Remarkable catalytic activity of silica nanoparticle in the bis-Michael addition of active methylene compounds to conjugated alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.01.154

We have demonstrated the remarkable catalytic activity of silica nanoparticles (NPs) in the unusual bis-Michael addition of active methylene compounds to conjugated alkenes at room temperature. The catalyst silica NPs were reused up to seven runs without appreciable loss of catalytic activity.

Full text of DOI:10.1016/j.tetlet.2009.01.154

Tetrahedron Letters 50 (2009) 2037–2040
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Tetrahedron Letters
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Remarkable catalytic activity of silica nanoparticle in the bis-Michael
addition of active methylene compounds to conjugated alkenes
a,b,c,
Subhash Banerjee a, , Swadeshmukul Santra
*
*
a NanoScience Technology Center, University of Central Florida, 12424 Research Parkway, Suite 400, Orlando, FL 32826, USA
b Department of Chemistry, University of Central Florida, 4000 Central Florida Blvd., Orlando, FL 32816, USA
c Biomolecular Science Center, University of Central Florida College of Medicine, 4000 Central Florida Blvd., Orlando, FL 32816, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have demonstrated the remarkable catalytic activity of silica nanoparticles (NPs) in the unusual bis-
Michael addition of active methylene compounds to conjugated alkenes at room temperature. The cata-
lyst silica NPs were reused up to seven runs without appreciable loss of catalytic activity.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 December 2008
Revised 29 January 2009
Accepted 30 January 2009
Available online 5 February 2009
Keywords:
Silica nanoparticle
Catalysis
Conjugate addition
Bis-adducts
Reuse of catalyst
In recent years, nanoparticles (NPs) have attracted tremendous
attention in catalysis because of their improved efficiency under
mild and environmentally benign conditions in the context of
‘Green’ synthesis.1,2 Due to their enormously large and highly reac-
tive surface area, NPs have potential to exhibit superior catalytic
activity in comparison to bulk counterparts.3 Commonly used
metallic/bi-metallic nanocatalysts4–8 are expensive and toxic.
Moreover, unsupported nanoparticles are usually unstable, and
the coagulation of the nanoparticles during reaction is frequently
unavoidable.9 Thus, until now, the investigation of native nanopar-
ticles as catalysts has been rare, although it is an important tool to
gain a fundamental understanding of catalysis.10 Recently, we have
reported a native silica NPs catalyzed anti-Markovnikov addition of
thiols to alkenes and alkynes.11 This observation motivated us to
explore the use of silica NPs in useful synthetic reactions, such as
carbon–carbon (C–C) bond formation.
addition of active methylene compounds to conjugated carboxylic
esters and nitriles. Moreover, these reagents failed to initiate the
bis-Micheal addition of active methylene compounds to conju-
gated ketones even at elevated temperature. Thus, there is a de-
mand for the development of a milder reagent for a general bis-
Michael addition of active methylene compounds to
rated ketones, esters, and nitriles in a single step.
a,b- unsatu-
In this study, we are highly motivated to evaluate the catalytic
activity of native silica NPs in a Michael addition. Unexpectedly, we
observed remarkable catalytic activity of native silica NPs in an
unusual bis-Michael addition of active methylene compounds to
conjugated ketones, carboxylic esters, and nitriles (Scheme 1).
Interestingly, no mono addition product was obtained in all the
cases studied herein.
Silica NPs were synthesized using the well-established Stober
method27 that involved basic hydrolysis and condensation reaction
The Michael addition is one of the most useful C–C bond-form-
ing reactions with wide synthetic applications in organic synthe-
sis.12,13 This reaction is conventionally catalyzed by strong bases
that often lead to undesirable side reactions.14 A number of re-
agents15–23 have been developed for the mono-Michael addition
reaction. To date, a few reagents, such as ruthenium complex24
and basic ionic liquid,25,26 have been reported for the bis-Michael
E1
E1
X
Silica NPs
X
E2
RT
E2
X
E1, E2 = COMe, COOEt, CN etc
X = COMe, COOMe, CN etc
* Corresponding authors. Tel.: +1 407 882 2848; fax: +1 407 882 2819 (S.B.).
E-mail addresses: subanerj@mail.ucf.edu (S. Banerjee), ssantra@mail.ucf.edu
(S. Santra).
Scheme 1. Silica NPs catalyzed bis-Michael addition of active methylene com-
pounds to conjugated alkenes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.154

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S. Banerjee, S. Santra / Tetrahedron Letters 50 (2009) 2037–2040
of tetraethoxyorthosilane (TEOS) in 1:1 (V/V) water–ethanol mix-
ture at room temperature. Silica NPs of different sizes were synthe-
sized by simply adjusting the water to ethanol ratio. The silica NPs
were characterized by transmission electron microscopy (TEM)
(Fig. 1). The catalytic activity of these silica NPs has been tested
in the Michael addition of active methylene compounds to conju-
gated alkenes.
Initially, we selected the Michael addition of malononitrile to
methyl vinyl ketone (MVK) as a model reaction for investigation
of different reaction parameters. The results are summarized in Ta-
ble 1. We have observed that only 10 wt % of silica NPs were suffi-
cient to push the reaction forward. In absence of catalyst, the
Michael addition reaction did not progress at all. The general
experimental procedure29 for the bis-Michael addition reaction is
given below.
We have also screened effect of different solvents with varying
polarity and protic nature. It was observed that water proved to be
the best choice for the Michael addition reaction over any organic
solvents such as tetrahydrofuran and toluene. It was also observed
that the rate of the Michael addition reaction increased with
decreasing particle size. We have used ꢀ50 nm silica NP for all
reactions.
Figure 1. TEM image of silica NPs (size ꢀ 50 nm).
To explore the generality and scope of the bis-Michael addition
reaction, the reaction of various active methylene compounds and
conjugated alkenes was carried out under optimized conditions.
The results are summarized in Table 2.
Table 1
Optimization of reaction conditions
Interestingly, all open-chain and cyclic active methylene com-
O
NC
NC
COMe
COMe
NC
pounds (with two active
a-C–H) such as a ethyl acetoacetate,
silica NP
RT
diethyl malonate, ethyl cyanoacetate, 5,5-dimethyl-1,3-cyclohex-
adione, and malononitrile participated in bis-Michael additions
with MVK, methyl acrylate, and acrylonitrile to produce the corre-
sponding bis-adducts exclusively in high yields. These products are
very useful synthons, two representative examples of conversion of
these adducts to annulated bicyclic and tricyclic conjugated ke-
tones are shown below (Eqs. 1 and 2).
NC
Entry
Reaction medium
Catalyst (mol %)
Time (h)
Yielda (%)
1
2
3
4
5
6
H2Ob
10
0
10
10
10
10
2
24
6
8
12
12
95
0
70
77
25
20
H2Ob
Neat
Ethanol
THF
CO2Et
O
O
a
Toluene
ð1Þ
CO2Et
O
a
Isolated yield.
b
Reactions were carried out in 0.5 ml H2O.
86 %
Table 2
Silica NP catalyzed Michael addition of active methylene compounds to conjugated alkenes
Entry
Active methylene compound
Conjugated alkene
Product
Time (h)
Yielda (%)
85
Ref.
28a
COMe
MeOC
MeOC
Me
O
1
3.5
6.0
3.5
6.0
4.0
EtO2C
MeOC
EtO2C
MeOC
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
MeOC
EtO2C
MeOC
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
COMe
CO2Me
OMe
O
2
3
4
5
78
82
81
86
26
CO2Me
CN
28b
26
CN
CN
CO2Me
OMe
O
CO2Me
CN
28c
CN
CN

S. Banerjee, S. Santra / Tetrahedron Letters 50 (2009) 2037–2040
2039
Table 2 (continued)
Entry
Active methylene compound
Conjugated alkene
Product
Time (h)
4.0
Yielda (%)
85
Ref.
28d
COMe
NC
EtO2C
NC
NC
Me
O
6
EtO2C
NC
COMe
CO2Me
OMe
O
7
8
5.0
4.5
2.0
2.5
2.5
3.0
5.0
4.5
3.0
80
79
95
92
94
90
85
87
90
26
26
26
26
26
26
26
26
28f
EtO2C
NC
EtO2C
NC
CO2Me
CN
CN
EtO2C
EtO2C
NC
CN
COMe
NC
NC
NC
NC
NC
NC
Me
O
9
NC
COMe
CO2Me
NC
OMe
O
10
11
12
13
14
15
16
NC
CO2Me
CN
NC
CN
NC
O
CN
Me
O
O
CO2Et
COMe
CO2Et
O
O
OMe
O
O
O
CO2Et
CO2Me
CO2Et
CO2Et
CO2Et
CN
CN
O
O
Me
O
COMe
COMe
O
O
O
O
O
OMe
O
CO2Me
CO2Me
4.0
4.0
85
90
28g
28g
O
O
O
O
CN
CN
17
CN
O
a
Yields refer to those of pure isolated products characterized by spectroscopic data.
O
HO
100
O
COMe
COMe
a
80
60
40
20
0
ð2Þ
O
O
75 %
Reagents (a): Pyrrolidine and acetic acid in ethyl acetate.
The use of 1 equiv (or less) of conjugated alkene in these reac-
tions did not produce any monoaddition product, only the bis-ad-
ducts were isolated in proportionate yields. The formation of bis-
adducts in one step with methyl acrylate, and acrylonitrile was re-
ported previously in two procedures.24–26 However, these reagents
are not applicable as they failed to initiate the bis-Michael addition
of conjugated ketones even at elevated temperatures. Other
restrictions involved long reaction times (48–96 h) at 50–70 °C24
and low isolated yields (24–89%). Interestingly, the silica NPs
1
2
3
4
5
6
7
Recycle times
Figure 2. Recycle of the catalyst.

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S. Banerjee, S. Santra / Tetrahedron Letters 50 (2009) 2037–2040
O
O
O
O
H
H
O
O
O
O
H
O
O
O
HO
R
O
R
R
R
H
R
O
O
O
O
H
Scheme 2. Plausible mechanism for silica NP catalyzed bis-Michael addition.
3. Lewis, L. N. Chem. Rev. 1993, 93, 2693–2730.
efficiently catalyzed the bis-addition of MVK, methyl acrylate and
acrylonitrile within a reasonable time period (2–6 h) at room tem-
perature with high yields (78–95%). This observation is highly sig-
nificant in the context of establishing a simplified method of
forming two C–C bonds in a single step. We anticipate that these
adducts, containing important functional groups (e.g., ketones, es-
ters, and nitriles) will find wide-spread synthetic applications. We
have demonstrated a two-step synthesis of 10-hydroxy-8,8-di-
methyl-tricyclo[8.4.0.01,6]tetradec-5-ene-4,12-dione, (Eq. 2) form
5,5-dimethyl-1,3-cyclohexadione, in which a bis-Michael addition
was the key step.
4. Bhadra, S.; Saha, A.; Ranu, B. C. Green Chem. 2008, 10, 1224–1230.
5. Chauhan, B. P. S.; Rathore, J. S.; Glloxhani, N. Appl. Organomet. Chem. 2005, 19,
542–550.
6. Hu, J.; Liu, Y. B. Langmuir 2005, 21, 2121–2123.
7. Lim, D. C.; Lopez-Salido, I.; Kim, Y. D. Surf. Sci. 2005, 598, 96–103.
8. Park, J. H.; Kim, E.; Kim, H. M.; Choi, S. Y.; Chung, Y. K. Chem. Commun. 2008,
2388–2390.
9. Rao, C. N. R.; Muller, A.; Cheetham, A. K.. In The Chemistry of Nanomaterials:
Synthesis and Applications; Wiley-VCH: Weinheim, 2004; Vol. 1.
10. Abdelsayed, V.; Alsharaeh, E.; El-Shall, M. S. J. Phys. Chem. B 2006, 110, 19100–
19103.
11. Banerjee, S.; Das, J.; Santra, S. Tetrahedron Lett. 2009, 50, 124–127.
12. Jung, M. E. In Comprehensive Organic Synthesis; 1991; Pergamon: Oxford;
Vol. 4.
To evaluate the stability of the catalytic activity and the poten-
tial for recycling, we completed several catalytic cycles. In each cy-
cle, the reaction mixture was centrifuged, and the NPs were
washed with ethanol and dried under vacuum to remove the resid-
ual solvent. The particulate nature of the used catalyst was con-
firmed by TEM. The catalyst could be reused for seven times with
a minimal loss of activity (Fig. 2).
The reason for this unusual behavior of the silica NP toward bis-
Michael addition is unknown at this stage. We believe that silica
surface chemistry plays an important role in this reaction. At neu-
tral pH, silica NPs are present in partly de-protonated, providing
both the –Si–OH and –Si–Oꢁ groups on the NP surface. The –Si–
OH group stabilizes the enol form of active methylene compounds
and polarizes the conjugated alkene via H-bonding with carbonyl
oxygen. The Si–Oꢁ promotes the nucleophilic attack of the enolized
active methylene compound (Scheme 2).
13. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992.
14. Kobayashi, S. Synlett 1994, 689–701.
15. Bensa, D.; Constantieux, T.; Rodriguez, J. Synthesis-Stuttgart 2004, 923–
927.
16. Christoffers, J. Eur. J. Org. Chem. 1998, 1259–1266.
17. Dell’Anna, M. M.; Gallo, V.; Mastrorilli, P.; Nobile, C. F.; Romanazzi, G.; Suranna,
G. P. Chem. Commun. 2002, 434–435.
18. Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001, 42, 6299–6301.
19. Ranu, B. C.; Saha, M.; Bhar, S. Synth. Commun. 1997, 27, 621–626.
20. Shimizu, K.; Miyagi, M.; Kan-no, T.; Kodama, T.; Kitayama, Y. Tetrahedron Lett.
2003, 44, 7421–7424.
21. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114.
22. Yadav, J. S.; Reddy, B. V. S.; Baishya, G.; Narsaiah, A. V. Chem. Lett. 2005, 34, 102–
103.
23. Zhang, Z.; Dong, Y. W.; Wang, G. W.; Komatsu, K. Synlett 2004, 61–64.
24. Alvarez, S. G.; Hasegawa, S.; Hirano, M.; Komiya, S. Tetrahedron Lett. 1998, 39,
5209–5212.
25. Ranu, B. C.; Banerjee, S. Org. Lett. 2005, 7, 3049–3052.
26. Ranu, B. C.; Banerjee, S.; Jana, R. Tetrahedron 2007, 63, 776–782.
27. Stöber, W.; Fink, A.; Bohn, E. J. Colloid Interface Sci. 1968, 26, 62–69.
28. (a) Bergmann, E. D.; Corett, R. J. Org. Chem. 1956, 21, 107–110; (b) Hou, Z.;
Koizumi, T.; Fujita, A.; Yamazaki, H.; Wakatsuki, Y. J. Am. Chem. Soc. 2001, 123,
5812–5813; (c) Volcho, K. 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: Chem. 2003, 195, 263–274; (d) Tu, T.; Assenmacher, W.; Peterlik, H.;
Weisbarth, R.; Nieger, M.; Doetz, K. H. Angew. Chem., Int. Ed. 2007, 46, 6368–
6371; (e) Henecka, H. Chem. Ber. 1948, 81, 197–209; (f) Houbrechts, Y.; Laszlo,
P.; Pennetreau, P. Tetrahedron Lett. 1986, 27, 705–706; (g) Nazarov, I. N.;
Zav’yalov, S. I. Zh. Obshch. Khim. 1955, 25, 477–483.
29. General experimental procedure for the silica nanoparticle catalyzed Michael
addition of active methylene compounds to conjugated alkenes:
Representative example for the Michael addition of malononirile to methyl
vinyl ketone (Table 2, entry 9): Methyl vinyl ketone (140.18 mg, 2 mmol) was
added to a mixture of malononitrile (66 mg, 1 mmol) and silica NP (ꢀ5 mg,
10 wt %) in water (0.5 mL), and the mixture was stirred for 2 h until completion
of reaction (TLC). Ethyl acetate (10 mL) was added to the reaction mixture and
was stirred for 5 min. The reaction mixture was centrifuged, precipitate
catalyst was washed with ethanol and finally dried for subsequent runs. The
organic layer was separated by separating funnel, dried over anhydrous
Na2SO4, and evaporated the solvent to leave crude product, which was purified
by short column chromatography over silica gel (ethyl acetate/hexane 1:9) to
provide pure bis-Michael adduct, 2,2-bis-(3-oxo-butyl)-malononitrile as
brownish solid in excellent yield (195 mg, 95%). The product was
characterized by its IR and 1H NMR and 13C NMR spectroscopic data, and
was compared with reported28a one.
In conclusion, we have successfully demonstrated remarkable
catalytic activity of silica NPs in the Michael addition of active
methylene compounds to conjugated alkenes under neutral reac-
tion conditions. In particular, we were able to develop a robust pro-
tocol for the bis-addition of
a,b-unsaturated ketones with active
methylene compounds in one step. The present synthesis strategy
is simple and straight-forward, and catalyst silica NP is stable, easy
to synthesize, and reusable. Certainly, this observation provides
great promise toward additional useful applications.
Acknowledgments
This work was partly supported by National Science Foundation
(NSF CBET-63016011 and NSF-NIRT Grant EEC-056560). We are
also pleased to acknowledge Dr. S. Biswas.
References and notes
1. Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44, 7852–7872.
2. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.