'On water' Knoevenagel condensation of isatins with malononitrile

Article abstract of DOI:10.1016/j.mencom.2011.07.018

Grinding of isatins with malononitrile in the presence of 1-5 equiv. of water for 15 min at room temperature affords the corresponding (2-oxo-1,2-dihydro-3H-indol-3-ylidene)malononitriles, the Knoevenagel condensation products, in 89-99% yields.

Full text of DOI:10.1016/j.mencom.2011.07.018

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 224–225
‘On water’ Knoevenagel condensation of isatins with malononitrile
Dmitry V. Demchuk, Michail N. Elinson* and Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail elinson@ioc.ac.ru
DOI: 10.1016/j.mencom.2011.07.018
Grinding of isatins with malononitrile in the presence of 1–5 equiv. of water for 15 min at room temperature affords the corresponding
2-oxo-1,2-dihydro-3H-indol-3-ylidene)malononitriles, the Knoevenagel condensation products, in 89–99% yields.
(
Knoevenagel condensation is a nucleophilic addition of active
hydrogen compound to carbonyl group followed by dehydration
in which molecule of water is eliminated.1 The reaction is
Table 1 Solvent-free and ‘on water’ condensation of isatins 1a–f with
malononitrile.a
–3
Isatin
Equiv. H O
Product
Yield (%)b
2
3
–11
catalyzed by various amines, ammonium salts or Lewis acids
and can be effected by microwave irradiation in the absence
1
1a
a
–
1
3
1
1
1
1
3
5
1
3
5
2a
2a
2a
2b
2c
2d
2e
2e
2e
2f
75
81
99
99
99
99
81
85
93
78
89
96
1
2–15
of the solvent.
Particularly, in recent years, reactions under
1
1
1
1
1
1
1
1
a
b
c
d
e
e
e
f
solvent-free conditions have continuously attracted the attention
of the researchers due to significant simplification of the pro-
cedure.
Condensation of aromatic aldehydes with malononitrile could
not been achieved under solvent-free conditions at room tempe-
1
6
rature, however, it was accomplished as melt reaction at 150°C
1
6
in 1 h. An improved procedure for solvent-free condensation of
aromatic aldehydes with malononitrile by 45 min grinding was
1f
1f
2f
2f
1
7
reported. The yields in the case of liquid aromatic aldehydes
were 80–95%, except for benzaldehyde (only 68% of condensa-
tion product) because this aldehyde is volatilized during the
a1a (2 mmol), malononitrile (2 mmol), 20°C, grinding 15 min. Isolated
b
yields.
1
3
grinding. Recently an effective method was reported for the
solvent-free condensation of benzaldehyde with malononitrile
in 10 min with the mechanochemical mixing in the presence of
MgO as the catalyst.18
First, to evaluate the synthetic potential and to optimize the
procedure proposed, the condensation of isatin 1a with malono-
nitrile leading to the product 2a was studied (Table 1).
In fact, grinding of 2 mmol isatin 1a with 2 mmol malonitrile
for 15 min resulted in formation of 2a in 75% yield. Surprisingly,
the yield of 2a in this procedure was raised to 99% by preliminary
adding 3 equiv. of water to the reaction mixture. Under similar
conditions the other substituted isatins 1b–f were also effi-
ciently converted into the corresponding adducts 2b–f in 15 min
in 89–99% yields.
The indole scaffold including isatin (1H-indole-2,3-dione)
represents the important structural subunit for the discovery of
new drug candidates.19 Isatin 3-positioned carbonyl group is
known to be active in various condensation reactions.
Here, we report our results on the solvent-free condensation of
isatins with malononitrile under grinding conditions (Scheme 1,
†
Table 1).
The Knoevenagel condensation is strongly solvent-dependent.
The first step (aldol addition) is facilitated in the solvents with
the high polarity and the second step (1,2-elimination) is inhibited
NC
grinding,
15 min/
H2O
CN
O
O
R2
R2
CN
CN
2,3
by protic solvents. Our experiments indicate that grinding
O
+
room
temperature
promotes the elimination step. To our knowledge, this is the first
example of the Knoevenagel condensation between two solid com-
pounds promoted by grinding at room temperature in the absence
of solvents and any catalyst.
N
R1
N
R1
1
a–f
2a–f
1
2
1
2
Note that 1–3 equiv. water additive caused raising the yield
of the condensation product between 1a and malononitrile from
75 to 99%. In the case of isatins bearing electron-withdrawing
substituents 1e,f the best results were obtained with adding 5 equiv.
of water. Meanwhile, for isatins 1b–d with electron-donating sub-
stitutents, 1 equiv. of water was sufficient to reach the yields of 99%.
Isatins 1a–f are insoluble in water. Being grinded, a mixture
of isatin 1, malononitrile and water form two phase solid–liquid
system. The solid phase consists of isatin 1 and partly malono-
nitrile, and liquid phase is the solution of malononitrile in water.
Then, reaction of the water solution of malononitrile with solid
isatins 1a–f is activated by grinding in the same manner as in the
a R = R = H
b R = Me, R = H
c R = Et, R = H
d R = CH2Ph, R = H
1
2
1
2
e R = H, R = Cl
1
2
1
2
f
R = H, R = Br
Scheme 1
†
General procedure. A mixture of isatine (2 mmol), malononitrile (145 mg,
.2 mmol) and water (36–180 mg, 2–10 mmol) (Table 1) was mixed
2
thoroughly in a mortar with pestle followed by grinding for 15 min. The
resultant mixture was air dried to cause crystallization of the product. In
somecasesanalyticalsamplesoftheproductwereadditionallycrystallized
from ethanol.
For characteristics of (2-oxo-1,2-dihydro-3H-indol-3-ylidene)malono-
nitriles 2a–f, see Online Supplementary Materials.
1
7
case of liquid aldehydes.
– 224 –
©
2011 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2011, 21, 224–225
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Apparently, in the present study water should facilitate the
aldol formation step as solvent, while the second step (1,2-eli-
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This work was supported by the Presidential Scholarship
Program for State Support of Leading Science Schools of the
Russian Federation (project no. 4945.2010.3).
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.07.018.
References
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Received: 24th December 2010; Com. 10/3650
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