Table 1. Results of reactions of 2-aminopyridine (1) with 2-hydroxyacetophenone (2a) in various
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solventsa
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Entry
Solvent
MeCN
Toluene
CH2Cl2
THF
Yield (%)
1
2
3
10
12
2
4
6
a
All reactions were performed under the following constant conditions: 1st step: 4 h at 110 °C
followed by overnight stirring at 70 °C; 2nd step: excess aqueous NaOH (45%), 100 °C, 1 h.
Inspired by these preliminary results, we initiated a systematic study of solvent-free reaction
conditions. The experiments were focused on the number of equivalents of 2-aminopyridine (1) used
(Table 2). For these experiments, the second step (cyclization reaction) was carried out under conditions
of excess aqueous alkali to create apparent-zero-order reaction conditions with respect to the aqueous
base.
Scheme 1.
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1
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Table 2. Optimization of relative quantities of reagents in the reaction of 2-aminopyridine (1) with 2-
hydroxyacetophenone (2a)a
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Entry
Ratio 1:2a Iodine (equiv. vs. 2a)
Yield (%)
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1.20
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a
All reactions were performed under the following constant conditions: 1st step: solvent free, 4 h at
110 °C followed by overnight stirring at 70 °C; 2nd step: excess aqueous NaOH (45%), 100 °C, 1 h.
During this study, it was found that the reaction is sensitive to the molar ratio between reagents.
It seems that a key requirement of the reaction is a minimum twofold excess of 2-aminopyridine and
slight excess of iodine with respect to ketone (Table 2, entries 2-5). Further increases to the amounts of
these components did not lead to any increase in the yield of the reaction, but caused difficulties in the
isolation and purification of the final product (Table 2, entries 6-7). Under the reaction conditions
(110°C) 2-aminopyridine becomes a liquid and dissolves all components of the reaction sufficiently.
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These data are in good agreement with the data obtained in kinetic36 and other studies28-34 of the
Ortoleva-King reaction.
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Table 3. Scope of the synthesis of imidazo[1,2-a]pyridines directly from acetophenones.
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N
1. I2
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R
R COCH3
2. NaOH (45%, aq.)
N
N
NH2
1
2a-j
3a-j
R
Imidazo[1,2-a]pyridine
Ketone
2a
Yield
57%
3a
3b
OH
OH
61%
53%
2b
O
Br
2c
3c
OH
56%
39%
2d
2e
3d
3e
Br
OH
OH
HO
3f
41%
2f
N
OH
55%
54%
2g
2h
3g
3h
N
43%
51%
2i
2j
3i
3j
N
H
S
The optimized procedure (Table 2, entry 5: 1 eq. ketone, 1.20 eq. of iodine, excess (2.3 eq.) 2-
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aminopyridine) was subsequently used in the preparation of various 2-substituted imidazo[1,2-
a]pyridines. Acetophenones 2b-2f with diverse substituents (OMe, Br, OH, NEt2) were reacted with 2-
aminopyridine (1) (Table 3). All reactions gave rise to the corresponding 2-substituted imidazo[1,2-
a]pyridines 3b-3f in moderate-to-good yields (39-61%). Subsequently, we have shown that this
methodology may be the extended to other acetophenones including heterocyclic substrates (2g-2j).
Imidazo[1,2-a]pyridines 3g-3j, bearing both electron-donating and electron-withdrawing moieties, were
obtained in good yields (Table 3).
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To demonstrate the scalability of this process, a multi-gram preparation of imidazo[1,2-a]pyridine 3a
was attempted. The reaction of 2-aminopyridine (1) with 2-hydroxyacetophenone (2a) performed at a 37
mmol (5 g) scale (20 times larger than the experiments described in Table 3) furnished 3.94 g of
imidazo[1,2-a]pyridine 3a in a very similar yield (51%).
The spectral characteristics of imidazo[1,2-a]pyridines 3a-3f were examined and compared to those of
imidazo[1,2-a]pyridines 3g-3j (Table 4). Optical measurements were performed in several solvents:
toluene (non-polar, aprotic), dichloromethane (moderately polar, aprotic), acetonitrile (polar, aprotic),
methanol (polar, protic). The most notable feature of all of the imidazo[1,2-a]pyridines is an intense UV
absorption band (λabs = 320-360 nm) regardless of the substituent at position 2. The absorption maxima
shifted hypsochromically with increased solvent polarity (Table 4). The emission spectra of all of the
studied compounds that possess a 2-hydroxyphenyl substituent strongly depend on the nature of the
solvent. In all aprotic solvents, the emission is very weak (Φfl = 1-3% typically) and is situated around
560 nm. In polar but aprotic CH3CN compounds 3a-f showed both blue and orange fluorescence (Table
4). While Stokes shifts in unpolar solvents reach 11000 cm-1, in CH3CN they are even higher (up to
13000 cm-1) mainly due to the hypsochromically shifted absorption. By contrast, the emission spectrum
in methanol shows a stronger non-ESIPT emission band in the blue region (λmax = 370-390 nm, Φfl = 5-
17%). Stokes shifts are moderate in MeOH (2500-4600 cm-1). The only exception is compound 3f,
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which possesses an additional strongly electron-donating Me2N group at position 4 of the phenyl ring.
Both absorption and emission of 3f in MeOH are significantly bathochromically shifted when compared
with imidazo[1,2-a]pyridines 3a-3e (Table 4). The resulting Stokes shift reaches 6700 cm-1 in this case.
The dramatic increase in the fluorescence quantum yield of compounds 3a-3f in MeOH can be
attributed to the fact that, as reported by Douhal et al.,13 in hydrogen-bonding media (such as MeOH),
solvated structures such as 3aiii, which emit in near-UV/blue-violet region, are favored and consequently
ESIPT is prevented (Scheme 2). These results indicate that blue fluorescence is due to direct emission
from a localized excited state, and that orange fluorescence is the ESIPT fluorescence from zwitterionic
3aii. Interestingly, for dyes 3c and 3d containing bromine atom, ESIPT-type emission was also visible in
MeOH (albeit very weak, Table 4). Emission of the remaining compounds 3g-3j, which are not capable
of ESIPT, is not so strongly solvent-dependent. Upon excitation at 330 nm, 3g-3j show strong blue
fluorescence at 370-380 nm. Again the exception is imidazo[1,2-a]pyridine 3i, which possesses a
strongly electron-donating pyrrole moiety. In this case the emission maximum is shifted into the violet
region (390-410 nm). The nearly identical emission wavelengths for compounds 3a and 3g (λmax = 372-
376 nm) is evidence that their geometries in the excited state are very similar. For non-ESIPT
imidazo[1,2-a]pyridines, the Stokes shift is moderate (~4200 cm-1), except for compound 3i in polar
solvents (~5500 cm-1). The notable difference is that Φfl of dyes 3g-3j in MeOH is very high (40-80%).
Of particular interest is the fact that the values of the Stokes shifts are essentially the same for groups of
compounds regardless of whether they possess the proton donor necessary for ESPIT. Stokes shifts
lower than 6000-8000 cm-1 can typically be explained based on a “solute-solvent” polarizable
continuum model of interaction. This “solute-solvent” model of interaction considers only a change in
the dipole interaction energy of the fluorophore, which is induced by the electric field of the solvent by
increasing the dipole moment of the fluorophore in the excited state. Thus, a red shift is associated with
the macroscopic rate of solvent: dielectric constant and refraction index. The optical properties of
compound 3g-3j can be explained according to this model. The assumptions applied are in a good
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agreement with data published by Douhal et al.13
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Scheme 2.
Araki and-coworkers reported14 that the ESIPT process, accompanied by a large Stokes shift (~
9700 cm-1) and dependent on the structure of polymorphs, in imidazo[1,2-a]pyridines derivatives is
strongly visible in the solid state. The idea developed by Acuña and co-workers and presented in
Scheme 2 provides a satisfactory explanation of the observed large Stokes shift of the blue-green-yellow
emission in the solid state. 2’-Hydroxy derivatives of 2-phenylimidazo[1,2-a]pyridine in solid state do
not experience solvation effects, allowing them to stay in the zwitterionic ESIPT-active form 3aiii.13,14
We performed solid-state emission measurements for imidazo[1,2-a]pyridines 3a-j (Table 5). Strong
fluorescence was observed for ESIPT-capable imidazopyridines 3a-f (λem = 490-520 nm). The emission
maximum for compound 3a (494 nm) perfectly correlates with properties of polymorph BG described
by Araki and co-workers.14b Again, emission maximum is strongly bathochromically shifted for
imidazopyridine 3f (546 nm). Two out of non-ESIPT imidazopyridines also display luminescence in the
solid state, however emission is weak and hypsochromically shifted (Table 5).
Table 4. Spectroscopic properties of compounds 3a-3j
a
Compo Solvent λabs
/
λem
/
Φfl
Stokes shift
ε
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und
nm
351
345
328
nm
573
573
380
577
375
560
572
385
579
385
561
370
378
583
372
562
541
(cm-1)
11000
11500
4200
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8
toluene
CH2Cl2
CH3CN
8800
7900
0.011
0.005
0.006
0.003
0.084
0.036
0.010
0.002
0.001
0.124
0.036
0.013
0.002
0.003
0.046
0.002
0.087
3a
3b
3c
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12100
13100
3800
MeOH
toluene
CH2Cl2
CH3CN
328
340
334
330
12000
13900
14900
15000
11500
12500
4300
13000
4200
MeOH
toluene
CH2Cl2
CH3CN
331
352
347
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15000
10000
10800
10600
10600
1800
2600
11900
3100
MeOH
toluene
330
351
14600
11800
12200
10000
3d
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CH2Cl2
CH3CN
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12200
11700
541
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583
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572
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378
0.055
0.002
0.015
0.059
0.010
0.048
0.019
0.004
0.002
0.168
0.034
0.015
0.002
0.002
0.092
0.607
0.552
0.555
10300
2700
1
2
3
4
5
6
7
8
11100
2500
9
10
11
12
13
14
15
16
17
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43
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45
46
47
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49
50
51
52
53
54
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59
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MeOH
342
11000
10600
10300
10600
4400
toluene
CH2Cl2
CH3CN
355
351
331
12100
13400
13300
3e
13100
4700
MeOH
toluene
CH2Cl2
CH3CN
332
361
354
350
11900
20300
22700
23500
10200
11000
6600
3f
11500
6700
MeOH
toluene
CH2Cl2
CH3CN
350
332
328
325
22600
8100
8200
8500
3900
3g
3900
4300
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The Journal of Organic Chemistry
MeOH
toluene
CH2Cl2
CH3CN
MeOH
toluene
CH2Cl2
CH3CN
MeOH
toluene
CH2Cl2
CH3CN
MeOH
321
333
330
328
323
342
355
333
333
351
333
331
327
8900
8600
374
382
378
377
374
393
401
406
410
383
380
382
377
0.796
0.571
0.515
0.525
0.480
0.590
0.427
0.544
0.481
0.585
0.660
0.644
0.767
4400
3900
3900
4000
4200
3800
3200
5400
5600
2400
3700
4000
4100
1
2
3
4
5
6
7
8
9
3h
8400
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8500
9600
11500
11600
11000
11800
6900
3i
3j
10600
10500
11300
a Determined in MeOH using quinine sulphate in 0.5 M H2SO4 as a standard
Table 5. Solid state emission maxima of compounds 3a-j.
Compound
λ
em max [nm]
494
3a
3b
3c
520
483
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492
3d
3e
3f
1
2
3
4
5
6
7
8
503
546
-
3g
3h
3i
-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
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36
37
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40
41
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45
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49
50
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58
59
60
395
390
3j
Conclusions
In summary, we have developed a new method for the direct preparation of imidazo[1,2-a]pyridines
from acetophenones and 2-aminopyridine, via an Ortoleva-King reaction followed by ring closure. We
have demonstrated that the initially-formed pyridinium salts undergo efficient ring-closure in the
presence of base. The reaction is functional group tolerant and allows for the preparation of an
unprecedented library of derivatives including compounds bearing a strongly electron-donating group at
position 2. Imidazo[1,2-a]pyridines possessing a 2-hydroxyphenyl substituent at position 2 exhibit
ESIPT in the majority of solvents, resulting in weak but highly bathochromically-shifted emission
peaks. In MeOH however, ESIPT is prevented by intermolecular hydrogen bonding; as a result,
compounds emit in the violet-blue region. Solid state emission maxima follow the same trend as
fluorescence in the solution i.e. the presence of strongly electron-donating groups at phenyl ring shift
emission from blue-green region to yellow one. Imidazo[1,2-a]pyridines possessing aryl substituents at
position 2 display strong emission bands in the blue region (fluorescence quantum yields = 0.40-0.80).
These results are not only of theoretical significance in that they provide new insight into factors
influencing the optical properties of imidazo[1,2-a]pyridines, but they may also open the door to
practical applications. The use of the described approach can open the way to the synthesis of a wide
range of these heterocycles, which can serve as an ideal platform to obtaining more complex systems.
Experimental Section
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The Journal of Organic Chemistry
1
2
3
General. All chemicals were used as received unless noted otherwise. Reagent grade solvents
4
5
(CH2Cl2, hexanes) were distilled prior to use. Spectrophotometric grade solvents were used without
6
7
1
13
further purification. All reported H NMR and C NMR spectra were collected using 500 or 600 MHz
spectrometers. Chemical shifts (δ ppm) were determined with TMS as an internal standard; J values are
given in Hz. The UV/Vis absorption spectra were recorded on a spectrophotometer in toluene, CH2Cl2,
acetonitrile or methanol. Emission spectra were recorded on a fluorescence spectrophotometer in
methanol. Emission spectra are presented in photon units with the extinction coefficient in M-1 cm-1 in
brackets, and have been corrected for instrumental factors. Fluorescence quantum yields (Φfl) were
measured with quinine sulphate in 0.5 M H2SO4 as a reference and were corrected for the refractive
index of the solvent. Melting points were determined using a capillary-type apparatus. Chromatography
was performed on silica (230-400 mesh). Dry column vacuum chromatography (DCVC) was performed
on preparative thin-layer chromatography alumina. Mass spectra were obtained via electron impact
mass spectrometry with double focusing sector mass analyzer (EI-MS).
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Exemplary procedure for the preparation of imidazo[1,2-a]pyridines starting from 2-
aminopyridine (1). 2-(Imidazo[1,2-a]pyridin-2-yl)phenol (3a). A sealed tube was charged with 1-(2-
hydroxyphenyl)ethanone (2a) (250 mg, 1.84 mmol), 2-aminopyridine (1) (398 mg, 4.23 mmol) and
iodine (560 mg, 2.21mmol). The reaction mixture was stirred at 110 °C. After 4 h the mixture was
cooled to 70 °C and stirred overnight. The residue was diluted with 5 mL distilled water and an excess
of aqueous sodium hydroxide (45%) was added. The reaction mixture was stirred at 100 °C for 1 h.
After cooling to room temperature, the reaction mixture was diluted with 25 mL CH2Cl2. 10 % aqueous
HCl was added to the water-organic mixture until a neutral pH was obtained. The mixture was then
extracted with CH2Cl2. The organic layer was washed with water, dried over Na2SO4 and concentrated
under reduced pressure. The solid was isolated by column chromatography (silica, CH2Cl2/hexanes 1:2
→ CH2Cl2/hexanes 3:1). The pure product was obtained as a solid after crystallisation from ethanol –
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water (219 mg, 57 %). Data for 3a: mp 142-143 °C (lit.13a mp 141-142 °C); 1H NMR (500 MHz, CDCl3,
δ) 6.79 (t, 1H, J=6.6 Hz), 6.84 (t, 1H, J=7.4 Hz), 7.02 (d, 1H, J=8.2 Hz), 7.17-7.25 (m, 2H), 7.52 (t, 2H,
1
2
3
4
5
6
13
J=8.6 Hz), 7.78 (s, 1H), 8.08 (d, 1H J=6.6 Hz), 12.81 (broad s, 1H); C NMR (125 MHz, CDCl3, δ)
7
8
9
106.9, 113.3, 115.5, 116.4, 116.8, 117.8, 119.1, 125.3, 125.6, 125.7, 125.9, 129.8, 157.5; EI-HR obsd
210.0797, calcd exact mass 210.0793 (C13H10N2O).
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2-(Imidazo[1,2-a]pyridin-2-yl)-5-methoxyphenol (3b). Prepared following exemplary procedure
from 1-(2-hydroxy-4-methoxyphenyl)ethanone (2b) (250 mg, 1.50 mmol), 2-aminopyridine (1) (325
mg, 3.46 mmol) and iodine (426 mg, 1.81 mmol). The solid was isolated by column chromatography
(silica, CH2Cl2/hexanes 1:2 → CH2Cl2/hexanes 3:1). The pure product was obtained as a solid after
1
crystallisation from ethanol (220 mg, 61 %). Data for 3b: mp 153-155 °C; H NMR (500 MHz, CDCl3,
δ) 3.82 (s, 3H), 6.46 (dd, 1H, J1=2.5 Hz, J2=8.6 Hz), 6.58 (d, 1H, J=2.5 Hz), 6.81 (t, 1H J=6.7 Hz), 7.18
(t, 1H, J=7.8 Hz), 7.46 (d, 1H, J=8.6 Hz), 7.54 (d, 1H, J=9.0 Hz), 7.74 (s, 1H), 8.11 (d, 1H, J=6.7),
12.86 (broad s, 1H); 13C NMR (125 MHz, CDCl3, δ) 55.4, 101.9, 105.7, 106.7, 109.5, 113.1, 116.6,
125.0, 125.4, 126.8, 143.5, 145.6, 159.0, 161.2; EI-HR obsd 240.0892, calcd exact mass 240.0899
(C14H12N2O2).
4-Bromo-2-(imidazo[1,2-a]pyridin-2-yl)phenol (3c). Prepared following exemplary procedure from
1-(5-bromo-2-hydroxyphenyl)ethanone (2c) (250 mg, 1.16 mmol), 2-aminopyridine (1) (252 mg, 2.67
mmol) and iodine (353 mg, 1.39 mmol). The solid was isolated by column chromatography (silica,
CH2Cl2/hexanes 1:2 → CH2Cl2/hexanes 3:2). The pure product was obtained as a solid (178 mg, 53 %).
Data for 3c: mp 208-209 °C; 1H NMR (500 MHz, CDCl3, δ) 6.87-6.92 (m, 2H), 7.24-7.27 (m, 1H), 7.28
(dd, 1H, J1=2.4 Hz, J2=8.8 Hz), 7.58 (d, 1H, J=9.0 Hz), 7.68 (d, 1H, J=2.4 Hz), 7.84 (s, 1H), 8.15 (d,
1H, J=6.7), 12.75 (broad s, 1H); 13C NMR (125 MHz, CDCl3, δ) 107.2, 110.8, 113.6, 117.0, 118.2,
119.7, 125.6, 125.7, 132.3, 143.6, 144.1, 156.6; EI-HR obsd 287.9904, calcd exact mass 287.9898
(C13H9BrN2O).
5-Bromo-2-(imidazo[1,2-a]pyridin-2-yl)phenol (3d). Prepared following exemplary procedure from
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1-(4-bromo-2-hydroxyphenyl)ethanone (2d) (210 mg, 0.98 mmol), 2-aminopyridine (1) (211 mg, 2.25
mmol) and iodine (297 mg, 1.17 mmol). The solid was isolated by column chromatography (silica,
CH2Cl2/hexanes 1:1 → CH2Cl2). The pure product was obtained as a solid (158 mg, 56 %). Data for 3d:
mp 154-155 °C; 1H NMR (500 MHz, CDCl3, δ) 6.85 (t, 1H, J=5.9 Hz), 6.97-6.99 (m, 1H), 7.19 (s, 1H),
7.22 (d, 1H, J=7.8 Hz), 7.38 (t, 1H, J=7.0 Hz), 7.55 (dd, 1h, J1=2.7 Hz, J2=8.7 Hz), 7.8 (d, 1H, J=6.3
1
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13
Hz), 8.12 (t, 1H, J=5.0 Hz), 12.94 (broad s, 1H); C NMR (125 MHz, CDCl3, δ) 106.9, 113.5, 115.4,
116.9, 120.9, 122.3, 122.7, 125.6, 126.8, 126.9, 143.5, 144.6, 158.3; EI-HR obsd 287.9890, calcd exact
mass 287.9898 (C13H9BrN2O).
4-(Imidazo[1,2-a]pyridin-2-yl)benzene-1,3-diol (3e). Prepared following exemplary procedure from
1-(2,4-dihydroxyphenyl)ethanone (2e) (150 mg, 0.99 mmol), 2-aminopyridine (1) (213 mg, 2.27 mmol)
and iodine (300 mg, 1.18 mmol). The solid was isolated by column chromatography (silica,
CH2Cl2/ethyl acetate 1:1). The pure product was obtained as a solid (87 mg, 39 %). Data for 3e: mp
114-115 °C (lit.37 mp 115 °C); 1H NMR (500 MHz, DMSO-d6, δ) 6.33 (d, 2H, J=11.6 Hz), 6.94 (t, 1H,
J=6.4 Hz), 7.28 (t, 1H, J=7.6 Hz), 7.60-7.64 (m, 1H), 8.28 (s, 1H), 8.56 (d, 1H, J=6.4 Hz), 9.52 (s, 1H),
12.09 (broad s, 2H); 13C NMR (125 MHz, DMSO-d6, δ) 103.4, 107.7, 107.9, 109.1, 113.2, 115.9, 125.8,
127.1, 127.9, 143.2, 144.2, 158.1, 159.1; EI-HR obsd 226.0739, calcd exact mass 226.0742
(C13H10N2O2).
5-(Diethylamino)-2-(imidazo[1,2-a]pyridin-2-yl)phenol (3f). Prepared following exemplary
procedure from 1-(4-(diethylamino)-2-hydroxyphenyl)ethanone (2f) (250 mg, 1.21 mmol), 2-
aminopyridine (1) (261 mg, 2.77 mmol) and iodine (367 mg, 1.45 mmol). The solid was isolated by
column chromatography (silica, ethyl acetate/CH2Cl2 3:2). The pure product was obtained as a solid
1
(139 mg, 41 %). Data for 3f: mp 167-169 °C; H NMR (500 MHz, DMSO-d6, δ) 1.09 (t, 6H, 6.8 Hz),
3.34 (d, 4H, J=6.5 Hz), 6.14 (s, 1H), 6.25 (d, 1H, J=8.5 Hz), 6.92 (t, 1H, J=6.6 Hz), 7.26 (t, 1H, J=7.8
Hz), 7.54 (dd, 2H J1=8.8 Hz, J2=15.5 Hz), 8.22 (s, 1H), 8.53 (d, 1H, J=6.6 Hz), 12.04 (broad s, 1H); 13C
NMR (125 MHz, DMSO-d6, δ) 12.6, 43.7, 98.5, 103.6, 104.6, 106.4, 125.1, 126.4, 127.3, 142.8, 144.6,
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148.6, 157.8; EI-HR obsd 281.1536, calcd exact mass 281.1528 (C17H19N3O).
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5
6
7
8
2-Phenyl-imidazo[1,2-a]pyridine (3g). Prepared following exemplary procedure from acetophenone
(2g) (500 mg, 4.16 mmol), 2-aminopyridine (1) (901 mg, 9.57 mmol) and iodine (1268 mg, 5.00 mmol).
The solid was chromatographed by DCVC (alumina, CH2Cl2/hexanes 1:2 → CH2Cl2). The pure product
9
1
was obtained as a solid (445 mg, 55%). Data for 3g: mp 133-134 °C (lit.18 mp 134 °C); H NMR (500
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MHz, CDCl3, δ) 6.75 (t, 1H, J=6.6 Hz), 7.15 (t, 1H, J=7.8 Hz), 7.32 (t, 1H, J=7.3 Hz), 7.42 (t, 2H, J=7.6
13
Hz), 7.62 (d, 1H, J=9.0), 7.86 (s, 1H), 7.95 (d, 2H, J=7.3 Hz), 8.10 (d, 1H, J=6.7 Hz); C NMR (125
MHz, CDCl3, δ) 108.1, 112.4, 117.6, 124.57, 124.64, 125.6, 126.1, 128.0, 128.7, 133.8, 145.7, 145.9;
EI-HR obsd 194.0836, calcd exact mass 194.0844 (C13H10N2).
2-(Pyridin-2-yl)-imidazo[1,2-a]pyridine (3h). Prepared following exemplary procedure from 1-
(pyridin-2-yl)ethanone (2h) (250 mg, 2.06 mmol), 2-aminopyridine (1) (447 mg, 4.75 mmol) and iodine
(629 mg, 2.48 mmol). The solid was chromatographed by DCVC (alumina, CH2Cl2/hexanes 1:1 →
1
CH2Cl2). The pure product was obtained as a solid (217 mg, 54%). Data for 3h: mp 139-140 °C; H
NMR (500 MHz, DMSO-d6, δ) 6.90 (t, 1H, J=6.7 Hz), 7.25 (t, 1H, J=7.8 Hz), 7.30 (t, 1H, J=5.9 Hz),
7.60 (d, 1H, J=8.8 Hz), 7.86 (t, 1H, J=7.5 Hz), 8.11 (d, 1H, J=7.8 Hz), 8.49 (s, 1H), 8.57-8.60 (m, 2H);
13C NMR (125 MHz, DMSO-d6, δ) 111.3, 113.5, 117.0, 119.8, 122.7, 125.3, 127.2, 137.0, 144.7, 144.8,
149.4, 152.8; EI-HR obsd 195.0789, calcd exact mass 195.0797 (C12H9N3).
2-(Pyrrol-2-yl)-imidazo[1,2-a]pyridine (3i). Prepared following exemplary procedure from 1-
(pyrrol-2-yl)ethanone (2i) (150 mg, 1.37 mmol), 2-aminopyridine (1) (298 mg, 3.16 mmol) and iodine
(419 mg, 1.65 mmol). The solid was isolated by column chromatography (silica, CH2Cl2/ethyl acetate
5:1 → CH2Cl2/ethyl acetate 1:1). The pure product was obtained as a solid (108 mg, 43 %). Data for 3i:
1
mp 198-199 °C; H NMR (500 MHz, DMSO-d6, δ) 6.10 (d, 1H, J=2.6 Hz), 6.48 (s, 1H), 6.79 (s, 1H),
6.82 (t, 1H J=6.7 Hz), 7.17 (t, 1H, J=7.48 Hz), 7.47 (d, 1H, J=9.00 Hz), 8.04 (s, 1H), 8.50 (d, 1H, J=6.65
13
Hz), 11.32 (s, 1H); C NMR (125 MHz, DMSO-d6, δ) 105.9, 106.5, 108.6, 111.8, 115.8, 118.6, 124.3,
126.3, 126.6, 139.6, 144.4; EI-HR obsd 183.0796, calcd exact mass 183.0797 (C11H9N3).
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2-(Thiophen-2-yl)-imidazo[1,2-a]pyridine (3j). Prepared following exemplary procedure from 1-
(thiophen-2-yl)ethanone (2j) (250 mg, 1.98 mmol), 2-aminopyridine (1) (429 mg, 4.56 mmol) and
iodine (603 mg, 2.38 mmol).The solid was chromatographed by DCVC (alumina, CH2Cl2/hexane 1:1 →
CH2Cl2). The pure product was obtained as a solid (202 mg, 51 %). Data for 3j: mp 151-153 °C (lit.38
mp 137-138 °C); 1H NMR (500 MHz, CDCl3, δ) 6.75 (t, 1H, J=6.7 Hz), 7.08 (dd, 1H, J1=3.7 Hz, J2=4.9
Hz), 7.14 (t, 1H, J=7.9 Hz), 7.30 (d, 1H, 5.0 Hz), 7.47 (d, 1H, J=3.5 Hz), 7.60 (d, 1H, J=9.0 Hz), 7.76 (s,
1H), 8.06 (d, 1H, 6.7 Hz); 13C NMR (125 MHz, CDCl3, δ)107.6, 112.7, 117.5, 123.8, 124.9, 125.2,
125.6, 127.9, 137.7, 141.0, 145.6; EI-HR obsd 200.0403, calcd exact mass 200.0408 (C11H8N2S).
Multi-gram scale preparation of 2-(imidazo[1,2-a]pyridin-2-yl)phenol (3a). A sealed tube was
charged with 1-(2-hydroxyphenyl)ethanone (2a) (5.000 g, 36.72 mmol), 2-aminopyridine (1) (7.948 g,
84.47 mmol) and iodine (11.183 g, 44.06 mmol). After cooling to room temperature, the reaction
mixture was diluted with 25 mL CH2Cl2. 10 % aqueous HCl was added to the water-organic mixture
until a neutral pH was obtained. The mixture was then extracted with CH2Cl2. The organic layer was
washed with water, dried over Na2SO4 and concentrated under reduced pressure. The solid was isolated
by column chromatography (silica, CH2Cl2/hexanes 1:2 → CH2Cl2/hexanes 3:1). The pure product was
obtained as a solid (3.937 g, 51 %).
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Acknowledgement: A. J. S., M. K. C. and D.T. G. gratefully acknowledge the Foundation for Polish
Science for supporting this work under MPD/2010/4 project “Towards Advanced Functional Materials
and Novel Devices - Joint UW and WUT International PhD Programme”. We thank Heather Buckley
(UC Berkeley) for amending the manuscript.
Supporting Information Available: 1H NMR and 13C NMR spectra of compounds 3a-3j. This material
is available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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(2) (a) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J.-C.; Blache, Y.; Chapat, J.-P.; Chavignon, O.;
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(3) (a) Lacerda, R. B.; De Lima, C. K.; Da Silva, L. L. Bioorg. Med. Chem. Lett. 2009, 17, 74. (b)
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