Clean synthesis in water. Part 2: Uncatalysed condensation reaction of Meldrum's acid and aldehydes

Article abstract of DOI:10.1016/S0040-4039(01)00978-9

The environment-friendly condensation of Meldrum's acid and aromatic, heteroaromatic and hindered aliphatic aldehydes is performed carrying out the reaction in water at 75°C for 2 h, avoiding the addition of any catalyst.

Full text of DOI:10.1016/S0040-4039(01)00978-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5203–5205
Clean synthesis in water. Part 2: Uncatalysed condensation
reaction of Meldrum’s acid and aldehydes
Franca Bigi,* Silvia Carloni, Leonetto Ferrari, Raimondo Maggi, Alessandro Mazzacani and
Giovanni Sartori
Dipartimento di Chimica Organica e Industriale dell’Universita`, Parco Area delle Scienze 17/A, I-43100 Parma, Italy
Received 6 June 2001
Abstract—The environment-friendly condensation of Meldrum’s acid and aromatic, heteroaromatic and hindered aliphatic
aldehydes is performed carrying out the reaction in water at 75°C for 2 h, avoiding the addition of any catalyst. © 2001 Elsevier
Science Ltd. All rights reserved.
The use of water as a solvent in organic chemistry was
rediscovered in the 1980s by Breslow,1 who showed that
hydrophobic effects can strongly enhance the rate of
several organic reactions. Previously the scant solubility
of the reactants was the main reason that ruled this
solvent out from studies.
have investigated the condensation reaction of Mel-
drum’s acid and aldehydes.
The reactivity of the Meldrum’s acid (2,2-dimethyl-1,3-
dioxan-4,6-dione) as a methylene active compound was
explored about 40 years after its preparation, when the
structure was correctly attributed by Davidson and
Bernhard5 assigning the acidic proton to the central
carbon, and its high acidity is still object of study.6
Further reasons that make water unique among sol-
vents are that it is cheap, not inflammable, and more
importantly, it is not toxic. Choice of solvent is one of
the problems to face in order to perform eco-efficient
processes. The reaction promoters also deserve to be
reinvestigated, because large amounts of waste are pro-
duced in the fine-chemicals industry, mainly due to
stoichiometric reactions and to organic and inorganic
salt formation during the quenching procedure.2
It is known that the Meldrum’s acid undergoes stan-
dard Knoevenagel condensation with aromatic and het-
eroaromatic aldehydes furnishing the corresponding
arylidene derivatives, which are versatile substrates for
different kinds of reactions.7 They are useful intermedi-
ates for cycloaddition reaction and for the synthesis of
heterocyclic compounds with potential pharmacological
activity.8 The 1,4-addition of nucleophiles has been
widely used synthetically, displaying some advantages
over the acyclic malonate analogues, and the conju-
As part of our research program concerning the use of
water as an eco-compatible reaction solvent3 and keep-
ing in mind that ‘the best catalyst is no catalyst’,4 we
Scheme 1. Knoevenagel condensation of Meldrum’s acid and aldehydes.
Keywords: Meldrum’s acid; water; uncatalysed reaction; Knoevenagel condensation; arylidene Meldrum’s acid; environmentally benign synthesis.
* Corresponding author. Tel.: +39-0521-905411; fax: +39-0521-905472; e-mail: bigi@unipr.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00978-9

5204
F. Bigi et al. / Tetrahedron Letters 42 (2001) 5203–5205
gated reduction is the way most often used to prepare
5-monoalkyl Meldrum’s acids, also applied to obtain
deuterated carboxylic acids.9
Our recent results on uncatalysed preparation of
ylidenemalononitriles3b have prompted us to investigate
the reaction of 2,2-dimethyl-1,3-dioxan-4,6-dione 2 and
4-chlorobenzaldehyde 1a in water without adding any
catalyst. As desired we succeeded in obtaining the
unsaturated product 3a in 60% yield carrying out the
reaction at 75°C for 2 h without adding any catalyst
(Scheme 1).
The Knoevenagel condensation of aldehydes and Mel-
drum’s acid is generally catalysed by bases, such as
pyridine5,10 or by piperidine/glacial acetic acid in ben-
zene with water removal,11 often using an excess of
aldehyde to minimise the undesired formation of a bis
adduct, due to the Michael addition with a second
molecule of the methylene component.7c Uncatalysed
reaction was reported in the literature using DMF or
DMSO as solvent (solvents that are toxic, teratogenic
and suspected carcinogens), giving mixtures of unsatu-
rated and Michael addition products.12 More recently
anhydrous zinc chloride was reported to promote the
reaction in absence of any solvent.13
To investigate this reaction we first examined the sol-
vent effect employing solvents with different properties,
like polarity, proticity and dielectric constant.
The data reported in Table 1 show that the reaction is
favoured in water, although it involves the elimination
of a molecule of water. Similar unusual solvent effects
have been previously found by other authors14 and by
ourselves,3 but usually in the presence of a catalyst.
Table 1. Solvent effect in the reaction between 4-
chlorobenzaldehyde 1a and Meldrum’s acid 2
It is interesting to observe the remarkable difference
between the protic solvents water and ethanol. In etha-
nol the reaction was unselective, due to Michael addi-
tion and transesterification processes. We suggest that
water is the best solvent because it favours the Mel-
drum’s acid dissociation, due to its high m value, that
generates the nucleophilic species able to attack the
aldehydic carbon. Although the reaction carried out
without any solvent gave a similar result we selected
water as the medium of choice because it offers some
Entry
Solvent
Yield (%)
1
2
3
4
Water
60
38
23
30a
Toluene
Dioxane
Ethanol
a Unselective reaction.
Table 2. Uncatalysed condensation between Meldrum’s acid and aldehydes

F. Bigi et al. / Tetrahedron Letters 42 (2001) 5203–5205
5205
advantages, in addition to its low cost and no
References
inflammability. It also gives easy isolation of the
product by Buckner filtration and the possibility of
employing every kind of aldehyde, liquid as well as solid
ones without any stirring problems.
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This uncatalysed process was extended to different alde-
hydes, aromatic, heteroaromatic and hindered aliphatic
ones (Table 2).15
3. (a) Bigi, F.; Chesini, L.; Maggi, R.; Sartori, G. J. Org.
Chem. 1999, 64, 1033–1035; (b) Bigi, F.; Conforti, M. L.;
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The different reactivity of variously substituted alde-
hydes could be rationalised taking into account that the
reaction occurs in two steps, i.e. the nucleophilic attack
and the dehydration (Scheme 1). Electron-withdrawing
substituents facilitate the first step, meanwhile electron-
donor substituents facilitate the loss of water giving a
conjugated stabilised olefin. Further, in these latter cases
no trace of bis adduct was observed. This uncatalysed
reaction could be extended to hindered aliphatic alde-
hyde 1g furnishing the corresponding product 3g in
good yield.
4. This comment was written in ChemWeb, The Alchemist
May 2000, regarding our previous work on uncatalysed
preparation of ylidenemalononitriles.
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It is noteworthy that all of the products 3 are easily
isolated by simple Buchner filtration.
In order to check the reaction selectivity, detecting the
possible formation of a bis adduct, we have examined
1
the reaction crude mixture and products by H NMR
spectroscopy observing a dramatic solvent effect. It is
necessary to use dilute solution in CDCl3 as solvent,
completely avoiding DMSO-d6, in which the bis adduct
converts in an equimolar mixture of olefin and Mel-
drum’s acid. The same retro-addition process occurs
when DMSO-d6 is added to a sample in CDCl3.
13. Rao, P. S.; Venkataratnam, R. V. Indian J. Chem. B
1993, 32, 484–486.
In conclusion we have shown that the condensation
reaction of Meldrum’s acid and aldehydes efficiently
occurs in water without adding any catalyst, by heating
at 75°C for 2 h, providing a convenient, salt-free and
efficient synthesis of 5-arylidene and alkylidene Mel-
drum’s acids.
14. (a) Laszlo, P. Acc. Chem. Res. 1986, 19, 121–127; (b)
Kloestra, K. R.; van Bekkum, H. J. Chem. Soc., Chem.
Commun. 1995, 1005–1006; (c) Lednor, P. W.; de Ruiter,
R. J. Chem. Soc., Chem. Commun. 1991, 1625–1626.
15. The general procedure for the synthesis of unsaturated
compounds 3 is as follows: A mixture of Meldrum’s acid
(5.5 mmol) and the selected aldehyde (5 mmol) in water
(10 ml) was stirred at 75°C for 2 h. After cooling to room
temperature the solid product was filtered on Buchner
and dried under vacuum. The purification from traces of
starting aldehyde, when present, was performed by crys-
tallisation. All products 3a–h were characterised (1H
NMR, IR and MS) and their melting points compared
with literature reported values.
Acknowledgements
We acknowledge the support of the Ministero dell’Uni-
versita`
e della Ricerca Scientifica e Tecnologica
(MURST), Italy, and the University of Parma (National
Project ‘Processi puliti per la Chimica Fine’). We are
also grateful to the Centro Interfacolta` Misure (CIM)
for the use of NMR and mass spectrometry instruments.
.