Effect of nanosized TiO2-SiO2 covalently modified by chiral molecules on the asymmetric Biginelli reaction

Article abstract of DOI:10.1016/j.cattod.2014.01.035

The method for immobilization of chiral molecules (menthol and proline derivatives) on the mixed nanooxide TiO₂-SiO₂ surface has been developed. The synthesized nanocomposites were used as catalysts of the Biginelli reaction. It was

Full text of DOI:10.1016/j.cattod.2014.01.035

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Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules
on the asymmetric Biginelli reaction
Yulia Titovaa,∗, Olga Fedorovaa, Gennady Rusinova, Aleksey Vigorova, Victor Krasnova,
Anna Murashkevichb, Valery Charushina
a Postovsky Institute of Organic Synthesis of RAS, Ural Branch, S. Kovalevskoy/Akademicheskay Street, 22/20, 620990 Ekaterinburg, Russia
b Belarusian State Technological University, Sverdlova Street, 13a, 220006 Minsk, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
The method for immobilization of chiral molecules (menthol and proline derivatives) on the mixed
nanooxide TiO2–SiO2 surface has been developed. The synthesized nanocomposites were used as cat-
alysts of the Biginelli reaction. It was shown that inactive chiral molecules, when covalently bonded to
the nanooxide surface, acquired properties of a chiral inducer in the asymmetric Biginelli reaction.
© 2014 Elsevier B.V. All rights reserved.
Received 3 October 2013
Received in revised form 24 January 2014
Accepted 27 January 2014
Available online xxx
Keywords:
Asymmetric catalysis
Biginelli reaction
Nanosized metal oxides
Surface-modification
1. Introduction
oxides are promising catalysts for chemical reactions, including
asymmetric reactions [4,13,14]. They can be used alone or as a
4-Aryl-substituted dihydropyrimidines (the Biginelli reaction
products) attract much attention because of their high activity
as cardiotropic [1,2], antineoplastic and antihypertensive agents
[3–5].
3,4-Dihydropyrimidinones (DHPMs) are well known hetero-
cyclic units in the realm of natural and synthetic organic chemistry
due to their therapeutic and pharmacological properties. For exam-
ple, compound 1 is an efficient antihypertensive agent, compound 2
possesses antiviral and antibacterial activities, monastrol 3 exhibits
excellent anticancer activity (Fig. 1) [2,5–7].
support for an organic catalyst.
Previously, we showed the possibility of the stereoselective
Biginelli reaction in the presence of nanosized metal oxides [15].
Commercially available quinine sulfate, l-proline and l-tartaric
acid were used as chiral inducers, and nanosized CuO, Al2O3, ZnO,
NiO, MgO were used as heterogeneous catalysts. Adding nanooxide
to inactive chiral inducer increased the enantiomeric excess (ee) of
the reaction product from 0 to 20% in favor of (S)-enantiomer.
The aim of this study was to investigate the effect of nanooxides
covalently modified by chiral molecules on enantioselectivity of the
Biginelli reaction.
Nowadays, one of the main problems in DHPMs synthesis is
to obtain them in enantiopure form. Indeed, both enantiomers of
DHPMs have been found to show distinct or opposite pharmaco-
logical activities [3,5,8].
2. Experimental
The chiral inducers using in the asymmetric Biginelli reac-
tion (primary amines, proline derivatives, BINOL-based phosphoric
acids and others) were recently thoroughly reviewed [9–12]. How-
ever, the chiral inducers supported on heterogeneous catalysts
were not used in the asymmetric Biginelli reaction.
Mixed nanooxide TiO2–SiO2 (8% TiO2) prepared by co-
precipitation method was selected as
a support. Nanooxide
TiO2–SiO2 had a specific surface area value of 405 m2 g−1 and a
particle size of 10–30 nm. The TiO2 content in the composite sam-
ple was determined by photocolorimetric method. Specific surface
area was measured by adsorption method using phenol (solution
in heptane) as an adsorbate [16].
According to the literature, due to high surface area and avail-
ability of active sites having different nature and strength, metal
The IR spectra were recorded on a FTIR spectrometer 6700
(Thermo Electron Corporation) with ATR accessory. Elemental
analysis was performed on a Perkin Elmer 2400 II analyzer and
EuroVector EA3000 analyzer.
∗
Corresponding author. Tel.: +7 3432 3623058.
E-mail addresses: titova@ios.uran.ru, jull 5@mail.ru (Y. Titova).
0920-5861/$ – see front matter © 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.cattod.2014.01.035
Please cite this article in press as: Y. Titova, et al., Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules on the
asymmetric Biginelli reaction, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.01.035

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Table 1
2
F
*
F
Elemental analysis data for compounds 5, 7, 10, 11, 14.
OH
O2N
Compound
C, %
H, %
N, %
S, %
5
7
10
11
14
11.54
13.62
14.14
10.09
12.20
3.62
3.43
2.42
3.12
3.06
4.56
3.47
3.21
3.75
3.42
–
–
–
–
iPrO2C
Me
CONH2
O
EtO2C
Me
H
S
iPrO2C
Me
CONHR
O
N
N
*
*
N
N
H
N
H
N
H
1.43
3 Monastrol
1 SQ-32926
2
Fig. 1. Structures of some biologically active DHPMs.
2.4. Asymmetric Biginelli reaction
2.4.1. Without nanooxide
Benzaldehyde (1.06 g, 10 mmol), urea (0.6 g, 10 mmol) and
10 mol% chiral organic catalyst 6, 8, 9 or 12 were dispersed in
tetrahydrofuran (10 mL). The reaction mixture was stirred for
30 min at room temperature, and then ethyl acetoacetate (1.30 g,
10 mmol) was added. The reaction mixture was stirred for 40 h at
room temperature. Then the solvent was evaporated. The reaction
mixture was analyzed by HPLC.
Analytical HPLC was performed with an YMC-Pack, Chiral-NEA-
R (4.6 × 250 mm, 5 ␮m) column, with a flow rate of 1 mL/min, and
by using a tunable UV detector set at 254 nm. Mixtures of acetoni-
trile and H2O were used as the mobile phases.
Morphological studies of particles were performed using a
transmission electron Philips CM30 microscope (TEM).
2.1. Synthesis of TiO2–SiO2 nanoparticles
2.4.2. In the presence of a suspension of chiral compound and
nanooxide
Sodium carbonate and solution of TiCl4 in HCl were added
sequentially into aqueous solution of waterglass under stirring. The
TiCl4 solution was prepared by dissolving titanium powder in HCl
followed by oxidation of Ti3+ to Ti4+ by nitric acid. The suspen-
sion was stirred for 1 h, and then the precipitate was separated
and washed with water until complete removal of the chlorine
anions and the sodium cations. Then nanoparticles were dried in a
microwave oven at 120 ◦C to constant weight and calcined at 550 ◦C
for 3 h.
Benzaldehyde (1.06 g, 10 mmol), urea (0.6 g, 10 mmol), 10 mol%
chiral organic catalyst 6, 8, 9 or 12 and nanooxide TiO2–SiO2 (70 mg,
1 mmol) were dispersed in tetrahydrofuran (10 mL). The reaction
mixture was stirred for 30 min at room temperature, and then ethyl
acetoacetate (1.30 g, 10 mmol) was added. The reaction mixture
was stirred for 40 h at room temperature. Then the suspension was
centrifuged to separate the nanooxide, the solvent was evaporated,
the resulting precipitate was washed with ether and water, dried
and analyzed by HPLC.
2.2. Preparation of (3-aminopropyl)silane modified TiO2–SiO2
(APS-modified TiO2–SiO2)
2.4.3. With the chirally modified nanooxide
Benzaldehyde (1.06 g, 10 mmol), urea (0.6 g, 10 mmol) and chi-
rally modified TiO2–SiO2 7, 10, 11 or 14 (the amount of nanooxide
was calculated relative to 10 mol% of the chiral compound frag-
ment) were dispersed in tetrahydrofuran (10 mL). The reaction
mixture was stirred for 30 min at room temperature, and then ethyl
acetoacetate (1.30 g, 10 mmol) was added. The reaction mixture
was stirred for 40 h at room temperature. Then the suspension was
centrifuged to separate the nanooxide, the solvent was evaporated.
The reaction mixture was analyzed by HPLC.
TiO2–SiO2 nanoparticles (1 g) were dispersed in dry toluene
(60 mL), and 2 mL of (3-aminopropyl)triethoxysilane 4 (APTES) was
added dropwise. The dispersion was heated at 60 ◦C and stirred
for 18 h. APS-modified TiO2–SiO2 was centrifuged, sequentially
washed with toluene (2 times), EtOH (2 times) and dried at 90 ◦C.
APS-modified TiO2–SiO2 5 was characterized by IR spectroscopy
and elemental analysis.
2.3. Coupling of APS-modified TiO2–SiO2 with chiral molecules
3. Results and discussion
Method A. APS-modified TiO2–SiO2 5 (0.3 g) was added to solu-
tion of (−)-chloromethyl menthyl ether 6 (0.2 g) and Et3N (0.15 g)
in dry tetrahydrofuran (10 mL). The suspension was heated to 60 ◦C
and stirred for 9 h. Then nanooxide 7 was centrifuged, sequentially
washed with 5% aqueous NaHCO3, H2O, EtOH and dried at 90 ◦C.
Method B. Appropriate proline derivative 8 or 9, 2 equiv. N,N-
diisopropylethylamine (DIPEA) and 1 equiv. O-(1H-benzotriazol-1-
yl)-N,N,Nꢀ,Nꢀ-tetramethyluronium tetrafluoroborate (TBTU) were
dissolved in dry CH2Cl2. The solution was stirred at room tem-
perature for 25–30 min. After that, APS-modified TiO2–SiO2 5 was
added. The suspension was stirred at room temperature for 6 h.
Then nanooxide 10 or 11 was centrifuged, sequentially washed
with 5% aqueous NaHCO3, H2O, EtOH and dried at 90 ◦C.
Nanooxide TiO2–SiO2 was studied by IR spectroscopy. It was
established, that active sites of the surface, like the previously
studied copper and aluminum nanooxides [18], are metal (ele-
ments) atoms surrounded by the oxygen atoms (ꢀE O: 1040,
795–440 cm−1), the free hydroxy groups (ꢀOH: 3237, 940 cm−1),
the coordinated water molecules (ꢀOH, ıH2O: 1633 cm−1), and oxy-
gen atoms of the carboxy groups of hydroxycarbonate (ꢀO
C O:
1435 cm−1) formed by adsorption of carbon dioxide from the air.
To obtain APS-modified TiO2–SiO2 5, nanoparticles were treated
with APTES 4 in dry toluene (Scheme 1).
The immobilization of APTES 4 on TiO2–SiO2 was confirmed by
the IR spectroscopy and elemental analysis. The FTIR spectra of the
Method C. Acyl chloride 13 was synthesized according to the
described method [17]. Et3N (0.1 g) and APS-modified TiO2–SiO2
(0.3 g) were added to a solution of acyl chloride 13 (0.42 g) in dry
CH2Cl2. The suspension was stirred at room temperature for 10 h.
Then nanooxide 14 was centrifuged, sequentially washed with 5%
aqueous NaHCO3, H2O, EtOH and dried at 90 ◦C.
EtO
EtO Si
EtO
NH2
OH
OH
OH
4
O
O
O
SiO2-TiO2
SiO2-TiO2
Si
NH2
Toluene, 60оС
5
Chirally modified TiO2–SiO2 7, 10, 11, 14 were characterized by
IR spectroscopy and elemental analysis (Table 1).
Scheme 1. Synthesis of APS-modified TiO2–SiO2.
Please cite this article in press as: Y. Titova, et al., Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules on the
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1
1901
698
645
1386
1411
1599
1347
3367
3291
1464
862
2940
2840
1191
817
787
2
3
1083
1328
1573
1444
1435
3193
2929
1633
1039
3237
1029
1000
940
4000,0
3600
3200
2800
2400
2000
1800
1600
1400
1200
800
600
450,0
Wavenumber, cm–
1
Fig. 2. IR spectra: (1) APTES, (2) APS-modified TiO2–SiO2, and (3) unmodified TiO2–SiO2.
unmodified TiO2–SiO2, APS-modified TiO2–SiO2 5, and APTES 4 are
shown in Fig. 2.
The nanomaterials 7, 10, 11, 14 were characterized by IR
spectroscopy and elemental analysis. The FTIR spectra of chirally
modified TiO2–SiO2 are shown in Fig. 3. For example, a band ampli-
fication in the range from 1620 to 1675 cm−1, corresponding to the
valence vibrations C O (Amide I band) and in the range from 1630
In Fig. 2 (spectrum 2), a shift in the higher-frequency region
and an increase in the intensity of the band corresponding to
valence Ti(Si) O vibrations (1039 cm−1) bonds, compared with
the corresponding band in the spectrum of the initial TiO2–SiO2
(1029 cm−1), indicate the formation of additional Si O bonds from
APS-moiety.
to 1660 cm−1 corresponding to the deformation vibrations N
H
(Amide II band) of an amide bond (Fig. 3, spectra 2, 3, 5) indicate an
amide bond formation.
In the spectrum of the modified TiO2–SiO2, the disappearance
of the band corresponding to valence vibrations of surface OH-
groups of the nanooxide (1633 cm−1) and the emergence of the
bands in the range from 1300 to 1600 cm−1 corresponding to the
deformation vibrations of C H and N H bonds are also observed.
In addition, bands corresponding to asymmetric (2940 cm−1) and
symmetric (2840 cm−1) valence vibrations of C H bonds are less
pronounced (band with the shoulder at 2929 cm−1) compared with
the initial APTES.
The above changes in the IR spectra of compound 5 point to a
covalent bond formation between aminosilane 4 and TiO2–SiO2-
nanoparticle surfaces. According to the elemental analysis data
the degree of immobilization of APS on the TiO2–SiO2 surface is
4.5 mmol/g nanooxide.
The second phase of the study was a coupling of chiral molecules
to APS linker. Compounds 6, 8, 9, 12 (Scheme 2) were selected as
chiral molecules. According to the literature, a (−)-menthyl bonded
silica was used successfully as a stationary phase for the chromato-
graphic separation of enantiomers [19]. Proline derivatives were
selected, since they are extensively used as chiral inducers in the
homogeneous Biginelli reaction [20,21].
We used three routes for binding the chiral catalyst to APS
linker (Scheme 2). Commercially available (–)-chloromethyl men-
thyl ether was coupled to APS-modified TiO2–SiO2 by nucleophilic
substitution of the chlorine atoms by amino groups (Method A).
Coupling of (2S,4R)-4-hydroxyproline 8 or (S)-5-oxoproline 9 to
APS-modified TiO2–SiO2 5 was carried out in the presence of DIPEA
and TBTU as a coupling agent (Method 2). Compound 14 was syn-
thesized by coupling of acyl chloride 13 to compound 5 (Method
3).
Fig. 3. IR spectra (the range from 1300 to 1900 cm−1): (1) APS-modified TiO2–SiO2
4, (2) compound 11, (3) compound 14, (4) compound 7, and (5) compound 10.
Please cite this article in press as: Y. Titova, et al., Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules on the
asymmetric Biginelli reaction, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.01.035

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CH3
CH3
Method A
Et3N,
THF
O
Cl
,
H3C CH3
6
O
O
O
O
TiO2-SiO2
Si
N
H
H3C
CH3
7
R
OH
X
TBTU, DiPEA
CH2Cl2
Method B
O
O
O
N
TiO2-SiO2
R
O
H
Si
NH2
,
O
8, 9
O
O
X
5
TiO2-SiO2
Si
N
N
H
H
O
10, 11
TsHN
TsHN
8, 10 R = OH, X = CH2
9, 11 R = H, X = CO
OH
SOCI2
Cl
Et3N
CH2Cl2
O
Method C
N
Ph
O
N
Ph
,
O
O
NHTs
O
12
13
O
O
TiO2-SiO2
O
O
Si
N
H
N
Ph
14
Scheme 2. Synthesis of chirally modified TiO2–SiO2.
H
NH
H
NH
CHO
+
EtO2C
Me
cat. (10 mol%)
THF, r.t., 40 h
EtO2C
Me
EtO2C
Me
NH2
O
+
O
H2N
N
H
O
N
H
O
(S)-15
(R)-15
Scheme 3. Enantioselective Biginelli reaction.
According to the TEM, no significant changes in the morphology
of the particles were detected (Fig. 4)
Further, the effect of nanooxides covalently modified by chiral
molecules 7, 10, 11, 14 on enantioselectivity of the Biginelli reac-
tion, namely on the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
15, was investigated (Scheme 3).
For comparison, compounds 6, 8, 9, 12 were used as chiral
inducers in the absence of nanooxide and in a mixture with it. It
was found that above chiral compounds in the free form and in a
mixture with nanooxide did not exhibit enantiocatalytic proper-
ties in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones 15. In
The amount of immobilized compounds 7, 10, 11, 14 was cal-
culated based on the elemental analysis data by subtraction of the
carbon mass fraction of the original APS-modified TiO2–SiO2 from
the carbon mass fraction of chirally modified TiO2–SiO2. The degree
of immobilization of chiral molecules was not high (10–20%). On
average, only one of the five APS amino groups was bound to a
chiral molecule.
Fig. 4. TEM images and electron diffraction pattern of (a) unmodified TiO2–SiO2, (b) chirally modified TiO2–SiO2 (compound 7).
Please cite this article in press as: Y. Titova, et al., Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules on the
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Table 2
3-aminopropylsilane and after that with chiral molecules (menthol
and proline derivatives) through covalent bonding. The chirally
modified nanooxides were used as catalysts of the Biginelli reac-
tion. It was shown that inactive by themselves the chiral molecules
being covalently bonded to the surface of the nanooxide acquired
properties of a chiral inducer in the Biginelli reaction (ee from 0 up
to 22%).
Asymmetric Biginelli reaction catalyzed by the free chiral inducers, a mixture of
chiral inducers and nanooxide, and the chirally modified nanooxides.
Entry
Catalyst
Yield 15, %
ee, %
1
2
3
4
5
6
7
8
9
6
20
20
17
50
44
15
54
45
20
0
6 + TiO2–SiO2
7
12
12 + TiO2–SiO2
14
8
0
22 (S)
0
0
Acknowledgments
14 (S)
0
0
8 (S)
8 + TiO2–SiO2
10
This work was supported by the Ural Branch of the Russian
Academy of Sciences (project nos. 12-P-234-2003 and 12-P-3-
1030), by the Russian Foundation for Basic Research (grants
12-03-31614 mol a, 14-03-31357 mol a, 12-03-90039-Bel a, and
13-03-12188-ofi m) and by the State Program for the Support of
Leading Scientific Schools (grant NSh 3656.2014.3).
contrast, the use of immobilized compounds 7, 10, 14 as a cata-
lyst led to increase in the ee up to 8–22% (Table 2, entries 3, 6, 9).
Compound 11 did not affect the ee of the reaction product. It was
surprising that compound 14 gave the highest ee (Table 2, entry 6),
because it is known that unsubstituted nitrogen atom of the pyrro-
lidine is necessary for the formation of key chiral intermediate of
the reaction [20,21].
References
[1] R.A. Janis, P.J. Silver, D.J. Triggle, Adv. Drug Res. 16 (1987) 309.
[2] C.O. Kappe, Tetrahedron 49 (1993) 6937.
Previously, we have shown that the rate of the Biginelli reac-
tion decreases in the presence of metal nanooxides in comparison
with the classical acid catalysis, however, an increase in the reac-
tion time made it possible to obtain product 15 in good yield [15].
Firstly, in the presence of nanooxides, the Biginelli reaction pro-
ceeds by both conventional mechanism via N-acyliminium ion [22]
and the carbocationic mechanism [23]. Secondly, the adsorption
and desorption of the reactants in the Biginelli reaction on nanoox-
ides play an important part. Therefore, the amount of nanooxide
affects the reaction rate. The data from Table 2 confirm this fact. The
TiO2–SiO2 amount in experiment 3, 6, 9 exceeded the TiO2–SiO2
amount in experiment 2, 5, 8, because the loading of catalysts 7, 10
and 14 was calculated relative to 10 mol% of chiral compound frag-
ment, and the ratio of chiral compound to TiO2–SiO2 in catalysts
was set as 2: 8 in weight. This explains the lowest yield of DHPM
15 in presence of modified catalysts 7, 10, 14.
[3] K.S. Atwal, B.N. Swanson, S.E. Unger, D.M. Floyd, S. Moreland, A. Hedberg, B.C.
O’Reilly, J. Med. Chem. 34 (1991) 806.
[4] D.J. Triggle, Cell. Mol. Neurobiol. 23 (2003) 293.
[5] C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043.
[6] C.O. Kappe, Acc. Chem. Res. 33 (2000) 879.
[7] S.S. Sandhu, J.S. Sandhu, ARKIVOC i (2012) 66.
[8] M.B. Gawande, R.K. Pandeyb, R.V. Jayaram, Catal. Sci. Technol. 2 (2012) 1113.
[9] M.M. Heravi, Sh. Asadi, B.M. Lashkariani, Mol. Divers. 17 (2013) 389.
[10] C. Graaff, E. Ruijter, R.V.A. Orru, Chem. Soc. Rev. 41 (2012) 3969.
[11] G. Guillena, D.J. Ramon, M. Yus, Tetrahedron: Asymmetry 18 (2007) 693.
[12] J.E. Biggs-Houck, A. Younai, J.T. Shaw, Curr. Opin. Chem. Biol. 14 (2010) 371.
[13] A.H. Ahmed, J. Appl. Sci. Res. 6 (2010) 1142.
[14] A. Corma, S. Iborra, Adv. Catal. 49 (2006) 239.
[15] O.V. Fedorova, M.S. Valova, Yu.A. Titova, I.G. Ovchinnikova, A.N. Grishakov, M.A.
Uimin, A.A. Mysik, A.E. Ermakov, G.L. Rusinov, V.N. Charushin, Kinet. Catal. 52
(2011) 226.
[16] A.N. Murashkevich, O.A. Alisienok, I.M. Zharskii, Kinet. Catal. 52 (2011) 809.
[17] V.P. Krasnov, I.A. Nizova, A.Y. Vigorov, T.V. Matveeva, G.L. Levit, P.A. Slepukhin,
M.A. Ezhikova, M.I. Kodess, Eur. J. Org. Chem. 10 (2008) 1802.
[18] O.V. Fedorova, O.V. Koryakova, M.S. Valova, I.G. Ovchinnikova, Y.A. Titova, G.L.
Rusinov, V.N. Charushin, Kinet. Catal. 51 (2010) 566.
[19] B. Lynch, J. Glennon, Ch. Troltzsch, U. Menyes, M. Pursch, K. Albert, Anal. Chem.
69 (1997) 1756.
[20] J. Xin, L. Chang, Z. Hou, Chem. Eur. J. 14 (2008) 3177.
[21] S. Saha, J.N. Moorthy, J. Org. Chem. 76 (2011) 396.
[22] C.O. Kappe, J. Org. Chem. 62 (1997) 7201.
[23] F. Sweet, J.D. Fissekis, J. Am. Chem. Soc. 95 (1973) 8741.
4. Conclusions
Mixed nanooxide TiO2–SiO2 was obtained using the co-
precipitation method. This nanooxide was modified with
Please cite this article in press as: Y. Titova, et al., Effect of nanosized TiO2–SiO2 covalently modified by chiral molecules on the
asymmetric Biginelli reaction, Catal. Today (2014), http://dx.doi.org/10.1016/j.cattod.2014.01.035