Table 1 Influence of different catalysts and reaction conditions on the yield of 1b
Entry
1a/CH2(CN)2 molar ratio
Catalyst
Temperature (◦C)
Yield/time (%/h)
1
2
3
4
5
6
1 : 1.2
1 : 1.2
1 : 1.2a
1 : 1.2a
1 : 1.2a
1 : 1.2a
CH3COO NH4
100
80
100
80
100
120
46/1
72/2
76/1
82/2
86/1
92/1
Piperidine (morpholine)
Piperidine (morpholine)
Morpholine–MSA
Morpholine–MSA
Morpholine–MSA
a Second portion of malononitrile (1.2 mol equiv.) was added after 30 min.
and monitored by means of TLC. The products were iso-
lated by column chromatograpy or crystallization (Table 2,
Entry 7). However, in most cases flash chromatography
SiO2/toluene led to compounds of a purity (above 93% on
the basis on 1H NMR spectra) suitable for most of our
purposes.
Syntheses of cycloalkylidenemalononitriles were done on
50 mmol scale in order to make distillation of products more
convenient. First, we tried to apply free morpholine as a
catalyst but polymerisation of the products under solvent-
free conditions resulted in a very low yield of the expected
cycloalkylidenemalononitriles 9b and 10b. This process was
most striking in the case of morpholine-catalyzed condensation
of cyclopentanone at 100 ◦C, when after short period of
time (5 min) only a small quantity of product 9b could be
isolated.
a few drops of glacial acetic acid which prevented further
dimerization.
It is also noteworthy that in the case of 4-aminoacetophenone
(17a), the amine group works as a catalyst and only a small
amount of MSA should be added to the reaction mixture.
The less-reactive benzophenone 19a failed to condense with
malononitrile under these conditions.
Conclusions
In conclusion we have demonstrated that a major improve-
ment is achieved when Knoevenagel condensation of ketones
with malononitrile is performed under solvent-free condi-
tions. Most available Knoevenagel condensation procedures
published to date require long reaction time, addition of
solvents, continuous removal of water or use of an expen-
sive catalyst. The reported procedure is low-cost, simple and
safe.
Moreover, cycloalkylidenemalononitriles required additional
washing with water before distillation to avoid degrada-
tion. Although compounds 11b and 12b are much less
prone to polymerization, attempted distillation of crude cy-
clopentylidenemalononitrile 9b resulted in the formation of
a polymer.
Experimental
All ketones were purchased from Aldrich and used without
further purification or synthesized according to known methods.
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded
on a Bruker Avance II spectrometer.
On the other hand, condensation of cyclooctanone with
malononitrile after 15 minutes yielded 82% of the crude product
contaminated with approximately 9% of unchanged ketone (on
1
the basis on H NMR spectrum). The addition of the second
portion of malononitrile and prolonging the reaction time to
1 hour allowed the complete conversion of ketone 12a, but the
yield of 12b was lower (69%).
Typical procedure
Our attention turned to the study of the utility of this protocol
in condensation of conjugated ketones with malononitrile. As
was expected the reactions were more difficult with aromatic
ketones. We attempted to optimize the reaction conditions but
yields of the products were significantly lower than in the case
of alkyl ketones (Table 3).
Applying a slightly modified procedure we noted that the
yield of corresponding olefins is in the order of 40–70%.
However, difficulties were still encountered in reactions of
these ketones with malononitrile, especially at the purification
stage. Apart from the dimerization4 process leading to com-
pounds which can be separated using flash chromatography
(SiO2/toluene) we found that column chromatography is not
suitable for the isolation of products. Therefore all products
outlined in Table 3 were, after flash chromatography, crys-
tallized from the appropriate solvent10 with the addition of
In a 10 mL flask was placed 2-(1-naphthyl)cyclopentanone
1a (2.10 g, 10.0 mmol), malononitrile (790 mg, 12.0 mmol),
morpholine (50.0 mg, 0.57 mmol) and methanesulfonic acid
(50.0 mg, 0.52 mmol). The flask was equipped with a drying
tube (or small reflux condenser), placed into a preheated
oil bath and stirred for 30 min. Then a second portion of
malononitrile (790 mg, 12.0 mmol) was added and the reaction
mixture was stirred for an additional 30 min. After allowing
the mixture to cool to room temperature, the flask content
was extracted with toluene (3 ¥ 5 mL). Combined organic
extracts were washed with water (2 ¥ 20 mL) and concentrated in
vacuo. Product was purified by column chromatography (SiO2/
toluene) to give 2-(1-naphthyl)cyclopentylidenemalononitrile
1b (2.37 g, 9.2 mmol, 92%) as a yellowish, viscous oil
which crystallized after 2 days yielding yellow needles mp
81–83 ◦C.
864 | Green Chem., 2009, 11, 863–867
This journal is
The Royal Society of Chemistry 2009
©
Gora
