Michael reaction of 1,3-dicarbonyls with enones catalyzed by a hydroxyapatite-bound La complex

Article abstract of DOI:10.1016/j.tetlet.2005.04.099

A hydroxyapatite-bound La complex, which functioned as an efficient heterogeneous catalyst for the Michael reaction of 1,3-dicarbonyls with enones under aqueous or solvent-free conditions, was prepared using a cation-exchange method. Further application to an asymmetric version by a fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid is also described.

Full text of DOI:10.1016/j.tetlet.2005.04.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4283–4286
Michael reaction of 1,3-dicarbonyls with enones catalyzed by
a hydroxyapatite-bound La complex
Kohsuke Mori, Michitaka Oshiba, Takayoshi Hara, Tomoo Mizugaki,
Kohki Ebitani and Kiyotomi Kaneda*
Department of Materials Engineering Science, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama,
Toyonaka, Osaka 560-8531, Japan
Received 6 April2005; revised 25 April2005; accepted 27 April2005
Abstract—A hydroxyapatite-bound La complex, which functioned as an efficient heterogeneous catalyst for the Michael reaction of
1,3-dicarbonyls with enones under aqueous or solvent-free conditions, was prepared using a cation-exchange method. Further appli-
cation to an asymmetric version by a fluoroapatite-bound La complex catalyst modified with (R,R)-tartaric acid is also described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The Michaelreaction is wideyl recognized as one of the
most important carbon–carbon bond-forming reactions,
leading to functionalized adducts of high synthetic
value.1 In a quest for improving the reaction, various
transition metal complexes including chiral version have
been developed instead of traditional strong bases.2
Among them, rare earth metaltrifluoromethanesuflon-
ates [RE(OTf)3] are considered to be effective for aque-
efficiently catalyze the oxidation of alcohols,5a amines,5b
and silanes5c under an atmospheric pressure of molecu-
lar oxygen. The present work reports the synthesis of a
hydroxyapatite-bound La complex (LaHAP) and its
evaluation as a recyclable heterogeneous catalyst for
the Michaelreaction of 1,3-dicarbonysl with enones
under aqueous or solvent-free conditions (Scheme 1).
We also describe a novel heterogeneous chiral catalyst
generated by modification of a fluoroapatite-bound La
complex with (R,R)-tartaric acid (TA-LaFAP). To the
best of our knowledge, this is the first demonstration
of an asymmetric reaction utilizing an apatite catalyst.6
3
ous Michaelreactions. The use of homogeneous metal
catalysts, however, is faced with a number of disadvan-
tages including the loss of expensive metals and difficul-
ties in catalysts separation and recovery of the catalysts.
In this context, conducting the reaction by heteroge-
neous catalysts under aqueous or solvent-free conditions
instead of using harmful organic solvents could make a
contribution to improve environmentaloutcomes and
simplify organic synthesis.4
The LaHAP was synthesized according to our previ-
ously reported cation-exchange method in an aqueous
medium.5a Thus, treatment of the stoichiometric
hydroxyapatite (2.0 g), Ca10(PO4)6(OH)2, with an aque-
ous solution of La(OTf)3 (1.3 · 10ꢀ3 M) at room tem-
perature for 9 h, yielded LaHAP (La content:
0.16 mmolg ꢀ1) as a white powder. Characterization by
means of XRD, IR, XPS, and La K-edge XAFS proves
that a monomeric LaIII complex surrounded by one
Recently, we disclosed a new strategy for the design of
high-performance heterogeneous catalysts utilizing
hydroxyapatite (HAP) as a macroligand for catalytically
active centers.5 For example, the cation-exchange ability
of the HAP enables an equimolar substitution of Ru3+
for Ca2+ on their surface, which gives a monomeric
Ru3+ phosphate species (RuHAP).5a This RuHAP could
R1
R3
R1
R3
O
O
O
O
R4
R5
R2
R4
LaHAP
R2
R5
+
H2O or
solvent-free
Keywords: Michael reaction; 1,3-Dicarbonyls; Heterogeneous catalyst;
Lanthanum; Apatite; Asymmetric.
O
O
*
Corresponding author. Tel./fax: +81 6 6850 6260; e-mail: kaneda@
cheng.es.osaka-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.099

4284
K. Mori et al. / Tetrahedron Letters 46 (2005) 4283–4286
hydroxyland three weakyl coordinated aqua ilgands
was created on the surface of the HAP.
ous conditions provided higher yields than those using
other organic solvents (58% toluene; 35% acetonitrile;
30% 1,2-dichloroethane; 9% THF; trace amount
DMF). It is notable that a 25mmol-scale experiment
for 1a with 2a was performed to give 90% yield of Mi-
chaeladduct after 12 h; the corresponding TON and
TOF approached 4500 and 375 hꢀ1, respectively.8
Unfortunately, diethyl malonate (1g, pKa = 13.3) proved
to be poor donor, affording the corresponding Michael
adduct in 65% yield, even when 2.0 mol % La catalyst
was employed at 130 ꢁC. The present catalyst also
showed specific activity only toward 1,3-dicarbonyls as
Michaeldonors; other active methyelne compounds
such as ethylcyanoacetate (pKa = 9), which has similar
pKa value to that of acetylacetone (1e), did not yield Mi-
chaelproducts under identicalconditions. Upon com-
pletion of the Michael reaction, the LaHAP catalyst
was easily separated from the reaction mixture by a sim-
As can be seen from Table 1, the LaHAP exhibited high
catalytic activity for the Michael reaction of 1,3-dicar-
bonyls with enones under solvent-free (method A) or
aqueous conditions (method B), affording the corre-
sponding 1,5-dioxo compounds in excellent yields.7 In
all cases, the desired 1,4-addition products were ob-
tained exclusively without the formation of aldol-type
compounds. Acyclic and cyclic enones were found to
be good acceptors for the reaction with ethyl2-oxocyc-
lopentanecarboxylate (1a) (entries 1–9). 3-Buten-2-one
(2a) successfully reacted with a variety of b-keto esters
and 1,3-diketones (entries 10–18). Moreover, the
LaHAP catalyst was applicable to a less reactive accep-
tor of methylacryal te ( 2e) under solvent-free conditions
(entry 9). Among the solvents examined, neat and aque-
Table 1. Michaelreaction catayl zed by LaHAP
c
Entry
Donora
Acceptor
Methodb
La (mol%)
Time (h)
Yield (%)
O
2a
2b
1a
O
1
2
A
B
0.5
0.5
0.5
0.5
>99
>99
COOEt
O
3
4
A
B
0.5
0.5
1
4
97
85
1a
1a
1a
2c
5
6
A
B
1.0
1.0
6
24
86
89
O
2d
7d
8d
A
B
1.5
1.5
13
27
95
64
O
2e
COOMe
9d
1a
A
A
2.0
1.0
24
1
>99
98
1b
O
COOEt
10
2a
2a
1c
O
O
O
11d
12d
A
B
1.0
1.0
3
3
97
99
1d
O
13d
14d
A
B
1.25
1.25
6
24
83
90
2a
2a
1e
O
O
15
16
A
B
0.5
0.5
4
9
99
99
1f
O
O
17
18
A
B
0.5
0.5
2
3
95
99
2a
2c
O
1g
19e
A
2.0
24
65
CO2Et
CO2Et
a The pKa values of donors are as follows: 1a (10.5), 1b (11.5), 1c (7.8), 1d (10.1), 1e (9.0), and 1g (13.3).
b Method A: donor (2 mmol), acceptor (3 mmol), solvent-free, Ar atmosphere, 50 ꢁC; method B: donor (0.5 mmol), acceptor (0.75 mmol), H2O
(3 ml), Ar atmosphere, 50 ꢁC.
c Determined by GC analysis.
d 80 ꢁC.
e 130 ꢁC.

K. Mori et al. / Tetrahedron Letters 46 (2005) 4283–4286
4285
ple filtration using a filter paper. The recovered catalyst
was washed with acetone and dried under vacuum at
room temperature, which ICP analysis of the filtrate
confirmed that the La content was below the detection
limit. Moreover, the catalyst was filtered off after ca.
60% conversion at the reaction temperature. Further,
treatment of the filtrate under similar reaction condi-
tions did not afford any products. It can be said that
the present reaction undoubtedly proceeds on the
hydroxyapatite surface, which effectively serves as a
promising macroligand for the catalytically active La
species.
Building upon the initial success of the LaHAP, further
investigations were conducted to develop an effective
heterogeneous catalyst for the asymmetric Michael
reaction.13 Preliminary screening revealed that the
fluoroapatite-bound La complex modified with (R,R)-
tartaric acid (4a) (TA-LaFAP; La: 1.2 mol%) in
toluene at room temperature efficiently catalyzed the
asymmetric Michaelreaction of methyl1-oxoindan-2-
carboxylate (1g) with 2a, affording (S)-methyl1-oxo-
2-(30-oxobutyl)-2-indanecarboxylate ((S)-3a) in 97%
yield with a good enantioselectivity of 60% (entry 1
in Table 2).14 It is noted that the combination of
La(OTf)3 and 4a showed low activity with no enantio-
selectivity (entry 2). The use of the HAP instead of
the FAP gave high chemicalyiedl , but a ol wer enantio-
selectivity was obtained with an opposite configura-
tion (entry 3). Among the solvents examined,
diethylether and n-hexane were good solvents, while
dichloromethane and water gave poor results with
respect to enantiomeric excess. When the reaction tem-
perature was lowered to 10 ꢁC, the yield significantly
decreased to 5% with 40% ee, whereas the reaction at
a higher temperature of 40 ꢁC resulted in decrease of
enantioselectivity to 50% in spite of high chemical yield
(>99%). Other organic modifiers such as (S)-malic acid
(4b) and (R,R)-O,O0-dibenzoyltartaric acid (4c) favored
excess formation of the (R)-isomer with moderate
enantioselectivity (entries 4 and 5).
Treatment of 1a with D2O in the presence of the LaHAP
led to H–D exchange reaction, giving the a-deuterated
compounds in 15% yield.9 Addition of benzoic acid to
the reaction mixture of 1a with 2a significantly de-
creased the catalytic activity. These results demonstrate
that the LaHAP has a Brønsted base site, that is, La–
OH species.10 The IR spectrum of the LaHAP upon
treatment with 1e showed a shift of the m(C@O) band to-
ward 1560 cmꢀ1 in comparison with the free carbonyl
group at around 1700 cmꢀ1, suggesting the formation
of an 1,3-diketonato La species.11 On the basis of these
results, a plausible mechanism is proposed as follows.
Initially, a La–OH species abstracts an a-proton of the
donor to form a 1,3-diketonato La species. Next, an
acceptor coordinate to vacant sites of the La species at
the carbonyl oxygen, followed by an alkylation and a
hydrolysis to afford a Michael adduct along with the
regeneration of the La–OH species. Kinetic studies
showed zero-order dependence in 1a and first-order rela-
tionship in 2a.12 A kH/kD value of 1.0 was also observed
in the intermolecular competitive reaction between 1e
and acetylacetone-3,3-d2(CH3COCD2COCH3) with 2a
as a Michaelacceptor. These resutls suggest that the
alkylation might be a rate-determining step.
In summary, we have developed a method for the design
of nanostructured catalysts using apatites. A stable
monomeric La phosphate complex on the surface of
hydroxyapatite proved to be an efficient heterogeneous
catalyst with superior activity for the Michael reaction,
and possessed high reusability. Further developments
of asymmetric catalysts with enhanced enantioselectivity
are now underway.
Table 2. Asymmetric Michaelreaction of 1g with 2aa
O
O
O
catalyst
toluene, r. t.
+
2a
COOMe
COOMe
1g
(S)-3a
Entry
Catalyst
Ligand
Yield (%)b
ee (%)c
Confgn.d
HO
COOH
1
LaFAP
La(OTf)3
LaHAP
97
29
60
<1
30
S
S
R
2e
3
4a
4b
HO
H
COOH
COOH
COOH
>99
4
5
LaFAP
LaFAP
>99
>99
50
46
R
R
HO
PhOCO
COOH
4c
PhOCO
COOH
a Reaction conditions: catalyst (0.016 g, 1.2 mol % based on 1g), 1g (0.5 mmol), 2a (0.75 mmol), solvent (2 ml), room temperature, 6 h, Ar
atmosphere.
b Determined by GC.
c Determined by HPLC (DaiselChirapl ak AD-H).
d Assigned by opticalrotation.
e La(OTf)3 (3.4 · 10ꢀ3 g, 1.2 mol% based on 1g), 4a (8.6 · 10ꢀ4 g, 1.2 mol% based on 1g).

4286
K. Mori et al. / Tetrahedron Letters 46 (2005) 4283–4286
reaction of mercaptans with chalcone derivatives, but it
Acknowledgments
was found to be less effective under the present reaction
conditions, see: Zahouily, M.; Abrouki, Y.; Bahlaouan,
B.; Rayadh, A.; Sebti, S. Catal. Commun. 2003, 4, 521.
8. Into a reaction vesselequipped with a reflux condenser
This work is supported by the Grant-in-Aid for Scien-
tific Research from Ministry of Education, Culture,
Sports, Science, and Technology of Japan (16206078).
K.M. and T.H. also express special thanks for the JSPS
Research Fellowships for Young Scientists.
were successively placed the LaHAP (0.03 g, La3+
:
0.02 mol%), H 2O (20 ml), 1a (25 mmol), and 2a
(37.5 mmol). The reaction mixture was stirred at 80 ꢁC
under an Ar atmosphere for 12 h. After separation of the
catalyst, the aqueous layer was extracted with Et2 O and
organic solvent was dried with MgSO4. The solvent was
evaporated and the crude product was distilled to afford
pure ethyl 2-oxo-1-(3-oxobutyl)cyclopentanecarboxylate
as a colorless oil (90% isolated yield).
References and notes
1. (a) Jung, M. E. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 4, pp 1–67; (b) Ho, T.-L. Tactics of Organic Synthesis;
Wiley: New York, 1994.
9. Tateiwa, J.-I.; Hosomi, A. Eur. J. Org. Chem. 2001,
1445.
10. Because of the weak Lewis acidity of the La3+ ion,
homogeneous La(OR)3 complexes often act as a Brønsted
base and catalyze a number of carbonyl reactions involv-
ing an enolate intermediate, see: (a) Sasai, H.; Suzuki, T.;
Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992,
114, 4418; (b) Sasai, H.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1994, 116, 1571; (c) Dewa, T.; Saiki, T.;
Aoyama, Y. J. Am. Chem. Soc. 2001, 123, 502.
2. For an excellent review on transition metal-catalyzed
Michaelreaction of 1,3-dicarbonysl, see: Christoffers, J.
Eur. J. Org. Chem. 1998, 1259.
3. For examples of the Michael reaction in water, see: (a)
Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37, 1879;
(b) Kotsuki, H.; Arimura, K. Tetrahedron Lett. 1997, 38,
7583; (c) Mori, Y.; Kakumoto, K.; Manabe, K.; Koba-
yashi, S. Tetrahedron Lett. 2000, 41, 3107.
11. Kawabata, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J.
Am. Chem. Soc. 2003, 125, 10486.
4. (a) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem.
Commun. 2001, 2159; (b) Organic Synthesis in Water;
Grieco, P. A., Ed.; Blackie Academic and Professional:
London, 1998.
12. The kinetic results are in sharp contrast to those of
homogeneous La(OTf)3 catalysts, which follow first-order
dependence in 1a and zero-order relationship in 2a. We
believe this phenomenon can be attributed to strong
Brønsted basicity of the LaHAP catalyst.
13. For generalreviews of catayltic asymmetric Michael
reactions, see: (a) Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; (b) Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171; (c) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033.
5. (a) Yamaguchi, K.; Mori, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2000, 122, 7144; (b) Mori,
K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2001, 461; (c) Mori, K.; Tano, M.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. New J. Chem. 2002,
26, 1536; (d) Mori, K.; Yamaguchi, K.; Hara, T.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am. Chem.
Soc. 2002, 124, 11572; (e) Murata, M.; Hara, T.; Mori, K.;
Ooe, M.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahe-
dron Lett. 2003, 44, 4981; (f) Hara, T.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett.
2003, 44, 6207; (g) Mori, K.; Hara, T.; Mizugaki, T.;
Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2003, 125,
11460; (h) Mori, K.; Hara, T.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. J. Am. Chem. Soc. 2004, 126, 10657; (i) Hara,
T.; Mori, K.; Oshiba, M.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Green Chem. 2004, 6, 507.
14. Into a reaction vessel were successively placed the TA-
LaFAP (0.016 g, La3+: 1.2 mol %), toluene (2 ml), 1g
(0.5 mmol), and 2a (0.75 mmol). The reaction mixture was
stirred at room temperature under an Ar atmosphere for
6 h. After removalof the catalyst, the reaction mixture was
diluted with toluene and subjected to HPLC analysis. The
enantiomeric excess was determined by chiralHPLC
(Daisel Chiralpak AD-H, eluent: iPrOH/hexane = 1:9,
flow rate: 1.0 ml/min, 254 nm, tR of (S)-3a = 12.0 min, tR
of (R)-3a = 13.5 min). The absolute configuration was
6. For recent reviews of heterogeneous asymmetric catalysts,
see: (a) McMorn, P.; Hutchings, G. J. Chem. Soc. Rev.
2004, 33, 108; (b) Fan, Q.-H.; Li, Y.-M.; Albert, A. S. C.
Chem. Rev. 2002, 102, 3385; (c) Song, C. E.; Lee, S.-G.
Chem. Rev. 2002, 102, 3495.
25
determined by the opticalrotation of 3a ½aꢁD ꢀ41.8 (c
rt
0.24, benzene) for 60% ee, cf.: ½aꢁ578 ꢀ77.0 (c 2.0, benzene)
for (S)-isomer. Preparation of the TA-LaFAP was accom-
plished as follows. To a stirred aqueous solution of 1:1 of
La(OTf)3 and (R,R)-tartaric acid for 30 min was added a
fluoroapatite (FAP), Ca10(PO4)6F2, and then the mixture
was further reacted at 30 ꢁC for 24 h, affording the TA-
LaFAP (La content: 0.36 mmolg ꢀ1) as a white powder.
The ratio of La:TA was determined to be ca. 6:1 by the
CHN elemental analysis.
7. The order of activity of various catalysts for Michael
reaction conducted under the identicalreaction conditions
as those for entry
1
in Table
1
was LaHAP
(>99) > ScHAP (90) > YHAP (67) > La(OTf)3 (40) >
YbHAP (39) > HAP (30), where values in parentheses
indicate yields of Michael adducts. The parent HAP is
reported to act as a heterogeneous catalyst for the Michael