Solvent-free microwave-assisted synthesis of imidazo[1,5- a]pyridine and –quinoline derivatives

Article abstract of DOI:10.1080/00397911.2019.1650188

A quick and highly efficient microwave-assisted preparation of imidazopyridines and –quinolines is described, starting from the corresponding ketones and amines. The method requires no solvent and uses activated MnO₂ as an oxidant. A mechanism

Full text of DOI:10.1080/00397911.2019.1650188

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Solvent-free microwave-assisted synthesis of
imidazo[1,5- a]pyridine and –quinoline derivatives
Jasmin Martha Herr, Carina Rössiger, Georg Albrecht, Hisao Yanagi &
Richard Göttlich
To cite this article: Jasmin Martha Herr, Carina Rössiger, Georg Albrecht, Hisao Yanagi &
Richard Göttlich (2019): Solvent-free microwave-assisted synthesis of imidazo[1,5- a]pyridine and
–quinoline derivatives, Synthetic Communications, DOI: 10.1080/00397911.2019.1650188
To link to this article: https://doi.org/10.1080/00397911.2019.1650188
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https://doi.org/10.1080/00397911.2019.1650188
Solvent-free microwave-assisted synthesis of imidazo[1,5-
a]pyridine and –quinoline derivatives
Jasmin Martha Herra,b, Carina Rossigera,b, Georg Albrechtc,b, Hisao Yanagid, and
€
a,b
€
Richard Gottlich
b
aInstitute of Organic Chemistry, Justus-Liebig-University Giessen, Giessen, Germany; Center for
c
Materials Research (LaMa), Justus-Liebig-University Giessen, Giessen, Germany; Institute of Applied
d
Physics, Justus-Liebig-University Giessen, Giessen, Germany; Department of Materials Science, NAIST,
Nara, Japan
ABSTRACT
ARTICLE HISTORY
Received 2 July 2019
A quick and highly efficient microwave-assisted preparation of imida-
zopyridines and –quinolines is described, starting from the corre-
sponding ketones and amines. The method requires no solvent and
uses activated MnO2 as an oxidant. A mechanism for the cyclization
is proposed and discussed.
KEYWORDS
Condensation reaction;
microwave reaction; MnO2;
imidazo[1,5-a]pyridine;
rearrangement
GRAPHICAL ABSTRACT
Introduction
Unsaturated N-heterocycles can be found nearly everywhere in nature. Amongst these
are alkaloids like caffeine or the nucleobases of DNA. Furthermore, N-heterocycles have
found broad applications, ranging from pharmacy to material science.
A special structure class of N-heterocycles is imidazopyridines and –quinolines (IPs
and IQs), which are also found in nature.[1] Amongst these especially the 1,3-disubsti-
tuted imidazo[1,5-a]pyridines and –quinolines (Figure 1) have been receiving increasing
attention in the last years. They are bioactive substances, in relation to arterial
€
CONTACT Richard Gottlich
richard.goettlich@org.chemie.uni-giessen.de
Institute of Organic Chemistry, Justus-
Liebig-University Giessen, Heinrich-Buff-Ring 17, Giessen 35392, Germany.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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J. M. HERR ET AL.
Figure 1. Left: 1,3-disubstituded imidazo[1,5-a]pyridine (IP0); right: 1,3-disubstituded imidazo[1,5-
a]quinoline (IQ0); R and R’: aryl or alkyl.
thrombosis,[2] Alzheimer’s disease[3] or tumors.[4] Due to their strong fluorescence, IPs
and IQs can also be used as fluorescence probes[5–9] or as cell imaging reagents.[10]
Furthermore, because of their characteristic strong (and often blue) fluorescence[11]
(quantum yield up to 44%),[10] IPs and IQs are interesting for application in various
technical components. For example, Costa et al. prepared a light-emitting electrochem-
ical cell (LEC) based on an IP derivative.[12,13] Other groups investigated the applicabil-
ity of IPs and IQs for organic light-emitting diodes (OLEDs)[14–17] or for dye-sensitized
solar cells (DSSCs).[18] For such applications often the complexes instead of pure IPs
and IQs are used, due to triplet state harvesting. Complexes with many different metals
were investigated in this context (e.g., Ag,[19] Re,[20–22] Zn,[23] Cu,[13] and Ir[24]).
Additionally, there are first investigations of IPs as ligands for Pd-catalyzed
reactions.[25]
Luminescence materials for the application in OLEDs or comparable techniques are of
importance for the generation of power-efficient lighting and displays, thereby reducing
energy consumption and CO2 emissions. Therefore, efficient preparation of luminescence
materials for such applications is of general interest. We wanted to study the photo- and
electrochemical properties of new imidazopyridines and –quinolines and their derivatives
and were interested in an efficient synthetic approach to these compounds.
Currently, two synthetic approaches towards IPs and ICs are known (Scheme 1). The
first is a three-component condensation reaction between pyridin-2-yl-methanones,
aldehydes, and ammonium acetate in acetic acid.[26–28] This reaction can also be carried
out in a microwave reactor with addition of LiCl.[29] The advantage of this approach is
the wide scope of products. However, as the reaction is carried out in acetic acid, the
compounds must be stable under acidic conditions. The second approach is a condensa-
tion reaction between an amine and a carbonyl group including an oxidation step.[30]
This reaction is often catalyzed by copper salts with air as an oxidant[31,32] but also an
example with elemental sulfur as oxidant is known.[33] The disadvantage of this
approach is that the amines can react with oxygen under copper catalysis, leading to
undesired side products like imines or N-oxides.[34] Thus, an excess of amine is
required for a complete conversion of the carbonyl compound. This also renders the
adjustment of the amount of oxidant tricky. Other pathways towards the synthesis of
IPs avoid simple amines but use cyanides,[35] amino acids,[36] dithioesters,[37] or
nitriles.[38] These require either the use of toxic reagents or long reaction times.
In this work, we report a solvent-free microwave-assisted pathway to synthesize IPs and
the less well-known IQs in good yields and short reaction times. The synthesis is based on
a condensation reaction between a ketone and an amine, avoiding copper catalysts.

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Scheme 1. Synthetic approaches towards IPs and IQs; R and R’: aryl or alkyl.
Scheme 2. Imidazopyridines by condensation using air-oxidation.
Results and discussion
We earlier reported on the preparation of an imidazoquinoline (IQ2) in good yield
using a condensation reaction and air as the oxidant.[15] Upon applying the same reac-
tion conditions for the preparation of imidazopyridines the yield decreased significantly
(Scheme 2).
Unfortunately, the amount of the side product (SP, imine) increased even though
a syringe pump was used for a slow addition of the amine. Surprisingly, notable
amounts of reduction products of the ketone and imine were found too. Upon add-
ition of sulfur,[33] this reduction of the ketone could be avoided. Nevertheless, long
reaction times and a large excess of amine were necessary to obtain a complete con-
version of the ketone and still the yield of the desired product remained only mod-
erate (below 30%).
As many reactions can be drastically accelerated by the application of microwave
irradiation,[39] we performed the reaction in a closed microwave reactor. As anticipated
this led to a reduced reaction time but also to several unidentified side products. Thus,
the yield of the desired product could not be increased significantly. In our working
group, activated MnO2 is often used as a reagent for mild oxidations. Utilization of this

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J. M. HERR ET AL.
oxidant instead of S8, lead to higher yields and reduced amounts of side products
(Scheme 3). Using these conditions, the best yields were obtained when performing the
reaction under solvent-free conditions.
Another advantage of using MnO2 as the oxidant is its facile removal by filtration.
The best yield was obtained with a reaction temperature of 170 ꢀC as shown in
Scheme 3.
The next goal was to suppress the formation of side products, specifically the
above-mentioned oxidation of the amines.[34] The common technique to suppress
this reaction is to add the amine to the reaction mixture very slowly. To realize this
we had to carry out the reaction in an open microwave vessel equipped with a con-
denser. We used a Teflon tube to add the amine with a syringe pump. Hereby we
were able to reduce the required amount of amine to 1.6 eq. and at the same time
suppress the side reaction. However, the slow addition of the amine caused a longer
reaction time (Scheme 4).
Using these conditions, we further optimized the reaction by varying the amount of
added acid. This is required only in substoichiometric/catalytic amounts with 0.25 eq.
leading to the best yield of product (Scheme 4).
The last optimization step was the variation of the reaction time. The best yields (up
to 85%) were obtained with a reaction time of 5.5 h. Longer or shorter reaction times
led to reduced yields as depicted in Scheme 5.
Scheme 3. MnO2 as oxidant under microwave conditions. The yields are determined using NMR and
are not isolated.
Scheme 4. Slow addition of amine to an open microwave reaction, optimization of the added acid.

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Scheme 5. Optimization of the reaction time.
Scheme 6. Preparation of ketones as starting materials; E1/A1/K1 ¼ 2-pyridinyl, E2/A2/K2 ¼ 2-quino-
linyl; R ¼ naphtalenyl.
To check the scope of the reaction, we prepared additional ketones as depicted
in Scheme 6. We started using the aldehydes E1/E2 which reacted with the correspond-
ing Grignard reagent to obtain the secondary alcohols A1/A2. These were oxidized with
activated MnO2 to the aryl-quinoyl-ketones K1/K2 in excellent yields, which we used as
starting materials for our following condensation/oxidation procedure.
The results of these reactions are shown in Table 1. The obtained yields varied with
the amines used. For aromatic amines, the yields were best when substituted benzylic
amines were reacted. When the aromatic group was electron poor (pyridyl, furanyl, IP4,
IP7, and IP9) the yields were only moderate (around 45%). The same held true for IP8,
in which an alkylamine was applied. Compared to this, the nature of the ketone seems
to be less important (compare IP2 and IP10 as well as IP4 and IP9).
As our developed procedure seems to be rather general for the preparation of imida-
zopyridines, we wanted to check its applicability for the preparation of imidazoquino-
lines too. In previous publications, first blue-emitting devices with IQ2 as the emitter
were built. Based on these results, other new imidazoquinolines are required to investi-
gate the properties. It was possible to synthesize three new compounds (IQ1, IQ3, and
IQ4) as shown in Figure 2. Therefore, our method allows for an efficient and easy prep-
aration to the very interesting but neglected substance class of imidazoquinolines in
good yields.

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J. M. HERR ET AL.
Table 1: Preparation of imidazopyridines applying the optimized MnO2 and microwave conditions.
Entry
R
R’
Yield
IP1
IP2
IP3
IP4
IP5
IP6
IP7
IP8
IP9
IP10
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Methoxyphenyl
Phenyl
4-Fluorophenyl
2-Pyridinyl
3-CF3-phenyl
3-Methoxyphenyl
2-Furanyl
Hexyl
2-Pyridinyl
Phenyl
85%
72%
65%
41%
80%
61%
45%
42%
44%
79%
Naphthalenyl
Naphthalenyl
Figure 2. Preparation of imidazoquinolines applying the optimized MnO2 and microwave conditions.
As with the imidazopyridine examples, again the type of amine used seems to
have an influence on the yield obtained with the (pyridine-2-yl)methanamine pro-
ducing somewhat lower yields than substituted benzylic amines. Furthermore, the
benzylic amine carrying a þ M-substituent (Table 1, IP1, 4-methoxyphenyl) gave the

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Scheme 7. Proposed reaction mechanism.
highest yield. This observation can be explained by the proposed mechanism
(Scheme 7). In the first step, the ketone and the amine react to give the iminium
ion I1. This is in equilibrium (tautomerism) with the iminium ion I3. This surpris-
ing imine isomerization under acidic conditions is probably due to an intramolecular
deprotonation of the iminium ion by the pyridine group as shown below (via I2).
This could also be described as a 1,5-H-shift. The equilibrium between the two imi-
nium ions depends on the stabilizing effect of the amine-substituent, with electron-
donating substituents from the amine (R0) leading to a stronger preference of I3. I3
reacts further to the dihydro-imidazole moiety (C1 and C2) which is finally oxidized
to the imidazopyridine system.
From two products single crystals suitable for X-ray structural analysis could be obtained.
The obtained X-ray crystal structures of compound IQ4 and IQ3 are shown in Figure 3. IQ4
has a triclinic cell and P1 as space group. The cell dimensions are a ¼ 5.51904 Å,
b ¼ 13.4121Å, c ¼ 13.8725Å, a ¼ 115.390ꢀ, b ¼ 95.871ꢀ and c ¼ 94.686ꢀ. IQ3 has a triclinic
cell and P1 as space group, too. The cell dimensions are a ¼ 5.5566Å, b ¼ 13.4945Å,
c ¼ 13.5592Å, a ¼ 115.012ꢀ, b ¼ 99.583ꢀ and c ¼ 96.016ꢀ.
Conclusion
In summary, we have developed an alternative route to synthesize imidazo[1,5-a]pyri-
dines and even imidazo[1,5-a]quinolones in good yield. Our synthetic procedure is a
solvent-free condensation reaction carried out in a microwave reactor. The reaction
seems to have a wide scope and tolerates various functional groups, only with non-

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J. M. HERR ET AL.
Figure 3. Crystal structures of IQ3 and IQ4.
aromatic amines the yields drop significantly. The new compounds prepared are very
interesting for biological[10] as well as technical[12,14] applications. We are currently
studying the photochemical and electrochemical properties of these compounds; results
will be published in due course.
Experimental
General procedures for the preparation of imidazo[1,5-a]pyridine and
–quinoline derivates
Ketone (1.1 mmol), activated MnO2 (1.8 mmol), and pTsOH (0.3 mmol) were stirred
briefly in a 15 mL round bottom flask at room temperature for 5 min. Afterward, the
mixture was heated in an open microwave reactor (equipped with a condenser) for
5.5 h at 170 ꢀC (max. 300 W). During this time, the amine (1.6 mmol) was added with a
syringe pump (PTFE tube). The crude product was purified via flash chromatography
or recrystallization.
1
Full experimental detail, H, and 13C NMR spectra, crystallographic data. This mater-
ial can be found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
We thank Mr. Shohei Dokiya and Mr. Shohei Katao of the Nara Institute of Science and
Technology (Japan) for the XRD measurements.
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