Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2019.151244

An efficient, metal-free method for the synthesis of 3-formyl imidazo[1,2-a]pyridines is reported. The method utilises commercially available substrates and features a broad substrate scope. The intermediate enamine was isolated and a plausible reaction mechanism proposed.

Full text of DOI:10.1016/j.tetlet.2019.151244

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]
pyridines
a
b
a,
⇑
_
Damian Kusy , Waldemar Maniukiewicz , Katarzyna M. Błazewska
a Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego St. 116, 90-924 Lodz, Poland
b Institute of General and Ecological Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego St. 116, 90-924 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, metal-free method for the synthesis of 3-formyl imidazo[1,2-a]pyridines is reported. The
method utilises commercially available substrates and features a broad substrate scope. The intermediate
enamine was isolated and a plausible reaction mechanism proposed.
Received 9 August 2019
Revised 25 September 2019
Accepted 30 September 2019
Available online xxxx
Ó 2019 Published by Elsevier Ltd.
Keywords:
Imidazo[1,2-a]pyridine 3-carbaldehyde
Microwave heating
2-Aminopyridines
Bromomalonaldehyde
Introduction
aminooxygenation [10] and a number of copper-catalyzed trans-
formations, such as the intramolecular dehydrogenative
The imidazo[1,2-a]pyridine scaffold is present in a number of
biologically active compounds, including natural products [1]. Sev-
eral drugs (e.g. zolpidem, alpidem, olprinone, zolimidine, rifaximin,
minodronic acid) containing an imidazo[1,2-a]pyridine ring are
available on the market. Imidazo[1,2-a]pyridine containing com-
pounds show excited-state intramolecular proton transfer proper-
ties, which predispose them to applications in fluorescence
sensors, laser dyes and molecular switches [2]. A number of excel-
lent reviews on the synthesis and functionalization of compounds
containing the imidazo[1,2-a]pyridine scaffold have been recently
published (Scheme 1) [3–5].
aminooxygenation of N-allyl-2-aminopyridines [11], the use of
ethyl tertiary amines as a carbon source [12], the cyclization
of aminopyridines and propiolaldehyde [13], and the annulation
of 2-aminopyridines and bromomalonaldehyde [14,15]. Most of
the above described procedures require long reaction times (10–
24 h), heating at 100 °C or higher temperatures, the use of oxygen
gas and metal catalysts, or pre-formation of the substrates. Only
the latter approach (Scheme 1.3) combines advantages such as
the use of commercially available substrates and no need for a
metal catalyst. However, this method suffers from low yields and
the formation of unidentified side-products [14–16].
Due to the presence of the formyl group, imidazo[1,2-a]pyridine
3-carbaldehydes are popular building blocks used for the incorpo-
ration of this heterocycle into diverse structures. Two general
routes for the synthesis of imidazo[1,2-a]pyridine 3-carbaldehydes
can be recognized. In the first approach (Scheme 1.1) the formyl
group is appended to the imidazo[1,2-a]pyridine ring via a Vilsme-
ier-Haack reaction [6–8], Cu-catalyzed C3-formylation with DMSO
and molecular oxygen [3], and aerobic iron(III)-catalyzed formyla-
tion using DMSO as a carbon source [9]. The second approach
involves intramolecular closure of the imidazole ring in the imi-
dazo[1,2-a]pyridine, with concurrent introduction of the formyl
group (Scheme 1.2, 1.3). Within this route are silver-catalyzed
Herein, we present a simple and efficient approach for the
synthesis of diversely functionalized imidazo[1,2-a]pyridine 3-car-
baldehydes (Scheme 2). The reaction does not require any addi-
tives and proceeds to completion within 10 to 20 min in EtOH/
H2O as the solvent. We have also isolated the side products and
determined the factors promoting their formation. In addition,
we have also isolated and characterized an intermediate, for the
first time experimentally supporting one of the previously postu-
lated mechanisms [17].
Results and discussion
In the original work of Hayakawa and co-workers [14,15] the
reaction between 2-aminopyridine and bromomalonaldehyde
was performed at reflux in acetonitrile or in MeCN/ethanol. The
⇑
Corresponding author.
E-mail address: katarzyna.blazewska@p.lodz.pl (K.M. Błazewska).
_
https://doi.org/10.1016/j.tetlet.2019.151244
0040-4039/Ó 2019 Published by Elsevier Ltd.
_
Please cite this article as: D. Kusy, W. Maniukiewicz and K. M. Błazewska, Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151244

2
D. Kusy et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Selected methods for the synthesis of imidazo[1,2-a]pyridine 3-carbaldehydes. Only compounds unsubstituted at the C-2 position are shown, as they directly
correspond to the method reported herein.
Scheme 2. Optimised conditions for the synthesis of imidazo[1,2-a]pyridine
3-carbaldehydes.
products were isolated in moderate yields (28–52%). Our previous
studies have shown that under such conditions substantial
amounts of the side product imine 4 (formed through condensa-
tion of substrate 1 and product 3; Fig. 1) and an insoluble tar are
formed. The decomposition of bromomalonaldehyde was also
observed under these conditions. Therefore, we have optimized
Figure 1. Structures of the side products formed during synthesis of imidazo[1,2-a]
pyridine 3-carbaldehydes.
_
Please cite this article as: D. Kusy, W. Maniukiewicz and K. M. Błazewska, Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines,
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D. Kusy et al. / Tetrahedron Letters xxx (xxxx) xxx
3
the protocol, by adding bromomalonaldehyde portionwise (in total
4.5 eq, Table 1, entry 1) which led to reaction completion, giving
higher yields compared with the original work (Scheme 1.3)
[18,19].
In order to improve this protocol, we applied microwave (MW)
irradiation for the synthesis of the title compounds. Although
microwave-assisted synthesis was previously used for construct-
ing diversely substituted imidazo[1,2-a]pyridines [17,20], such
conditions were not optimal for the synthesis of imidazo[1,2-a]
pyridine 3-carbaldehydes.
the yield dropped to 48%, and significant amounts of the interme-
diate product enamine 5a was isolated (Fig. 1, Table 1, Entry 13).
We also examined the influence of both basic and acidic condi-
tions on the reaction outcome. Carrying out the reaction in the
presence of triethylamine or an inorganic base (Na2CO3), led to
the formation of enamine 5a, or recovery of the substrate (Entries
14–15). The addition of p-toluenesulfonic acid led to a decrease of
the yield to 57% (Entry 16). We also found that the optimized con-
ditions for 2-amino-5-bromopyridine were not suitable for the
methylated analog 1f (Entries 17–18).
A lower temperature
In the optimization studies 2-amino-5-bromopyridine 1a was
used as a model substrate. The reaction mixture was irradiated
in a pressure vial with MW (initial 150 W power) at 100–110 °C
for 5–20 min.
(100 °C), longer reaction time (20 min) and higher concentrations
of substrate 1 were required for efficient transformation (Entries
19–20).
The regioselectivity of the reaction was proven by single crystal
X-ray diffraction of aldehyde 3b (Fig. 2).
Summarizing the optimization results, MW irradiation signifi-
cantly reduced the time needed for reaction completion, from
hours to minutes (Scheme 2). Consequently, the bromomalonalde-
hyde could be used in lower amounts (1.5 eq.), compared with
standard heating, where its decomposition decreased the yield.
We recommend to use EtOH/H2O (1:1, v/v) as the solvent and
two sets of conditions, which should be selected based on the type
of substituents present in the 2-aminopyridines. For 2-aminopy-
ridines substituted with halogens the reaction should be carried
out at 110 °C for 10 min (Table 1, Entry 8); for methyl analogs a
lower temperature (100 °C) and a longer time (20 min) is required
The use of MeCN (as in Hayakawa and co-workers procedure
[14]), acetone or 1,4-dioxane as solvents at 100 °C led to mixtures
of unidentified products (Table 1, entries 2–4). Running the reac-
tion under solvent-free conditions led to decomposition (Entry
5). When ethanol:water (1/1, v/v) was used the desired product
3a was obtained in 54% yield (Entries 6–7). Additional improve-
ment was achieved by increasing the temperature from 100 °C to
110 °C (80% yield, entry 8). We also found that if none or a small
amount of water (<10%, v/v) was used, the corresponding acetals
may form (Entries 9, 11, and 12). Use of larger amounts of water
(up to 33% v/v) circumvented the acetal formation (Entries 8, 10).
On the other hand, when water was used as a reaction medium
Table 1
Optimization studies.a
Entry
Solvent
MeCN
Time [min]
Tb [oC]
Additive
–
Yield (%)
28
1a/3a
1
4 h / reflux
24 h / rt
5
5
20
20
10
20
10
5
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1f/3f
17
18
19
20
MeCN
acetone
1,4-dioxane
neat
EtOH:H2O 1:1
EtOH:H2O 1:1
EtOH:H2O 1:1
EtOH:H2O 2:0.1
EtOH:1,4-dioxane:H2O 1:1:1
EtOH:1,4-dioxane:H2O 1:2:0.1
1,4-dioxane:ethanol 2:1
H2O
100
100
100
100
100
100
110
100
110
110
100
110
110
110
110
–
–
–
–
–
–
–
–
–
–
–
–
n.d.c
n.d.c
n.d.c
n.d.c
54
54
80
n.d.
63d
n.d.
n.d.
48
n.d.
n.d.
57
10
5
10
10
10
10
10
EtOH:H2O 1:1
EtOH:H2O 1:1
EtOH:H2O 1:1
Et3N
Na2CO3
p-TsOH
EtOH:H2O 1:1
EtOH:H2O 1:1
EtOH:H2O 1:1
EtOH:H2O 1:1 (1.2 M)
10
5
20
20
110
110
100
100
–
–
–
–
42e
21
53f
73
a
Reactions were carried out using 1 (0.3 or 0.6 M) and 2 (1.5 eq.) unless indicated otherwise; under standard heating conditions 2 was used in a higher amount (4.5 eq.)
(Entry 1).
b
Reactions were performed using microwave irradiation, except for entry 1.
Not determined due to decomposition.
The same yields were obtained using both isolation methods: column chromatography with or without prior extraction.
Similar yields were obtained using 0.3 M or 0.6 M solutions of 1f.
Doubling the concentration to 2.4 M led to a lower yield (39%).
c
d
e
f
_
Please cite this article as: D. Kusy, W. Maniukiewicz and K. M. Błazewska, Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines,
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4
D. Kusy et al. / Tetrahedron Letters xxx (xxxx) xxx
In order to address the differences in the reactivity of 5- vs.
6-substituted 2-aminopyridines, we concentrated on the fact that
for both derivatives we have isolated intermediate 5. Presumably,
the propensity of intermediate 5 towards closure of imidazole ring
is responsible for the successful completion of the reaction. Such a
predisposition could be affected by two factors: steric hindrance
(for analogs with substituents on the C6 carbon, neighboring the
pyridine nitrogen), and the electron-withdrawing character of the
substituent near the pyridine nitrogen.
Firstly, the steric hindrance due to the substituent at C6 may
hinder the approach of the pyridine nitrogen toward the elec-
trophilic site [21,22]. On the other hand, the occurence of decar-
bonylation implies that while steric hindrance may prevent
intramolecular closure of the imidazole ring, the repulsive interac-
tions between the halogen and carbonyl may influence the stability
of the products [23]. Secondly, the moderate propensity of the 6-
methyl and 6-phenyl substituted 2-aminopyridines for cyclization
into aldehydes 3, compared with the complete lack of product for-
mation for 6-halogen substituted 2-aminopyridines (halogens: F,
Cl, Br), could be explained by the lower basicity/nucleophilicity
of the endocyclic nitrogen in such 2-aminopyridines, leading to
Figure 2. ORTEP plot of 3b at 50% ellipsoid probability.
(Entry 20). The side product imine 4, formed under the standard
heating conditions, and was not observed when microwave heat-
ing was applied.
enamine
5 only [24]. When we studied the reaction using
5-nitro-2-aminopyridine 1c the yield dropped to 54%. We con-
cluded that the combination of steric hindrance and the electron-
deficiency of aminopyridines prevents closure of the imidazole
ring in 5, terminating the reaction at the enamine stage. However,
if only one of these factors is involved, the product forms, albeit
with lower yields (Fig. 3, 3c, 3m, 3n).
Finally, we posed the question whether compound 5 was an
intermediate in the studied reaction. In the literature two
mechanisms for analogous reactions are proposed. According to
the first one (Scheme 3, route A), the reaction takes place via
attack of the exocyclic amine group on bromomalonaldehyde,
followed by the elimination of water and formation of an inter-
mediate imine 5a‘ or enamine 5a. Then, via intramolecular
cyclization and expulsion of the bromide anion, the final product
is formed [17]. The second mechanism [25,26] involves attack of
the endocyclic nitrogen atom, which expels the bromine anion,
forming a pyridinium salt, with subsequent closure of the imida-
zole ring (Scheme 3, route B). To the best of our knowledge, it
has never been experimentally determined which mechanism
operates in this reaction.
With the optimized procedure in hand, we investigated the
scope of the reaction, using various 2-aminopyridines 1 bearing
electron-withdrawing and electron-donating groups. All substrates
reacted with bromomalonaldehyde, in most cases affording the
desired aldehydes 3 with significantly improved yields (48–86%),
compared with the standard method (26–66%) [18] (Fig. 3,
Table S1). As shown for two representative examples, the reaction
can be also performed on a 10 times larger scale (1.2 vs. 12 mmol),
with ~15% decrease in the yield (Fig. 3).
Lower yields (23–35%) were obtained for 6-methyl and
6-phenyl substituted 2-aminopyridines 1m and 1n. In the case of
6-bromo-2-aminopyridine only trace amounts of the product were
detected, while the main product was enamine 5b, or decarbonyla-
tion product 6 when more forcing conditions were applied (150 °C)
(Fig. 1). The same outcome was observed for 6-chloro- and 6-flu-
oro-2-aminopyridines, leading to enamines 5c and 5d, instead of
the desired aldehydes 3. The enamine product 5a could be also iso-
lated from the reaction of 2-amino-5-bromopyridine. It precipi-
tated from the reaction mixture within a few minutes, before
microwave heating was applied.
Figure 3. Scope of the method. Reagents and conditions: (A) MW, EtOH:H2O (1:1, v/v), 2 (1.5 eq.), 110 °C, 10 min; (B) MW, EtOH:H2O (1:1, v/v), 2 (1.5 eq.), 100 °C, 20 min; *
Yields for the scale-up experiments (12 mmol).
_
Please cite this article as: D. Kusy, W. Maniukiewicz and K. M. Błazewska, Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151244

D. Kusy et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Scheme 3. Plausible reaction mechanisms. The isolated intermediate is presented in green.
Herein, evidence is provided for one of the proposed routes
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This work was supported by the National Science Centre, Poland
(2014/14/E/ST5/00491) and Faculty of Chemistry at Lodz Univer-
sity of Technology, Poland (W-3D/FMN/8G/2018).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151244.
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Please cite this article as: D. Kusy, W. Maniukiewicz and K. M. Błazewska, Microwave-assisted synthesis of 3-formyl substituted imidazo[1,2-a]pyridines,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2019.151244