Tandem catalytic condensation and hydrogenation processes in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2005.01.092

A domino reaction composed of a Knoevenagel condensation combined with a simultaneous catalytic hydrogenation is reported in an ionic liquid solvent under mild conditions (298-363 K and 300 kPa). No interference between the catalysts (Pd/C and amine acetate salt) of the two diverse steps was monitored. The product could be neatly extracted by diethyl ether and the solvent containing the catalysts could be recycled and reused five times without any loss in activity or selectivity. The same methodology in a common organic solvent such as DMA resulted in significant competing parallel hydrogenation of the aldehyde to alcohol.

Full text of DOI:10.1016/j.tetlet.2005.01.092

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1885–1887
Tandem catalytic condensation and hydrogenation
processes in ionic liquids
Mubeen Baidossi,a Asutosh V. Joshi,a Sudip Mukhopadhyayb and Yoel Sassona,*
aCasali Institute of Applied Chemistry, Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel
bDepartment of Chemical Engineering, University of California at Berkeley, Berkeley, CA 94720, USA
Received 1 October 2004; revised 11 January 2005; accepted 19 January 2005
Abstract—A domino reaction composed of a Knoevenagel condensation combined with a simultaneous catalytic hydrogenation is
reported in an ionic liquid solvent under mild conditions (298–363 K and 300 kPa). No interference between the catalysts (Pd/C and
amine acetate salt) of the two diverse steps was monitored. The product could be neatly extracted by diethyl ether and the solvent
containing the catalysts could be recycled and reused five times without any loss in activity or selectivity. The same methodology in a
common organic solvent such as DMA resulted in significant competing parallel hydrogenation of the aldehyde to alcohol.
Ó 2005 Elsevier Ltd. All rights reserved.
Tandem (or ÔdominoÕ) reactions are highly desirable for
increasing the efficiency of a synthetic route by inducing
multiple transformations of a substrate in one operation
with diminution in the separation and purification of
intermediates.1 The major challenge associated with the
design of new catalytic domino processes is the selection
of catalysts and reaction conditions in such a way that no
interference or cross contamination will take place be-
tween the concurrent catalytic reactions. Utilization of
unique multiphase solvent systems such as fluorous sol-
vents2 or ionic liquids3 can contribute to this aim.
In this study we have carried out a catalytic Knoevena-
gel condensation of a cyanoacetate ester with various
aldehydes and ketones under hydrogen pressure in the
presence of palladium on carbon using ionic liquids as
solvents. No disturbance was detected between the metal
hydrogenation catalyst and the ammonium salt conden-
sation catalyst and both processes proceeded smoothly
in a simultaneous manner.
Ionic liquids (IL) such as 1-butyl-3-methylimidazolium
tetrafluoroborate ([bmim]BF4) or hexafluorophosphate
([bmim]PF6) are very promising green solvents with uni-
que properties such as negligible vapor pressure, forma-
tion of a separate liquid phase both with water and with
common organic solvents, good capacity for solubilizing
organic substrates, ease of recycling and reuse and lack
of flammability.3
We were interested in merging a condensation step with
a subsequent catalytic hydrogenation step to provide a
methodology for a tandem synthesis of hydrocinnamic
acids and other phenethyl derivatives. In a previous re-
port4 we have disclosed the analogous combination of
a Heck reaction with a hydrogenation process to yield
1,2-diphenylethane in one (tandem) step starting with
styrene and chlorobenzene (Eq. 1):
Ionic liquids have been used as solvents in homogeneous
catalytic hydrogenation including asymmetric hydroge-
nation.5 ILs were found to stabilize the air sensitive chiral
homogeneous catalyst Rh–MeDuPHOS and in other in-
stances were used for recovery and recycling of the cata-
lyst.6 Ligand protected palladium nanoparticles have also
been used as hydrogenation catalysts in ionic liquids.7
CH=CH
Cl
2
Pd/C
+
ð1Þ
β-cyclodextrin
50%
100°C
+ HCO2- + H2O
+ HCO3- + HCl
100% conversion
Knoevenagel condensations are effectively conducted in
an IL using ethylenediammonium diacetate (EDDA) as
the catalyst.3 Ammonium and amine salts are long
known as better catalysts than the free amines in these
reactions.8
Keywords: Knoevenagel condensation; Pd/C; Ionic liquids;
Hydrogenation.
*
Corresponding author. Tel.: +972 2 6584530; fax: +972 2 6529626/
5667064; e-mail: ysasson@huji.ac.il
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.092

1886
M. Baidossi et al. / Tetrahedron Letters 46 (2005) 1885–1887
Table 1. Domino condensation and reduction results (Eq. 2)
We have developed the condensation reaction of ethyl
cyanoacetate with aldehydes or ketones combined with
the simultaneous reduction of the C@C bond under
300 kPa pressure of dihydrogen in the presence of a mix-
ture of the EDDA and Pd/C catalysts (Eq. 2)
Entry
Substrate
Time
(h)
Yield (%) and
conversion (%)
(based on GC)
1a
Benzaldehyde
4-Anisaldehyde
4.5
4.5
99(100)
85(100)
92(100)
90(100)
100(100)
71(100)
70(100)
2a
3a
2,4-Dimethoxybenzaldehyde
2,3-Dimethoxybenzaldehyde
4-Isopropylbenzaldehyde
2-Naphthaldehyde
4-Chlorobenzaldehyde
Propanal
4.5
4.5
4a
O
5a
4.5
4.5
6a
10% EDDA
10% Pd/C
[bmim]BF4
O
1
1
2
R
R
7a
5
(110209)2
O
H
2
CH CH
C
O
CN
+
+
+ H2O
8a,c
9a,c
10a,c
11a,c
12a
13a
14a
15b
16b
17b
300 kPa
25-90°
4-12 h
R2
R
CN
O
Butanal
Pentanal
Hexanal
1290(100)
1295(100)
10 90(100)
4.5
3
1
2
R1, R2 = H,alkyl or aryl
90-100%
ð2Þ
Phenylacetaldehyde
Acetophenone
Cyclohexanone
97(100)
85(30)
100(100)
98(75)
27(50)
98(90)
4
4
Unpredictably when reaction 2was carried out in a
common organic solvent such as DMA a considerable
amount of benzyl alcohol and toluene was formed by
competing direct hydrogenation of the starting alde-
hyde. Evidently the selective reaction 2is unique to
the IL environment.
Ethyl acetoacetate
Diethyl malonate
Ethyl cyanoacetate
15
17
5
a Ethyl cyanoacetate was used as substrate.
b 4-Anisaldehyde was used as substrate.
c The reaction was carried out at room temperature. Experimental
procedure: see text.
In a typical procedure, a 22 ml Parr autoclave equipped
with a magnetic stirrer was charged with 25 mg of 5%
Pd/C (Sigma–Aldrich, 0.05 mmol) dispersed in 1.0 g of
[bmim]BF4, this IL was prepared according to the liter-
ature,9) 113.0 mg (1 mmol) of ethyl cyanoacetate, 2,
15 mg EDDA (0.1 mmol) and 1 mmol of a ketone or
aldehyde, 1. The autoclave was purged three times with
dihydrogen and a pressure of 300 kPa was maintained
throughout the process. The autoclave was placed in a
thermostatic oil bath for the desired time. After cooling,
the reaction mixture was extracted four times with 3 ml
portions of diethyl ether. Analysis and mass balance
were accomplished using gas chromatography. The
combined extracts were evaporated under vacuum and
purified over a silica gel column using 20 ml of a 5:1
petroleum ether–ethyl acetate mixture as eluent. The
products were identified using mass spectroscopy. The
mass balance was calculated based on GC analysis using
authentic samples as standards.
hyde, 2-tolualdehyde, 4-anisaldehyde, 2,4-dimethoxy-
benzaldehyde, 2,3-dimethoxyacetaldehyde, 4-isoprop-
ylbenzaldehyde, 2-naphthaldehyde, 2-, 3- and 4-chloro-
benzaldehyde after 4.5 h (Table 1, entries 1–7).
The yield of the saturated aromatic products exceeded
95% in all cases with the exception of 2-naphth-
aldehyde (71% of the saturated product and 28% of
the unsaturated product). This is probably due to steric
hindrance affecting the hydrogenation rate (Table 1,
entry 6). The reactions of chlorobenzaldehydes suffered
from competing dehydrochlorination which decreased
the yields of the desired product to 70% (Table 1,
entry 7).
Ketones such as acetophenone and cyclohexanone re-
acted under the latter conditions to give complete con-
version and practically quantitative yields of the
saturated product (Table 1, entries 13–14).
Both the Pd/C and EDDA catalysts remained in the
ionic liquid after the extraction step with diethyl ether
and were consequently recycled for a second catalytic se-
quence. The combined solvent and catalyst mixture
could be used in five consecutive experiments without
any loss in activity and selectivity. The prompt disper-
sion of the Pd/C catalyst in [bmim]PF6 and its conve-
nient reuse were previously reported by Hagiwara
et al.10 who applied this system to the Heck reaction.
Other active methylene compounds such as ethyl aceto-
acetate, diethyl malonate, and ethyl cyanoacetate re-
acted with aliphatic and aromatic aldehydes in a
similar manner (Table 1, entries 15–17).
In view of a kinetic analysis of the second reaction with
acetaldehyde as an electrophile (based on GC analyses
of samples taken from the reaction mixture every
30 min), we asserted that the rate of the condensation
step is approximately an order of magnitude faster than
the hydrogenation step.
With aliphatic linear aldehydes as substrates, the second
reaction, took place swiftly at 25 °C. Thus acetalde-
hyde, propanal, butanal, pentanal, hexanal, and phen-
ylacetaldehyde all reacted according to Eq. 2 with
100% conversion after 12h with yields of the saturated
products exceeding 90% in all cases (Table 1, entries
8–12).
We verified that competing condensation reactions of
the aldehydes with the weakly acidic IL solvent (an
imidazole salt with a pKa = 24) reported by Mereu and
co-workers11 did not occur under our reaction
conditions.
Aromatic aldehydes required a higher temperature. At
95 °C complete conversion was recorded for benzalde-

M. Baidossi et al. / Tetrahedron Letters 46 (2005) 1885–1887
1887
5. Sheldon, R. Chem. Commun. 2001, 2399.
Other supported noble metals such as Ru/C, Rh/C and
Pt/C all gave poor hydrogenation performance in the
second reaction under the above conditions.
6. (a) Monteiro, A. L.; Zinn, F. K.; De Souza, R. F.;
Dupont, J. Tetrahedron: Asymmetry 1997, 8, 177; (b)
Chauvin, Y.; Mussmann, L.; Olivier, H. Angew. Chem.,
Int. Ed. Engl. 1996, 34, 2698; (c) Berger, A.; De Souza, R.
F.; Delgado, M. R.; Dupont, J. Tetrahedron: Asymmetry
2001, 12, 1825; (d) Brown, R. A.; Pollet, P.; McKoon, E.;
Eckert, C. A.; Liotta, C. L.; Jessop, P. G. J. Am. Chem.
Soc. 2001, 123, 1254; (e) Guernik, S.; Wolfson, A.;
Herskowitz, M.; Greenspoon, N.; Geresh, S. Chem.
Commun. 2001, 2314.
To conclude, we have demonstrated that a Knoevenagel
type condensation can be coupled effectively with cata-
lytic hydrogenation in an ionic liquid as a solvent, to
engender a tandem process directly leading to functional
saturated carboxylic acids.
References and notes
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