Natural phosphate and potassium fluoride doped natural phosphate: Efficient catalysts for the construction of a carbon-nitrogen bond

Article abstract of DOI:10.1016/j.tetlet.2004.03.164

The application of natural phosphates doped with potassium fluoride as heterogeneous catalysts for the Michael addition of aromatic and aliphatic amines to α,β-unsaturated carbonyl compounds is presented. The natural phosphate catalyst can be regenerated and reused without loss of activity, which makes it an attractive alternative to homogeneous basic reagents. Doping natural phosphate with potassium fluoride significantly enhances the rate and yield of the reaction.

Full text of DOI:10.1016/j.tetlet.2004.03.164

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4135–4138
Natural phosphate and potassium fluoride doped
natural phosphate: efficient catalysts for the
construction of a carbon–nitrogen bond
a
a
b
Mohamed Zahouily,a, Bouchaib Bahlaouan, Ahmed Rayadh and Saıd Sebti
*
€
aLaboratoire de Catalyse, Synthꢀese et Environnement, UFR de Chimie Appliquꢁee, Facultꢁe des Sciences et Techniques,
Universitꢁe Hassan II, Mohammadia B.P. 146, 20650 Morocco
bLaboratoire de Chimie Organique, Appliquꢁee et Catalyse (LCOAC), Facultꢁe des Sciences,
Ben M’Sik B.P. 7955, Casablanca, Morocco
Received 24 November 2003; revised 19 March 2004; accepted 24 March 2004
Abstract—The application of natural phosphates doped with potassium fluoride as heterogeneous catalysts for the Michael addition
of aromatic and aliphatic amines to a,b-unsaturated carbonyl compounds is presented. The natural phosphate catalyst can be
regenerated and reused without loss of activity, which makes it an attractive alternative to homogeneous basic reagents. Doping
natural phosphate with potassium fluoride significantly enhances the rate and yield of the reaction.
Ó 2004 Elsevier Ltd. All rights reserved.
Heterogeneous catalytic reactions are of interest1 due to
their well-documented advantages over homogeneous
catalytic systems. Natural phosphates (NP)2 have
emerged as ideal basic and acidic heterogeneous cata-
lysts as they are available from nature and are inex-
pensive. The surface of these phosphates presents
multi-catalytic active sites (basic3 and acidic4) and thus
increases their utility in both types of catalytic applica-
tions. The positive features of NP also include high
stability, ease of handling and regeneration, nontoxic
and other environmental hazards. In recent years, we
have developed several new applications of NP both
alone and doped with mineral salts in heterogeneous
catalytic reactions.5
Recently, Deshpande and co-workers9 have shown that
kaolinitic clay10 or commercially available montmoril-
lonite K1011 are excellent catalysts for the addition of
amines to a,b-ethylenic compounds. However, these
catalysts are only suitable for activating aliphatic amines
for addition towards a,b-ethylenic compounds and
failed for less nucleophilic aromatic amines. This
encouraged us to investigate the reaction with NP alone
or doped with potassium fluoride. We have previously
shown that various phosphate catalysts can promote
Michael additions forming carbon–carbon12 and
carbon–sulfur13 bonds. In this work we present the
efficient construction of carbon–nitrogen bonds using
natural phosphate and natural phosphate doped with
potassium fluoride (KF/NP).
The Michael condensation of an aliphatic or aromatic
amine and an a,b-unsaturated carbonyl compound is a
convenient route for the synthesis of b-amino carbonyl
compounds. This condensation is normally carried out
in the presence of a Lewis acid,6 although, in some cases
the reaction occurs with no special activation,7 in others,
stronger reaction conditions are required.8
Several a,b-unsaturated carbonyl compounds such as
chalcone,
p-methoxychalcone,
p-chlorochalcone,
p-methylchalcone and ethyl acrylate as Michael accep-
tors were subjected to this reaction with NP or KF/NP
as catalysts and aniline, p-methoxyaniline or benzyl-
amine as the nucleophilic amine (Scheme 1). The reac-
tions were carried out at room temperature.
Natural phosphate comes from an ore extracted in the
region of Khouribga (it is available in raw form or
treated form from CERPHOS Casablanca, Morocco).2
Prior to use this material requires initial treatments such
Keywords: Natural phosphate; Potassium fluoride; Heterogeneous
catalysis; b-amino derivatives; Recyclable catalyst.
* Corresponding author. Fax: +212-23-31-53-53; e-mail: m.zahouily@
univh2m.ac.ma
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.164

4136
M. Zahouily et al. / Tetrahedron Letters 45 (2004) 4135–4138
R
O
O
NH
Catalyst
+
R NH2
MeOH (R.T)
X
X
2
1
3
Scheme 1.
as crushing and washing. For use in organic synthesis,
the NP is treated by techniques involving attrition,
sifting, calcinations (900 °C), washing and recalcination.
These treatments lead to a fraction between 100 and
400 lm, which is rich in phosphate. The structure of NP
is similar to that of fluorapatite (Ca10(PO4)6F2),
as shown by X-ray diffraction and chemical analy-
sis.3d;13a The surface area of NP was measured at
1 m2 gꢀ1 (nitrogen adsorption) and the total pore volume
was 0.005 cm3 gꢀ1. KF/NP was prepared by adding 8 g
of NP to a 1 g aqueous KF solution. The mixture was
stirred, evaporated to dryness and then further dried at
150 °C for 2 h. The catalyst KF/NP (weight ratio
KF/NP:1/8)5c;13a is a grey powder, the colour of NP
itself.
Aniline and chalcone (X ¼ H, Scheme 1) were chosen as
model substrates to determine suitable reaction condi-
tions. The best weight ratio of KF/NP is 1/8.3
In the presence of KF/NP various solvents were tested.
Thus, after 1 h the yields of product 3a obtained were
95%, 87%, 63% and 11% in the presence of methanol,
ethanol, n-butanol and iso-propanol, respectively. In the
cases of acetone, dichloromethane, dimethylformamide,
tetrahydrofuran, dioxane and hexane no product was
observed, only the starting material was recovered. In
the absence of solvent, only a 10% yield of 3a was
obtained. This behaviour indicates that some solvent is
needed to facilitate contact between the reagents and the
active site.
Table 1. Synthesis of products 3 by Michael addition using NP
Yield/% (time/h)a
Products
R
X
NP
KF/NP
3a
3b
3c
H
25 (2); 96 (8)
80 (0.75); 95 (1)
Cl
71 (14)
66 (2), 95 (5)
OMe
60 (6); 93 (14)
67 (2); 95 (3.5)
3d
3e
Me
H
86 (14)
70 (2); 94 (4)
75 (6), 90 (14)
79 (0.5), 92 (1)
MeO
MeO
MeO
MeO
3f
3g
3h
3i
Cl
73 (14), 95 (19)
77 (14), 95 (19)
87 (16)
77 (3.5), 94 (5.5)
76 (3.5), 90 (5.5)
80 (4), 93 (5)
70 (5), 90 (24)
92 (5)
OMe
Me
H
64 (24)
CH2
CH2
CH2
CH2
3j
Cl
75 (24)
3k
3l
OMe
Me
23 (24)
50 (4), 75 (24)
55 (6), 91 (24)
55 (24)
a Yields of pure products isolated by chromatography and recrystallized from n-hexane/ethyl acetate. The products were identified by 1H, 13C NMR,
IR spectrometry and melting points.

M. Zahouily et al. / Tetrahedron Letters 45 (2004) 4135–4138
4137
The study of the influence of the volume of the solvent
showed that 0.5–1.5 mL of methanol resulted in optimal
yields. An increase in the volume of up to 2 mL slightly
decreased the reaction yield (66%), and this was reduced
further to 13% when a volume of 10 mL was used. The
large solvent volume reduced the overall reaction con-
centration, which explains the decreased yield.
In the presence of 0.01 g of KF alone (the present
quantity in the KF/NP:1/8 catalyst), no 1,4-addition
product was observed under the reaction conditions,
only the starting material was isolated. Products of
undesirable side reactions resulting from 1,2-addition,
polymerization and bis-addition were not observed. For
the catalytic activity of KF/NP in this Michael addition
we speculate that the reaction occurs at the surface
rather than inside tunnels present in the catalyst. The
acidic surface of NP4 probably induced the polarization
of the C@O bond and the basic sites3 deprotonate
RH2Nþ–C after addition to the C@C bond. The final
product is obtained after protonation of the resulting
enolate.
In general the use of NP alone as the heterogeneous
catalyst in Michael additions has allowed the isolation
of the 1,4-addition product in moderate to good yields
(Table 1).14 However, the rate of reaction was relatively
slow. Moreover, the use of NP is particularly interesting
since it can be regenerated by calcination at 500 °C over
15 min, and after seven successive recoveries, the prod-
uct 3a was obtained in the same yield.
The reactions of benzylamine and acrylates were inves-
tigated separately to establish conditions for the selec-
tive preparation of mono and bis-addition products.
Reaction of ethyl acrylate with an excess of benzylamine
in the presence of KF/NP furnished 4 as the sole product
(Scheme 2). The reaction of benzylamine with an excess
of ethyl acrylate in the presence of KF/NP gave bis-
addition product 5 in excellent yield. While compound 4
is a direct precursor of b-amino acids, 5 has been used as
a starting material for the synthesis of heterocyclic
compounds,15 and derivatives of nipecotic acids.16
Under the optimized conditions, the use of NP doped
with KF, remarkably, increased the catalytic activity
and decreased the reaction time of the Michael addition
(Table 1 and Fig. 1). The yields were very high (91–95%;
Table 1), except in one case, the reaction of benzylamine
with a Michael acceptor bearing a methoxy (X ¼ MeO)
in the para-position, which afforded only a moderate
yield (75%) of the 1,4-addition product.
In summary, we have developed a practical and novel
phosphate-catalyzed Michael-type addition reaction of
aliphatic and aromatic amines with a,b-unsaturated
carbonyl compounds at room temperature. The natural
phosphate catalyst can be regenerated and reused
without loss of activity, which makes it an attractive
alternative to homogeneous basic reagents. The use of
potassium fluoride doped natural phosphate enhances
the rate and the yield of the reaction.
100
80
NP
KF/NP
60
40
20
0
Acknowledgements
0
2
4
6
8
Time (h)
The authors thank the International Foundation for
Science for the Development of Science and Technology
in Morocco for financial support.
Figure 1. Time course of product 3a synthesis in the presence of NP
and KF/NP, respectively.
COR
N
R=OH : nipecotic acid
R=NH2, nipecotamide
H
CO2Et
EtO2C
Excess
CO2Et
PhCH2 NH2
KF/NP (reflux)
CO2Et
95% (1 h)
N
CH2Ph
HO2C
NaOH/MeOH (65 °C)
CO2H
5
amine in excess
KF/NP (reflux)
N
92% (30 min)
72%
CH2Ph
NaOH/MeOH (65 °C)
69%
β-amino diacid
CO2H
CO2Et
PhCH2HN
PhCH2HN
β-amino acid
4
Scheme 2.

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M. Zahouily et al. / Tetrahedron Letters 45 (2004) 4135–4138
11. Purchased from Aldrich Chemicals.
References and notes
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