available reagents would extend the scope of the Knoevenagel-
Doebner reaction in organic synthesis. Recently, gem-dihalom-
ethylarenes have received considerable attention due to their
application in the preparation of aldehydes.6 To our knowledge,
the use of gem-dihalomethylarenes is limited to the synthesis
of aldehydes and there is no literature on their use to synthesize
R,â-unsaturated carboxylic acids. In this Note, we report a new,
rapid, and efficient method for the Knoevenagel-Doebner
reaction via the reaction between a gem-dibromomethylarene
(as a substitute for aldehyde) and an active methylene compound
such as malonic acid, thus providing access to R,â-unsaturated
carboxylic acids.
The synthetic approach started from the commercially avail-
able benzal bromide. A mixture of benzal bromide 1a (1.0 equiv)
and malonic acid (2.0 equiv) with anhydrous pyridine in the
presence of a catalytic quantity (0.04 equiv) of piperidine was
stirred at reflux. The starting material was consumed in 1.5 h
as indicated by TLC analysis. After workup and purification
by crystallization, cinnamic acid 2a was isolated in 93% yield.
Use of 2 equiv of malonic acid was found to be optimal for the
complete conversion of 1a to 2a. Screening of various base
catalysts such as triethylamine, N-ethyldiisopropylamine, DBU,
DABCO, pyrrolidine, and morpholine was carried out. While
pyrrolidine and morpholine catalyzed the reaction to quantitative
yields in 2-3 h, the other bases were found to be inefficient in
promoting this reaction.
Next, we examined the progress of the reaction by omitting
piperidine. When a mixture of benzal bromide and malonic acid
was refluxed with anhydrous pyridine in the absence of
piperidine, 14 h were required for the reaction to afford 17%
of 2a along with 73% of benzaldehyde after aqueous workup.
With a catalytic amount of piperidine, the reaction took barely
an hour for completion. Encouraged by this success, the other
gem-dibromomethylarenes 1b-p were subjected to the Kno-
evenagel-Doebner reaction with malonic acid to yield the
corresponding R,â-unsaturated carboxylic acids in excellent
yields. The results are depicted in Table 1.
Herein, we report a general approach to R,â-unsaturated
carboxylic acids in high yields by subjecting the easily accessible
gem-dibromomethylarenes to malonic acid in refluxing pyridine.
Benzal bromide is known to produce a fairly stable bis-
pyridinium cation on refluxing with pyridine. Kro¨hnke has
shown that the bis-pyridinium cation of benzal bromide is slowly
hydrolyzed in water to benzaldehyde and pyridine.7 As the
formation of benzaldehyde was not observed at any stage of
the reaction, we speculated a reaction involving nucleophilic
catalysis between the bis-cation and malonic acid followed by
gem-Dibromomethylarenes: A Convenient
Substitute for Noncommercial Aldehydes in the
Knoevenagel-Doebner Reaction for the Synthesis
of r,â-Unsaturated Carboxylic Acids
John Kallikat Augustine,*,† Yanjerappa Arthoba Naik,‡
Ashis Baran Mandal,† Nagaraja Chowdappa,† and
Vinuthan B. Praveen†
Syngene International Ltd., Biocon Park, Plot Nos. 2 and 3,
Bommasandra IV Phase, Jigani Link Road,
Bangalore-560 100, India, and Department of Chemistry,
KuVempu UniVersity, Shankaraghatta Post,
Shimoga-577 451, India
ReceiVed September 4, 2007
A facile synthesis of R,â-unsaturated carboxylic acids from
gem-dibromomethylarenes is described. gem-Dibromom-
ethylarenes are employed for the first time in the Knoev-
enagel-Doebner reaction as aldehyde equivalents for the
efficient synthesis of R,â-unsaturated carboxylic acids.
R,â-Unsaturated carboxylic acids compose a relatively large
family of organic acids, which are important reagents in organic
synthesis both as intermediates and final products. For example,
they have been used to prepare compounds of biological
relevance such as terahydromyricoid1 or the antibacterial
reutericyclin.2 Also, they are present in some natural products
(e.g., the secretion of juice of honeybee queen3 and caffeic acid4)
and are versatile building blocks in organic synthesis. For their
application in the food industry, polymer industry, perfume
industry, medicine, and technical applications, they are synthe-
sized on a commercial scale. Of the various methods, the
Knoevenagel-Doebner reaction is widely recognized as the
leading method to access the carbon-carbon double bond
necessary to provide the R,â-unsaturated carboxylic acid.5
Though the Knoevenagel-Doebner reaction has been exten-
sively documented, substitution of the aldehyde component with
an alternative functional group has not been documented.
Therefore, the development of a simple and stable substitute
for these aromatic aldehydes by using inexpensive and readily
(5) (a) Knoevenagel, E. Ber. 1898, 31, 2596 and 2619. (b) Doebner. O.
Ber. 1900, 33, 2104. (c) Kingsbury, C. A.; Max, G. J. Org. Chem. 1978,
43, 3131-3139. (d) Mogilaiah, K.; Reddy, G. R. Synth. Commun. 2004,
34, 2, 205-210. (e) McNulty, J.; Steere, J. A.; Wolf, S. Tetrahedron Lett.
1998, 39, 44, 8013-8016. (f) Manitto, P.; Monti, D.; Zanzola, S.; Speranza,
G. J. Org. Chem. 1997, 62, 19, 6658-6665. (g) Masuno, M. N.; Pessah, I.
N.; Olmstead, M. M.; Molinski, T. F. J. Med. Chem. 2006, 49, 4497-
4511. (h) Tokunaga, N.; Hayashi, T. Tetrahedron: Asymmetry 2006, 17,
607-613. (i) Arun, K. S.; Anuj, S.; Bhupendra, P. J. Tetrahedron 2007,
63, 960-965 and references cited therein.
* Address correspondence to this author. Phone: +91 80 2808 3131. Fax:
+91 80 2808 3150.
† Syngene International Ltd.
‡ Kuvempu University.
(1) Song, J.; Hesse, M. Tetrahedron 1993, 49, 6797-6804.
(2) Marquardt, U.; Schmid, D.; Jung, G. Synlett 2000, 1131-1132.
(3) Callow, R. K.; Johnston, N. C. Bee World 1960, 41, 152-153.
(4) Cho, H.; Ueda, M.; Tamaoka, M.; Hamaguchi, M.; Aisaka, K.; Kiso,
Y.; Inoue, T.; Ogino, R.; Tatsuoka, T.; Ishihara, T.; Noguchi, T.; Morita,
I.; Murota, S. J. Med. Chem. 1991, 34, 1503-1505.
(6) (a) Mandal, A. B.; Augustine, J. K.; Quattropani, A.; Bombrun, A.
Tetrahedron Lett. 2005, 46, 6033-6036. (b) Coleman, G. H.; Honeywell,
G. E. Organic Syntheis; John Wiley and Son: New York, 1943; Collect.
Vol. II, pp 89-91.
(7) Kro¨hnke, F.; Leister. H. Chem. Ber,. 1958, 91, 1295.
10.1021/jo701888m CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
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J. Org. Chem. 2007, 72, 9854-9856