Animal bone meal as an efficient catalyst for crossed-aldol condensation

Article abstract of DOI:10.1016/j.tetlet.2010.10.056

α,α′-Bis(substituted benzylidene)cycloalkanones were efficiently prepared from cycloalkanones and benzaldehydes in water by using animal bone meal (ABM) or ABM modified as a catalyst. It is shown that ABM modified can be quantitatively recovered and be reused effectively for many times. A comparison of catalytic activity of these catalysts is discussed.

Full text of DOI:10.1016/j.tetlet.2010.10.056

Tetrahedron Letters 51 (2010) 6715–6717
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Tetrahedron Letters
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Animal bone meal as an efficient catalyst for crossed-aldol condensation
Y. Riadi a, R. Mamouni b, R. Azzalou a, R. Boulahjar a,d, Y. Abrouki a, M. El Haddad c, S. Routier d,
a,
G. Guillaumet d, , S. Lazar
⇑
⇑
a Laboratoire de Biochimie, Environnement & Agroalimentaire, URAC 36, Université Hassan II Mohammedia-Casablanca, Mohammedia, Morocco
b Laboratoire de Chimie Organique, Equipe de Chimie Bio-Organique Appliquée, Université Ibn Zohr, Agadir, Morocco
c Faculté Poly-disciplinaire de Safi, Université Cadi Ayyad, Safi, Morocco
d Institut de Chimie Organique & Analytique, UMR CNRS 6005, Université d’Orléans, Orléans, France
a r t i c l e i n f o
a b s t r a c t
a,
a0-Bis(substituted benzylidene)cycloalkanones were efficiently prepared from cycloalkanones and
benzaldehydes in water by using animal bone meal (ABM) or ABM modified as a catalyst. It is shown that
ABM modified can be quantitatively recovered and be reused effectively for many times. A comparison of
catalytic activity of these catalysts is discussed.
Article history:
Received 4 June 2010
Revised 6 October 2010
Accepted 11 October 2010
Available online 23 October 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
ABM modified
a,
a0-Bis(substituted
benzylidene)cycloalkanones
Crossed-aldol condensation
O
CHO
1. Introduction
O
Cat.
+
The crossed-aldol condensation is an effective way of synthesiz-
ing of
( )n
( )n
H2O, reflux
R
a,
a0-bis(substituted benzylidene)cycloalkanones as precur-
R
sors for the synthesis of bioactive pyrimidine derivatives.1–3
These compounds have gained a lot of attention due to their uses
as agrochemical, pharmaceutical and perfume intermediates and
as liquid crystal polymer units.4–7 Among these reactions, the aldol
condensation is useful for the formation of carbon–carbon bonds in
many kinds of carbonyl compounds.8–10 Crossed-aldol can be oper-
ated with the aid of strong acids or bases.2,11
3
2
1 R
n = 1, 2
R = H, CH3, NO2, OCH3, Cl
Scheme 1. Crossed-aldol condensation catalyzed by ABM or Na/ABM.
Our group has recently developed the preparation and use of
animal bone meal (ABM) as a natural catalyst for C–S bond forma-
tion by thia-Michael addition.34 This new natural heterogeneous
method led to b-sulfinyl adduct in very high yields after only a
few minutes.
In continuation of our research program concerning the devel-
opment of this natural catalyst, we report in this paper an efficient
catalyst for crossed-aldol condensation affording
tuted benzylidene)cycloalkanones (Scheme 1).
Improvements have been achieved by application of KF sup-
ported reagents under microwave mediation12 and ultra-sound
irradiation.13 Lewis acid catalysis using Yb(OTf)3,14 iodotrimeth-
ylsilane,15 TiCl3(SO3CF3),16 RuCl3,17 Pd/C-Me3SiCl,18 SOCl2,19
SmI3,20 I2,21 LiOH,22 KOH,23,24 TMSCl,25 LiClO4, TMSNEt2,26 TCT,27
a,
a0-bis(substi-
SiO2–OK,28 or FeCl3 in ionic liquids are also employed.
29
Numerous organic reactions have been carried out in solid/li-
quid heterogeneous media. Therefore, several types of catalysts
or solid supports have been studied as basic catalysts, we can
mention fluorapatite,30 diphosphate Na2CaP2O7,31 natural
phosphate,32 and hydroxyapatite.33
A comparison of catalytic activity of two catalysts (ABM and
Na/ABM) was also realized.
2. Experimental
2.1. Preparation of catalysts ABM, Na/ABM
⇑
Corresponding authors. Tel.: +33 238 417 073; fax: +33 238 417 281 (G.G.); tel.:
Animal bones were collected from nearby butcher shops. All of
the attached meat and fat were removed and cleaned from the
bones. The bones were then washed several times with tap water
+212 523 315 352; fax: +212 523 315 353 (S.L.).
E-mail addresses: gerald.guillaumet@univ-orleans.fr (G. Guillaumet), lazar_said@
yahoo.fr (S. Lazar).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.10.056

6716
Y. Riadi et al. / Tetrahedron Letters 51 (2010) 6715–6717
and left in open air for several days to get rid of odors. Later, they
were transferred to the oven at 80 °C for drying. The dried bones
were crushed and milled into different particle sizes in the range
in excellent yields using an inexpensive and recyclable ABM mod-
ified catalyst.
The reaction was carried out under reflux conditions by taking
1:2 mole ratios of cycloalkanones and aldehydes in water in the
presence of modified bones to give the desired bis(arylmethyli-
dene)cycloalkanones36 in excellent yields (Table 1). Under similar
conditions in the absence of the bones, only the starting material
was regenerated, thus highlighting the role of this catalyst.
When acetone is used as a ketone only the starting material is
regenerated.
45–200 lm then calcined for 2 h at 800 °C. The residue was
washed with water and was used after drying for 24 h at 80 °C.
The residue was washed with water and was dried overnight at
100 °C in a conventional drying oven, and then calcined at a heat-
ing rate of 2 °C/min to 400 °C, and kept at this temperature for 4 h.
The resulting material was denominated ABM. The catalysts ob-
tained were characterized by X-ray diffraction (Fig. 1).
The modified bones Na/ABM was prepared by impregnating the
bones with an aqueous solution of sodium nitrate.35 The weight ra-
tio used was NaNO3/bones = 1/2. The mixture was stirred vigor-
ously at room temperature, evaporated to dryness, dried, and
calcined at 800 °C for 2 h. The new catalysts obtained were charac-
terized by X-ray diffraction (Fig. 2).
Elemental analysis of ABM showed high levels of phosphate
(56.3%) and calcium (36.8%), with a Ca/P ratio of 1.55, compared
with small amounts of magnesium (3.72%), carbon (0.17%), hydro-
gen (0.15%), and nitrogen (0.36%). Only the strong characteristic
phosphate bands were observed in IR spectra. X-ray diffraction
analysis confirmed the presence of hydroxyapatite.
A mixture of aldehyde (2 mmol) and ketone (1 mmol) in H2O
(5 mL) was well stirred in the presence of 0.1 g ABM or Na/ABM
catalyst under reflux conditions until completion of the reaction.
The reaction mixture was filtered and the catalyst was washed
with dichloromethane (2 ꢀ 5 mL). After concentrating the filtrate
under reduced pressure, the precipitate was recrystallized from
ethyl acetate (column chromatography was not required). Isolated
yields of products were above 90%. Physical and spectral character-
ization of the products was confirmed by comparison with avail-
able literature data.13–15,25
In general, the use of ABM as the heterogeneous catalyst in the
crossed-aldol condensation has allowed the isolation of our prod-
ucts in satisfactory yields (Table 1). The reactions are relatively
slow.
Under similar conditions, the use of ABM doped with NaNO3 de-
creases remarkably the reaction time and the attempted products
were isolated in good yields only after few minutes (10–20 min)
(Table 1).
The EE geometry of the double bonds in the above compounds
(3a–j) was based on earlier literature reports. It is reported that
the vinylic protons are in proximity to the carbonyl group which
exerted an anisotropic effect, resulting in the downfield shifting
and overlapping of the vinylic protons with the aromatic protons,
and appearance of vinylic protons in the region of d 7.15–
7.95 ppm is an indication of such compounds with E-configuration
and in the region of d 6.8 ppm indicates Z-configuration. As for
example, the olefinic protons of Z-2-phenyl methylenecyclohexa-
nones and Z-2-phenyl methylene-6,6-diphenyl cyclohexanones
are generally observed at d 6.27 and 6.22 ppm.23
The EE geometry of the two double bonds was further substan-
tiated by NOE experiment on a prototype compound (3c). The
vinylic proton at d 7.8 ppm showed NOE with the aromatic ortho
protons and at the same time it did not show any NOE with the
methylene protons at C-3 (d 2.7 ppm) (Fig. 3).
In this Letter, we wish to report a simple, efficient, and practical
method for the preparation of bis(arylmethylidene)cycloalkanones
When the reactions were examined in different organic solvents
such as methanol, toluene, chloroform, water and THF, we found
that water is the best solvent due to high yields and shorter reac-
tion times (Table 2).
It has been shown that of the five solvents used, water gave the
highest yield for the desired product (Table 2, entry 5). When THF
or toluene was used as the solvent, the reaction could not be com-
pleted after reflux or stirring for 10 min and we have obtained a
mixture of starting materials and final products. Moreover, using
water as the reaction medium made the separation process much
Table 1
Condensation of various aromatic aldehydes with cyclic ketones in the presence of
modified bones
Figure 1. X-ray diffraction patterns of ABM.
O
( )n
R
R
3
Entry
n
Product
Yields/time (min)
ABM
Yields/time (min)
Na/ABM
1
2
3
4
5
6
7
8
9
2
2
2
2
2
1
1
1
1
1
3a (R = H)
3b (R = Cl)
3c (R = NO2)
3d (R = OCH3)
3e (R = CH3)
3f (R = H)
76/75
81/45
87/45
83/75
83/45
87/45
72/50
81/45
86/45
84/45
96/20
94/10
91/10
90/15
92/10
98/10
91/10
92/10
97/15
93/10
3g (R = Cl)
3h (R = NO2)
3i (R = OCH3)
3j (R = CH3)
10
The analytical data were identical to those reported in the literature.26,27
Figure 2. X-ray diffraction patterns of Na/ABM.

Y. Riadi et al. / Tetrahedron Letters 51 (2010) 6715–6717
6717
NOe
NOe
Table 4
Comparison of the condensation reaction of p-chlorobenzaldehyde and cyclohexa-
none in the presence of different catalysts
H
H
O
1
H
H
Entry
Catalyst
Time (min)
Yield (%)
2
1
2
3
4
5
6
7
Na/ABM
TiCl3ꢂSO3CF3
SiO2–OK
I2
TCT
Yb(OTf)3
RuCl3
10
120
180
270
16
94
9616
8828
9421
9027
9514
9417
3
4
H
H
H H
O2N
NO2
NOe
NOe
Figure 3. NOE in EE geometry.
720
720
Table 2
Effect of solvent on the synthesis of 3f catalyzed by Na/ABM
support which can contribute to the development of catalytic pro-
cesses and reduced environmental problems and it is the first use
of this material as the catalyst.
Entry
Solvent
Reaction time (min)
Isolated yield (%)
1
2
3
4
5
THF
10
10
10
10
10
38
22
45
66
98
Toluene
Methanol
Chloroform
Water
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Reaction conditions: solvent (2 mL), benzaldehyde (2 mol), cyclopentanone
(1 mmol), and Na/ABM (0.1 g).
easier than using other solvents. For example, with water as the
solvent, the product could be obtained with high purity through
simple filtration and rinsing of the filtrates with a little amount
of dichloromethane.
However, when toluene, THF, chloroform, and methanol were
used as solvents, a homogenous mixture of product and starting
materials was obtained at the end of the reaction; this product
has the same stereoselectivity of the product obtained when we
use water as the solvent. We clearly show that water increases
the catalytic activity of both ABM alone and with Na/ABM, in all
cases.37
After filtration of the product, Na/ABM was recovered quantita-
tively by simple filtration and regenerated by calcination at 400 °C
for several hours for each new reuse. Investigations of benzalde-
hyde and cyclopentanone as model substrates showed that succes-
sive reuse of the recovered catalyst in the same reaction gave the
product in yield almost as high as that of the first round (Table 3).
It should be noted that even in the sixth round, reuse of the cat-
alyst recovered can produce the corresponding product 3f in fairly
good yield.
To obtain further evidence we studied the effects of different
catalysts on the condensation reaction of p-chlorobenzaldehyde
with cyclohexanone. The results of this study are presented in
Table 4.
Comparison of the results obtained by our method with some of
those reported shows the efficiency of this method because of
shorter reaction times, high yields, and application of an inexpen-
sive and readily available catalyst.
In conclusion, the present method is an efficient and selective
procedure for the synthesis of
a,
a0-bis(substituted benzyli-
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35. Sebti, S.; Solhy, A.; Tahir, R.; Abdelatif, S.; Boulaajaj, S.; Mayoral, J. A.; García, J.
I.; Fraile, J. M.; Kossir, A.; Oumimoun, H. J. Catal. 2003, 213, 1.
dene)cycloalkanones from cyclic ketones with aromatic aldehydes
in refluxing water.
A simple procedure and the use of water as a solvent are ex-
pected to contribute to the development of more benign crossed-
aldol reactions. The ABM is a new, inexpensive, and attractive solid
Table 3
Studies on the reuse of Na/ABM in the synthesis of product 3f
36. General procedure for the synthesis of product 3.
A mixture containing
(1.0 mmol) of cyclohexanone and (2.0 mmol) of benzaldehyde in water and
Na/ABM (0.1 g) was stirred at reflux until completion of the reaction. The
reaction mixture was filtered and the catalyst was washed with CH2Cl2
(2 ꢀ 5 mL). After concentrating of the filtrate under reduced pressure, the
residue was subjected to recrystallization (EtOAc).
Round
Yield
Na/ABM recovered (%)
1
2
3
4
5
6
98
95
94
89
89
84
99
96
96
98
96
96
Spectral data of 3a: IR (KBr): d max cmꢁ1 3071, 1721, 1603; 1H NMR (CDCl3) d
(ppm) 7.33–7.50 (m, 10H), 7.25 (s, 2H), 2.90 (t, 4H, J = 3.5 Hz), 1.74–1.85 (m,
2H); 13C NMR (CDCl3) d (ppm) 28.4, 128.3, 128.5, 130.3, 136.3, 136.9, 190.4.
37. Sebti, S.; Solhy, A.; Tahir, R.; Smahi, A. Appl. Catal. 2002, 235, 273.