An efficient, eco-friendly, one-pot protocol for the synthesis of 2-oxazolines promoted by ionic liquid/indium chloride

Article abstract of DOI:10.1071/CH06061

2-Oxazolines have been synthesized using a solventless ionic liquid melt in good yields at ambient temperatures. The efficiency of various Lewis acid catalysts for the same reaction has been compared. The effectiveness of different alkyl chains in the ionic liquids for the synthesis of oxazolines has been studied and a butylmethylimidazolinium chloride/indium chloride melt has been found to be the best media for promoting the reaction. CSIRO 2006.

Full text of DOI:10.1071/CH06061

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 463–467
An Efficient, Eco-Friendly, One-Pot Protocol for the Synthesis
of 2-Oxazolines Promoted by Ionic Liquid/Indium Chloride
R. KamakshiA and Boreddy S. R. ReddyA,B
A Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India.
B Corresponding author. Email: induchem2000@yahoo.com
2-Oxazolines have been synthesized using a solventless ionic liquid melt in good yields at ambient temperatures.The
efficiency of various Lewis acid catalysts for the same reaction has been compared. The effectiveness of different
alkyl chains in the ionic liquids for the synthesis of oxazolines has been studied and a butylmethylimidazolinium
chloride/indium chloride melt has been found to be the best media for promoting the reaction.
Manuscript received: 23 February 2006.
Final version: 24 May 2006.
Introduction
moderators in analytical processes, and as conformationally
rigid peptide mimics in medicinal chemistry.
2-Oxazolines are an important class of heterocycles that have
held the fascination of many synthetic chemists.[1] They
have very high synthetic utility and a wide range of appli-
cations. An important advantage of the oxazoline group is
its comparative stability towards hydrolysis and oxidation.
2-Oxazolines have been used as chiral auxiliaries, ligands
for metal entrapment, and also importantly as a protecting
group for carboxylic acids as well as amino alcohols.[2] The
well-defined reactivity of chiral oxazolines has given rise to
numerous highly efficient strategies for asymmetric synthe-
sis including their use as ligands in asymmetric catalysis.[3]
It is possible to generate stereogenic centres that neighbour
the coordinating nitrogen atom of the oxazoline ring held in
close proximity to the metal, which exerts a strong stereo-
chemical influence on the outcome of the metal-catalyzed
reactions. Substituted 2-oxazolines offer a simple route to
many synthetic intermediates.
2-Oxazolines have been reported to be present in nature
and are important structural entities in natural products. Var-
ious drugs with active carboxylic acid groups have been
rendered more active by converting them to hydrolyzable
2-oxazoline pro-drug moieties.[4] Various unique proper-
ties have dictated their use in a multitude of dissimilar
applications, such as monomers in polymer production, as
Methods to synthesize 2-oxazolines have largely been
explored. However, many of them suffer from the use
of harsh reagents such as SOCl2 and very high thermal
conditions[5] over several hours. Traditionally, the direct
method to obtain these heterocyclic compounds requires a
high energy level with very high temperatures or azeotropic
water removal. Lewis acids have been identified as catalysts
for the synthesis of 2-oxazolines. 2-Oxazolines have been
synthesized from carboxylic acids, aldehydes, esters, nitriles,
and orthoesters.[6–10] A synthetically concise approach that
combinestheamidebondformationandcyclicdehydrationin
a single-pot synthesis using ionic liquids has been attempted
for the first time.The protocol affords good yield of products.
Herein, we report the synthesis of substituted 2-oxazolines in
indium chloride/ionic liquid media (Scheme 1).
Ionic liquids are molten salts that exert essentially no
vapour pressure.[11] Room-temperature ionic liquids (RTILs)
exhibit excellent chemical and thermal stabilities. They are
aprotic and their properties, such as viscosity, melting point,
density, and hydrophobicity, may be modified to meet the
desired conditions by variation in the cations and anions.
They offer an excellent and alternate medium to organic
solvents.[12] The solubility of an ionic liquid and its ability to
R
N
COOH
R
O
[bmim]Cl/InCl3
OH
ꢀ H2N
60°C
Scheme 1. Synthesis of 2-oxazolines in ionic liquid/indium chloride.
© CSIRO 2006 10.1071/CH06061
0004-9425/06/070463

464
R. Kamakshi and B. S. R. Reddy
augment reaction rates depend on the nature of the counter
ions. Thus, they are much sought after eco-friendly ‘green
designer’ solvents. Most ionic liquids are soluble in water
and this makes the isolation of the product relatively simple.
Although their eco-friendliness has attracted a lot of attention
towards their synthesis, it is only recently that their kinetic
behaviour and their exact mechanisms have been extensively
studied.[13]
The ionic liquids are easily accessible by the alky-
lation of commercially available 1-methylimidazole with
n-haloalkane to give the corresponding 1-alkyl-
3-methylimidazolinium chloride. Many condensation reac-
tions, which include Friedlander’s synthesis of quinolines,
havebeenstudiedinthepresenceofionicliquids.[14] Thenov-
elty of the paper lies in the ease of synthesis of 2-oxazolines
in the ionic liquid media.
In this article, the synthesis of 2-oxazolines in the presence
of InCl3/[bmim]+Cl− at 60◦C is described (bmim = 1-butyl-
3-methylimidazolium). The acid and the amino alcohols are
completely soluble in the ionic media. The melt is com-
pletely soluble in water and considerably easy to handle. The
2-oxazolines are formed in 70–85% yields and are suffi-
ciently pure. The ionic liquid, [bmim]+Cl−, is synthesized
by refluxing N-methylimidazole and butyl chloride under a
nitrogen atmosphere for 72 h.
In a typical procedure, 2.5 mg of Lewis acid catalyst was
added to 1 mL of the ionic liquid, followed by the addition
of 1 mmol of carboxylic acid and 1 mmol of amino alcohol.
The reaction mixture was stirred at 60◦C for three hours.
After completion of the reaction, 20 mL of distilled water
was poured into the reaction mixture and the precipitate was
filtered off. It was then purified by column chromatography
and the product obtained was analyzed using FTIR and NMR
spectroscopy, and mass spectrometry.
InCl3 was found to be more effective than the other Lewis
acid catalysts. This could be due to the formation of polynu-
clear ions in indium chloride similar to aluminum chloride as
discussed by various groups,[11a,c] which makes the ionic liq-
uid/indium chloride combination more effective. The effect
of the alkyl chain of the ionic liquid was also studied for the
reaction between aminoethanol and benzoic acid. Although
the pentyl and hexyl methylimidazoles were found to be less
viscous than butyl imidazole, it was noted that there was no
significant change in the percentage yield of the product.
During the course of the reaction, the reaction mixture
was analyzed and it was found to contain some amount of the
N-2-hydroxyethylbenzamide. This undergoes cyclodehydra-
tion to yield 2-oxazoline (Scheme 2). The reaction may be
aided by the high polarity of the ionic liquid. The yields of
the various oxazolines and oxazines synthesized from substi-
tuted aromatic acids are given in Table 2. It was found that
p-nitrobenzoic acid gave the maximum yields with all the
amino alcohols (entries 2, 6, and 8).The 3,5-dimethylbenzoic
acid (entry 4) yielded the minimum product.The higher reac-
tivity of the acids with electron-withdrawing groups may be
explained by the electrophilicity of the carbonyl carbon being
enhanced by the presence of electron-withdrawing groups in
the phenyl ring. This lowers the energy required to remove
the hydroxy group.[16] The reverse occurs for the electron-
donating substituents (entry 4). The methylene and dimethyl
groups (entries 7, 8, 9, and 10) may hinder the attack in step
2 through which there is an elimination of a water molecule.
Reactionsthathavebeenperformedbyconventionalmeth-
ods are now being studied using ionic liquids. Ionic liquids
offer a convenient synthetic method that is more beneficial
for high atom efficiency, benign protocols, and ease in han-
dling. Although a large number of synthetic methods for
various reactions exist, the factors that influence the reac-
tions in ionic liquids are now being attributed to their (a)
complexing ability, (b) nucleophilicity, and (c) hydrogen-
bonding effects.The nucleophilicity of anions in ionic liquids
is greatly enhanced compared to other solvents.[17] The polar-
izability and the hydrogen-bonding capacities of the ionic
Results and Discussion
The reaction of benzoic acid with 2-aminoethanol (Table 1)
was studied as a model reaction to optimize the catalyst and
conditions. The reaction, when performed without the pres-
ence of an ionic liquid (entry 1) in chlorobenzene under reflux
conditions with InCl3 as a catalyst, yielded only 50% of the
product. The reaction was also performed with other Lewis
acids such as ZnCl2, CuCl2, and BiCl3.
Table 1. Reaction of benzoic acid with 2-aminoethan-1-ol under
various conditions
Entry
Ionic liquid
Catalyst
Temp. [◦C]
Yield [%]
1
2
3
4
5
6
7
—
InCl3
ZnCl2
CuCl2
BiCl3
InCl3
InCl3
InCl3
120A
60
60
60
60
51
57
63
65
80
75
78
[bmim]+Cl−
[bmim]+Cl−
[bmim]+Cl−
[bmim]+Cl−
[pmim]+Cl−
[hmim]+Cl−
60
60
A Reaction carried out under reflux conditions with 5 mg of InCl3 for
every 1 mmol of acid.
O
O
OH
O
ꢁH2O
OH
ꢁH2O
N
N
H
H2N
OH
Scheme 2.

Synthesis of 2-Oxazolines with Ionic Liquid/Indium Chloride
465
Table 2. Synthesis of 2-oxazolines in ionic liquid/indium chloride
Entry
1
Acid
Amino alcohol
Product
Yield [%]
80
N
COOH
COOH
OH
O
O
H2N
N
OH
2
85
76
68
75
81
62
70
65
74
H2N
O2N
O2N
N
COOH
OH
O
3
H2N
HO
HO
N
COOH
OH
O
4
H2N
C2H5
N
COOH
COOH
C2H5
5
OH
O
H2N
C2H5
N
N
N
C2H5
6
OH
O
H2N
O2N
O2N
O2N
O2N
COOH
COOH
OH
OH
H2N
7
O
O
H2N
8
O2N
N
COOH
COOH
OH
9
H2N
O
N
OH
10
O
H2N
O2N

466
R. Kamakshi and B. S. R. Reddy
Typical Reaction Procedure for 2a
1.432
1.100
[bmim]+Cl− (1 mL) was placed in a 25 mL round-bottom flask
equipped with a stirrer bar, and InCl3 (2.5 mg), 4-nitrobenzoic acid
(167 mg, 1 mmol), and 2-aminoethan-1-ol (61 mg, 1 mmol) were added.
The resulting mixture was stirred at 60◦C for 3 h and then cooled.
Distilled water (20 mL) was added and the pale yellow precipitate
was filtered off. The precipitate formed was sufficiently pure and was
charged onto a column containing silica gel (60–120 mesh) and eluted
with petroleum ether/ethyl acetate (50:50 v/v). The product obtained
was analyzed using FTIR, 1H, and 13C NMR spectroscopy, and mass
spectrometry.
1.992
1.530
ꢂE ꢃ 65.7 kcal molꢁ1
Transition state
Spectroscopic Data for the Compounds 1a–10a
2-Phenyl-4,5-dihydro-1,3-oxazole 1a
νmax (KBr)/cm−1 1647, 1499. δH (500 MHz, CDCl3) 3.74 (t, 2H),
4.2 (t, 2H), 7.29–7.5 (m, 5H, Ar-H). δC (125 MHz, CDCl3) 41, 59, 124,
128.5, 131.7, 134, 167. m/z 147 (M+), 119.5, 105.
Fig. 1. Optimized geometry of a feasible transition state.
liquids are generally very high. Hydrogen-bonding effects
are also noted in certain cases wherein the reactions are aug-
mented and rendered viable in the presence of a solvent with
hydrogen-bonding capability. The hydrogen-bonding effects
in ionic liquids have been studied in the Diels–Alder reac-
tion for acrylates and it was found that the reactions were
more feasible and selective in ionic liquids due to these
effects.[18] Such hydrogen-bonding interactions, if prevalent,
wouldgreatlyincreasethenucleophilicityoftheaminegroup,
thus rendering it more effective.
An insight for the energy constraints for the reaction to
occur can be obtained from the gas-phase calculations of
step 1 of the reaction. The analysis of the reaction shows
that the activation energy required for the formation of the
amide with the removal of water through a concerted mecha-
nism (Scheme 2) is very high, of the order of 65.7 kcal mol−1
(Fig. 1). However, this is not the exact energy barrier that
needs to be surmounted: the presence of solvent would
considerably lower the energy barrier. However, the reac-
tion requires refluxing in chlorobenzene at a temperature of
120◦C to yield 50% of the product. Since the reaction takes
place at ambient temperature, in the presence of an ionic liq-
uid, it may be suggested that the ionic liquid stabilizes the
reaction due to its Coulombic interactions.
2-(4-Nitrophenyl)-4,5-dihydro-1,3-oxazole 2a
νmax (KBr)/cm−1 730, 1599, 1612. δH (500 MHz, CDCl3) 3.68 (t,
2H), 3.51 (t, 2H), 8.26 (m, 2H), 8.34 (m, 2H). δC (125 MHz, CDCl3)
42.8, 61.7, 134.1, 127.2, 145.1, 169. m/z 192.6 (M+).
2-(4-Hydroxyphenyl)-4,5-dihydro-1,3-oxazole 3a
νmax (KBr)/cm−1 1566, 1642, 3411br, s. δH (500 MHz, CDCl3) 3.8
(t, 2H), 4.2 (t, 2H), 7.37–7.7 (m, 4H, Ar-H), 8.1 (s, 1H). δC (125 MHz,
CDCl3) 43.3, 63.2, 129.4, 132.3, 153.7, 162.4. m/z 163 (M+).
2-(3,5-Dimethylphenyl)-4,5-dihydro-1,3-oxazole 4a
νmax (KBr)/cm−1 1607, 1577, 765, 2855. δH (500 MHz, CDCl3) 2.3
(s, 6H), 3.65 (t, 2H), 4.1 (t, 2H), 7.1–7.4 (m, 3H Ar-H). δC (125 MHz,
CDCl3) 19.7, 20.13, 47.1, 51.6, 127.8, 128.7, 129.6, 134.4, 157.3. m/z
175 (M+).
4-Ethyl-2-(phenyl)-4,5-dihydro-1,3-oxazole 5a
νmax (KBr)/cm−1 1522, 1620. δH (500 MHz, CDCl3) 0.98 (t, 3H),
1.4 (m, 2H), 3.3 (m, 1H), 3.54 (dd, 1H), 3.68 (dd, 1H), 7.1–7.7 (m, 5H,
Ar-H). δC (125 MHz, CDCl3) 21, 30, 42, 60.8, 127, 134, 145, 167. m/z
175 (M+).
4-Ethyl-2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole 6a
νmax (KBr)/cm−1 727, 1566, 1622. δH (500 MHz, CDCl3) 1.01 (t,
3H), 1.6 (m, 2H), 3.3 (m, 1H), 3.54 (dd, 1H), 3.68 (dd, 1H), 8.1–8.24
(m, 4H, Ar-H). δC (125 MHz, CDCl3) 21, 30, 42, 60.8, 127, 134, 145,
167. m/z 220 (M+).
Conclusions
A novel and an environmentally friendly method for the syn-
thesis of 2-oxazolines promoted by ionic liquids has been
described. Itwasfoundthatindiumchlorideisabettercatalyst
than other Lewis acids.The yields are good and the procedure
offers products that can be purified with considerable ease.
2-Phenyl-4,5-dihydro-1,3-oxazine 7a
νmax (KBr)/cm−1 1626, 1580. δH (500 MHz, CDCl3) 2.3 (t, 2H),
3.4 (m, 2H), 3.7 (m, 2H), 7.1–7.8 (m, 5H, Ar-H). δC (125 MHz, CDCl3)
27.1, 38, 58.5, 122, 126, 130.3, 132, 164. m/z 161 (M+).
Experimental
Materials and Methods
2-(4-Nitrophenyl)-4,5-dihydro-1,3-oxazine 8a
νmax (KBr)/cm−1 1588, 1630. δH (500 MHz, CDCl3) 2.7 (m, 2H),
3.6 (m, 2H), 3.9 (m, 2H), 8.24–8.3 (m, 4H,Ar-H). δC (125 MHz, CDCl3)
19.1, 40.2, 61.8, 126, 133, 145, 165. m/z 206 (M+).
1-Methylimidazole, butyl chloride, and indium chloride were purchased
from Aldrich. The aminoethanols were obtained from Fluka Chemi-
cals. N-Methylimidazole was quaternized with 1-chlorobutane to form
1-butyl-3-methylimidazolium chloride under reflux. A similar proce-
dure was adopted for the synthesis of 1-pentyl-3-methylimidazolium
chloride ([pmim]+Cl−) and 1-hexyl-3-methylimidazolium chloride
([hmim]+Cl−) using the respective chloroalkanes. Analytical thin-layer
chromatography was performed on pre-coated plastic silica gel plates
of 0.25 mm thickness containing PF 254 indicator (Merck). IR spec-
tra were recorded neat on a Perkin Elmer RX I FTIR spectrometer. 1H
and 13C NMR spectra were recorded in [D4]methanol on a 500 MHz
JEOL spectrometer (chemical shifts in δ, ppm) using tetramethylsilane
as an internal standard. Mass analysis was performed on a JEOL mass
analyzer.
4,4-Dimethyl-2-phenyl-4,5-dihydro-1,3-oxazole 9a
νmax (KBr)/cm−1 1567, 1602. δH (500 MHz, CDCl3) 1.27 (s, 6H),
3.7 (s, 2H), 7.2–7.9 (m, 5H, Ar-H). δC (125 MHz, CDCl3) 12.3, 35.2,
46, 124, 126.3, 129, 132, 164. m/z 160 (M+).
4,4-Dimethyl-2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole 10a
νmax (KBr)/cm−1 716, 1577, 1607. δH (500 MHz, CDCl3) 1.3 (s,
6H), 3.8 (s, 2H), 8.15–8.26 (m, 4H, Ar-H). δC (125 MHz, CDCl3) 27,
43.3, 62.5, 128, 135, 162. m/z 220 (M+).

Synthesis of 2-Oxazolines with Ionic Liquid/Indium Chloride
467
Computational Details
[8] E. J. Corey, Z. Wang, Tetrahedon Lett. 1993, 34, 4001.
doi:10.1016/S0040-4039(00)60600-7
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dranathan, A. V. Bedekar, Tetrahedron Lett. 1998, 39, 459.
doi:10.1016/S0040-4039(97)10575-5
All calculations have been carried out using the HF/6-31G* method
implemented in the Gaussian 98W package.[15] The reactants, transition
states (TSs), and products have been characterized with the help of
frequency calculations. It was verified that the reactants and products
were the minimum energy conformations, while the TS was a saddle
point on the potential energy surface. The activation energy (ꢀE‡) was
measured using the following equation.
[10] (a) K. Kamata, I. Agata, A. I. Meyers, J. Org. Chem. 1998, 63,
3113. doi:10.1021/JO971161X
(b) R. Luisi,V. Capriati, S. Florio, E. Piccolo, J. Org. Chem. 2003,
68, 10187. doi:10.1021/JO035360U
[11] (a) P. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 2000,
39, 3772. doi:10.1002/1521-3773(20001103)39:21<3772::AID-
ANIE3772>3.0.CO;2-5
ꢀE‡ = (energy of TS) − (energy of reactants)
Acknowledgments
(b) J. Dupont, R. F. deSouza, P. A. S. Suarez, Chem. Rev. 2002,
102, 3667. doi:10.1021/CR010338R
(c) T. Welton, Chem. Rev. 1999, 99, 2071.
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The authors thank Dr V. Subramanian, Chemical Laboratory,
CLRI, for his valuable help with the computational studies.
R.K. thanks CSIR-New Delhi for fellowships.
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