1-(1-Alkylsulfonic)-3-methylimidazolium chloride Br?nsted acidic ionic liquid catalyzed Skraup synthesis of quinolines under microwave heating

Article abstract of DOI:10.1016/j.tetlet.2014.04.047

1-(1-Alkylsulfonic)-3-methylimidazolium chloride Br?nsted acidic ionic liquids are shown as excellent catalysts and reaction mediums for Skraup synthesis of quinolines under microwave conditions without the use of nitrobenzene as an oxidant and metal catalysts.

Full text of DOI:10.1016/j.tetlet.2014.04.047

Accepted Manuscript
1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquid
catalyzed Skraup synthesis of quinolines under microwave heating
Ananda S. Amarasekara, Muhammad A. Hasan
PII:
S0040-4039(14)00659-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.047
TETL 44509
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2014
10 April 2014
14 April 2014
Please cite this article as: Amarasekara, A.S., Hasan, M.A., 1-(1-Alkylsulfonic)-3-methylimidazolium chloride
Brönsted acidic ionic liquid catalyzed Skraup synthesis of quinolines under microwave heating, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.047
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1
1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted
acidic ionic liquid catalyzed Skraup synthesis of quinolines
under microwave heating
Ananda S. Amarasekara*, Muhammad A. Hasan
Department of Chemistry, Prairie View A&M University, Prairie View, Texas 77446, USA
E-mail: asamarasekara@pvamu.edu Tel: +1 936 261 3107; fax: +1 936 261 3117
______________________________________________________________________________
Abstract: 1-(1-alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquids
are shown as excellent catalysts and reaction mediums for Skraup synthesis of quinolines
under microwave conditions without the use of nitrobenzene as an oxidant and metal
catalysts.
________________________________________________________________________
Keywords: Skraup synthesis, quinolines, acidic ionic liquid, microwave
1. Introduction
Quinolines are an important class of heterocyclic compounds as this ring system occurs
in many natural products and biologically active compounds1. There are several classical
named reactions that can be used to assemble the quinoline structural core, such as;
Skraup2,3,4,5
,
Doebner–Miller6,5, Friedlander7, Combes8, Conrad–Limpach9 and
Pfitzinger10 reaction. Generally these reactions involve a cyclo-condensation of aniline or
aniline derivative with a carbonyl compound, followed by an aromatization with
dehydration/oxidation reactions. The only exception is the Skraup reaction where
glycerol is used as one of the starting materials; in this process the carbonyl compound
acrolein is believed to be generated in situ by the dehydration glycerol. The use of
glycerol, which is the main byproduct in the rapidly developing biodiesel industry as
one of the starting materials is an attractive feature in the Skraup reaction and is in align
with current interest in developing technologies for the utilization of renewable
feedstocks for the preparation of useful chemicals and intermediates. Classical quinoline
synthesis involves a heating of a mixture of aniline, glycerol, and sulfuric acid with an
oxidizing agent like nitrobenzene, arsenic acid, ferric oxide or vanadic acid to 120-130
°C for several hours11,12. There are a number of drawbacks in the original method such as

2
harsh reaction conditions requiring high temperature, highly acidic conditions, violent
reactions in large scale operations, use of toxic substances like arsenic oxide, tedious
isolation from complex reaction mixtures to poor yields. Later reports have shown that
addition of boric acid or acetic acid can be used to control the violent reactions in Skraup
synthesis, however in many cases an equivalent amount of oxidizing agent such as
nitrobenzene is required to produce the quinoline product3.
There are a few recent attempts to improve the glycerol based quinoline synthesis by
heating under microwave conditions13,14,15,16. In one example Găină et.al. reported the use
of microwave heating for the synthesis of 7-amino-8-methylquinoline by Skraup
synthesis15. In this experiment, a mixture of 2,6-diaminotoluene, glycerol and excess of
arsenic (V) oxide as an oxidant were subjected to microwave heating in concentrated
sulfuric acid to produce 7-amino-8-methylquinoline in 32% yield.
Ionic liquids are an emerging class of materials; first recognized as non-volatile reaction
mediums, but in recent years branched in to variety of applications such as catalysts, gas
adsorbents, and chromatography stationary phases. The sulfonic acid group
functionalized ionic liquids are a special class in ionic liquid arena; these new molecular
architectures can combine acid properties and ionic liquid characteristics into a single
material and often used as highly effective acid catalysts under mild conditions17,18,19
.
The enhanced catalytic activity of the acidic ionic liquid systems are frequently attributed
to their ability to bind with substrates by polar interactions such as hydrogen bonds20. Our
interests in the applications of sulfonic acid group functionalized Brönsted acidic ionic
liquids (BAILs) in dehydration of carbohydrates and biomass processing21,22,23,24,25,26 has
led us to explore the acidic ionic liquid catalyzed dehydration of glycerol to acrolein and
application in the Skraup quinoline synthesis.
Imidazolium cation based sulfonic acid group functionalized ionic liquids were selected
for the study due to their distinct ability to dehydrate carbohydrates under mild
conditions27,20. The Brönsted acidic ionic liquids 1a,b used in this study were prepared by
condensation of methyl imidazole with 1,3-propane or 1,4-butane sultone and

3
acidification of the zwitterion with concentrated HCl as shown in figure 121. The general
reaction of using Brönsted acidic ionic liquids 1a,b as catalysts as well as solvents for the
Skraup quinoline synthesis is shown in figure 2. In our preliminary investigations we
have attempted to substitute Brönsted acidic ionic liquids for sulfuric acid under thermal
and microwave (MW) heating conditions. Where we have studied mixtures of aniline
(2a), glycerol (3), BAIL (1a), and nitrobenzene in 1: 3: 1.5: 1.1 molar ratios, as shown in
entries 1, and 2 of table 1. In the first experiment, conventional thermal reaction was
tested by heating the mixture in an oil bath at 120 °C, for 6 h (entry 1). This reaction
produced only 10% yield of quinoline. Next microwave heating was tested on second
reaction mixture of similar composition. The microwave heating for 100 s (five 20 s MW
exposures with 5 s cooling intervals between pulses) produced 71% yield of quinoline as
shown in the second entry in table 1. The 1H NMR analysis of the crude reaction mixture
showed that all the nitrobenzene used remains unaffected, suggesting that either
nitrobenzene is not required for the oxidation step or acting as a catalyst in the reaction.
In the next experiment we have omitted nitrobenzene in order to identify the role of
nitrobenzene, and used a mixture of aniline, glycerol, and BAIL in 1: 3: 1.5 molar ratio,
as shown in entry 3 of table 1. Interestingly, this reaction produced 74% yield of
quinoline showing that it is not necessary to use nitrobenzene or other oxidant for the
oxidation step in the Skraup quinoline synthesis when BAIL is used in place of sulfuric
acid and under microwave heating conditions. We believe that oxygen from air acts as
the oxidant under the current reaction conditions.
In the next step we have explored the possibility of reducing the amount of BAIL catalyst
used for the reaction. In this experiment only a 0.1 equivalent of BAIL was used in
comparison to aniline as shown in entry 4. However, this reaction failed to turn out a high
yield of quinoline as in the previous experiment, produced only 12% yield of quinoline
and most of the glycerol remained unreacted. This low catalyst loading experiment
demonstrated that it is necessary to use equivalent amounts of BAIL to act as a catalyst as
well as the solvent medium for the glycerol to acrolein dehydration step.
In order to prove the general applicability of the reaction on substituted anilines we have
tested the method on two other aromatic amines p-toluidine (2b) and o-chloroaniline (2c)

4
using BAIL catalyst 1a as shown in entries 5 and 6. These reactions also produced
corresponding quinolines 6-methylquinoline (4b) and 8-chloroquinoline (4c) in good
yields and the products were identified by comparison of 1H and C NMR spectra with
13
published data28,29,30. The analogous Brönsted acidic ionic liquid 1-(1-butylsulfonic)-3-
methylimidazolium chloride (1b) was also tested in the Skraup quinoline synthesis for the
preparation of quinolines 4a-c using general quinoline synthesis procedure (see the
supporting information) and the results of these experiments are shown in entries 7-9 in
table 1. We are currently working on recovering the ionic liquid from the aqueous phase
after separation of the product and reusing in the Skraup synthesis. A comparison of 1H
NMR spectra of the ionic liquid recovered with the fresh ionic liquid showed that no
decomposition occurs under the microwave reaction conditions used.
In conclusion we have shown that 1-(1-alkylsulfonic)-3-methylimidazolium chloride
Brönsted acidic ionic liquids are excellent catalysts and reaction mediums for Skraup
synthesis of quinolines, where acrolein is generated in situ by dehydration of glycerol
under microwave conditions. There are a number of advantages of using 1-(1-
alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquids as reaction
mediums and catalysts in the Skraup synthesis. This include; shorter reaction time, better
yields, ease of isolation of the quinoline product and most importantly elimination of the
use nitrobenzene or other oxidizing agents and additional metal catalysts.
Acknowledgments
We thank NSF grants CBET-0929970, CBET-1336469, HRD-1036593, and USDA grant
CBG-2010-38821-21569 for financial support.

5
Table 1. Product yields and reaction conditions used in the Brönsted acidic ionic liquid
catalyzed Skraup synthesis of quinolines
Entry Ar-NH2 BAIL Ar-NH2:glycerol:BAIL, Conditions
Product, Yield %
1
2
1: 3: 1.5,
nitrobenzene, oil-bath heating 120 °C, 6 h
with 1.1 equivalent of 4a, 10%
2a
2a
1a
1a
1: 3: 1.5,
with 1.1 equivalent of 4a, 71%
nitrobenzene, MW for 100 s
1: 3: 1.5, MW for 100 s
3
4
5
6
7
8
9
4a, 74%
4a, 12%
4b, 78%
4c, 70%
4a, 73%
4b, 76%
4c, 67%
2a
2a
2b
2c
2a
2b
2c
1a
1a
1a
1a
1b
1b
1b
1: 3: 0.1, MW for 100 s
1: 3: 1.5, MW for 100 s
1: 3: 1.5, MW for 100 s
1: 3: 1.5, MW for 100 s
1: 3: 1.5, MW for 100 s
1: 3: 1.5, MW for 100 s

6
O
O
S O
1.
-
Cl
+
n
o
H3C
H3C
SO3H
N
N
N
N
100 C, 12 h
n
1a, n = 1
1b, n = 2
conc. HCl,
r.t. 12 h
2.
Figure 1. Synthesis of Brönsted acidic ionic liquids (1a,b)
R1
R1
OH
NH2
N
MW
+
R2
OH OH
-
R2
Cl
3
H3C
SO3H
N
N
+
2a, R 1= H, R2 = H
2b, R 1= H, R2 = CH3
2c, R 1= Cl, R2 = H
n
4a, R 1= H, R2 = H
4b, R 1= H, R2 = CH3
4c, R 1= Cl, R2 = H
1a, n = 1
1b, n = 2
Figure 2. Brönsted acidic ionic liquid (1a,b) catalyzed synthesis of quinolines (4a-c)

7
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8
1-(1-Alkylsulfonic)-3-methylimidazolium chloride Brönsted acidic ionic liquid
catalyzed Skraup synthesis of quinolines under microwave heating
Ananda S. Amarasekara*, Muhammad A. Hasan
Department of Chemistry, Prairie View A&M University, Prairie View, Texas 77446, USA
E-mail: asamarasekara@pvamu.edu Tel: +1 936 261 3107; fax: +1 936 261 3117
_____________________________________________________________________________
R1
R1
H3C
N
SO3H
N
N
OH
+
n
NH2
-
Cl
R2
+
OH OH
R2
MW
67-78% yield