Silica-immobilized piperazine: A sustainable organocatalyst for aldol and Knoevenagel reactions

Article abstract of DOI:10.1016/j.tetlet.2010.10.080

Silica-supported piperazine was found to be an efficient catalyst for aldol reactions of aromatic aldehydes and ketones with straightforward product isolation and catalyst reuse. Furthermore, the catalyst is active in Knoevenagel-type reactions to afford coumarin derivatives, using 2-methyltetrahydrofuran (2-MeTHF) as a novel bio-based solvent.

Full text of DOI:10.1016/j.tetlet.2010.10.080

Tetrahedron Letters 51 (2010) 6670–6672
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Silica-immobilized piperazine: A sustainable organocatalyst for aldol
and Knoevenagel reactions
Saravanakumar Shanmuganathan , Lasse Greiner a,b, Pablo Domínguez de María a,
a
⇑
a
Institute of Technical and Macromolecular Chemistry (ITMC), RWTH Aachen University, Worringerweg 1, 52074 Aachen, Germany
DECHEMA e.V., Karl-Winnacker-Institut, Theodor-Heuss-Allee 25, 60486 Frankfurt am Main, Germany
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Silica-supported piperazine was found to be an efficient catalyst for aldol reactions of aromatic aldehydes
and ketones with straightforward product isolation and catalyst reuse. Furthermore, the catalyst is active
in Knoevenagel-type reactions to afford coumarin derivatives, using 2-methyltetrahydrofuran (2-MeTHF)
as a novel bio-based solvent.
Received 19 September 2010
Revised 11 October 2010
Accepted 13 October 2010
Available online 21 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2
-Methyltetrahydrofuran
Aldol reaction
Knoevenagel condensation
Immobilized organocatalyst
Piperazine
Sustainable chemistry
Proline-like organocatalysis represents a promising entry to af-
ford important building blocks under mild reaction conditions,
1
N
Si
NH
bio-mimicking the performance of some aldolases (C–C bond for-
2
mation). The field has experienced an enormous development in
Figure 1. Silica-immobilized piperazine assessed as immobilized organocatalyst
last years with examples of highly selective amines designed as
see technical details in Section 1).6
(
1
catalysts. However, high organocatalyst loadings are often needed
to afford efficient syntheses. To overcome this, catalysts have been
immobilized on a range of supports. In some cases these supports
3
for comparison with a non-immobilized amine, the same reaction
was conducted with pyrrolidine as soluble catalyst (Table 1).7
Silica-immobilized piperazine is an efficient organocatalyst for
the C–C bond formation between aromatic aldehydes and acetone
at room temperature, leading to full conversion within 16 h. Nota-
bly, the addition of carboxylic acids as co-catalysts was not needed
to afford high efficiencies, in contrast to previous works with
may also mimic the role that a protein scaffold (enzyme) induces
over an organic cofactor (e.g., providing an adequate hydrophobic
3
a
micro-environment).
Despite the number of secondary amines as organocatalysts, the
4
use of piperazines (and analogues) has been scarce. Interestingly,
piperazine chemistry may provide straightforward possibilities for
catalyst design, together with a simple immobilization procedure
compared to other less-functionalized organocatalysts.5 Herein,
4
a,7
analogous amines.
Interestingly, variations in the product
distribution between aldol 3 and Mannich-type product 4 were
observed. With immobilized piperazine, benzaldehyde afforded
some proportion of Mannich-type product 4, whereas furfural led
to a complete selective process in favour of the aldol product 3.8
That suggests differences between catalytic routes depending on
the substrate. Mannich-type routes have been mostly observed
6
the assessment as an organocatalyst of a commercially available
silica-immobilized piperazine is reported (Fig. 1).
In a first set of experiments, aldol condensations with aromatic
aldehydes (benzaldehyde and furfural) and excess of acetone were
evaluated. Organocatalysis involving secondary amines may occur
via enamine or iminium routes, affording either aldol 3 or Man-
nich-type condensation 4, respectively. Low conversions have been
reported for these reactions when free piperazine is used.4d Thus,
7
for secondary amines as organocatalysts, consistent with the re-
sults obtained with pyrrolidine (Table 1). Therefore, silica-support
is not a mere inert structure in the reaction, but it is apparently
influencing the catalytic role of piperazine. Notably, furfural-based
aldol- and Mannich-products are presently being considered as
promising candidates to further produce liquid alkanes as biofu-
⇑
Corresponding author. Tel.: +49 241 8020468; fax: +49 241 8022177.
E-mail address: dominguez@itmc.rwth-aachen.de (P. Domínguez de María).
9
els. Obviously, an immobilized organocatalytic-based approach
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.080

S. Shanmuganathan et al. / Tetrahedron Letters 51 (2010) 6670–6672
6671
Table 1
Cross condensation of aromatic aldehydes with acetone catalyzed by silica-immobilized piperazine. Aldehyde: 1 mmol; acetone: 10 mmol. Total volume: 3 mL. Catalyst loading:
immobilized piperazine: 100 mg (0.1 mmol); pyrrolidine: 10 mol %. 16 h, room temperature. Conversions and yields based on 1H NMR assessment. Aliphatic aldehydes afforded
lower conversions (10–15% in 16 h), together with some self-condensation products (data not shown)
O
O
O
Organocatalyst, rt
OH
O
+
+
Ar
Ar
H
Ar
1
2
3
4
Organocatalyst
Aldehyde
Conversion (%)
Aldol 3 (%)
Mannich-type 4 (%)
30
O
N
N
Si
NH
NH
100
70
24
H
O
N
H
100
76
H
O
O
Si
O
O
1
1
00
00
100
79
0
H
H
21
N
H
leading to these syntheses under those conditions and at room
temperature might be a promising entry for the bio-based society.
Subsequently, catalyst recovery and reuse was evaluated taking
the condensation of benzaldehyde with acetone as a model reac-
tion, and showing that the immobilized catalyst could be effi-
ciently re-used. Likewise, the ratio between the aldol product 3
and the Mannich-type one 4 remained unaltered within the error
margin (Fig. 2).
The catalytic scope of the silica-immobilized piperazine was
also assessed for the Knoevenagel condensation between salicylal-
dehyde 5 and diethyl malonate 6. The base-mediated reaction of
o-hydroxyaromatic aldehydes with malonic esters leads to couma-
rins. Consistently, silica-immobilized piperazine afforded couma-
rin 7 in high conversions (99%) and moderate yields under
non-optimized work-up (Scheme 1).
1
00
9
0
0
0
0
0
0
0
0
0
1
0
8
7
6
5
4
3
2
1
For this reaction, 2-methyltetrahydrofuran (2-MeTHF) was used
as a solvent. 2-MeTHF can be derived from bio-based resources,11
and presents promising properties (boiling point of 80 °C, almost
non-miscible with water), being considered a sustainable solvent.
Until now, 2-MeTHF has been scarcely used in several metal-
1
2
13
catalyzed procedures as well as in biocatalysis. Assessing its
use in further organocatalyzed-reactions may represent an interest-
ing approach for more sustainable organic processes. Likewise, for
the Knoevenagel-type reaction herein reported, 2-MeTHF may
provide proper conditions that could avoid by-product formation of-
ten reported in the literature for piperazine-based organocatalysts.4
f
0
1
2
3
In summary, the use of
a commercially available silica-
Number of Cycles
immobilized piperazine as an organocatalyst has been assessed,
and proof-of-principle results are herein reported. Efficient con-
densations between aromatic aldehydes and ketones have been
conducted at room temperature, providing different aldol—
Mannich-type bias depending on the substrate. Immobilized
Figure 2. Catalyst recovery and recycling. Black: yield of aldol 3; grey: yield of
Mannich-type product 4. Aldehyde: 1 mmol; acetone: 10 mmol. Total volume:
mL. Catalyst loading: 100 mg (0.1 mmol). 16 h, room temperature. Conversions
3
1
and yields based on H NMR assessment.
O
COOEt
Immobilized Organocat.
-MeTHF, rt, 16 h
H
+
EtOOC
COOEt
2
O
O
OH
7
5
6
Conversion 99% (Yield 55%)
Scheme 1. Knoevenagel-type condensation of salicylaldehyde 5 with diethyl malonate 6 to afford coumarin-type adduct 7. Reagents and conditions: 1 equiv aldehyde,
equiv malonate. Catalyst loading: 100 mg (0.1 mmol). 2-MeTHF as solvent (3 mL), 16 h, room temperature. Conversion and yield based on 1H NMR assessment.
1

6
672
S. Shanmuganathan et al. / Tetrahedron Letters 51 (2010) 6670–6672
organocatalysts may be recovered and reused for several cycles.
Furthermore, Knoevenagel-type reactions have also been studied
in 2-MeTHF as a promising, bio-based, sustainable solvent for
organocatalysis.
3
(100 MHz, CDCl ): 163.0, 155.3, 148.5, 136.7, 134.3, 129.4, 125.7,
124.8, 117.7, 116.8, 62.0, 14.2.
Note added in proof
1
1
. Experimental
During the peer-review assessment of this article, the use of
-MeTHF as solvent for organocatalysis has also been addressed
by another group, showing also promising properties as bio-based
solvent for these reactions (see: Yang, H.; Mahapatra, S.; Cheong,
P.H.Y.; Carter, R.G. J. Org. Chem. 2010, doi:10.1021/jo1015008.
2
.1. Materials
Immobilized piperazine was kindly donated by dichrom GmbH
(
formerly SeQuant GmbH)—SilicycleÒ Inc., Lot# 21354. Technical
À1
details: Catalyst loading: 1.01 mmol g
;
surface coverage
À2
Acknowledgements
(l
mol m ) based on molecular loading: >1.91; particle size: 40–
2
À1
6
3
lm; pore diameter (Å, BJH): 60; specific surface area (m g
,
À1
Financial support was obtained from DFG training group 1166
‘BioNoCo” (‘‘Biocatalysis in Non-conventional Media”). Additional
support from the Cluster of Excellence ‘‘Tailor-Made Fuels from
Biomass” (funded by the Excellence Initiative of the German
Research Foundation to promote science and research at German
BET): 470–530; specific pore volume (mL g , BJH): 0.70–0.85.
Other reagents and solvents were pure analytical grade materials
purchased from commercial sources and were used without fur-
ther purification.
‘
universities) is also acknowledged. We thank Dr. Harald Dibowski
1
.2. Aldol reaction
Ò
(dichrom GmbH (formerly SeQuant GmbH)—Silicycle Inc.) for
kindly donating a sample of the silica-immobilized piperazine.
The reaction was typically performed by mixing benzaldehyde
(
105 mg, 1 mmol), acetone (580 mg, 10 mmol) and silica-pipera-
À1
zine catalyst (100 mg, 1.01 mmol g ) in screw cap vial, and stir-
ring the mixture for 16 h at room temperature. The reaction
mixture was filtered, and the filtrate was concentrated in vacuum
to afford the crude product. The conversion was determined from
NMR. For recycling the catalyst, the solid filtrate was washed with
acetone (5 Â 2 mL), and dried, being ready for a new catalytic
reaction.
References and notes
1.
(a) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (b)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
2. Gröger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529.
3.
(a) Domínguez de María, P.; Shanmuganathan, S. Curr. Org. Chem. in press.; (b)
Cozzi, F. Adv. Synth. Catal. 2006, 348, 1367; (c) McNamara, C. A.; Dixon, M. J.;
Bradley, M. Chem. Rev. 2002, 102, 3275.
4.
(a) Zumbansen, K.; Döhring, A.; List, B. Adv. Synth. Catal. 2010, 352, 1135; (b)
Barros, M. T.; Phillips, A. M. F. Eur. J. Org. Chem. 2007, 178; (c) Wen, X. Ind. J.
Chem. 2006, 45B, 762; (d) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346; (e) Nikbin, N.; Watts, P. Org. Process Res. Dev. 2004, 8,
942; (f) Yang, G.; Chen, Z.; Xu, G.; Nie, X. Catal. Commun. 2004, 5, 75; (g) Kubota,
Y.; Goto, K.; Miyata, S.; Goto, Y.; Fukushima, Y.; Sugi, Y. Chem. Lett. 2003, 32,
1
.3. Knoevenagel reaction
In screw cap vial charged with salicylaldehyde (61 mg,
0
.5 mmol), diethylmalonate (80 mg, 0.5 mmol) and 2-methylte-
2
34; (h) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975; (i) Simpson, J.;
Rathbone, D. L.; Billington, D. C. Tetrahedron Lett. 1999, 40, 7031.
5. Carpino, L. A.; Mansour, E. M. E.; Knapczyk, J. J. Org. Chem. 1983, 48, 666.
À1
trahydrofuran (4 mL), silica-piperazine (100 mg, 1.01 mmol g
was aggregated. The reaction was stirred for 16 h at room tempera-
ture and the reaction mixture was extracted with ethyl acetate
)
Ò
6
7
.
.
Commercialized by dichrom GmbH (formerly SeQuant GmbH)—Silicycle Inc.
(a) Erkkilä, A.; Pihko, P. M. Eur. J. Org. Chem. 2007, 4205; (b) Erkkilä, A.; Pihko, P.
M. J. Org. Chem. 2006, 71, 2538.
(
3 Â 10 mL). After removal of solvents, the crude product was puri-
fied by silica chromatography (petroleum ether/ethylacetate
8. Incubation of the immobilized-piperazine with the mixture of 3 and 4 during
longer times (48 h) did not lead to changes in the 3/4 distribution,
demonstrating that 4 was produced catalytically, and not by dehydration of 3.
9. Alonso, D. M.; Bond, J. Q.; Dumesic, J. A. Green Chem. 2010, 12, 1493.
10. Ranu, B. C.; Jana, R. Eur. J. Org. Chem. 2006, 3767.
8
0:20) to afford the pure yellow solid as product (61 mg, 55%).
1
Mixture of compounds 3 and 4: H NMR (400 MHz, CDCl
3
): 7.8–
1
7
.1 (m, 10H), 6.7 (d, J = 12 Hz, 0.3 H of H) 5.1 (d, J = 7.0, 3.0 Hz, 0.7
1
1
1
H of H), 2.7–2.9 (m, 1.4H of H), 2.3 (s, 2.1H of H), 2.1 (s, 0.9H of
11. Geilen, F. M. A.; Engendahl, B.; Harwardt, A.; Marquardt, W.; Klankermayer, J.;
Leitner, W. Angew. Chem., Int. Ed. 2010, 47, 5510.
1
13
H); C NMR (100 MHz, CDCl
3
): 209.1, 198.5, 143.5, 142.6, 133–
1
2. (a) Pace, V.; Hoyos, P.; Fernández, M.; Sinisterra, J. V.; Alcántara, A. R. Green
Chem. 2010, 12, 1380; (b) Milton, E. J.; Clarke, M. L. Green Chem. 2010, 12, 381;
(c) Robert, T.; Velder, J.; Schmalz, H. G. Angew. Chem., Int. Ed. 2008, 40, 7718; (d)
Aycock, D. F. Org. Process Res. Dev. 2007, 11, 156; (e) Brown Ripin, D. H.;
Vetelino, M. Synlett 2003, 2353.
3. (a) Shanmuganathan, S.; Natalia, D.; van den Wittenboer, A.; Kohlmann, C.;
Greiner, L.; Domínguez de María, P. Green Chem. 2010, doi:10.1039/
COGCO059H; (b) Simeó, Y.; Sinisterra, J. V.; Alcántara, A. R. Green Chem.
1
25, 68.8, 52.0, 30.9, 27.5.
Compound 3 (from furfural): H NMR (400 MHz, CDCl
1
3
): 7.3 (m,
1
2
1
H), 6.3 (m, 1H), 6.2 (d, J = 3 Hz, 1H), 5.1–5.1 (m, 1H), 2.8–3.0 (m,
1
3
H), 2.2 (s, 3H); C NMR (100 MHz, CDCl
3
): 212.1, 155.0, 142.2,
1
10.3, 106.3, 64.0, 48.1, 31.0.
1
Compound 7: H NMR (400 MHz, CDCl
3
): 8.5 (s, 1H), 7.5–7.6 (m,
2
009, 11, 855.
13
2
H), 7.2–7.3 (m, 2H), 4.4 (q, J = 7.0, 2H), 1.4 (t, J = 7.0, 3H); C NMR