FeCl3-catalyzed Pechmann synthesis of coumarins in ionic liquids

Article abstract of DOI:10.1080/00397910802219569

The synthesis of coumarin derivatives via Pechmann reaction using anhydrous FeCl3 as Lewis acid catalyst in ionic liquid medium has been carried out. The best results were obtained (yields as high as 89%) with ionic liquids having bis(triflic)imide as a counteranion. The ionic liquid could easily be recovered and reused. Copyright Taylor & Francis Group, LLC.

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FeCl3-Catalyzed Pechmann
Synthesis of Coumarins in Ionic
Liquids
Vineet Kumar a , Shilpi Tomar b , Ronak Patel a ,
Ahmad Yousaf a , Virinder S Parmar b & Sanjay V
Malhotra a
a Department of Chemistry and Environmental
Science, New Jersey Institute of Technology,
University Heights, Newark, New Jersey, USA
b Department of Chemistry, University of Delhi,
Delhi, India
Available online: 09 Sep 2008
To cite this article: Vineet Kumar, Shilpi Tomar, Ronak Patel, Ahmad Yousaf, Virinder S
Parmar & Sanjay V Malhotra (2008): FeCl3-Catalyzed Pechmann Synthesis of Coumarins
in Ionic Liquids, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:15, 2646-2654
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Synthetic Communications1, 38: 2646–2654, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802219569
FeCl3-Catalyzed Pechmann Synthesis of
Coumarins in Ionic Liquids
Vineet Kumar,1 Shilpi Tomar,2 Ronak Patel,1 Ahmad Yousaf,1
Virinder S. Parmar,2 and Sanjay V. Malhotra1
1Department of Chemistry and Environmental Science, New Jersey Institute of
Technology, University Heights, Newark, New Jersey, USA
2Department of Chemistry, University of Delhi, Delhi, India
Abstract: The synthesis of coumarin derivatives via Pechmann reaction
using anhydrous FeCl3 as Lewis acid catalyst in ionic liquid medium has been
carried out. The best results were obtained (yields as high as 89%) with ionic
liquids having bis(triflic)imide as a counteranion. The ionic liquid could easily
be recovered and reused.
Keywords: Coumarins, ionic liquids, pachmann condensation, recyclability
INTRODUCTION
Coumarins are naturally occurring polyphenolics distributed widely in
plants, fungi, and bacteria and have found applications for centuries in
traditional medicine. Because of their potential applications in fragrance,
pharmaceutical, and agrochemical industries,[1] they occupy an important
position in natural and synthetic organic chemistry. They are used as
anticoagulants, additives in food and cosmetics, and in the preparation
of insecticides,[1] optical brighteners,[2] and dispersed fluorescent and
laser dyes.[3] Many compounds containing the coumarin subunit exhibit
useful HIV-1 inhibition properties.[4] In our ongoing studies, we have
explored the potential anti-oxidant and anti-inflammatory capabilities
of 4-methylcoumarins.[5]
Received in the USA April 25, 2008
Address correspondence to Sanjay V. Malhotra, Laboratory of Synthetic
Chemistry, SAIC Frederick Inc., National Cancer Institute at Frederick, 1050
Boyles Street, Frederick, MD 21702, USA. E-mail:malhotrasa@mail.nih.gov
2646

FeCl3-Catalyzed Pechmann Synthesis of Coumarins
2647
Several methods used for synthesis of coumarins include
Pechmann,[6] Perkin,[7] Knoevenagel,[8] Reformatsky,[9] and Wittig reac-
tions.[10] Among these, the Pechmann reaction is the most extensively
applied method. It involves the condensation of phenols with b-ketonic
esters in the presence of an acidic catalyst to give 4-substituted coumar-
ins.[6,11] Various catalysts employed for this reaction include sulfuric
acid,[6] phosphorus pentoxide,[12] aluminium chloride,[13] and trifluoroa-
cetic acid.[14] In all cases, an excess of the catalyst is required (up to
10–12 equivalents in some cases), and their corrosive nature makes them
difficult to handle and often leads to the formation of several side pro-
ducts. Furthermore, the disposal of hazardous acid waste causes environ-
mental problems. These difficulties have led to attempts to find
alternative, environmentally benign synthetic routes. Various methods
using Nafion-H,[15] zeolite H-BEA, Amberlyst 15,[16] montmorillonite
clay,[17] and microwave irradiation[17,18] have been employed for
Pechmann condensation. However, most of these methods have disad-
vantages such as expensive reagents, long reaction time, difficult purifi-
cation, low selectivity, and use of large amounts of solid supports. An
alternative approach is the use of ionic liquids as reaction media, which
could offer a solution to solvent emission and catalyst recyclability pro-
blems. Ionic liquids possess advantages such as negligible vapor pressure,
reasonable thermal stability, recyclability, and the ability to dissolve
many organic and inorganic substrates. The possibilities of structural
variations offer flexibility for chemists to design an ideal solvent suitable
for the needs of any particular process. Apart from tunable physical and
chemical properties of ionic liquids, their immiscibility with various
organic solvents enables the biphasic separation of the desired pro-
ducts.[19] Earlier attempts of coumarin synthesis via Pechmann conden-
sation have been made with chloroaluminate ionic liquid, where the
ionic liquid plays dual role of solvent and a Lewis acid catalyst.[20] How-
ever, the major disadvantage associated with chloroaluminates is
their moisture sensitivity because even traces of water can change the
composition of the melt and the concentration of protons, which makes
it difficult to accurately control the acidity of these ionic liquids.
Also, chloroaluminate ionic liquids cannot be stored for a long time
and are prepared just before the reaction. The chloroaluminate wastes
generated also cause a major environmental hazard. One recent report
showed the use of neutral ionic liquid in the presence of POCl3 as cata-
lyst, which is highly toxic and difficult to use.[21] Our earlier attempts
to find environmentally friendly catalysts for reactions in neutral ionic
liquids led to highly efficient protocols using anhydrous FeCl3 as cata-
lyst.[22] Iron salts are inexpensive, easy to handle, and environment
friendly compared to other Lewis acids.[23] Recently, we reported the

2648
V. Kumar et al.
application of 1-methoxyethyl-3-methylimidazolium [MoeMIm]–based
ionic liquids for enhanced solubility and selective benzoylation of
nucleosides.[24] In continuation of our efforts to develop cleaner synthetic
methodologies, herein we report the catalytic capabilities of anhydrous
FeCl3 as a Lewis acid catalyst in ionic liquid medium for the synthesis
of coumarins via Pechmann condensation.
RESULTS AND DISCUSSION
We started our studies with the Pechmann condensation between resorci-
nol and ethyl acetoacetate in different ionic liquids using anhydrous
FeCl3 as catalyst. The ionic liquids used in our study were 1-methoxy-
ethyl-3-methylimidazolium
1-methoxyethyl-3-methylimidazolium
tetrafluoroborate
hexafluorophosphate
[MoeMIm][BF4],[25]
[Moe-
MIm][PF6],[25] 1-methoxyethyl-3-methylimidazolium trifluoroacetate
[MoeMIm][CF3COO],[24] 1-methoxyethyl-3-methylimidazolium bis(triflic)-
imide [MoeMIm][Tf2N],[25] and 1-butyl-3-methylimidazolium bis(triflic)-
imide [BMIm][Tf2N][25] (Fig. 1). With the exception of the ionic liquid
[MoeMIm][CF3COO], the reaction went smoothly in all ionic liquids
giving the product 7-hydroxy-4-methylcoumarin in good yields. All reac-
tions were carried out under similar conditions at 70ꢀC using 20 mol%
anhydrous FeCl3 (with respect to the substrate resorcinol) (Table 1).There
was no change in the reaction profile observed when more than 20 mol%
of FeCl3 was used, and very slow conversion was observed at smaller con-
centrations of FeCl3. When similar reactions were carried out in absence
of the catalyst, approximately 5–10% conversion was observed on the
thin-layer chromatography (TLC) in 2 days. The moderate temperature
(70ꢀC) was also necessary for high conversions, though TLC indicated
that a small amount of substrate (<5%) remained unreacted and
could not be recovered. It is also worth mentioning that in the case of
[MoeMIm][CF3COO], no reaction occurred even when an excess of
catalyst was used and the temperature was raised to 120 ꢀC.
Figure 1. ILs screened for Pechmann synthesis of coumarins.

FeCl3-Catalyzed Pechmann Synthesis of Coumarins
2649
Table 1. Pechmann reaction of resorcinol and ethyl acetoacetate in different ionic
liquids using anhyd. FeCl3 as catalyst
S. no.
Ionic liquid
Time (h)
Yield (%)
1
2
3
4
5
[MoeMIm][BF4]
[MoeMIm][PF6]
[MoeMIm][CF3COO]
[MoeMIm][Tf2N]
[BMIm][Tf2N]
10
8
24
12
12
80
89
No reaction
80
85
One of the major advantages of using ionic liquids in organic syn-
thesis is their reusability, which makes the process more economical
and benign. We attempted to recover ionic liquids form the Pechmann
condensation of resorcinol, but unfortunately all efforts to recover the
[MoeMIm][BF4] and [MoeMIm][PF6] failed. The ionic liquid
[MoeMIm][BF4] is hydrophilic, remained dissolved in water during
workup along with the catalyst, and could not be recovered by extraction.
It is reported in the literature that ionic liquids with [PF6] anion liberate
hydrogen fluoride (HF) in the presence of moisture.[21] Because water is
the by-product of the Pechmann reaction, we believe that as the reaction
proceeds, the ionic liquid [MoeMIm][PF6] is decomposed, liberating HF,
which was observed as fumes inside the condenser during our studies.
Therefore, even when 10% aqueous NaOH solution was added to the
reaction mixture, no trace of [MoeMIm][PF6] was observed despite of
its hydrophobic nature. On the other hand, hydrophobic ionic liquids
[MoeMIm][Tf2N] and [BMIm][Tf2N] were successfully recovered from
the reaction mixture and were recycled up to four times without promi-
nent loss in the product yields (Table 2). These two ionic liquids were
further used for Pechmann condensation of other phenols with ethyl acet-
oaetate to give corresponding coumarins in good yields (Table 3). All
these coumarin derivatives are known in literature and were characterized
1
by matching their melting points and H and 13C NMR data with those
reported in the literature.[26,27]
In conclusion, anhydrous FeCl3 was successfully used as a Lewis acid
catalyst for the Pechmann condensation between ethyl acetoacetate and
different phenols using nonchloroaluminate ionic liquids as reaction
medium to give corresponding coumarin derivatives in good yields. The
ionic liquids [MoeMIm][Tf2N] and [BMIm][Tf2N] proved to be the best,

2650
V. Kumar et al.
Table 2. Recycling of ILs [MoeMIm][Tf2N] and [BMIm][Tf2N] for Pechmann
condensation of resorcinol and ethyl acetoacetate
Run
0
Ionic liquid
Time (h)
Yield (%)
[MoeMIm][Tf2N]
[BMIm][Tf2N]
[MoeMIm][Tf2N]
[BMIm][Tf2N]
[MoeMIm][Tf2N]
[BMIm][Tf2N]
[MoeMIm][Tf2N]
[BMIm][Tf2N]
12
12
12
12
12
14
14
14
14
14
80
85
74
82
70
72
70
70
67
68
1
2
3
4
[MoeMIm][Tf2N]
[BMIm][Tf2N]
could be easily recovered from the reaction, and could be recycled up to
four runs.
EXPERIMENTAL
Ionic liquids were synthesized by following the procedures given in the
literature.[25] All other chemicals and reagents were of analytical grade
and were used as obtained commercially.
General Procedure for Pechmann Condensation
The ionic liquid (1 ml) was placed in a round-bottomed flask equipped
with a distillation condenser and nitrogen balloon, followed by the
addition of anhydrous FeCl3 (20 mol% of the substrate). After the
catalyst was completely dissolved in the ionic liquid, the required
amounts of phenol (2 mmol) and ethyl acetoacetate (1 equiv, 2 mmol)
were added to the ionic liquid=FeCl3 mixture. The reaction mixture
was stirred at 70 ꢀC, and its progress was monitored on silica-gel TLC
plates using 10% MeOH=CHCl3 as the solvent system. At the point
when maximum obtainable conversion was seen and no further product
formation observed, the reaction mixture was cooled to room tempera-
ture and quenched with 10% NaOH solution. The product dissolved in
the NaOH solution was precipitated by neutralization with 6 N HCl,
leaving FeCl3 in the solution. The crude product was filtered off and
purified by column chromatography over silica gel using MeOH=CHCl3
as the solvent system.

FeCl3-Catalyzed Pechmann Synthesis of Coumarins
2651
Table 3. Pechmann synthesis of coumarin derivatives using anhydrous FeCl3 as
catalyst in ILs [MeoMIM][Tf2N] and [BMIM][Tf2N]
Using
Using
[MeoMIM] [BMIM]
[Tf2N]
at 70ꢀC
[Tf2N]
at 70ꢀC
Mp(ꢀC)
Time Yield Time Yield
S. no.
1
Substrate
Product
(h) (%) (h) (%)
12
10
80
72
12
10
85 184–186
185–187[26]
2
74 234–235
236–239[26]
3
10
75
10
77 282–284
281–283[26]
4
13
7
13
71 152–154
154–156[26]
5
14
68
13
65 182–183
183–184[27]

2652
V. Kumar et al.
Recycling of Ionic Liquids [MoeMIm][Tf2N] and [BMIm][Tf2N]
After quenching the reaction with 10% NaOH solution, the ionic liquid
(settled in the round-bottomed flask) was extracted from the aqueous
solution by dichloromethane. The dichloromethane layer was washed
twice with 10% NaOH solution to remove any residual coumarin or
other acidic impurities and was further washed with water, followed
by drying over anhydrous sodium sulphate. Finally, dichloromethane
was removed under vacuum, and the recovered ionic liquid was dried
in a high vacuum oven for 6–10 h at 50 ꢀC and 0.01 in. Hg pressure
prior to reuse.
ACKNOWLEDGMENT
A. Y. acknowledges Bristol Myers Squibb for partial support through an
undergraduate research grant. R. P. thanks the American Chemical
Society SEED program for summer support.
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