Highly efficient C-C bond-forming reactions in aqueous media catalyzed by monomeric vanadate species in an apatite framework

Article abstract of DOI:10.1021/jo0614745

A calcium vanadate apatite (VAp), in which PO₄^3- of hydroxyapatite (HAP), Ca₁₀(PO₄)₆(OH) ₂, is completely substituted by VO₄^3- in the apatite framework, was synthesized. Physicochemical analysis of the VAp reveals the presence of isolated VO₄ tetrahedron units with a pentavalent oxidation state. The VAp acts as a high-performance heterogeneous base catalyst for various carbon-carbon bond-forming reactions such as Michael and aldol reactions in aqueous media and the H-D exchange reactions using deuterium oxide. For example, a 200-mmol-scale Michael reaction under triphasic conditions proceeded rapidly, with an extremely high turnover number of up to 260 400 and an excellent turnover frequency of 48 s^-1. No vanadium leaching was detected during the above reactions, and the catalyst was readily recycled with no loss of activity.

Full text of DOI:10.1021/jo0614745

Highly Efficient C-C Bond-Forming Reactions in Aqueous Media
Catalyzed by Monomeric Vanadate Species in an Apatite
Framework
Takayoshi Hara, Satoko Kanai, Kohsuke Mori, Tomoo Mizugaki, Kohki Ebitani,
Koichiro Jitsukawa,† 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 July 16, 2006
3-
A calcium vanadate apatite (VAp), in which PO4 of hydroxyapatite (HAP), Ca10(PO4)6(OH)2, is
completely substituted by VO43- in the apatite framework, was synthesized. Physicochemical analysis of
the VAp reveals the presence of isolated VO4 tetrahedron units with a pentavalent oxidation state. The
VAp acts as a high-performance heterogeneous base catalyst for various carbon-carbon bond-forming
reactions such as Michael and aldol reactions in aqueous media and the H-D exchange reactions using
deuterium oxide. For example, a 200-mmol-scale Michael reaction under triphasic conditions proceeded
rapidly, with an extremely high turnover number of up to 260 400 and an excellent turnover frequency
of 48 s-1. No vanadium leaching was detected during the above reactions, and the catalyst was readily
recycled with no loss of activity.
Introduction
carbon bond-forming reactions has lagged far behind.3 The
ability to precisely control the architecture of active vanadium
centers is expected to lead to the discovery of new synthetic
methods involving fascinating and atom-economical carbon-
carbon bond formations.
The use of water as a reaction medium instead of organic
solvents is another approach to elucidating novel synthetic
methodologies. Reports on aqueous reactions have become
increasingly frequent and specialized over the past few years.4
Unique reactivity and selectivity that cannot be achieved under
dry conditions are often observed in aqueous reactions due to
Vanadium is one of the most essential metals in catalysis
due to its versatile redox potential, unique oxygen-transfer
ability, and highly Lewis acidic properties.1 These characteristics
have facilitated the development of a diverse array of oxidative
transformations that cannot be achieved using other transition
metal catalysts,2 but the use of vanadium catalysts in carbon-
* Corresponding author. Tel: +81-6-6850-6260. Fax: +81-6-6850-6260.
† Present address: Department of Applied Chemistry, Graduate School of
Engineering, Nagoya Institute of Technology, Showa-ku, Nagoya 466-8555,
Japan.
(1) (a) Crans, D. C.; Smee, J. J. In ComprehensiVe Coordination
Chemistry II; McCleverty, J. A., Meyer, T. J., Ed.; Pergamon: London,
2004; Vol. 4, pp 175-239. (b) Bolm, C. Coord. Chem. ReV. 2003, 237,
245. (c) Misono, M. Top. Catal. 2002, 21, 89. (d) Gao, X.; Wachs, I. E.
Top. Catal. 2002, 18, 243. (e) Hirao, T. Chem. ReV. 1997, 97, 2707.
(2) The regio- and stereoselective epoxidation of allylic alcohols using
oxovanadium compounds in combination with tert-butyl hydroperoxide have
been especially studied in detail. For example: (a) Sharpless, K. B.;
Michaelson, R. C. J. Am. Chem. Soc. 1973, 95, 6136. (b) Ito, T.; Jitsukawa,
K.; Kaneda, K.; Teranishi, S. J. Am. Chem. Soc. 1979, 101, 159.
(3) Recent notable reports for oxovanadium-catalyzed carbon-carbon
bond formations. See: (a) Trost, B. M.; Jonasson, C.; Wuchrer, M. J. Am.
Chem. Soc. 2001, 123, 12736. (b) Trost, B. M.; Oi, S. J. Am. Chem. Soc.
2001, 123, 1230.
(4) Advantages of organic syntheses under aqueous conditions have been
highlighted in the following literatures. See: (a) Li, C.-J., Chan, T.-H., Eds.;
Organic Reactions in Aqueous Media; Wiley: New York, 1997. (b)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209. (c) Manabe,
K.; Kobayashi, S. Chem. Eur. J. 2002, 8, 4095.
10.1021/jo0614745 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/23/2006
J. Org. Chem. 2006, 71, 7455-7462
7455

Hara et al.
FIGURE 1. Variation of XRD patterns upon the calcination temperature for VAp: (a) uncalcined, (b) 200 °C, (c) 400 °C, (d) 600 °C, (e) 800 °C,
(f) recovered VAp after the aqueous Michael reaction of 1a with 2a, and (g) treatment with water by Soxhlet’s extractor after calcination at 800
°C. The peaks labeled (b) are originated from CaO.
the hydrophilic and hydrogen-bonding properties of water, even
when solid catalysts are employed. Conducting reactions under
aqueous conditions also provides the advantages such as reduced
pollution, low cost, and simplicity in process and handling.
These factors are especially important in an industry aiming at
Green & Sustainable Chemistry.
Here, we present a new strategy for the design of a
nanoconstructed heterogeneous catalyst and the synthesis of a
calcium vanadate apatite (VAp), Ca10(VO4)6(OH)2, by substitut-
3-
3-
ing VO4 for PO4 in the whole apatite matrix. With water
as a reaction medium, the VAp exhibited exceptionally high
catalytic activities for carbon-carbon bond-forming reactions.
Our catalytic system possesses remarkably attractive features
for organic synthesis: (i) high catalytic efficiency under mild
reaction conditions, (ii) a simple procedure which allows for
large-scale operation, (iii) no requirement for organic solvents,
and (iv) easy separation and recycling of the solid catalyst. To
the best of our knowledge, this is the first report of successful
carbon-carbon bond-forming reactions under aqueous condi-
tions using vanadium as a Brønsted base catalyst.
Apatites and related compounds are of great interest because
of their structural stability and their potential for cationic and
anionic isomorphous substitution.5 The hexagonal hydroxya-
patite (HAP) structure comprises Ca2+ sites surrounded by
3-
PO4 tetrahedra. The chemical composition of HAP can be
modified from the stoichiometric form, Ca10(PO4)6(OH)2 (Ca/P
) 1.67), to the nonstoichiometric Ca-deficient form, Ca10-Z
-
(HPO4)Z(PO4)6-Z(OH)2-Z (0 < Z e 1, 1.5 e Ca/P < 1.67). We
have previously focused on doping the apatite surface with
various transition metal cations, which can function as catalyti-
cally active centers, via cation exchange at Ca2+ sites.6 For
example, the introduction of La3+ cation into the apatite can
generate stable monomeric phosphate complexes, which act as
efficient heterogeneous catalysts for the Michael reaction of 1,3-
dicarbonyls with enones under aqueous or solvent-free condi-
tions.6b,6c
Results and Discussion
Catalyst Preparation and Characterization. The VAp was
synthesized by modification of a previously reported procedure.7
A mixture of CaSO4‚2H2O and Na3VO4 in aqueous solution
was refluxed for 2 h with excess NaOH. The resulting white
slurry was cooled to room temperature, filtered, washed with
deionized water and dried, followed by calcination in air at 800
°C for 3 h, yielding the VAp as a white powder. Based on
elemental analysis, the amounts of Ca and V were found to be
35.03 and 26.58 wt %, respectively, and the Ca/V ratio of the
VAp was 1.67 in agreement with the stoichiometric value of
the apatite components. The Brunauer-Emmett-Teller (BET)
surface area was found to be 1.1 m2‚g-1. The powder X-ray
diffraction (XRD) patterns of the VAp calcined at various
temperatures are shown in Figure 1. The intensities of the
(5) Elliott, J. C. Structure and Chemistry of the Apatites and Other
Calcium Orthophosphates; Elsevier: Amsterdam, 1994.
(6) (a) Mori, K.; Mitani, Y.; Hara, T.; Mizugaki, T. Ebitani, K.; Kaneda,
K. Chem. Commun. 2005, 3331. (b) Mori, K.; Oshiba, M.; Hara, T.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2005, 46, 4283.
(c) Mori, K.; Oshiba, M.; Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
New. J. Chem. 2006, 30, 44. (d) Mori, K.; Hara, T.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 10657. (e) Mori, K.; Hara,
T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2003, 125,
11460. (f) Mori, K.; Yamaguchi, K.; Hara, T.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2002, 124, 11572. (g) Yamaguchi, K.; Mori,
K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2000, 122,
7144.
(7) Mayer, I.; Wahnon, S.; Cohen, S. Mater. Res. Bull. 1979, 14, 1479.
7456 J. Org. Chem., Vol. 71, No. 19, 2006

C-C Bond-Forming Reactions in Aqueous Media
TABLE 1. Michael Reaction of 1a with 2aa
diffraction peaks of VAp lattice increased with increasing
calcination temperatures: the uncalcined VAp showed an
amorphous phase, whereas the VAp samples calcined at more
than 600 °C exhibited sharp peaks together with small peaks
of a CaO phase at around 32° and 38°.
Transmission electron microscopy (TEM) images of the VAp
calcined at 800 °C show that the VAp covered with amorphous
CaO phase was observed as a bright region in a dark field.8
The Ca/V ratio at various depths of the VAp matrix was
determined by XPS etched by Ar ion laser. First, enrichment
of Ca at the surface was observed due to the presence of the
CaO phase. As the etch treatment was continuously repeated,
the Ca/V ratio decreased, but then increased again. It seems
that the VAp consists of three phases: CaO, a nonstoichiometric
VAp shell, e.g. Ca9(HVO4)(VO4)5(OH),9 and a stoichiometric
VAp core from the surface.5 Allowing other characterization
results confirmed by several physicochemical methods,8 the
present methodology of catalyst preparation is a promising
protocol for creation of a nonstoichiometric apatite phase
containing stable and isolated tetrahedral Vanadium species with
an oxidation state of +5 on an apatite surface.
VAp-Catalyzed Aqueous Michael Reaction. The Michael
reaction of 1,3-dicarbonyl compounds with activated enones
provides access to 1,5-dioxo synthons, which can be easily
transformed into cyclohexanone derivatives for use as important
intermediates in steroid and terpenoid synthesis.10 Traditionally,
this reaction is promoted by strong bases such as alkali metal
alkoxides or hydroxides.11 In some cases, however, a number
of side- and subsequent reactions, e.g. ester solvolysis, aldol-
cyclizations, and retro-Claisen-type decompositions result in low
selectivity. One way to address these drawbacks is to avoid
Brønsted basic reaction conditions. To achieve this, a number
of catalytic systems employing neutral conditions have been
developed.12
entry
catalystb
solvent
water
water
water
water
water
neat
acetone
CH3CN
EtOH
EtOAc
DMF
DMSO
1,4-dioxane
CH3NO2
THF
toluene
water
water
water
water
convn (%)c
yield (%)c
1
2
3
VAp (800 °C)
VAp (600 °C)
VAp (400 °C)
VAp (200 °C)
VAp (uncalcined)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
VAp (800 °C)
Na3VO4
K3VO4
Mg2V2O7
NaVO3
VO(acac)2
V(acac)3
V2O5
VOSO4‚nH2O
VCl3
>99
20
11
2
38
0
>99
18
10
2
36
0
4
5d
6
7
8
9
0
0
0
0
0
0
0
0
0
0
41
33
19
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
39
32
17
0
0
0
0
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
water
water
water
water
water
water
water
0
0
0
0
0
0
HAP
none
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), catalyst (V: 0.012
mmol), solvent (3 mL). b Values in parentheses are calcination temperature.
c Determined by GC using an internal standard technique. d Vanadium
leaching was observed.
To investigate the abilities of the VAp catalyst, the Michael
reaction of 2-oxo-cyclopentane carboxylic acid ethyl ester (1a)
with 2-cyclohexen-1-one (2a) was carried out as a model
reaction at 50 °C in various solvents. The results are summarized
in Table 1.
It is noteworthy that the VAp showed high catalytic activity
for the Michael reaction under aqueous conditions, giving only
2-oxo-1-(3-oxocyclohexyl)-cyclopentane carboxylic acid ethyl
ester (3a) in a quantitative yield within 30 min (entry 1). The
reaction did not proceed at all without the VAp catalyst (entry
27), and no product was formed when any other polar or
nonpolar solvent was used (entries 6-16). Comparisons of the
catalytic activities of the VAp with those of various vanadium
compounds in a water solvent are also summarized in Table 1.
It appears that the calcination process of the VAp is indispen-
sable in the formation of the active VAp catalyst; as the
temperature of calcination increases to 800 °C, the catalytic
activity of the resulting VAp increases (Table 1, entries 1-5).
This result supports the finding of the XRD analysis, in which
the peak intensities of the resulting VAp lattice increase as the
calcination temperature is raised (Figure 1a-e). Orthovanadate
and pyrovanadate derivatives containing isolated VO4 tetrahedra,
such as Na3VO4, K3VO4, and Mg2V2O7 also gave 3a in
moderate yields of 39%, 32%, and 17%, respectively (entries
17-19), but these catalysts underwent severe deactivation
caused by the structural change from monomeric to polymerized
species during the reaction: the presence of charge-transfer
bands at wavelengths longer than 320 nm was confirmed by
UV-vis spectroscopy. The use of other vanadium reagents did
not afford any products (entries 20-25), and the reaction did
not proceed in the presence of the HAP by itself (entry 26).
These results support the contention that the presence of isolated
VO4 tetrahedral species on a solid surface plays a key role in
the success of the aqueous Michael reaction.
(8) See Supporting Information.
(9) The crystallographic structure of the Ca-deficient HAp is identical
to that of the stoichiometric one, and its charge deficiency due to the lack
of Ca2+ in the lattice is compensated by introduction of H+ into the PO4
3-
ion and removal of OH- in the parent unit cell.
(10) (a) Ho, T.-L. Tactics of Organic Synthesis; Wiley: New York, 1994.
(b) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Ed.; Pergamon: Oxford, 1991; Vol. 4; pp 1. (c) House, H. O. Modern
Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; p 595.
(11) (a) Perlmutter, P. Cojugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series, Vol. 9; Pergamon: Oxford, 1992.
(b) Oare, D. A.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227. (c)
Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 179.
(12) Pelzer, S.; Kauf, T.; van Wu¨llen, C.; Christoffers, J. J. Organomet.
Chem. 2003, 684, 308. For an excellent review on transition metal catalyzed
Michael reaction of 1,3-dicarbonyls, see: (b) Christoffers, J. Eur. J. Org.
Chem. 1998, 1259, 9.
The VAp-catalyzed Michael reaction in water was found to
be expandable to include various sets of donors and acceptors.
The results are summarized in Table 2. It was found that the
aqueous Michael reaction of 1a with 3-buten-2-one (2b)
proceeded efficiently in the presence of the VAp catalyst to
give 2-oxo-1-(3-oxobutyl)-cyclopentanecarboxylic acid ethyl
ester (3b) quantitatively in 10 min (entry 1). Methyl acrylate
(2c) and acrylonitrile (2d) also acted as good acceptors, giving
J. Org. Chem, Vol. 71, No. 19, 2006 7457

Hara et al.
TABLE 2. Aqueous Michael Reaction in the Presence of VAp Catalysta
a Donor (5 mmol), acceptor (5.5 mmol), VAp (0.05 g), H2O (5 mL), 30 °C. b Determined by GC using an internal standard technique. Values in parentheses
are isolated yield. c VAp (0.025 g). d 50 °C. e 2b (20 mmol), without solvent, 80 °C. f 2b (10 mmol), without solvent, 80 °C.
SCHEME 1
3c and 3d, respectively (entries 2 and 3). The reaction of 2b
with various â-keto esters, 1,3-diketones, and lactone with 2b
afforded high yields of the corresponding 1,5-dioxo compounds
(entries 4-12). The Michael reactions of diethylmalonate
derivatives (1c and 1d) with 2b, which did not easily proceed
by use of traditionally Lewis acid catalysts, gave the corre-
sponding products in excellent yields (entries 13 and 14).
In all cases, the 1,4-addition products were obtained exclu-
sively without formation of 1,2-adducts. Unfortunately, the use
of 2-acetylpentanone, acetylacetone, and ethyl benzoyl acetate,
which have low pKa values of 7.8, 9.0, and 9.413 as donors was
not effective in the present Michael reaction, and it resulted in
the dissolution of vanadium into the reaction mixture. This
leaching of vanadium may be the result of strong coordination
by the donors to the surface vanadium species, thus preventing
smooth reactions.14 In the reaction of 1a with acrolein (2e),
sequential intramolecular 1,2-addition reaction and acetylation
proceeded to give 4-acetoxy-8-oxobicyclo[3.2.1]-octan-1-car-
boxylic acid ethyl ester (3f) (Scheme 1).15
The workup procedure is straightforward due to the hetero-
geneous nature of the catalyst and the three-phase reaction
mixture, as shown in Figure 2.
The product was easily separated by extraction after filtering
out the solid catalyst. No spectral change was observed in the
UV-vis or XAFS spectra of the recovered VAp, which shows
that the vanadium species remained in the monomeric state
throughout the reaction. The catalyst was found to be reusable
at least four times without any reduction in activity during the
reaction of 1a and 2b.8 To further demonstrate the effectiveness
of the VAp, the catalyst was removed by filtration from the
reaction of 1b with 2b after 55% conversion. Continuation of
the reaction for 1 h under identical reaction conditions afforded
no product (Figure 3). Any vanadium leached in the aqueous
(13) Fu, Y.; Liu, L.; Li, R.-Q.; Liu, R.; Guo, Q.-X. J. Am. Chem. Soc.
2004, 126, 814.
(14) Selbin, J.; Maus, G.; Johnson, D. L. J. Inorg. Nucl. Chem. 1967,
29, 1735.
(15) (a) Buchanan, G. L.; McLay, G. W. Tetrahedron 1966, 22, 1521.
(b) Kraus, W.; Patzelt, H.; Sadlo, H.; Sawitzki, G.; Schwinger, G. Liebigs
Ann. Chem. 1981, 1826.
7458 J. Org. Chem., Vol. 71, No. 19, 2006

C-C Bond-Forming Reactions in Aqueous Media
catalyst,6b,6c montmorillonite-enwrapped Sc (Sc3+-mont),17a and
montmorillonite-enwrapped Cu (Cu2+-mont)17b gave TONs of
4500, 1000, and 400 and TOFs of 500, 29, and 28.5 h-1
,
respectively. The TON and TOF values of the VAp catalyst
are the highest ever reported for the transition metal catalyzed
Michael reactions so far: RuH2(PPh3)4 (TON 33.3, TOF 66.6
h-1),18 Yb(OTf)3/SiO2 (17, 0.7 h-1),19 CeCl3‚7H2O/NaI (5, 0.8
h-1),20 Ni(acac)2 (100, 100 h-1),21 Fe-mica (100, 5 h-1),22 InCl3
(10, 1.7 h-1),23 Yb(OTf)3 (100, 1.4 h-1 24
) and FeCl3‚6H2O (100,
100 h-1).25 We concluded that the present vanadium-based
catalytic system allows for simple and practical organic synthesis
while meeting the increasing criteria for environmentally
friendly chemical processes in the synthesis of fine chemicals
and pharmaceuticals.
FIGURE 2. Aqueous Michael reaction of 1b with 2b: (a) reaction
VAp-Catalyzed Aldol-Type Reaction. To explore the
promising catalytic activity of the VAp in the abstraction of
acidic R-hydrogenes from various carbonyl compounds, several
aldol-type reactions were examined under aqueous conditions.
It is well-known that Knoevenagel condensation of aldehydes
with active methylene compounds is a useful tool allowing
convenient carbon chain elongation along with functionalization
of aldehydes, giving R,â-unsaturated carbonyls or nitriles. This
reaction is usually catalyzed by bases such as amines, ammonia,
or sodium ethoxide in organic solvents.26
mixture and (b) three-phase separation by a centrifuge after the reaction.
Our previously reported LaHAP and Sc3+-mont and catalysts,
which were active for Michael reactions in water, did not
promote this type of condensation. In contrast, the VAp catalyst
exhibited high catalytic activity for the Knoevenagel reaction.
The range of substrates for the Knoevenagel reaction under
aqueous conditions is exemplified in Table 3. Preliminary
screening of solvents showed that water was superior to other
organic solvents for this reaction.27 The reaction is highly
stereoselective for the E-geometry, affording the corresponding
R,â-unsaturated nitriles in excellent yields. Both electron-rich
and electron-deficient benzaldehydes reacted well, giving high
product yields (entries 2 and 3). Aliphatic aldehydes such as
hexanal and octanal also underwent the condensation easily
(entries 4 and 5). It is notable that cinnamaldehyde reacted with
4a without formation of the 1,4-adduct (entry 7). The reaction
of phenylacetonitrile (4c), which has a large pKa value of
21.9,2828 proceeded efficiently in the presence of the VAp
FIGURE 3. Effect of removal of the VAp catalyst on the Michael
reaction of 1c with 2b: without removal of VAp (9); an arrow indicates
the removal of the VAp (2). Reaction conditions: 1c (5 mmol), 2b
(5.5 mmol), VAp (0.05 g), water (5 mL), 30 °C.
SCHEME 2
(17) (a) Kawabata, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem. Soc. 2003, 125, 10486. (b) Kawabata, T.; Kato, M.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. Chem. Eur. J. 2005, 11, 288.
(18) 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.
(19) Kotsuki, H.; Arimura, K. Tetrahedron Lett. 1997, 38, 7583.
(20) Bartoli, G.; Bosco, M.; Bellucci, M. C.; Marcantoni, E.; Sambri,
L.; Torregiani, E. Eur. J. Org. Chem. 1999, 617, 7.
(21) Saegusa, T.; Ito, Y.; Tomita, S.; Kinoshita, H. Bull. Chem. Soc.
Jpn. 1972, 45, 496.
phase was in amount small enough to be undetectable by ICP
analysis. These results show that this reaction proceeds on the
VAp surface and does not inVolVe dissolVed Vanadium species.
More significantly, the use of 8 mg of the VAp catalyst under
aqueous conditions allowed 32.2 g (200 mmol) of 1a to react
with 15.4 g (210 mmol) of 2b in a highly effective manner,
giving a 92% isolated yield (41.6 g) of 3b at 40 °C in 1.5 h, as
highlighted in Scheme 2. It has been reported that the surface
(22) Shimizu, K.-I.; Miyagi, M.; Kan-no, T.; Kodama, T.; Kitayama, Y.
Tetrahedron Lett. 2003, 44, 7421.
(23) Yadav, J. S.; Geetha, V.; Reddy, B. V. S. Synth. Commun. 2002,
32, 3519.
density of PO4 species of the HAP is 5 PO4 nm-2 16
.
3-
3-
3-
Adapting this calculation method, the amount of the VO4 in
the spent VAp was estimated to be 0.096 mmol‚g-1 for the
surface area. Based on the surface vanadium content, the VAp
catalyst showed a high turnover number (TON; mol of product
per mol of surface V content) of 260 400 and turnover frequency
(TOF; mol of product per mol of surface V content per second)
of 48 s-1. In contrast, our previously reported aqueous Michael
reactions using hydroxyapatite-supported La complex (LaHAP)
(24) Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879.
(25) Christoffers, J. J. Chem. Soc., Perkin Trans. 1 1997, 3141.
(26) (a) Marcaccini, S.; Pepino, R.; Pozo, M. C.; Basurto, S.; Garæia-
Valverde, M.; Torroba, T. Tetrahedron Lett. 2004, 45, 3999. (b) Shih, M.
H.; Yeh, M. Y. Tetrahedron 2003, 59, 4103. (c) Heathcock, C. H.
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, p 341.
(27) In the screening of various solvents as summarized in Table 1, 6a
was obtained in 26% (DMSO) and 11% (EtOH), respectively. The other
organic solvent resulted in no conversion of substrates.
(28) Martell, A. E.; Smith, R. M. In Critical Stability Constants; Plenum
Press: New York, 1974, 1975, 1977; Vol. 1-3.
(16) Tanaka, H.; Yasukawa, A.; Kandori, K.; Ishikawa, T. Colloids Surf.
A 1997, 125, 53.
J. Org. Chem, Vol. 71, No. 19, 2006 7459

Hara et al.
TABLE 3. Knoevenagel Condensation in Water Using VAp Catalysta
a Donor (1.5 mmol), acceptor (1 mmol), water (5 mL), VAp (0.05 g), 50 °C. b Determined by GC using an internal standard method. c 110 °C. d THF (1
mL) was used as a cosolvent, 60 °C.
TABLE 4. Synthesis of 1,3-Dinitrocompounds Catalyzed by VAp
in Watera
SCHEME 3
catalyst (entry 8), but was not catalyzed efficiently by RuH2-
(PPh3)4 as a typical metal complex, or cationic RuHAP.6f In
18
the case of phenylsulfonylacetonitrile (4d), the condensation
proceeded efficiently using THF as a cosolvent (entry 9). Other
vanadium compounds of VO(acac)2, V(acac)3, V2O5, VOSO4‚
nH2O, and VCl3 were also examined as potential catalysts for
this reaction, but all gave inferior results or showed no
conversion.29
Furthermore, a 100-mmol-scale condensation of ethyl cy-
anoacetate (4a, pKa ) 9.0) with benzaldehyde (5a) in water
produced (2E)-2-cyano-3-phenyl-2-propenoic acid ethyl ester
(6a) quantitatively (Scheme 3).
The use of nitromethane (6) as a donor instead of nitriles
under aqueous reflux conditions afforded the corresponding 1,3-
dinitro compounds predominantly, as shown in Table 4.30 These
1,3-dinitro compounds are known to be key building blocks for
biologically active substances including HIV-protease activity
inhibitors and NMDA receptor antagonists.31
a VAp (0.05 g), nitromethane (1 mL), acceptor (1 mmol), H2O (5 mL),
100 °C, 12 h. b Isolated yield.
Electronic variation of p-substituted benzaldehydes did not
strongly affect reaction rates. When the temperature was lowered
to 30 °C in the reaction of 6 with 5a, the corresponding nitro
alcohol was obtained quantitatively. This observation suggests
that the reaction may consist of three sequential reactions: aldol
condensation, dehydration, and Michael reaction.32 Furthermore,
(29) Orthovanadate salts such as Na3VO4 and K3VO4 showed catalytic
activity but resulted in poor yields.
(30) Syntheses of 1,3-dinitro compounds; see: (a) Ferro, A.; Rezende,
M. C.; Sepulveda-Boza, S.; Reyes-Parada, M.; Cassels, B. K. J. Chem. Res.
2001, 7, 294. (b) Alcantara, M. D.; Escribano, F. C.; Gomez-Sanchez, A.;
Dianez, M. J.; Estrada, M. B. Castro, A. L.; Perez-Garrido, S. Synthesis
1996, 64.
(31) Ballini, R.; Barboni, L.; Fiorini, D.; Giarlo, G.; Palmieri, A. Chem.
Commun. 2005, 2633.
(32) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A. Synthesis 2004,
1938.
7460 J. Org. Chem., Vol. 71, No. 19, 2006

C-C Bond-Forming Reactions in Aqueous Media
SCHEME 4
TABLE 5. Deuteration of Various Ketones by Use of VAp
Catalyst and D2Oa
FIGURE 4. TPD plots for CO2 absorbed on VAp catalysts: VAp
calcined at 800 °C, gray line; VAp-hw, black line. Peak intensity is
normalized to that of He (m/e ) 4).
Mechanistic Investigation. After the aqueous Michael reac-
tion of 1a with 2b (Table 2, entry 1) and removal of the catalyst
by filtration, 7% of Ca leached from the VAp calcined at 800
°C and the XRD spectrum of the catalyst showed the disap-
pearance of the CaO phase (Figure 1f). The Ca/V ratio of the
recovered VAp catalyst was determined to be 1.50. It was found
that pretreatment with hot water of the VAp calcined at 800
°C, abbreviated as VAp-hw, also led to a reduction of the Ca/V
ratio to 1.50 together with the disappearance of the CaO peaks
(Figure 1g). Moreover, the BET surface area of the VAp-hw
catalyst was found to be 11.6 m2‚g-1, which was similar to that
of the spent VAp catalyst. The distribution of calcium and
vanadium in the spent VAp was measured by XPS using an
etching technique, in which the surface of the spent VAp was
composed of a nonstoichiometric phase, while the inner was
stoichiometric. Figure 4 shows temperature-programmed de-
sorption (TPD) profiles of carbon dioxide absorbed as a probe
on the VAp calcined at 800 °C and the VAp-hw. From the peak
positions of the TPD profiles, it can be seen that the surface
basicity of the VAp-hw is stronger than that of the VAp calcined
at 800 °C. Furthermore, the base amounts in the VAp-hw was
approximately 0.32 mmol‚g-1, which was 2 orders of magnitude
greater than that of the VAp calcined at 800 °C (6.6 × 10-3
mmol‚g-1).
Furthermore, in the reaction of 1a with 2b, an addition of
1.5 equiv of benzoic acid based on the amount of surface
vanadium species resulted in a significant decrease in product
yield from 99% to 37% yield. These results show that water,
when used as a reaction medium, acts as a trigger to generate
a nonstoichiometric apatite phase by remoVal of the CaO phase
from the surface, and the distorted Vanadate species such as a
V-OH species acts as a Brønsted base sites. As described
above, the use of any other organic solvents, e.g. toluene or
ethanol, gave no Michael products, and Ca species were not
detected in the filtrates. In contrast to the above results, the
VAp-hw catalyst promoted the Michael reaction of 1a with 2a
even in organic solvents (Table 6) such as 1,2-dichloroethane,
toluene, and ethanol (entries 2-4). Moreover, in the recycling
experiments under aqueous conditions, further Ca dissolution
could not be detected in the filtrate.
a Substrate (5 mmol), VAp (0.05 g), D2O (5 mL), 50 °C, 2 h, Ar.
b Determined by 1H NMR. Values in parentheses are isolated yield. c THF
(2 mL) was used as a cosolvent.
2-benzylphenol was readily obtained from the reaction of 2a
with 5a in sequential reactions of aldol condensation, dehydra-
tion, and isomerization (Scheme 4).
Deuteration in D2O Using the VAp Catalyst. The absolute
and relative rates of many individual chemical proton transfer
processes have been well documented; however, the develop-
ment of an efficient deuterium incorporation procedure is still
a challenge. The base-catalyzed H-D exchange reaction of a
C-H bond adjacent to a carbonyl group has been widely used
for the syntheses of R-deuterated ketones.33 The results of
deuteration of several ketones using D2O as a deuterium source
in the presence of the VAp catalyst are shown in Table 5.
Treatment of 3-pentanone (7) with D2O at 50 °C for 2 h gave
deuterated 3-pentanone-2,2,4,4-d4 (8) in 94% yield. Moreover,
further treatment of the isolated product with D2O in the
presence of the VAp catalyst under identical conditions gave
analytically pure 8. Even for ketones with relatively high pKa
values, such as acetophenone (pKa ) 24.7), 1-indanone (pKa )
23.0), and cyclohexanone (pKa ) 26.4), efficient deuteration
took place to afford the corresponding labeled products in
excellent yields. In the VAp-catalyzed deuteration reaction, the
amounts of self-aldol products formed were not determined.
(33) (a) Klei, S. R.; Golden, J. T.; Tilley, T. D.; Bergman, R. G. J. Am.
Chem. Soc. 2002, 124, 2092. (b) Kingston, L.; Lockley, W. J. S.; Mather,
A. N.; Spink, E.; Thompson, S. P.; Wilkinson, D. J. Tetrahedron Lett. 2000,
41, 2705. (c) Ellames, G. J.; Gibson, J. S.; Herbert, J. M.; Kerr, W. J.;
McNeill, A. H. Tetrahedron Lett. 2001, 42, 6413. (d) Sajiki, H.; Hattori,
K.; Aoki, F.; Yasunaga, K.; Hirota, K. Synlett 2002, 1149.
J. Org. Chem, Vol. 71, No. 19, 2006 7461

Hara et al.
TABLE 6. Michael Reaction of 1a with 2a Catalyzed by VAp-hwa
2.50 (m, 4H), 2.71 (ddd, J ) 5, 9, and 17 Hz, 1H), 4.17 (q, J )
7.5 Hz, 2H); 13C NMR (105 MHz, CDCl3) δ 14.5, 20.0, 27.4, 30.3,
34.8, 38.4, 39.3, 59.4, 61.8, 171.8, 208.2, 215.3; IR (neat) 2976,
1747, 1718, 1166 cm-1. HRMS (EI): m/z calcd for C12H18O4
226.1205. Found: 226.1182.
A Procedure for the 100-mmol-Scale Aqueous Aldol Reaction
(Scheme 3). A mixture of 4a (11.3 g, 100 mmol), 5a (11.7 g, 110
mmol), VAp (0.025 g), and water (50 mL) was stirred at 30 °C.
The progress of the reaction was monitored by GC analysis. After
5 h, the VAp catalyst was separated from the reaction mixture by
a centrifuge. The filtrate was extracted with diethyl ether and then
dried over MgSO4. Removal of diethyl ether under the reduced
pressure, followed by recrystallization (n-hexane and ethyl acetate),
afforded analytically pure (2E)-2-cyano-3-phenyl- 2-propenoic acid
ethyl ester (6a) as a white powder (95% isolated yield): CAS
registry number [2025-40-3]; mp 52 °C; 1H NMR (400 MHz,
CDCl3) δ 1.45 (t, 3H, J ) 7.1 Hz), 4.42 (q, 2H, J ) 7.1 Hz), 7.48-
7.64 (m, 3H), 8.02 (m, 2H), 7.98-8.08 (s, 1H); 13C NMR (105
MHz, CDCl3) δ 14.2, 62.9, 103.7, 115.3, 128.3, 130.3, 132.3, 132.7,
153.6, 162.3; IR (KBr) 1200, 1610, 2240 cm-1. HRMS (EI): m/z
calcd for C12H11NO2 201.0790. Found: 201.0790.
A Procedure for the Synthesis of 1,3-Dinitro Compounds in
Water (Table 4). Into a reaction vessel with VAp (0.05 g), water
(5 mL), and nitromethane (1 mL) was added 5a (1 mmol), and
then the resulting mixture was stirred at 110 °C. After 12 h, the
VAp catalyst was readily separated from the reaction mixture by a
centrifuge. The filtrate was extracted with diethyl ether and then
dried over MgSO4. Removal of diethyl ether and nitromethane under
the reduced pressure, followed by column chromatography (n-
hexane/EtOAc ) 4/1), afforded analytically pure 2-nitro-1-(nitro-
methyl)ethylbenzene as a yellow oil (0.19 g, 91% isolated yield):
CAS registry number [117538-84-8]; 1H NMR (400 MHz, CDCl3)
δ 4.22-4.33 (m, 1H), 4.69-4.82 (m, 4H), 7.17-7.20 (m, 2H),
7.22-7.38 (m, 3H); 13C NMR (105 MHz, CDCl3) 42.0, 77.0, 127.6,
129.3, 129.7, 134.5; IR (KBr) 1736, 1560, 1654, 3034 cm-1. HRMS
(EI): m/z calcd for C9H10N2O4: 210.0641. Found: 210.0637.
Deuteration of Various Ketones by Use of VAp Catalyst
(Table 5). Acetophenone-2,2,2-d3 (entry 1): CAS registry No.
[17537-31-4]. Into a reaction vessel with VAp (0.05 g) and
deuterium oxide (5 mL) was placed acetophenone (0.60 g, 5 mmol),
and the mixture was stirred at 50 °C under Ar atmosphere. After 2
h, the VAp catalyst was readily separated from the reaction mixture
by a centrifuge. The reaction mixture was extracted with diethyl
ether. The organic layer was dried over MgSO4, filtered, concen-
trated, and distilled by Kugelrohr (120 °C/50 mmHg). Acetophe-
none-2,2,2-d3 [90% atom D] was obtained. Further treatment of
the isolated product with the VAp catalyst and D2O in the same
manner gave analytically pure acetophenone-2,2,2-d3 (0.55 g, 100%
atm D, 89% isolated yield). HRMS (EI): m/z calcd for C8H5D3O
123.0760. Found: 123.0747.
entry
solvent
convn (%)b
yield (%)b
1
2
3
4
water
>99
66
56
>99
66
54
1,2-dichloroethane
toluene
ethanol
35
33
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), VAp-hw (0.05 g),
solvent (3 mL), 50 °C, 0.5 h. c Determined by GC using an internal standard
technique.
The suggested mechanism of the VAp-catalyzed Michael
reaction is as follows. In situ generation of an extremely active
V-OH species abstracts an R-proton from the donor to form a
1,3-diketonato vanadium species on the VAp surface. An
acceptor subsequently coordinates to a vacant site of the
vanadium species through a carbonyl oxygen, and alkylation
and hydrolysis then take place, affording the Michael adduct
and the regenerated the V-OH species. Such V-OH species
can also induce aldol-type condensations and H-D exchange
reaction. The hydrophilic nature of the VAp and the structural
robustness of the isolated VO4 tetrahedron units on the solid
surface offer the possibility of performing diverse array of base-
mediated reactions under aqueous conditions.
Conclusions
The VAp, which contains isolated tetrahedral V5+ species,
has been developed as an extremely active base catalyst for C-C
bond-forming reactions such as Michael- and aldol-type reac-
tions under aqueous conditions. Moreover, the VAp was found
to be an effective heterogeneous catalyst for the synthesis of
R-deuterated ketones using D2O. We continue to refine the
catalyst design using apatite components with the aim of
developing a range of environmentally benign organic syntheses,
including asymmetric reactions.
Experimental Section
Preparation of VAp Catalyst. A mixture of CaSO4‚2H2O (11.5
g, 66.8 mmol) and Na3VO4 (7.36 g, 40.0 mmol) in aqueous solution
was refluxed for 2 h with excess NaOH (5.0 g). The white slurry
was then cooled to room temperature, filtered, washed with large
amount of deionized water and dried overnight at 110 °C, followed
by calcination at 800 °C for 3 h, yielding the VAp as a white
powder. Based on the elemental analysis, the amount of Ca and V
were found to be 35.03 and 26.58 wt %, respectively, and the Ca/V
ratio of VAp was estimated to be 1.67 in agreement with the
stoichiometric value of apatite component.
Acknowledgment. This work is supported by the Grant-in-
Aid for Scientific Research from Ministry of Education, Culture,
Sports, Science, and Technology of Japan and the center of
excellence program “Creation of Integrated EcoChemistry” of
Osaka University. A part of present experiments were carried
out by using a facility in the Research Center for Ultrahigh
Voltage Electron Microscopy, Osaka University. We thank Prof.
Masaharu Nomura (KEK-PF) for XAFS measurement and Dr.
Yusuke Yamada (AIST) for TPD measurement.
Typical Procedure for the 200-mmol-Scale Michael Reaction
of 1a with 2b in Water (Scheme 2). A mixture of 1a (32.2 g, 200
mmol), 2b (15.4 g, 220 mmol), VAp (0.008 g), and water (50 mL)
was stirred at 40 °C. After 1.5 h, GC analysis of the supernatant
showed complete conversion of 2b. The reaction mixture was
extracted with diethyl ether, washed with brine, and then dried over
Na2SO4. Diethyl ether was removed under the reduced pressure,
then the residue was distilled to give 41.6 g (92% isolated yield)
of analytically pure 2-oxo-1-(3-oxobutyl)-cyclopentanecarboxylic
acid ethyl ester (3b) as a colorless oil: bp 151-152 °C/6 mmHg;
Supporting Information Available: General procedures, char-
acterization of the VAp catalyst, product identification, experimental
section, and reuse of the VAp catalyst in Michael reactions.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
CAS registry number [61771-81-1]; H NMR (400 MHz, CDCl3)
δ 1.25 (t, J ) 7.5 Hz, 3H), 1.83-2.14 (m, 5H), 2.15 (s, 3H), 2.24-
JO0614745
7462 J. Org. Chem., Vol. 71, No. 19, 2006