Ionic liquid-mediated knoevenagel condensation of Meldrum's acid and aldehydes

Article abstract of DOI:10.1080/00397910600775218

A simple, efficient, and green protocol for Knoevenagel condensation of Meldrum's acid and aldehydes in ionic liquid at room temperature without any catalyst is described. The reaction has been performed in different ionic liquids. The enhancement in the

Full text of DOI:10.1080/00397910600775218

This article was downloaded by: [Duke University Libraries]
On: 08 October 2012, At: 16:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Ionic Liquid–Mediated Knoevenagel
Condensation of Meldrum's Acid and
Aldehydes
Nitin B. Darvatkar a , Amol R. Deorukhkar a , Sachin V. Bhilare a & Manikrao
M. Salunkhe a
a Department of Chemistry, Institute of Science, Mumbai, India
Version of record first published: 16 Feb 2007.
To cite this article: Nitin B. Darvatkar, Amol R. Deorukhkar, Sachin V. Bhilare & Manikrao M. Salunkhe
(2006): Ionic Liquid–Mediated Knoevenagel Condensation of Meldrum's Acid and Aldehydes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:20,
3043-3051
To link to this article: http://dx.doi.org/10.1080/00397910600775218
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 36: 3043–3051, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600775218
Ionic Liquid–Mediated Knoevenagel
Condensation of Meldrum’s Acid
and Aldehydes
Nitin B. Darvatkar, Amol R. Deorukhkar, Sachin V. Bhilare,
and Manikrao M. Salunkhe
Department of Chemistry, Institute of Science, Mumbai, India
Abstract: A simple, efficient, and green protocol for Knoevenagel condensation of
Meldrum’s acid and aldehydes in ionic liquid at room temperature without any
catalyst is described. The reaction has been performed in different ionic liquids. The
¨
enhancement in the rate is observed in Bronsted acidic ionic liquid 1-methylimidazo-
lium trifluoroacetate [Hmim]Tfa, which furnishes quantitative yields with 4–30 min in
most of the cases. Furthermore, ionic liquid is easily reused without any appreciable
loss in activity.
¨
Keywords: Bronsted acidic ionic liquid, Knoevenagel condensation, Meldrum’s acid,
recyclability, ylidenes
Knoevenagel condensation of Meldrum’s acid and aldehydes gives rise to
corresponding ylidene derivatives. The ylidene derivatives obtained are
versatile substrates for variety of reactions.[1] They are used in cycloaddition
reactions,[2] 1,4-conjugate addition reactions and preparation of monoalkyl
Meldrum’s acid derivatives,[3] preparation of deuterated carboxylic acid
derivatives,[4] and so forth. These derivatives are also used in the preparation
of ketenes by flash vacuum pyrolysis, which are then used for preparation of
different compounds such as cyclobutadiene derivatives, a,b-unsaturated
esters, a,b-unsaturated amides, and synthesis of phenols.[5]
Received in India March 30, 2006
Address correspondence to Manikrao M. Salunkhe, Department of Chemistry,
Institute of Science, 15 Madam Cama Road, Mumbai 400 032, India. E-mail:
mmsalunkhe@hotmail.com
3043

3044
N. B. Darvatkar et al.
Meldrum’s acid (2,2-dimethyl-4,6-dioxo-1,3-dioxane) has attracted
considerable attention because of its anomalously high acidity (pKa ¼ 7.3 in
DMSO at 258C)[6] and rigid cyclic structure. The Knoevenagel condensation
of Meldrum’s acid with aldehyde was carried out using a number of catalysts
such as K3PO4 in ethanol,[7] heterogeneous basic catalysts such as
Zr(O3POK),[8] anhydrous ZnCl2 under solvent-free conditions,[9] and piper-
idine/glacial acetic acid in benzene with water removal.[2] We have previously
reported such reactions catalyzed by clays under solvent-free conditions.[10] The
reaction has also been reported without any catalyst in an aqueous medium under
reflux conditions.[11] Hedge and colleagues have reported such reactions without
any catalyst at room temperature in highly polar solvents such as dimethyl
sulfoxide (DMSO) and dimethyl formamide (DMF), which are known to be
highly toxic and teratogenic and are suspected carcinogens.[12]
In recent years, ionic liquids have attracted considerable interest as a
green reaction media because of their fascinating properties such as negligible
vapor pressure, ability to solvate a wide range of both organic and inorganic
substrates, highly polar yet noncoordinating nature, and immiscibility with a
number of organic solvents, as well as (in some cases) water.[13] Further,
they are also regarded as designer solvents because their properties, such as
hydrophilicity/hydrophobicity, polarity, acidity/basicity, viscosity, and
recyclability, can be tuned by proper selection of cation and anion. Some of
the ionic liquids are found to play the dual roles of solvent and catalyst. We
have previously investigated a number of reactions in ionic liquids such as
Fries rearrangement, Knoevenagel condensation of malonic acid with
aldehydes, Pechmann condensation, synthesis of aryl keto acids, sulphonyla-
tion, sulfamoylation, and Michael reaction.[14] We have also investigated
acylation of nucleosides as well as some biotransformations in these
neoteric solvents.[15]
In an effort to exploit the potential of ionic liquid further and to explore
the effect of these neoteric polar media, we considered it worthwhile to inves-
tigate the Knoevenagel condensation of Meldrum’s acid with aldehydes in
ionic liquids (Scheme 1).
During our investigation, we have carried out the reaction in different ionic
liquids viz. 1-butyl-3-methylimidazolium hexafluorophosphate [bmim]PF6,
1-hexyl-3-methylimidazolium tetrafluoroborate [hmim]BF4, 1-butyl-3-
methylimidazolium tetrafluoroborate [bmim]BF4, and 1-methylimidazolium
Scheme 1. Knoevenagel condensation of Meldrum’s acid and aldehyde.

Knoevenagel Condensation of Meldrum’s Acid and Aldehydes
3045
trifluoroacetate [Hmim]Tfa. 4-Methoxy benzaldehyde was chosen as a model
substrate. The percentage conversion of aldehyde into product was monitored
using gas chromatography. Interestingly, it was found that after a specified
time, the product precipitates out of the reaction mixture. The results are
presented in Table 1. (Conversions in all cases were monitored with respect
to decay of aldehyde by GC. A gas chromatograph Nucon 5765 equipped
with FID and RH-17 capillary column was employed for analysis. The
column was programmed initially at 508C with a gradient of 108C/min to
2808C. The detector and injector temperature was set at 3008C.)
As evident from the results shown in Table 1, the ionic liquid [Hmim]Tfa
was found to be a better alternative compared to ionic liquids, namely
[bmim]PF6, [hmim]BF4, and [bmim]BF4. The stupendous increase in the
percentage conversion as well as in the rate of reaction of [Hmim]Tfa ionic
¨
¨
liquid may be attributed to its Bronsted acidic nature. The Bronsted acidic
nature of this ionic liquid has been already utilized in Mannich reaction by
Zhao et al.[16] Further, the isolation of product is also easier for [Hmim]Tfa.
It can be effected by adding water to the reaction mixture, which dissolves
the ionic liquid along with unreacted components, and the product can be
isolated merely by filtration. The product obtained after sufficient washings
with water was found to be pure. No bis-adduct was formed.
Because excellent results were obtained for [Hmim]Tfa ionic liquid, we
employed this particular ionic liquid for subsequent studies. To explore the
versatility of the reaction, we selected a number of different substituted ben-
zaldehydes and hetero-aromatic aldehydes. Good yields were obtained with
aldehydes that have activating groups, as well as with hetero aromatic
aldehydes, as shown in Table 2.
The recyclability of [Hmim]Tfa ionic liquid was tested in the reaction of
4-methoxybenzaldehyde with Meldrum’s acid under same experimental con-
ditions, and as shown in Table 3, no considerable change in activity of ionic
liquid was observed even after three consecutive runs.
In conclusion, [Hmim]Tfa-mediated Knoevenagel condensation of
Meldrum’s acid with various aromatic and hetero-aromatic aldehydes
presents an efficient, expeditious, and green route for the synthesis of
Table 1. Knoevenagel condensation of Meldrum’s acid
and 4-mehoxy benzaldehyde in different ionic liquids
Entry
Ionic liquid
Time
Conversiona (%)
1
2
3
4
[bmim]PF6
[hmim]BF4
[bmim]BF4
[Hmim]Tfa
24 h
24 h
24 h
0.5 h
54
77
76
94
aConversions based on gas chromatography analysis.

Table 2. Knoevenagel condensation of Meldrum’s acid and aldehydes in [Hmim]Tfa
Reaction
time (min)
Conversiona
(%)
Isolated
yield (%)
Mp (Lit.
mp)[1,9,10] (8C)
Entry
1
Aldehyde
Product
30
94
90
123 (124)
2
4
95
91
173 (174)
3
4
20
30
92
95
88
85
109 (109)
96 (97)

5
20
93
87
196 (197)
6
30
80
79
175 (175)
7
8
5
67
73
60
70
84 (85)
10
133 (133)
(continued)

Table 2. Continued
Reaction
time (min)
Conversiona
(%)
Isolated
yield (%)
Mp (Lit.
mp)[1,9,10] (8C)
Entry
9
Aldehyde
Product
10
71
69
162 (162)
10
10
69
67
217 (217)
11
20
50
49
119 (119)
aConversions based on gas chromatography analysis.

Knoevenagel Condensation of Meldrum’s Acid and Aldehydes
3049
Table 3. Recycling of [Hmim]Tfa
Conversiona
(%)
Isolated
yield (%)
No. of cycles
1
2
3
94
93
93
90
88
87
aConversions based on gas chromatography analysis.
various ylidene derivatives in good to excellent yields. Further, the ionic liquid
can be easily recycled without any appreciable loss in the yields.
EXPERIMENTAL
Meldrum’s acid and ionic liquids are prepared as per the procedures reported
in the literature.[1,13,16] The aldehydes were purchased from SRL and Sd Fine
Chemicals and were used as received. The product was characterized by
1
1H NMR and GC-MS. HNMR was recorded on a JEOL (300 MHz) instru-
ment using CDCl3 as solvent. GC-MS was recorded on a Schimadzu QP
2010 spectrophotometer equipped with a dp5 column.
Typical Procedure
In a typical experiment, 1 mmol of aldehyde is added to 200 mg of [Hmim]Tfa
in a 50-ml round-bottom flask equipped with efficient magnetic stirrer. Stirring
is continued until a homogeneous mixture is formed at room temperature.
To this, 1 mmol of Meldrum’s acid is added. The reaction is monitored
using thin-layer chromatography (TLC), and stirring is continued until the
specified time. The product precipitates out, and the reaction mixture solidi-
fies. To this mixture, water is added so that ionic liquid dissolves in it, and
the product is isolated simply by filtration. It is washed with water to
remove excess ionic liquid along with unreacted components to get the
crude product, which is found to be pure in most of the cases. However, in
case of chloro- and nitro-derivatives, the yields are comparatively low and
the crude product contains some amount of starting material, which is
removed by crystallization. The products are characterized using GC-MS
1
and H NMR. In the case of solid aldehydes, the [Hmim]Tfa is melted by
a little warming (ꢀ658C), and rest of the procedure is followed at room
temperature as given previously. The ionic liquid is recovered by removing
excess water from the filtrate under a vacuum in a rotary evaporator. The
unreacted components are removed by extracting with toluene to purify the
ionic liquid.

3050
N. B. Darvatkar et al.
Spectral Data of the Two Representative Compounds
Isopropylidene p-methoxybenzalmalonate (entry 1): 1H NMR (300 MHz,
CDCl3): d ¼ 1.79 (6H, s), 3.91 (3H, s), 6.98 (2H, d, J ¼ 9 Hz), 8.23 (2H, d,
J ¼ 9 Hz), 8.38 (1H, s). MS m/z (%): 262 (Mþ, 22.64), 204 (58.5), 160
(100), 145 (60.0), 117 (48.9).
Isopropylidene p-N,N-dimethylbenzalmalonate (entry 2): 1H NMR
(300 MHz, CDCl3): d ¼ 1.77 (6H, s), 3.16 (6H, s), 6.69 (2H, d, J ¼ 9 Hz),
8.25 (2H, d, J ¼ 9 Hz), 8.31 (1H, s). MS m/z (%): 275 (Mþ, 7.3), 173
(69.5), 172 (100), 144 (96.33).
ACKNOWLEDGMENTS
The authors are thankful to the Council of Scientific and Industrial Research
and the Department of Science and Technology (New Delhi) for the financial
support. N. B. D. and S. V. B. are thankful to CSIR for the award of junior
research fellowships.
REFERENCES
1. (a) McNab, H. Meldrum’s acid. Chem. Soc. Rev. 1978, 7, 345–358; (b) Tietze, L. F.;
Beifuss, U. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp. 341–394.
2. Kraus, G. A.; Krolski, M. E. Synthesis of a precursor to Quassimarin. J. Org.
Chem. 1986, 51, 3347–3350.
3. Huang, X.; Xie, L. One-pot synthesis of monosubstituted isopropylidene
malonates. Synth. Commun. 1986, 16 (13), 1701–1707.
4. Kadam, A. J.; Desai, U. V.; Mane, R. B. Labelled Comp. Radiopharm., 1999, 42,
835–842.
5. (a) Brown, R. C. F.; Eastwood, F. W.; Harrington, K. J. Methyleneketenes and
methylenecarbenes, I: Formation of arylmethyleneketenes and alkylideneketenes
by pyrolysis of substituted 2,2-dimethyl-1,3-dioxan-4,6-diones. Aust. J. Chem.
1974, 27, 2373–2384; (b) Brown, R. C. F.; McMullen, G. L. Methyleneketenes
and methylenecarbenes, II: A new phenolic ring synthesis: 2-Naphthol from
o-tolualdehyde. Aust. J. Chem. 1974, 27, 2385–2391.
6. Nakamura, S.; Hirao, H.; Ohwada, T. Rationale for the acidity of Meldrum’s acid:
Consistent relation of C-H acidities to the properties of localized reactive orbital.
J. Org. Chem. 2004, 69 (13), 4309–4316.
7. Desai, U. V.; Pore, D. M.; Mane, R. B.; Solabanavar, S. B.; Wadgaonkar, P. P.
One-pot synthesis of monoalkylated and mixed, dialkylated Meldrum’s acid
derivatives. Synth. Commun. 2004, 34 (1), 25–32.
8. Fildes, D.; Caignaert, V.; Villemin, D.; Jaffres, P. A. Potassium exchanged
zirconium hydrogen phosphate Zr(O3POK)2: A heterogeneous basic catalyst
Knovenagel reaction with out solvent. Green Chem. 2001, 3, 52–56.
9. Rao, P. S.; Venkataratnam, R. V. Anhydrous zinc chloride catalysis in carbonyl–
methylene condensations: Synthesis of arylidene acetonitriles and arylidene
heterocycles. Indian J. Chem. B 1993, 32, 484–486.

Knoevenagel Condensation of Meldrum’s Acid and Aldehydes
3051
10. Thorat, M. T.; Jagdale, M. H.; Mane, R. B.; Salunkhe, M. M.; Wadgaonkar, P. P.
Clay-catalysed Knoevenagel condensation. Curr. Sci. 1987, 56 (15), 771–772.
11. Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.; Mazzacani, A.; Sartori, G. Clean
synthesis in water, part 2: Uncatalysed condensation reaction of Meldrum’s acid
and aldehydes. Tetrahedron Lett. 2001, 42, 5203–5205.
12. Hedge, J. A.; Kruse, C. W.; Snyder, H. R. Some condensation reactions of isopro-
pylidene malonate. J. Org. Chem. 1961, 26, 3166–3170.
13. (a) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Chemical and biochemical
transformations in ionic liquids. Tetrahedron 2005, 61 (5), 1015–1060;
(b) Welton, T. Ionic liquids in catalysis. Coord. Chem. Rev. 2004, 248 (21–24),
2459–2477; (c) Zhao, H.; Malhotra, S. V. Applications of ionic liquids in
organic synthesis. Aldrichim. Acta 2002, 35, 75; (d) Dupont, J.; de Souza, R. F.;
Suarez, P. A. Z. Ionic liquid (molten salt) phase organometallic catalysis. Chem.
Rev. 2002, 102, 3667–3692; (e) Wasserscheid, P.; Keim, W. Ionic liquids—new
“solutions” for transition metal catalysis. Angew. Chem. Int. Ed. 2000, 39,
3772–3789.
14. (a) Nara, S. J.; Harjani, J. R.; Salunkhe, M. M. Friedel–Crafts sulfonylation in
1-butyl-3-methylimidazolium chloroaluminate ionic liquids. J. Org. Chem.
2001, 66, 8616–8620; (b) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M.
Coumarin synthesis via Pechmann condensation in Lewis acidic chloroaluminate
ionic liquid. Tetrahedron Lett. 2001, 42, 9285–9287; (c) Harjani, J. R.; Nara, S. J.;
Salunkhe, M. M. Lewis acidic ionic liquids for the synthesis of electrophilic
alkenes via the Knoevenagel condensation. Tetrahedron Lett. 2002, 43,
1127–1130; (d) Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M. Influence
of ionic liquids on the phase transfer-catalysed enantioselective Michael
reaction. Tetrahedron Lett. 2003, 44, 5351–5353; (e) Mohile, S. S.;
Potdar, M. K.; Salunkhe, M. M. An alternative route to syntheses of aryl keto
acids in a chloroaluminate ionic liquid. J. Chem. Res., Synop. 2003, 650–651;
(f) Naik, P. U.; Nara, S. J.; Harjani, J. R.; Salunkhe, M. M. Ionic liquid enabled
sulfamoylation of arenes: An ambient, expeditious and regioselective protocol
for sulfonamides. Tetrahedron Lett. 2004, 45, 1933–1936.
15. (a) Uzagare, M. C.; Sanghavi, Y. S.; Salunkhe, M. M. Application of ionic liquid
1-methoxyethyl-3-methylimidazolium methanesulfonate in nucleotide chemistry.
Green Chem. 2003, 5, 370–372; (b) Rasalkar, M. S.; Potdar, M. K.;
Salunkhe, M. M. Pseudomonas cepacia lipase-catalysed resolution of racemic
alcohols in ionic liquid using succnic anhydride: Role of triethylamine in enhance-
ment of catalytic acitivity. J. Mol. Cat. B 2004, 27, 267–270.
16. Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Juang, J.; Sun, D. Mannich reactions using
acidic ionic liquids as catalysts and solvents. Green Chem. 2004, 6, 75–77.