Reconstructed hydrotalcite as a highly active heterogeneous base catalyst for carbon-carbon bond formations in the presence of water

Article abstract of DOI:10.1021/jo060345l

The aldol reaction of carbonyl compounds is efficiently catalyzed by reconstructed hydrotalcites, obtained by treating the Mg-Al mixed oxide with water, as solid base catalysts in the presence of water. The catalysis of the reconstructed hydrotalcites is attributable to the surface base sites, created during the organization of the layered structure, with uniformly distributed strength. Furthermore, the reconstructed hydrotalcites provide a unique acid-base bifunctional surface capable of promoting the Knoevenagel and Michael reactions of nitriles with carbonyl compounds.

Full text of DOI:10.1021/jo060345l

Reconstructed Hydrotalcite as a Highly Active Heterogeneous Base
Catalyst for Carbon-Carbon Bond Formations in the Presence of
Water
Kohki Ebitani, Ken Motokura, Kohsuke Mori, Tomoo Mizugaki, and Kiyotomi Kaneda*
Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka UniVersity,
1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan
kaneda@cheng.es.osaka-u.ac.jp
ReceiVed February 19, 2006
The aldol reaction of carbonyl compounds is efficiently catalyzed by reconstructed hydrotalcites, obtained
by treating the Mg-Al mixed oxide with water, as solid base catalysts in the presence of water. The
catalysis of the reconstructed hydrotalcites is attributable to the surface base sites, created during the
organization of the layered structure, with uniformly distributed strength. Furthermore, the reconstructed
hydrotalcites provide a unique acid-base bifunctional surface capable of promoting the Knoevenagel
and Michael reactions of nitriles with carbonyl compounds.
Introduction
possess surface O2- species as Lewis base sites.7,8 The use of
the solid Lewis base catalysts in large-scale syntheses is limited
compared to that of solid acid catalysts because base solids are
very sensitive to CO2 in air to give carbonate species, which
are inactive and difficult to regenerate. Few studies on solid
Bro¨nsted base catalysts have been reported despite the potential
of hydroxyl anions to promote organic transformations.9
Hydrotalcites (HTs) are typical layered double-metal hydrox-
Solid base catalysts provide the opportunity for environmen-
tally friendly (“green”) syntheses of fine chemicals and phar-
maceuticals that conventionally involve large amounts of
harmful and unrecoverable reagents such as NaOH and KOH.1-6
Typical solid base catalysts, such as magnesium oxide (MgO),
2+
ides consisting of alternating cationic Mg6Al2(OH)16 as the
* To whom correspondence should be addressed. Phone and fax: +81-6-
6850-6260.
(1) Sheldon, R. A. CHEMTECH 1994, March, 38. Anastas, P. T.; Warner,
J. C. Green Chemistry; Theory and Practice; Oxford University Press:
Oxford, 1998. Clark, J.; Macquarrie, D. Handbook of Green Chemistry &
Technology; Blackwell Publishing: Oxford, 2002. Kelly, G. J.; King, F.;
Kett, M. Green Chem. 2002, 4, 392.
(2) (a) Pines, H.; Veseley, J. A.; Ipatieff, V. N. J. Am. Chem. Soc. 1955,
77, 6314. (b) Tanabe, K.; Misono, M.; Ono, Y.; Hattori, H. New Solid Acids
and Bases; Kodansha-Elsevier: Tokyo, Amsterdam, 1989. (c) Climent, M.
J.; Corma, A.; Iborra, S.; Velty, A. J. Mol. Catal. A 2002, 182-183, 327.
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Ed. Engl. 1997, 36, 2661. (b) Macquarrie, D. J. Tetrahedron Lett. 1998,
39, 4125. (c) Rodriguez, I.; Iborra, S.; Corma, A.; Rey, F.; Jorda´, J. L.
Chem. Commun. 1999, 593. (d) Choudary, B. M.; Kantam, M. L.; Sreekanth,
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361. (e) Bass, J. D.; Anderson, S. L.; Katz, A. Angew. Chem., Int. Ed.
2003, 42, 5219. (f) Bergbreiter, D. E.; Lalonda, J. J. J. Org. Chem. 1987,
52, 1601.
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P.; Kurbakova, S. Yu.; Korchagina, D. V.; Suslov, E. V.; Salakhutdinov,
N. F.; Toktarev, A. V.; Echevskii, G. V.; Barkhash, V. A. J. Mol. Catal. A
2003, 195, 263. (d) Doskocil, E. J. J. Phys. Chem. B 2005, 109, 2315.
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Pernot, H.; Che, M. J. Catal. 2005, 235, 413.
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Today 1997, 38, 321.
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and Related Compounds; Academic Press: New York, 1977.
10.1021/jo060345l CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/22/2006
5440
J. Org. Chem. 2006, 71, 5440-5447

HT as a Base Catalyst for C-C Bond Formations
CHART 1
brucite-like layer and anionic CO3 interlayers.10 Various
presence of water. Furthermore, this hydrotalcite catalyst system
can promote the aqueous Knoevenagel and Michael reactions
using nitriles. The origin and mechanism of the above unique
catalysis of the reconstructed HT is discussed on the basis of
the nature, strength, and amount of surface acid-base sites.
2-
heterogeneous catalysts can be developed using the unique
characteristics of the HTs,11-13 such as cation-exchange ability,
anion-exchange ability, surface adsorption capacity, surface
basicity, and reconstruction ability. For example, the HTs act
as efficient solid base catalysts for a wide variety of reactions,
e.g., monooxygenations using an aqueous hydrogen peroxide
as an oxidant11 and carbon-carbon bond formations including
aldol condensation, Knoevenagel reaction, and Michael addi-
tion.13
Development of water-tolerant solid base catalysts is strongly
motivated as one of the important challenges in the field of
heterogeneous catalysis since water is a nontoxic and economical
solvent that allows simple separation of product and the
possibility of unique catalytic reactions not observed under dry
conditions.14,15 However, typical solid Lewis bases do not
function under aqueous conditions because the surface base sites
are severely poisoned by water. Here, we demonstrate a catalysis
of the reconstructed HT, obtained by a regeneration of the HT
structure known as the “memory effect”.10a,16,17 This is the first
example of a solid base catalyst capable of promoting the aldol
reactions to produce â-hydroxy carbonyl deriVatiVes in the
Results
As illustrated in Chart 1, reconstrcuted HTs were prepared
-
by treating Mg-Al mixed oxide in water. The surface HCO3
2-
species and CO3 anions in the interlayer of the parent HT
were substituted for OH- anions in the reconstructed form. The
surface hydroxyl anion species of the reconstructed HT could
-
2-
act as base sites. The surface HCO3 and interlayer CO3
species were removed during the calcination of the parent HTs
to afford Mg-Al mixed oxides, and hydroxyl anions were
incorporated into the HT structure during the organization of
the layer assembly.
Aldol Reactions Catalyzed by Reconstructed Hydrotalcites
in the Presence of Water. The aldol reaction is a cornerstone
in synthetic organic chemistry to afford â-hydroxy carbonyls
used as valuable intermediates in the synthesis of pharmacologi-
cal compounds.18-20 Recently, the aldol reactions of unmodified
carbonyl compounds in place of preactivated enolates and enols
as donors have substantially progressed using amines,18 Lewis
acids,21 Lewis bases,22 bifunctional Lewis acid/Bro¨nsted base
complexes,23,24 proline as an aldolase mimic,25 imidazolidi-
none,26 and heterogeneous acid-base catalysts.13,27,28 The
development of solid base catalysts capable of promoting aldol
(10) (a) Miyata, S. Clays Clay Miner. 1980, 28, 50. (b) Cavani, F.; Trifiro´,
F.; Vaccari, A. Catal. Today 1991, 11, 173.
(11) (a) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Figueras, F.
Tetrahedron Lett. 1996, 37, 5995. (b) Ueno, S.; Yamaguchi, K.; Yoshida,
K.; Ebitani, K.; Kaneda, K. Chem. Commun. 1998, 295. (c) Yamaguchi,
K.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Org. Chem. 2000,
65, 6897. (d) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. J. Am. Chem. Soc. 2005, 127, 9674.
(12) Various types of HT-bound transition-metal species have also been
developed as highly functionalized heterogeneous catalysts. For selected
examples, see: (a) Sels, B.; De Vos, D.; Buntinx, M.; Pierard, F.; Kirsch-
De Mesmaeker, A.; Jacobs, P. A. Nature 1999, 400, 8565. (b) Nishimura,
T.; Kakiuchi, N.; Inoue, M.; Uemura, S. Chem. Commun. 2000, 1245. (c)
Choudary, B. M.; Choudary, N. S.; Madhi, S.; Kantam, M. Angew. Chem.,
Int. Ed. 2001, 40, 4620. (d) Motokura, K.; Nishimura, D.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 5662.
(e) Ebitani, K.; Motokura, K.; Mizugaki, T.; Kaneda, K. Angew. Chem.,
Int. Ed. 2005, 44, 3423. For an excellent review, see also: B. F. Sels, B.
F.; De Vos, D. E.; Jacobs, P. A. Catal. ReV. 2001, 43, 443.
(13) (a) Tichit, D.; Lhouty, M. H.; Guida, A.; Chiche, B. H.; Figueras,
F.; Auroux, A.; Bartalini, D.; Garrone, E. J. Catal. 1995, 151, 50. (b)
Kantam, M. L.; Choudary, B. M.; Reddy, Ch. V.; Rao, K. K.; Figueras, F.
Chem. Commun. 1998, 1033. (c) Tichit, D.; Bennani, M. N.; Figueras, F.;
Tessier, R.; Kervennal, J. Appl. Clay Sci. 1998, 13, 401. (d) Rao, K. K.;
Gravelle, M.; Sanchez, J.; Figueras, F. J. Catal. 1998, 173, 115. (e) Lopez,
J.; Jacquot, R.; Figueras, F. Stud. Surf. Sci. Catal. 2000, 130, 491.
(14) Advantages of organic syntheses under aqueous conditions have
been described in the literature. See: (a) Li, C.-J.; Chan, T.-H. Organic
Reactions in Aqueous Media; John Willey & Sons: New York, 1997. (b)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209.
(17) (a) Abello´, S.; Medina, F.; Tichit, D.; Pe´rez-Ram´ırez, J.; Groen, J.
C.; Sueiras, J. E.; Salagre, P.; Cesteros, Y. Chem.sEur. J. 2005, 11, 728.
(b) Abello´, S.; Medina, F.; Tichit, D.; Pe´rez-Ram´ırez, J.; Cesteros, Y.;
Salagre, P.; Sueiras, J. E. Chem. Commun. 2005, 1453.
(18) (a) Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1. (b)
Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31, 1.
(19) (a) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 139.
(b) Kim, M.-B.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 2, p 239. (c) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, Germany, 2004.
(20) (a) Knoevenagel, E. Justus Liebigs Ann. Chem. 1894, 281, 25. (b)
Jones, G. Org. React. 1942, 1, 210.
(21) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011.
(b) Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1. (c) Manabe,
K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.; Kobayashi, S. J. Am. Chem.
Soc. 2000, 122, 7202.
(22) (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33,
432 and references therein. (b) Miura, K.; Nakagawa, T.; Hosomi, A. J.
Am. Chem. Soc. 2002, 124, 536.
(23) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168 and references therein.
(24) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001, 123,
3367.
(15) Okuhara, T. Chem. ReV. 2002, 102, 3641.
(16) Rajamathi, M.; Nataraja, G. D.; Ananthamurthy, S.; Kamath, P. V.
J. Mater. Chem. 2000, 10, 2754 and references therein.
J. Org. Chem, Vol. 71, No. 15, 2006 5441

Ebitani et al.
SCHEME 1
reactions in the presence of water remains as one of the
paramount challenges in the field of organic syntheses using
solid catalysts.15,29 The aldol reaction under aqueous conditions
can be expected to give a favorable situation which can prevent
dehydration of â-hydroxy aldehydes into the corresponding
enones with respect to equilibrium issues. We found that the
reconstructed HT acted as an efficient heterogeneous base
catalyst for the aldol reaction of aldehydes in the presence of
water.
TABLE 1. Aldol Reaction of Propionaldehyde Using Various
Catalysts and Subsequent Methanolysisa
yieldb
(%)
entry
catalyst
cosolvent
Initial investigations revealed that the reconstructed HT with
a Mg/Al ratio of 3 promoted the aldol coupling of propional-
dehyde at room temperature to provide hemiacetal 1.26 The
formation of hemiacetal 1 was confirmed by 1H NMR analysis
of crude reaction mixtures. The hemiacetal was unstable during
the analyses using GC and GC-MS; however, methanolysis
1
2
3
4
5
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 3)
reconstructed HT (Mg/Al ) 4)
reconstructed HT (Mg/Al ) 5)
reconstructed HT (Mg/Al ) 2)
untreated HT (Mg/Al ) 3)
MgO
Mg(OH)2
Mg(OH)2 + Al(OH)3
Na2CO3
NaHCO3
CaCl2
NaOH
85
70
82
76
80
75
39
65
74
47
34
0
water
toluene
n-heptane
THF
DMF
CH2Cl2
6
of this hemiacetal in the presence of methanol using a Ti4+
-
7
8c
mont as a solid acid catalyst allows direct access to the 1,1-
dimethoxy-2-methyl-3-pentanol as a stable â-hydroxy dimeth-
ylacetal, 2 (Scheme 1).30,31
9
10
11
12
13d
14e
15f
16g
17g
18g
19g
As shown in Table 1, the reconstructed HT gave the
dimethylacetal in 85% yield within 1 h in the presence of water
used for the reconstruction of the HT (entry 1). With respect to
cosolvents, water was a good cosolvent to give the â-hydroxy
dimethylacetal in 70% yield (entry 2).32 The use of toluene and
n-heptane gave an aqueous/organic biphasic system in which
the HT catalyst was present in the aqueous phase, affording
82% and 76% yields of 2, respectively (entries 3 and 4). THF
and DMF also gave good yields of the corresponding product
(entries 5 and 6), while dichloromethane was significantly less
effective (entry 7).
0
0
0
0
0
0
3h
a Reaction conditions: aldol reaction, propionaldehyde (30 mmol, 2.4
mL), water (1 mL), cosolvent (2 mL), HT (0.15 g), rt, 1 h; methanolysis,
MeOH (50 mL), Ti4+-mont (0.45 g), rt, 4 h. b The yield and selectivity to
1,1-dimethoxy-2-methylpentan-3-ol were determined by GC using an
internal standard method. c The reconstructed HT was degassed at 100 °C
before use. d MgO (0.2 g) was used. e Mg(OH)2 (0.2 g) was used. f A
physical mixture of Mg(OH)2 (0.026 g, 0.45 mmol) and Al(OH)3 (0.012 g,
0.15 mmol) was used. g Five millimoles of catalyst was used. h (E)-2-
Methyl-2-pentenal was formed as the main product in 95% yield.
(25) (a) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H. Chem. ReV.
1996, 96, 443. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J.
Am. Chem. Soc. 2001, 123, 5260. (c) List, B.; Lerner, R. A.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2000, 122, 2395. (d) Northrup, A. B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2002, 124, 6798.
(26) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 6722.
Table 1 also compares the catalytic activity of the recon-
structed HT for the aldol reaction of propionaldehyde with those
of various homogeneous and heterogeneous catalysts under
aqueous conditions, e.g., without cosolvent. The reconstructed
HT with a Mg/Al ratio of 3 gave the highest yield of 2 (entry
1 vs entries 9-19). The parent HT and Mg(OH)2 as well as a
physical mixture of Mg(OH)2 and Al(OH)3 were inactive (entries
12, 14, and 15). MgO as a typical solid Lewis base3 did not
show any catalytic activity (entry 13), and conventional base
compounds such as Na2CO3, NaHCO3, and CaCl222b also were
inactive (entries 16-18). In contrast, NaOH, as a water-soluble
strong base, effectively catalyzed the aldol reaction to give (E)-
2-methyl-2-pentenal in 95% yield as a dehydration product of
2-methyl-3-hydroxypentanal (entry 19). When the reconstructed
HT was degassed at 100 °C before use, the yield of 2 was
depressed to 65% even in the presence of water (entry 1 vs
entry 8).
(27) (a) Climent, M. J.; Corma, A.; Forne´s, V.; Guil-Lopez, R.; Iborra,
S. AdV. Synth. Catal. 2002, 344, 1090. (b) Climent, M. J.; Corma, A.; Garcia,
H.; Guil-Lopez, R.; Iborra, S.; Forne´s, V. J. Catal. 2001, 197, 385.
(28) (a) Choudary, B. M.; Kantam, M. L.; Kavita, B.; Reddy, Ch. V.;
Rao, K. K.; Figueras, F. Tetrahedron Lett. 1998, 39, 3555. (b) Choudary,
B. M.; Kantam, M. L.; Kavita, B.; Reddy, Ch. V.; Figueras, F. Tetrahedron
2000, 56, 9357. (c) Choudary, B. M.; Kantam, M. L.; Neeraja, V.; Rao, K.
K.; Figueras, F.; Delmotte, L. Green Chem. 2001, 3, 257.
(29) Mori, K.; Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem. Soc. 2003, 125, 11460.
(30) In ref 26, amberlyst-15 was used as a solid acid for the methanolysis
of the hemiacetal product. For this methanolysis, the amberlyst could be
replaced by the Ti4+-exchanged montmorillinite (Ti4+-mont) as a hetero-
geneous Bro¨nsted acid catalyst. For typical examples for the Ti4+-mont-
catalyzed reactions, see: (a) (acetalization) Kawabata, T.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2001, 42, 8329. (b) (esterification)
Kawabata, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2003,
44, 9205. (c) (deprotection) Kawabata, T.; Kato, M.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Chem. Lett. 2003, 32, 648.
(31) Treatment of 1,1-dimethoxy-2-methylpentan-3-ol (2) with water in
the presence of the Ti4+-mont catalyst exclusively afforded 3-hydroxy-2-
methylpentanal as an aldol product of propionaldehyde.
(32) The amount of water as a solvent is a crucial factor for the catalytic
activity of the reconstructed HT. The yield of 2 gradually decreased with
increasing amount of water: 78% (1 mL), 70% (2 mL), and 25% (3 mL).
As summarized in Table 2, the reconstructed HT could also
promote a 100 mmol scale self-aldol reaction of various aliphatic
aldehydes. For example, 5.8 g (100 mmol) of propionaldehyde
was converted efficiently with 0.15 g of reconstructed HT within
5442 J. Org. Chem., Vol. 71, No. 15, 2006

HT as a Base Catalyst for C-C Bond Formations
TABLE 2. Aldol Reactions of Aldehydes Catalyzed by
Reconstructed Hydrotalcitea
retention of its high activity and selectivity; the yield of 2 in
the reaction of propionaldehyde remained greater than 80%
during the recycling experiment. These aldol reactions clearly
occurred on the surface of the reconstructed hydrotalcite.
This is the first example of aldol reactions to produce
â-hydroxy carbonyl compounds catalyzed by the reconstructed
hydrotalcites.
Reactions of Nitriles by Reconstructed Hydrotalcite Cata-
lyst in the Presence of Water. The reconstructed HT was
applied to other carbon-carbon bond formations such as the
Knoevenagel and Michael reactions34,35 using nitriles in the
presence of water.
In the presence of the reconstructed HT catalyst, the Kno-
evenagel reaction of an equimolar mixture of malononitrile (pKa
) 11.2)36 with benzaldehyde afforded benzylidenemalononitrile
in 96% yield in 1 h,37 and ethyl cyanoacetate (pKa ) 9.0) also
gave (E)-ethyl 2-cyano-3-phenyl-2-propenoate in 94% yield,
whereas this reaction required 10 h to attain quantitative yield
(Table 3, entries 11 and 12).
Furthermore, the reconstructed HT catalyst smoothly pro-
moted the Knoevenagel reaction of activated nitriles such as
2-cyanoacetamide and 2-pyridineacetonitrile in DMF as a water-
miscible solvent, as shown in Table 3 (entries 9 and 10).
Surprisingly, the Knoevenagel reaction of phenylacetonitrile
with a large pKa value of 21.936 proceeded efficiently in the
presence of the reconstructed HT catalyst, whereas RuH2(PPh3)4
as a typical metal complex for the reaction of nitriles38 could
not efficiently catalyze the above reaction using phenylaceto-
nitrile. The representative results with phenylacetonitrile are also
included in Table 3.39 Reactions with benzaldehyde and 2-furan-
carboxaldehyde afforded (Z)-1,2-diphenylethylidenenitrile and
(Z)-2-furanylmethylenebenzeneacetonitrile in 1 h, respectively
(entries 1 and 3). Aliphatic aldehydes of n-octanaldehyde,
isobutyraldehyde, and cyclohexanecarboxaldehyde gave the
corresponding condensation products in high yields (entries
4-6). The reaction of phenylacetonitrile with unsaturated
aldehyde such as cinnamaldehyde exclusively gave the corre-
sponding nitrile as a 1,2-addition product with retention of the
double bond configuration (entry 7).13b,40 The reaction of an
aliphatic nitrile, e.g., n-octanenitrile with benzaldehyde did not
yield any products.
a Reaction conditions: substrate (100 mmol), water (1 mL), HT (0.15
g), rt. b Isolated yields. For self-aldol reactions, the isolated yields of the
corresponding â-hydroxy dimethoxyacetals are shown. c A 0.1 mol %
concentration of DTMAB was added. d GC yield. e Donor (20 mmol),
acceptor (10 mmol), water (0.3 mL). f Donor (100 mmol), acceptor (10
mmol), water (0.5 mL). n-Butyraldehyde was added stepwise into the
reaction mixture. See the Experimental Section for details. g Only the syn
1
product was isolated, determined by H NMR.
1 h to afford 2 in 89% isolated yield (entry 2). As the hydrophilic
reconstructed HTs existed in the aqueous phase,11 water-
insoluble aldehyde such as n-butyraldehyde resulted in a low
yield (entry 4). Addition of a cationic surfactant, i.e., n-
dodecyltrimethylammonium bromide (DTMAB), however, could
accelerate the aldol reaction of n-butyraldehyde to give a 90%
yield of the corresponding product within 2 h (entry 3).33
Furthermore, this catalyst system is extended to the cross-
aldol reaction with aliphatic aldehydes using excess ketones to
avoid self-aldolization of the aldehyde. The results are also
included in Table 2. Acetone reacted with isovaleraldehyde to
give 4-hydroxy-6-methyl-2-heptanone in 67% yield for 1 h
(entry 5). The R-substituted aldehydes required a longer reaction
time; the reaction of acetone with isobutyraldehyde produced
4-hydroxy-5-methyl-2-hexanone in 78% yield in 10 h (entry
6). In the reaction of acetone with n-butyraldehyde, homodimer-
ization of n-butyraldehyde prevailed over the cross-aldol reac-
tion, but a stepwise addition of n-butyraldehyde into acetone
suppressed the homocoupling of n-butyraldehyde, thus giving
4-hydroxy-2-heptanone as the cross-aldol product in good yield
(entry 8).
In the reaction of phenylacetonitrile with enones, 1,4-addition
occurred exclusively to give the corresponding Michael adducts,
as summarized in Table 4.41,42 For example, phenylacetonitrile
(34) Jones, G. Org. React. 1967, 15, 204.
(35) (a) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin:
Menlo Park, CA, 1072. (b) Jung, M. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4. (c) Ho, T.-L. Tactics of Organic Synthesis; Wiley: New York, 1994.
(36) (a) Martell, A. E.; Smith, R. M. In Critical Stability Constants;
Plenum Press: New York, 1974, 1975, 1977; Vols. 1-3. (b) Pearson, R.
G.; Dillon, R. L. J. Am. Chem. Soc. 1953, 75, 2439. (c) Bordwell, F. G.
Acc. Chem. Res. 1988, 21, 456.
(37) The Knoevenagel reaction of malononitrile with benzaldehyde
without any catalyst in the presence of water has been reported. See: Bigi,
F.; Conforti, M. L.; Maggi, R.; Piccinno, A.; Sartori, G. Green Chem. 2000,
2, 101. Under our reaction conditions, the reaction of malononitrile with
benzaldehyde gave 82% of the corresponding product.
(38) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno, M.; Takaya, H.;
Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano, M.; Fukuoka,
A. J. Am. Chem. Soc. 1995, 117, 12436.
The solid catalyst was removed by filtration from the reaction
mixture at about 50% conversion of propionaldehyde under an
Ar atmosphere, and then further treatment of the colorless filtrate
at room temperature for 5 h did not give any additional products.
Furthermore, the spent HT catalyst could be reused once with
(33) In the 100 mmol scale aldol reaction of n-butyraldehyde using the
reconstructed HT, the following reactivity of surfactants was observed:
DTMAB (90) > sodium dodecyl sulfate (35) > Triton X 100 (13) > non
(8). The values in parentheses are yields of 1,1-dimethoxy-2-ethyl-3-hexanol.
Without the reconstructed HT catalyst, the aldolization did not occur even
in the presence of DTMAB.
(39) An excess acceptor was used to avoid the Michael reaction.
(40) Cabello, J. A.: Campelo, J. M.; Garcia, A.; Luna, D.; Marinas, J.
M. J. Org. Chem. 1984, 49, 5195.
(41) Ethyl cyanoacetate also reacted with 2-cyclohexen-1-one to afford
the 1,4-addition product selectively. However, the yield of the Michael
product was lower than 50%.
J. Org. Chem, Vol. 71, No. 15, 2006 5443

Ebitani et al.
TABLE 3. Knoevenagel Reaction of Nitriles with Various
Carbonyl Compoundsa
TABLE 4. Reconstructed Hydrotalcite-Catalyzed Michael
Reaction of Nitriles with r,â-Unsaturated Compoundsa
a Reaction conditions: donor (6 mmol), acceptor (3 mmol), water (0.3
mL), 1,4-dioxane (2 mL), HT (0.15 g), 80 °C. b Yields were based on the
acceptor and were determined by GC using an internal standard method.
Values in parentheses are isolated yields.
SCHEME 2
SCHEME 3 a
a Reaction conditions: donor (3 mmol), acceptor (6 mmol), water (0.3
mL), DMF (2 mL), HT (0.15 g), 80 °C. b Determined by GC using an
internal standard method. Values in parentheses are isolated yields.
c Diethylamine (4 mmol) was used as a catalyst. d 1,4-Dioxane (2 mL) was
used as a cosolvent. e At 40 °C, donor (1 mmol), acceptor (3 mmol). f Donor
(10 mmol), acceptor (10 mmol), water (1 mL), 60 °C. g The corresponding
coupling product was obtained in 82% yield in the absence of the
reconstructed hydrotalcite catalyst.
a Reagents and conditions: (a) donor (10 mmol), acceptor (8 mmol),
water (2 mL), acetone (2 mL), HT (0.30 g), 60 °C, 48 h; (b) donor (5
mmol), acceptor (5 mmol), water (1 mL), THF (4 mL), HT (0.15 g), 30
°C, 24 h.
reacted with 2-cyclohexen-1-one, affording R-(3-oxycyclohexyl)-
phenylacetonitrile in high yield without formation of a 1,2-
addition product (entry 1). The reaction with 3-nonen-2-one,
benzalacetone, and cinnamonitrile as acceptors gave the Michael
products in high yields; however, the reaction required prolonged
reaction times (entries 2-4). Furthermore, a bulky nitrile such
as 1-naphthylacetonitrile could be used as a donor to produce
R-(3-oxocyclohexyl)-1-naphthylacetonitrile in high yield (Scheme
2).
reactions of various unmodified carbonyl compounds and nitriles
in the presence of water. Nitriles are good donors rather than
1,3-dicarbonyl compounds for the carbon-carbon bond forming
reactions catalyzed by reconstructed HT. The above specific
reactivity will be discussed in the next section.
Discussion
The reaction of 2,4-pentanedione, which has a pKa (9.0)
similar to that of ethyl cyanoacetate,36 with benzaldehyde did
not afford any products. In contrast, the same reaction using
KOH as a homogeneous Bro¨nsted base gave a mixture of
3-benzylidene-2,4-pentanedione and benzalacetone.43 The Michael
reaction of ethyl acetoacetate with 3-buten-2-one or methyl
acrylate proceeded, but required prolonged reaction times
(Scheme 3).
The reconstructed hydrotalcite described here provides the
first example of the aldol reaction of aliphatic aldehydes in the
presence of water, which is in sharp contrast to the HT catalysts
pioneered by Figueras et al.13 The significant difference between
two HT catalysts arises from their preparation procedures17 as
well as the target reaction and the amount of water used as a
solvent. Figueras et al. prepared HTs by treating the Mg-Al
mixed oxide with water, followed by their use as catalysts after
treatment under a Vacuum to remoVe the water for the aldol
reaction of acetone and benzaldehyde in 12 mL of water.13e In
contrast, the present reconstructed HTs were synthesized by
hydration of the Mg-Al mixed oxides and then subjected to
the aldol reactions of aliphatic aldehydes in 1 mL of water
without the above evacuation of the water-covered HTs. We
found that the drying treatment of the hydrated HTs and the
amount of water definitely influenced the catalytic activity for
Conclusively, the reconstructed hydrotalcite is an efficient
heterogeneous catalyst for the carbon-carbon bond forming
(42) Michael reaction of nitriles using a homogeneous catalytic system.
See: (a) (CsF/Si(OR)4) Boyer, J.; Corriu, R. J. P.; Reye, R. P. et C.
Tetrahedron 1983, 39, 117. (b) (NaOH/calix[n]arenes) Shimizu, S.;
Shirakawa, S.; Suzuki, T.; Sasaki, Y. Tetrahedron 2001, 57, 6169.
(43) Benzalacetone is formed by base-catalyzed condensation of 2,4-
pentanedione with benzaldehyde followed by deacylation. See: Tsuboi, S.;
Uno, T.; Takeda, A. Chem. Lett. 1978, 1325.
5444 J. Org. Chem., Vol. 71, No. 15, 2006

HT as a Base Catalyst for C-C Bond Formations
SCHEME 4
the aldol reaction of aliphatic aldehydes.44 The yield of the
product in the reaction of propionaldehyde was depressed even
in the presence of water once the reconstructed HTs were dried
under a vacuum (Table 1, entry 8). Furthermore, the yield of 2
gradually decreased with increasing amount of water.32 Presum-
ably, the small amount of water maintains the hydroxyl groups
as base sites on the surface of the reconstructed hydrotalcites,
while the generated OH- species were weakly adsorbed on the
surface of the HT, and therefore were easily removed as H2O
by the evacuation. The elimination of adsorbed water might
result in the formation of O2- species as Lewis base sites that
are easily poisoned by water.
FIGURE 1. IR spectra of (A) phenylacetonitrile, (B) adsorbed
phenylacetonitrile on reconstructed hydrotalcite, and (C) the phenyl-
acetonitrile from (B) after the reaction with benzaldehyde. Note that
spectrum C is identical to that of (Z)-1,2-diphenylethylenenitrile as the
product of the Knoevenagel reaction of phenylacetonitrile with ben-
zaldehyde.
the parent HT for this Michael reaction was 10-fold less than
that of the reconstructed HT. The titer to diminish the catalytic
activity is a measure of the effective base amount. The base
amount of the reconstructed HT (Mg/Al ) 3) was approximately
4.0 mmol‚g-1, which is larger than that of the untreated HT
(0.7 mmol‚g-1). The latter is associated with anionic species
such as HCO3-, which compensate for the positive charge of
the Brucite-like layer. Increasing the Mg/Al ratio from 3 to 5
decreased the base amount (2.6 mmol‚g-1), which well cor-
relates with the catalytic activity in the aldol reaction of
propionaldehyde (Table 1, entry 1 vs entry 10). The turnover
number (TON) normalized to the above base amount of the
reconstructed HT (Mg/Al ) 3) was 150. It is notable that this
TON value is significantly larger than those for the imidazo-
lidinone, e.g., TON ≈ 9,26 and L-proline, e.g., TON ≈ 8, which
is an efficient organocatalyst for the aldol reaction.25d
Reaction Mechanism. (A) Aldol Reaction of Carbonyl
Compounds. A proposed mechanism is shown in Scheme 4
where the above surface OH- species of the reconstructed HT
efficiently acts as a Bro¨nsted base site in the presence of water.
The surface OH- species abstracts an acidic hydrogen of
aldehyde as a pronucleophile in the aqueous phase to generate
a carbanion intermediate, which can be paired with the cationic
surface of the hydrotalcite. The tuned base strength between
10.72 and 11.2 on the pKa scale depressed the dehydration of
the aldol products, leading to high selectivity for the putative
3-hydroxy aldehydes. 3-Hydroxy aldehydes are reacted with
another aldehyde to afford the corresponding hemiacetal com-
pounds by a base-catalyzed mechansim.26
In the following, the strength and amount of base sites in
our reconstructed HTs are discussed to elucidate the origin of
their remarkable catalyses for the aldol reaction of aldehydes
and the reactions with nitriles.
Surface Basicity of Reconstructed Hydrotalcite Catalyst.
We found that the rate of the aldol reaction of n-butyraldehyde
was sensitive to the pKa of amines. Use of diethylamine (pKa
) 10.98)36 and piperidine (pKa ) 11.2) gave 1,1-dimethoxy-
2-ethylhexan- 3-ol as the corresponding aldol product in 92%
and 80% yield for 3 h, respectively, whereas the reaction did
not take place with triethylamine (pKa ) 10.72). Therefore, it
might be said that the base strength of the reconstructed HTs
in the presence of water may exist within a very narrow pKa
range of 10.72-11.2. Figueras et al. and Corma et al. have
independently reported that the HTs had base sites with a pKa
value of at least 11 by comparing the activities of HTs with
those of amines.13a,45
The base amount of the HT catalyst is estimated by titration
using benzoic acid (pKa ) 4.2) as a titer in the Michael reaction
of ethyl acetoacetate with methyl acrylate in the presence of
water (Scheme 3b), which was chosen as the test reaction to
compare the catalytic activities between the reconstructed and
parent HTs under identical conditions. The catalytic activity of
(44) Recently, Medina et al. have reported the structure and catalysis of
hydrated HTs prepared by different procedures in the liquid or gas phase.
See ref 17a. Despite the marked difference in catalytic activity between
two reconstructed HTs in the aldol condensation of citral with acetone, the
number and nature of OH- groups are indistinguishable. We think that the
identical basicity of the HTs prepared by different methods may arise from
the evacuation and/or exposure of the hydrated HTs to air before the
condensation reaction.
The surface of the reconstructed HT in the aqueous phase
provides a highly hydrophilic environment for the above aldol
reaction. Therefore, the reaction of hydrophilic aldehydes such
as propionaldehyde efficiently proceeded on the polar surface
of the reconstructed HT in the aqueous phase. The reaction of
(45) Corma, A.; Forne´s, V.; Mart´ın-Aranda, R. M.; Rey, F. J. Catal.
1992, 134, 58.
J. Org. Chem, Vol. 71, No. 15, 2006 5445

Ebitani et al.
SCHEME 5
a hydrophobic aldehyde such as n-butyraldehyde requires
DTMAB as a cationic surfactant (vide supra). Under these
phase-transfer conditions,11b the surface hydroxyl anion species
interacts with quaternary ammonium cation (Q+) and then passes
into the organic phase by forming an ion pair such as a Q+OH-
species to react with a lipophilic aldehyde substrate at the
interface as a reaction zone.
followed by a coupling reaction with a carbonyl compound to
yield the R,â-unsaturated nitrile and H2O. The Hammett F value
in the Knoevenagel reaction of para-substituted phenylaceto-
nitrile and benzaldehyde catalyzed by reconstructed HT is 2.3,
which is larger than 0.97 using KOH. This indicates a formation
of highly polar intermediates on the surface of the reconstructed
HT.
(B) Reactions of Nitriles. In contrast to the aldol reaction
of n-butyraldehyde, diethylamine hardly promoted the reaction
of phenylacetonitrile with benzaldehyde (Table 3, entry 2).
Furthermore, the reactivity of the donors was not associated
with their pKa values. For example, ethyl cyanoacetate showed
a significantly low reactivity compared with malononitrile (pKa
) 11.2) despite having a lower pKa value of 9.0 (Table 3, entry
11 vs entry 12).46 Therefore, the catalysis of the reconstructed
HT in the Knoevenagel reaction cannot be explained in terms
of the surface basicity alone.
The Lewis acid site of the reconstructed HT also initiates
the reaction of phenylacetonitrile with enones by the coordina-
tion of the nitrile to afford the 1,4-addition product exclusively.
The same regioselectivity toward the 1,4-addition has been
observed for the reaction using homogeneous and heterogeneous
catalytic systems.3a,41
Conclusions
The present preparation method, which utilizes the facile
structural change of HTs, could be a powerful protocol for the
immobilization of hydroxyl groups on the HT surface for use
as hydrophilic heterogeneous base catalysts for selective
carbon-carbon bond forming reactions in the presence of water.
Furthermore, the reconstructed hydrotalcite possesses a highly
effective acid-base bifunctional surface capable of mediating
the Knoevenagel and Michael reactions of nitriles with carbonyl
compounds. Our strategy to design a highly functionalized metal
hydroxide surface without any transition and rare earth metals
offers the possibility of performing diverse and environmentally
benign carbon-carbon bond forming reactions.
As shown in Figure 1B, the ν(CN) band of phenylacetonitrile
adsorbed onto the reconstructed HT appeared at 2170 cm-1
,
which is lower than that of the free phenylacetonitrile (2253
cm-1). This peak is assignable to an [Al]+[PhCHCN]- species47
and clearly demonstrates the coordination of the nitrile with
the Lewis acid center of the reconstructed HT surface. The shift
of ν(CN) observed for the reconstructed HT of 83 cm-1 is
smaller than that for the cationic RuHAP catalyst using ethyl
cyanoacetate.29 The surface Lewis acid sites of reconstructed
HTs, e.g., Al cations, react with nitriles, which increases the
acidity of the R-hydrogens of the nitriles in a fashion similar to
that of the Ru-catalyzed reaction of nitriles.29,38 A possible
reaction mechanism via coordination of nitriles is illustrated in
Scheme 5.
The initial step in the mechanism is a coordination of the
cyano group to the Al cation as a Lewis acid site, which
increases the acidity of the R-hydrogen of the nitrile. A
neighboring base site of hydroxyl anion abstracts the R-hydrogen
to form an ion pair of the carbanion species and Al cation,
Experimental Section
Preparation of Reconstructed Hydrotalcite. A 0.15 g sample
of the above HT was placed in a Pyrex glass reactor (30 mm i.d.)
and then heated at 450 °C for 7 h in a continuous Ar flow. After
the sample was cooled in the Ar flow, decarbonated water, typically
1 mL, was poured onto the sample, followed by stirring at room
temperature for 8 h, giving a reconstructed HT. The elemental
analysis of the solid demonstrated retention of the initial Mg/Al
ratio. Retention of the Mg/Al ratio in the reconstructed HT samples
also was confirmed by the EDX (energy-dispersive X-ray) mea-
surement of the powder.
(46) The same phenomenon has been reported for the Knoevenagel
condensation of methylene compounds with benzaldehyde catalyzed by the
CsX zeolite as a solid Lewis base.2c
(47) Pasynkiewicz, S.; Starowieyski, K.; Rzepkowska, Z. J. Organomet.
Chem. 1967, 10, 527.
Aldol Reaction of Aldehydes. A typical example for the HT-
catalyzed aldol reaction of aldehyde is as follows. Onto the wet
5446 J. Org. Chem., Vol. 71, No. 15, 2006

HT as a Base Catalyst for C-C Bond Formations
reconstructed HT (0.15 g) was added the freshly distilled propi-
onaldehyde (5.8 g, 100 mmol). After the heterogeneous mixture
was stirred at room temperature for 1 h under an Ar atmosphere,
the HT catalyst was separated by filtration. All procedures must
be operated under an Ar atmosphere to aVoid adsorption of carbon
dioxide on the surface. After treatment of the collected filtrate with
the reconstructed HT and water (0.3 mL) were successively added
DMF (2 mL), phenylacetonitrile (3 mmol), and benzaldehyde (6
mmol). After the reaction mixture was stirred at 80 °C for 1 h, the
HT was separated by filtration. GC analysis showed a 98% yield
of (Z)-1,2-diphenylethylidenenitrile. The filtrate was collected and
subjected to column chromatography on the silica gel with a mixture
of n-hexane and ethyl acetate (4/1) to afford 0.50 g of pure (Z)-
1,2-diphenylethylidenenitrile (81% yield).
Titration of the Catalytic Activity of Hydrotalcites. To the
reaction vessel containing the reconstructed HT and water (1 mL)
were successively added THF (4 mL), an appropriate amount of
benzoic acid, ethyl acetoacetate (5 mmol), and methyl acrylate (5
mmol). After the reaction mixture was stirred at 30 °C for 12 h,
the HT catalyst was separated by filtration. The filtrate was
subjected to GC analysis to determine the amount of the corre-
sponding Michael adduct 2-acetylpentanedioic acid 1-ethyl 5-methyl
diester. The amount of benzoic acid necessary to diminish the
catalytic activity is defined as the amount of base sites of the
surface.
IR Measurement. The IR spectra of the reconstructed HT were
obtained at room temperature in transmission mode. The recon-
structed HT (0.15 g) was treated with 1 mmol of phenylacetonitrile
at 80 °C for 15 min in the presence of water (0.3 mL). Subsequently,
2 mmol of benzaldehyde was added to the heterogeneous reaction
mixture. In each step, the solid was pressed into a disk with KBr
after removal of solvent by evaporation and subjected to IR
measurement. Treatment of the adsorbed phenylacetonitrile on the
HT surface with benzaldehyde afforded an IR peak at 2218 cm-1
(Figure 1C), which is identical to that of (Z)-1,2-diphenylethyl-
enenitrile as the product (2219 cm-1).
Hammett Plot. The Hammett plots for the Knoevenagel reaction
of para-substituted phenylacetonitriles (X ) OCH3 and Cl) with
benzaldehyde were obtained in a competitive reaction. The het-
erogeneous mixture of reconstructed HT (0.05 g), para-substituted
phenylacetonitrile (5 mmol), phenylacetonitrile (5 mmol), benzal-
dehyde (5 mmol), water (0.1 mL), and 1,4-dioxane (5 mL) was
stirred at 80 °C for 30 min. The KOH-promoted Knoevenagel
reaction was performed using 0.3 mmol of KOH for 5 min.
MgSO4 and concentration in vacuo, methanol (50 mL) and Ti4+
-
mont (0.45 g) as a solid acid catalyst30 were added. The hetero-
geneous solution was stirred at room temperature until the reaction
was judged complete by GC analysis (4 h). The Ti4+-mont was
removed by filtration, and the filtrate was concentrated in vacuo.
Column chromatography on Florisil with a mixture of n-hexane
and ethyl acetate (9/1) afforded 4.93 g of pure 1,1-dimethoxy-2-
methyl-3-pentanol (89% yield).
The HT-mediated aldol reaction of n-butyraldehyde (100 mmol)
was performed in the presence of water (1 mL) and 0.1 mmol of
n-dodecyltrimethylammonium bromide at room temperature for 2
h. After the methanolysis of the hemiacetal according to the
procedure described above, column chromatography on Florisil with
a mixture of n-hexane and ethyl acetate afforded 5.69 g of pure
1,1-dimethoxy-2-ethyl-3-hexanol (90% yield).
Deprotection of 1,1-Dimethoxy-2-methylpentan-3-ol. To the
reaction vessel containing Ti4+-mont (0.2 g) were successively
added CH3CN (25 mL), H2O (5 mL), and 1,1-dimethoxy-2-
methylpentan-3-ol (2) (1 g, 6.2 mmol). After the heterogeneous
reaction mixture was stirred at 55 °C for 1 h, Ti4+-mont was
removed by filtration. The filtrate was concentrated to about 15
mL under vacuum at room temperature. The residue was extracted
with ether, and then the organic layer was dried with MgSO4 and
carefully concentrated in an ice-water bath to avoid acetalization
of the aldol. The NMR analysis showed a complete conversion of
2 into 3-hydroxy-2-methylpentanal without formation of 2-methyl-
2-pentenal and the acetal of the aldol.
Reuse of the Catalyst. The spent HT was washed with acetone,
followed by heating at 450 °C and treated with water again. Then
the HT catalyst was recyclable once without losing high selectivity
in the aldol reaction of propionaldehyde.
Acknowledgment. This work is supported by Grants-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan (16206078 and
17360387). We thank the Center of Excellence (21COE)
program “Creation of Integrated EcoChemistry” of Osaka
University and the Department of Materials Engineering Sci-
ence, Graduate School of Engineering Science, Osaka Univer-
sity, for their scientific support with the gas hydrate analyzing
system.
Cross-Aldol Reaction of Ketones with Aldehydes. A typical
example is for cross-aldolization of acetone and n-butyraldehyde.
n-Butyraldehyde (10 mmol) was successively added (2.5 mmol ×
4 in 1 h) onto a heterogeneous mixture of acetone (100 mmol) and
reconstructed HT (0.15 g) with 0.5 mL of decarbonated water. The
mixture was stirred at room temperature for 13 h, and then the
solid catalyst was removed by filtration. The GC analysis of the
filtrate showed a 75% yield of 4-hydroxy-2-heptanone, based on
n-butyraldehyde, as a cross-coupling product. The filtrate was
concentrated in vacuo, and column chromatography on silica gel
(WAKO gel C-200) with a mixture of n-hexane and ethyl acetate
(4/1) afforded 1.1 g of pure 4-hydroxy-2-heptanone (70% yield).
Knoevenagel Reaction of Nitriles with Carbonyl Compounds.
A typical example is as follows. To the reaction vessel containing
Supporting Information Available: General procedure, char-
acterizations of products and reconstructed hydrotalcite, XRD,
Hammett plot, and discussion on the location of base sites on the
hydrotalcite surface (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060345L
J. Org. Chem, Vol. 71, No. 15, 2006 5447