Calcite and fluorite as catalyst for the Kn?venagel condensation of malononitrile and methyl cyanoacetate under solvent-free conditions

Article abstract of DOI:10.1016/S0040-4039(02)02431-0

When milled together with calcite or fluorite, malononitrile and methyl cyanoacetate readily underwent Kn?venagel condensation with aromatic aldehydes, giving the corresponding arylidenemalononitriles and (E)-α-cyanocinnamic esters in good to excellent yi

Full text of DOI:10.1016/S0040-4039(02)02431-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 399–401
Calcite and fluorite as catalyst for the Kno¨venagel condensation
of malononitrile and methyl cyanoacetate under
solvent-free conditions
Shinobu Wada and Hitomi Suzuki*
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda 669-1337, Japan
Received 24 September 2002; revised 24 October 2002; accepted 25 October 2002
Abstract—When milled together with calcite or fluorite, malononitrile and methyl cyanoacetate readily underwent Kno¨venagel
condensation with aromatic aldehydes, giving the corresponding arylidenemalononitriles and (E)-a-cyanocinnamic esters in good
to excellent yield. © 2002 Elsevier Science Ltd. All rights reserved.
The Kno¨venagel condensation has been an important
tool for constructing the a,b-unsaturated structure unit
from a carbonyl and an active methylene components.1
The reaction is usually carried out in the presence of a
weak base, which includes aliphatic amines such as
ethylenediamine and piperidine or corresponding
ammonium salts,2 amino acids such as glycine and
b-alanine,3 and potassium fluoride.4 The reaction is
strongly dependent on solvents and the solvents of
choice are benzene, ethanol and N,N-dimethylform-
amide (DMF). In recent years, soft Lewis acids,5
modified inorganic solids,6 resins,7 and phase-transfer
agents8 have been introduced as new catalysts.
Microwave and infrared irradiation have also shown its
utility in Kno¨venagel condensation under solvent-free
conditions.9,10
erals are intrinsically basic substances, but they cannot
be used as inorganic base in solution chemistry due to
the insolubility in organic solvents and water. Herein,
we wish to report that these minerals can work as a
mild catalyst for the Kno¨venagel condensation of mal-
ononitrile and methyl cyanoacetate with aromatic car-
bonyl compounds under ball-milling conditions, i.e. dry
and neutral conditions. In these two decades, solvent-
free organic synthesis has received considerable atten-
tion due to growing worldwide concerns over chemical
wastes and future resources. From these points of view,
the present methodology offers advantage over tradi-
tional ones that have been performed in organic sol-
vents (Scheme 1).
Iceland spar (Mohs hardness, 3), a transparent variety
of natural calcium carbonate, and colorless fluorspar
(Mohs hardness, 4) were purchased in the form of
crystalline block and hammered into pieces of 1–3 mm
in size before use. The mineral reagent thus obtained
was placed, together with small stainless balls of 7 mm
Alkaline earth carbonate and fluoride are found as
limestone (calcite) and fluorspar (fluorite) in Nature.
They occur in huge quantities and serve as sources for
calcium- and fluorine-based products. These rock min-
Scheme 1.
Keywords: Kno¨venagel condensation; solid phase synthesis; nitriles; catalysts.
* Corresponding author. Fax: +81-795-65-9077; e-mail: hsuzuki@ksc.kwansei.ac.jp
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02431-0

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S. Wada, H. Suzuki / Tetrahedron Letters 44 (2003) 399–401
diameter, in a stainless cylinder (1.2×4 cm) with a screw
cap and a 1:2-molar mixture of an aromatic aldehyde
and malononitrile was introduced. The reaction vessel
was closed and shaken using a laboratory ball-mill
apparatus at a rate of 30 Hz for 0.5 h at room
temperature. The resulting pale yellow to light brown
powder or pasty solid was extracted with ethyl acetate
by trituration. The extract was filtered on a thin bed of
a Celite and evaporated to leave the expected product.11
As can be seen from Table 1, the yields obtained were
good to excellent. Even in the presence of excess min-
eral, neither the telomerization of malononitrile nor the
polymerization of condensation products was observed.
When methyl cyanoacetate was similarly allowed to
react with aldehydes, the reaction occurred with the
stereoselective formation of (E)-cyanocinnamic esters.
However, oxidative loss of aldehydes became serious.
The addition of a small amount of hydroquinone as
antioxidant was found to solve the problem (entries
16–18).
Reagent-grade calcium carbonate and fluoride are com-
mercially available in the form of fine powder which,
however, proved to be unsatisfactory for the Kno¨ve-
nagel condensation under milling conditions. Thus, it
may be pertinent to speculate on the role of calcite and
fluorite employed. When the minerals are mechanically
crushed, the newborn solid surface should be highly
activated with the naked ionic species in situ generated.
The naked carbonate and fluoride anions act as a
strong base capable of deprotonating the active methyl-
ene compounds, with the consequent formation of a
carboanion stabilized via the coordination with calcium
cation, which combines with a carbonyl compound,
eventually leading to the Kno¨venagel product.
Aldehydes bearing an electron-withdrawing group
afforded the highest yields relative to other ones, while
aldehydes bearing an electron-donating group led to
lower yield. The reaction vessel was not airtight, so
benzaldehyde and p-tolualdehyde suffered extensive
oxidation during milling, lowering the yield of conden-
sation products (entries 5 and 7). However, the Michael
addition reaction of the initial product with a second
molecule of active methylene component to form a
1:2-addition product was not observed under the condi-
tions employed. The reaction appears to be subject to
considerable steric effect. Thus, in the case of aromatic
ketones, acetophenone was quite sluggish to react, giv-
ing the expected product only in 23% yield under the
same conditions. As expected, benzophenone failed to
react.
In summary, we have developed an attractive alterna-
tive to the classical Kno¨venagel condensation. The
reaction proceeds on the mechanically crushed mineral
surface under completely solvent-free and neutral con-
ditions. It is fast, clean and of low cost, work-up
procedure is simple, and yield is good to excellent. The
present methodology was also found to be applicable to
the aldol-type condensation between active methylene
and carbonyl compounds,13 the details of which will
appear in a forthcoming paper.
Table 1. Calcite/fluorite-mediated Kno¨venagel reaction of
aromatic aldehydes with malononitrile and methyl
cyanoacetate
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S. Wada, H. Suzuki / Tetrahedron Letters 44 (2003) 399–401
401
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