Supported l-proline on zirconium phosphates methyl and/or phenyl phosphonates as heterogeneous organocatalysts for direct asymmetric aldol addition

Article abstract of DOI:10.1016/j.jcat.2011.06.004

Zirconium phosphates methyl and/or phenyl phosphonates-supported l-proline have been prepared as amorphous solids by precipitation of (4R)-4-(phosphonooxy) -l-proline, methyl and/or phenyl phosphonic acid with ZrOCl₂. The supported l-proline ca

Full text of DOI:10.1016/j.jcat.2011.06.004

Journal of Catalysis 282 (2011) 112–119
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Supported L-proline on zirconium phosphates methyl and/or phenyl phosphonates
as heterogeneous organocatalysts for direct asymmetric aldol addition
⇑
Salvatore Calogero, Daniela Lanari, Mara Orrù, Oriana Piermatti , Ferdinando Pizzo, Luigi Vaccaro
Laboratory of Green Synthetic Organic Chemistry, CEMIN – Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto, 8, Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Zirconium phosphates methyl and/or phenyl phosphonates-supported L-proline have been prepared as
Received 15 March 2011
Revised 5 May 2011
Accepted 2 June 2011
Available online 7 July 2011
amorphous solids by precipitation of (4R)-4-(phosphonooxy)-
phonic acid with ZrOCl . The supported -proline catalysts were tested on the direct asymmetric aldol
addition of cyclohexanone to p-nitrobenzaldehyde in DMF/H O (9:1) and in sole water. The hydrophobic
groups on solid surface favor reagents’ diffusion toward proline chiral moiety increasing the catalytic
activity of supported -proline. High diastereoselectivity (anti/syn up to 94:6) and high enantiomeric
excess up to 97% have been obtained.
L-proline, methyl and/or phenyl phos-
2
L
2
L
Keywords:
Chiral heterogeneous catalysts
Supported L-proline
Ó 2011 Elsevier Inc. All rights reserved.
Zirconium phosphates
Aldol addition
Aqueous medium
1
. Introduction
In addition, the application of inorganic materials as heteroge-
neous supports offers a numbers of advantages: their rigid structure
does not allow the aggregation of active catalysts, they do not swell
and are insoluble in organic solvents and water [6]. Inorganic
supports possess better thermal and mechanical stability under
catalysis conditions. Among these, the class of zirconium phosphate
and/or phosphonates represents a valid choice thanks to their inter-
esting physical–chemical properties and high versatility [7]. The
layered inorganic backbone of this compounds may be considered
as a hook onto which organic groups with different functionality
may be attached (e.g. acidic, basic, polar, and hydrophobic), allowing
to control both the reactivity and selectivity of the organic process
[7,8]. These materials can be easily prepared by a self-assembly
approach, and since they are insoluble in water and organic solvents
they can be easily recovered and reused [7–9]. Only a few papers
report the use of zirconium phosphonate, as a solid support for chiral
ligands [3a,5a,8a,10,11]. Zirconium phosphate containing chiral
functionalities such as BINOL or BINAP has been prepared, and the
amorphous materials have been efficiently used as heterogeneous
catalysts in the stereoselective addition of diethylzinc to benzalde-
hyde, aldol condensation, hydrogenation of aromatic ketones and
of b-keto esters [10a–10c]. Cinconidine with different arm lengths
was covalently immobilized onto the backbone of zirconium
phosphate to afford mesoporous materials that were used in the
stereoselective addition of diethylzinc to aldehydes [10d].
Zirconium phosphonates have been used for the preparation of sup-
ported oxidation catalysts by the immobilization of Mn(III) phor-
phyrins [10e] and chiral salen Mn(III) complex [10f]. Chiral borane
In recent years, significant achievements in the area of solid-
phase chemistry have resulted in an enormous progress on the
interdisciplinary research devoted to stereoselective heteroge-
neous catalysis [1]. While homogeneous catalysts may boast a
higher activity and selectivity, potential advantages of heteroge-
neous catalysis, such as easier product isolation, efficient catalyst
recycling, minimization of metal traces in the product, and
improved process control, are recognized to be very effective in
reducing the cost of a chemical transformation. Benefits of both
homogeneous and heterogeneous catalysis should be combined
to reach the overall highest efficiency [2].
Although not fully understood, the support plays an important
role in determining the accessibility to the active sites, and there-
fore, it crucially influences the course of an enantioselective trans-
formation [3]. In this concern, several different approaches have
been explored, including the use of organic polymers, porous inor-
ganic oxides, dendrimers, membrane supports, aqueous biphasic
systems, and ionic liquids [1–4]. Recently, a new class of hybrid
organic–inorganic material prepared from organic linkers and
metal nodes has received great attention since they are synthe-
sized under mild conditions and in principle allow to incorporate
and fine-tuning the desired chemical and physical properties by
a judicious choice of the building blocks [5].
⇑
Corresponding author. Fax: +39 0755855560.
E-mail address: oriana@unipg.it (O. Piermatti).
of layered a-zirconium-N-(m-solfophenyl)-L-valine-phosphonate
0
021-9517/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2011.06.004

S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
113
methanphosphonate has been used in the asymmetric Mukaiyama
aldol reaction [8a].
On the other hand, organic catalysts have attracted the interest
of chemists since they are water and air tolerant and offer mild,
tary analysis were performed by EA1108 CHN Fison Instruments.
Nitrogen adsorption–desorption isotherms [31] were determined
with a Micromeritics ASAP 2010 instrument at 77 K on samples
outgassed overnight at 373 K. The specific surface area was calcu-
lated by B.E.T. method [32]. Micropore volume and external surface
practical and generally simple method. In this context, L-proline
and its derivative have been widely used as organic catalysts for
a wide range of enantioselective transformations [12], in particular
area were evaluated by t-plot [33] method using non-porous a-ZrP
as reference material [34]. Mesopore characterization has been
performed by Barrett, Joyner, Halenda method [35]. Centrifugation
was performed at 12,000 rpm for 15 min. Thin-layered chromatog-
raphy analysis was performed on silica gel on aluminum plates
(Silica gel 60 F254, Fluka). Column chromatographies to purify the
aldol products were performed by using silica gel 230–400 mesh
(Silica gel 60, Merk) eluting with petroleum ether/ethyl acetate
80:20.
asymmetric aldol [13], Michael [14], Mannich [15],
16], Diels–Alder [17], Baylis–Hillman [18] reactions.
Also, proline and its derivatives have been immobilized [19]
a-amination
[
onto various types of materials, and several examples are reported
in the literature: poly-(ethylene glycol)-supported proline [20],
polystyrene-supported proline [21], and
mesoporous materials [22]. Alternative strategies involve (i) sim-
ple physisorpion of -proline on -Al [23], (ii) ion-exchange
method: -proline has been intercalated into layered materials
L-proline supported on
1
L
c
2
O
3
The anti/syn ratio was determined by H NMR of crude product
L
3
in CDCl ; CHOH d: syn 5.48 ppm, J = 2.2 Hz; anti: 4.90 ppm,
such as double hydroxides (LDH) [24], hydrotalcite clays [25] or
layered montmorillonites (MMT) [26], and (iii) the use of sup-
ported ionic liquid phase for L-proline recycling [27].
J = 8.4 Hz. The enantiomeric excess (ee%) was determined by chiral
HPLC analysis with CHIRALPACK AD-H, eluting with n-hexane/iso-
propanol 75:25, flow rate 0.5 mL/min and UV detector (k =
According to the urgent needs for a more environmentally
responsible chemistry, alternative reaction media are currently
taking a leading role in the development of efficient and cleaner or-
ganic chemistry. Among the alternative reaction media, water is
one of the most intriguing due to its peculiar properties. It is
known that water used as substoichiometric additive or in large
excess (as reaction medium) plays an important role in the devel-
opment of new synthetic processes both by improving the chemi-
cal efficiency and reducing the environmental impact [28].
264 nm): T
R
20.9 min (anti minor), T
R
26.3 min (anti major). The
0
major product had (2S,1 R) absolute stereochemistry in accord with
L-proline catalyzed aldol addition [13,21b].
2.2. Synthesis of (4R)-4-phosphonooxy- -proline
L
In a flask of 500 mL equipped with a traps for the HCl, under
stirring and N atmosphere, POCl (23 mL, 0.25 mol) was added
dropwise over a period of 1 h to 9 mL of water (0.5 mol). During
2
3
Recently, we have been involved in the development of novel
solid catalysts to be used in benign reaction media for the defini-
tion of chemically and environmentally efficient organic processes
the addition, the temperature was kept under 25 °C. After
30 min, the trans-4-hydroxy-L-proline (6.55 g, 0.05 mol) was added
at 60 °C, under stirring, in 15 min and the mixture was stirred at
60 °C for 2 h. After cooling to r.t., water (3.6 mL) and HCl 1 N
(15 mL) were added. The mixture was heated at 100 °C for
[
8b–8d,29,30]. We reported the preparation and characterization
of new amorphous zirconium hydrogen phosphate alkyl and/or
aryl phosphonates of general formula Zr(PO R)
(with R = R = Me, Ph, Pr or R = Me R = Ph) [8d]. The pres-
3
OH)2-(x+y)(PO
3
x
2
20 min under N , and then, in sequence, ethanol (60 mL) and
1
1
1
(
PO
3
R )
y
diethyl ether (200 mL) were slowly added with the formation of
a white suspension. The flask was allowed to stand overnight at
4 °C, and a viscous oil was separated at the bottom of the flask.
The supernatant was removed, 20 mL of ethanol was added, and
magnetic stirring was kept until a finely dispersed solid was ob-
ence of hydrophobic groups as Me, Ph, and Pr is associated with a
high micro- and mesopore volume and an extraordinary specific
2
surface area (200–380 m /g). They efficiently catalyze (conversion
up 99%) the direct aza-Diels–Alder reaction of 2-cyclohexen-1-one
with N-PMP-pCl-benzaldimine in water without any additive [8d].
Based on this excellent result, we have decided to use, for the
first time, zirconium phosphate as inorganic support for the immo-
bilization of a covalently linked chiral organic catalyst based on
tained. The solid (4R)-4-phosphonooxy-L-proline was separated
from ethanol by centrifugation, dried under reduced pressure
and then purified by leaving it under magnetic stirring for 4 days
in ethanol/water 60:2 solution. The solvent was removed by centri-
L-proline moiety. The
L-proline functionalized phosphate/phospho-
fugation, the solid (4R)-4-phosphonooxy-L-proline washed twice
nates have been prepared as amorphous solids by using the
self-assembly approach. The catalytic activity has been modulated
by inserting different hydrophobic R group (R = Me, Ph) on solid
surface in order to steer the reagents toward the proline catalytic
site.
with ethanol to remove the traces of water and finally dried under
reduced pressure (7.1 g, 68% yield).
1
White solid, mp 160–165 °C, [
(400 MHz, D O) d: 2.06 (ddd, 1H, C
(ddd, 1H, C HH, J = 14.4, 7.9, 1.2 Hz), 3.33 (ABX system, 2H, H
4.36 (dd, 1H, H
(100.6 MHz, D O) d: 36.1 (d, C
(s, C ), 74.0 (d, C , J = 4.8), 171.8 (s, COOH); P NMR (200 MHz,
O) d: – 1.2 ppm.
a]
D
– 26.1 (c = 1.2, H
2
O); H NMR
2
3
HH, J = 14.4, 10.6, 4.2 Hz), 2.45
),
C NMR
, J = 5.2), 58.4
3
5
13
In this paper, we report the preparation of these novel
L-proline-
2
, J = 10.6, 7.9), 4.73 (m, 1H, H
, J = 4.1), 52.5 (d, C
4
);
based solid catalysts and the results obtained by testing their
catalytic activity in the aldol addition of cyclohexanone to
2
3
5
3
1
2
4
p-nitro-benzaldehyde in DMF/H
2
O 9:1 and in sole water as reac-
D
2
tion media.
2.3. General procedure for preparation of
L-proline functionalized
zirconium phosphate/phosphonates
2
. Experimental
.1. General remarks
All chemicals were purchased and used without any further
A ZrOCl
slowly added, under stirring, at r.t. to an aqueous solution of
4R)-4-phosphonooxy- -proline and methyl and/or phenylphos-
2
aqueous solution (2 mmol in 4 mL of water) was
2
(
L
phonic acids (6 mmol in 18 mL of water). The molar ratio between
phosphoric acid and phosphonic acid used during the preparation
is reported in Table 2. The preparation conditions were as follows:
1
13
31
purification. H NMR, C NMR, and P NMR spectra were recorded
at 400 MHz, 100.6, and 161.9 MHz, respectively. TG and DTA anal-
ysis were performed by STA 449 C Jupiter (thermal analyzer). P and
Zr elementary analysis were performed by Inductively Coupled
Plasma-Optical Emission Spectrometers (ICP-OES). C, H, N elemen-
IV
molar ratio P/Zr = 3, precipitation temperature 25 °C, precipita-
tion time 15 h. The obtained
L-proline functionalized zirconium
phosphate/phosphonates were separated from aqueous medium

1
14
S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
Table 1
The 1H NMR, 13C NMR, and 31P NMR spectral data of solids CAT1, CAT2, and CAT3.a
COOH
2
NH
4
OH
P
O
P
CH3
P
P
1H NMR
13C NMR
31P NMR
d (ppm)
0.0
H
–
Molt.
–
d (ppm)
J (Hz)
C
–
Molt.
–
d (ppm)
J (Hz)
P-OH
–
–
–
–
P-Prol
C
C
C
H
H
(3)HH
(3)HH
ddd
dd
ABX
dd
2.02
2.38
3.26
4.33
4.69
14.5, 10.5, 4.1
14.5, 7.9
–
10.5, 7.9
–
C
C
C
C
3
5
2
4
d
d
s
s
s
35.5
52.2
57.7
74.7
170.5
3.8
5.4
–
–
–
ꢂ1.3
(5)
H
2
2
4
m
COOH
P-C
6
H
5
H
H
H
3
4
2
, H
5
6
m
t
dd
7.19
7.27
7.43
–
7.4
13.6, 8.0
C
C
C
C
3
2
4
1
, C
, C
5
6
d
d
d
d
128.3
130.1
132.1
129.8
15.0
10.6
2.9
17.4
30.8
, H
183.8
P-Me
CH
3
d
1.15
17.4
CH
3
d
11.2
134.4
a
Recorded in D
2
O/HF solution.
by centrifugation, washed with water (4 ꢀ 100 mL), and finally
dried at 80 °C for 24 h.
precipitation in the absence of hydrofluoridric acid. It is possible to
vary the acid properties of the phosphates from neutral (e.g. P-CH
or weak acid (e.g. P-CH COOH) to strong acid (e.g. P-C SO H) or
even to basic (e.g. P-C NH ), or to anchor chiral ligands
8a,10,11]. The only limitation to the synthesis is the use of organic
3
)
Table 1 reports the 1H NMR, 13C NMR, and 31P NMR spectral
H
2
6
4
3
data of
L
-proline-based solid catalysts.
H
2 4
2
[
2
2.4. General procedure for aldol addition with catalyst CAT3
groups with a cross section equal to or less than 24 Å . This is the
free area around each phosphorous atom on the surface of the lay-
In a 2-mL vial, DMF/H
150 L) was added to 4-nitrobenzaldehyde (18.9 mg, 0.125 mmol)
and catalyst CAT3 (27.5 mg, 0.062 mmol of solid catalyst,
.0375 mmol of P-Prol groups (30 mol%)). The mixture was stirred
for 10 min at r.t., and then, cyclohexanone (64.5 L, 0.625 mmol,
equiv.) was added. The mixture was left under stirring for 4 days
at 30 °C and then diluted with water. The products were extracted
with ethyl acetate (3 ꢀ 1 mL). The organic phase was separated by
centrifugation, and the combined organic layers were dried
2
O (9:1) solution (200
lL) or water
ers. However, more voluminous groups may be attached to the
a-
(
l
layers if their dimensions are compensated by introducing a small
0
0
group R (R being H, OH, CH
3
) to obtain bifunctional compounds of
[7b,36].
0
0
formula Zr(PO
3
R)2ꢂx(PO
3
R )
x
l
With the aim to obtain new and efficient chiral heterogeneous
catalyst and to understand the role of support on the stereoselec-
tivity of the aldol addition reaction, in this work, we have prepared
5
new zirconium phosphate/phosphonates-supported
L-proline by
direct amorphous precipitation of suitable phosphoric and/or
IV
(
Na
SO
2 4
) and evaporated under reduced pressure. The crude prod-
phosphonic acid with ZrClO
(4R)-4-(Phosphonooxy)-
chosen for the preparation of zirconium phosphate/phospho-
nates-supported -proline. It has been synthesized by treatment
of trans-4-hydroxy- -proline with chloro-phosphonic acid, pre-
pared in situ from PO Cl and water according to a procedure de-
scribed for the preparation of phosphoserine [37] (Scheme 1).
2
(P/Zr = 3).
ucts were purified by column chromatography eluting with petro-
leum ether/ethyl acetate 80:20.
L-proline is the alkyl phosphoric acid
L
L
3
. Results and discussion
3
3
3.1. Catalysts preparation and characterization
3
1
The P NMR spectra of the product showed only one detectable
signal at –1.2 ppm, typical for a phosphate monoester group [38],
highlighting that the phosphorylation was highly O-selective.
Three different functionalized zirconium phosphates methyl
and/or phenylphosphonates have been prepared from: (i) (4R)-4-
The preparation of zirconium phosphate and phosphonates is
closely related to the methods employed for the preparation of
-Zr(HPO O ( -ZrP), i.e. refluxing the amorphous precipitates
a
4
)
2
ꢁH
2
a
in phosphoric or phosphonic acid solutions, or by precipitation of
(
(
(
phosphonooxy)-
4R)-4-(phosphonooxy)-
1:1); (iii) (4R)-4-(phosphonooxy)-
L
-proline and methylphosphonic acid (1:1); (ii)
-proline and phenylphosphonic acid
-proline, methylphosphonic
an aqueous solution containing the suitable phosphoric or
L
phosphonic acids with ZrOCl
These organic–inorganic materials have
similarly to
2
in presence of hydrofluoridric acid.
layered structure
a-ZrP; amorphous materials can be obtained by direct
L
a
and phenylphosphonic acids (1:1:1).
Table 2
Chemical and surface properties of prepared solids CAT1–3.
Solid
R
P-Prol/P-R solution
molar ratio
P-Prol/P-R solid
molar ratio
Molecular formula
P/Zr molar
ratio
MW
(u)
B.E.T. surface
area (m /g)
2
CAT1
CAT2
CAT3
Me
Ph
Ph, Me
1/1
1/1
1/1/1
1/1.2
1/1.2
1/1.5/1.1
Zr(PO
Zr(PO
Zr(PO
3
-OC
3
-OC
3
-OC
5
H
5
H
5
H
8
O
8
O
8
O
2
2
2
N)0.93(PO
N)1.02(PO
N)0.60(PO
3
3
3
Me)1.15ꢁ1.5H
Ph)1.23ꢁ1.6H
Ph)0.92(PO
Me)0.66ꢁ0.9H
2
O
2
O
2.08
2.25
2.19
420.7
525.1
439.3
2.4
5.2
4.1
3
2
O

S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
115
Table 3
POCl3
+
2 H O
2 HCl
+
ClPO(OH)2
H O P O
2
Elemental analysis of CAT1, CAT2, and CAT3.
%
Zr
% P
% C
% H
% N
HO
+
2
3
CAT1
CAT2
CAT3
Calcd.
Found
21.68
21.26
15.32
15.68
16.54
15.90
3.30
3.38
3.09
2.95
ClPO(OH)2
COOH
COOH
N
H
N
H
Calcd.
Found
17.37
17.69
13.28
13.28
28.52
27.95
3.33
3.45
2.72
2.49
(
4R)-4-(phosphonoxy)-L-proline
Calcd.
Found
20.76
20.74
15.45
15.77
25.10
24.56
3.00
3.17
1.91
1.89
Scheme 1. Synthesis of (4R)-4-(phosphonooxy)- -proline.
L
H
N
H
N
and 180 °C, corresponds to the loss of 3.6% of the initial weight and
is due to the water of crystallization, the second, between 180 and
1000 °C, corresponds to the loss of 36% of the initial weight and is
due to the oxidation of the organic groups. At 1000 °C, the forma-
HOOC
HOOC
R
P
O
P
R1
P
O
P
R
P
2 7
tion of cubic ZrP O is considered, as shown by the XRPD spectrum
Zi nr oO rgain ioc r gl aa yn ei cr layer
6
of a sample heated at 1000 °C (data not shown). These data to-
gether with the P-Prol/P-Ph/P-Me molar ratio (1:1.5:1.1) allow to
obtain the molecular formula of solid CAT3 (Table 2).
The chemical compositions of solid are in good agreement with
those obtained by P, Zr, performed by ICP, and C, H, N elemental
analysis (Table 3).
P
O
P
R
P
O
P
R
P
O
1
COOH
COOH
COOH
N
H
N
H
N
H
CAT1: R = R1 = Me CAT2: R = R1 = Ph CAT3: R = Me, R1 = Ph
2
The prepared solids show low specific surface area (2.4–5.2 m /g)
3
and are not micro and mesoporous (Vmicro and Vmeso < 0.01 cm /g)
Fig. 1. Schematic arrangement of phosphate and phosphonate groups on the layer
of
L
-proline functionalized zirconium phosphate methyl and/or phenyl
(data not shown).
phosphonates.
3
.2. Catalytic activity
The obtained solids CAT1, CAT2, CAT3 have been characterized
by H NMR, C NMR and P NMR, TG DTA, ICP-OES and by nitro-
gen adsorption–desorption isotherms at 77 K analysis.
Table 2 reports the molar ratio between phosphoric and phos-
phonic acid used during the preparation, the molar ratio between
phosphonate groups (P-R, R = Me and/or Ph) and L-proline phos-
phate group (P-Prol) in the solid with the molecular formula and
molecular weight, the Zr/P molar ratio and the calculated B.E.T.
surface area. Fig. 1 shows the schematic arrangement of phosphate
and phosphonate groups on the layer of L-proline functionalized
zirconium phosphate methyl and/or phenylphosphonates.
The molecular formulas were obtained by thermogravimetric
1
13
31
Among the
has been deeply investigated since it is one of the most important
tools in organic synthesis for the C–C bond formation [39]. -Pro-
L-proline-mediated organic reactions, aldol addition
L
line-mediated aldol addition is typically performed in organic sol-
vent, such as DMSO, DMF, or chloroform, and although addition of
a small amount of water often accelerates reactions and/or im-
proves enantioselectivities, addition of a large amount of water
as reaction solvent has typically resulted in low yield with low or
no enantioselectivity [40]. Recently, several papers have described
the role of water in proline-mediated aldol reactions [28j,28l,41].
The aldol addition of p-nitrobenzaldehyde to cyclohexanone to
give anti and syn diasteromers of 2-[hydroxy(p-nitrophenyl)
methyl]cyclohexanone was chosen as test reaction for evaluating
(
TG) and differential thermal analysis (DTA) curves and P-Prol/P-
31
R molar ratio determined by P NMR analysis. As a representative
example, the TG–DTA curves of catalyst CAT3 are reported in Fig. 2.
Thermal decomposition occurs in two steps: the first, between 50
the catalytic activity of L-proline functionalized zirconium phos-
phate methyl and/or phenylphosphonates.
We started the study with the solid CAT1 that presents
the methyl group as spacer for the voluminous
Table 4).
In the absence of any solvent at 30 °C, both the reactivity and
the selectivity were low (Table 4, Entry 1). In the presence of traces
of water (1.1 L), the reactivity increased slightly, but the selectiv-
ity remained unchanged (Table 4, Entry 2). Similar results were ob-
tained in DMF or DMF/H O 1:1 (Table 4, Entries 3 and 4). The best
selectivity was obtained at 30 °C in DMF/H O (9:1) with a 86/14
L-proline groups
(
l
2
2
anti/syn ratio and an enantiomeric excess of the major anti product
of 91%, but the conversion was still too low (16%) (Table 4, Entry 5).
Increasing the reaction temperature to 50 °C, we observed a slight
increase of the reactivity with a significant decrease of enantiose-
lectivity (Table 4, Entry 6).
In our previous work, we developed new zirconium hydrogen
phosphate alkyl and/or aryl phosphonates as heterogeneous
Brønsted acid catalysts for the direct aza-Diels–Alder reaction of
2
-cyclohexen-1-one with N-PMP-pCl-benzaldimine in sole water,
and we observe that the presence of hydrophobic groups, such as
Me, Ph, and Pr, on the solid surface catalyst favors reagents’ diffu-
sion toward the acidic sites, aiding proton transfer to the reagents,
Fig. 2. Thermogravimetric (TG) and differential thermal analysis (DTA) curves of
catalyst CAT3 obtained at a heating rate of 10 °C/min under air atmosphere.

1
16
S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
Table 4
Aldol addition reaction of p-nitrobenzaldehyde to cyclohexanone catalyzed by L-proline functionalized zirconium phosphates CAT1, CAT2, and CAT3.
O
O
O
OH
O
OH
+
+
NO2
Medium
NO
2
NO2
Entrya
Solid (mol%)
T (°C)
Conv.b,c (%)
anti/sync
eed (%)
1
2
3
4
5
6
7
8
9
CAT1
CAT1
CAT1
CAT1
CAT1
CAT1
CAT2
CAT3
CAT3
CAT3
CAT3
CAT3
SolFC
SolFC
DMF
30
30
30
30
30
50
30
30
30
30
25
25
17
32
14
18
16
27
30
54 (50)
75
63/37
66/34
65/35
88/12
86/14
79/21
80/20
94/6
68
70
64
84
91
75
84
96
93
78
97
96
e
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
DMF/H
2
2
2
2
2
2
2
2
2
O (1:1)
O (9:1)
O (9:1)
O (9:1)
O (9:1)
O (9:1)
O (9:1)
O (9:1)
O (9:1)
f
91/9
86/14
94/6
g
1
1
1
0
1
2
35
34
70 (64)
f
93/7
a
b
c
d
e
f
Reaction conditions: p-nitrobenzaldehyde 0.125 mmol, cyclohexanone 5 equiv., medium 200
The complement to 100% is unreacted p-nitrobenzaldehyde.
lL, catalyst 30 mol% in P-Prol groups, reaction time 4 days.
Determined by 1H NMR of crude product. The yield of isolated products is given in parentheses.
Determined by chiral HPLC analysis for anti product.
In the presence of 1.1 lL of water.
Medium 100
lL.
g
Medium 400
lL.
increasing the catalytic activity of the prepared solids compared
with -zirconium hydrogen phosphate ( -ZrP) [8d].
Based on these results, we supposed that the insertion of more
hydrophobic groups on the surface of -proline functionalized zir-
Table 5
Catalytic activity of solid CAT3 in aqueous medium.
a
a
Entrya
Conv.b,c
(%)
eed
(%)
Medium
pH
anti/
sync
L
conium phosphate should lead to an increase of catalytic activity.
For this purpose, the catalysts CAT2 (P-Prol/P-Ph = 1:1.2) and
CAT3 (P-Prol/P-Ph/P-Me = 1:1.5:1.1) were tested under the best
condition used for CAT1 (Table 4, Entries 7 and 8 vs. Entry 5).
The presence of phenyl group in CAT2 (Table 4, Entry 6) in-
creases the hydrophobicity of solid catalyst surface but makes
the system very rigid. In fact, we observed an increase of reactivity
but the selectivity decreased in comparison to CAT1 (84% vs. 91%).
When both P-Me and P-Ph group are present together with the
1
2
3
4
6
7
SolFC
–
–
–
60
46
57
51
71
49
70/30
73
H
2
H
2
H
2
H
2
O (1.1
O (50
O (150
O (100
l
L)
61/39 43
76/24 81
89/11 93
85/15 91
84/16 92
lL)
l
l
L)
1.9
L) + NaOH 0.2 M (50
l
L) 3.5
6.0
NaOH 0.2 M (150 lL)
a
Reaction conditions: p-nitrobenzaldehyde 0.125 mmol, cyclohexanone 5 equiv.,
catalyst CAT3 (30 mol% in P-Prol groups), at 30 °C for 4 days.
b
The complement to 100% is unreacted p-nitrobenzaldehyde.
c
Determined by 1H NMR of crude product. The yield of isolated products is given
L
-proline group (CAT3), we obtained the best results with a conver-
sion of 54%, an anti/syn ratio of 94:6 and ee of anti product of 96%
Table 4, Entry 8). The presence of P-Me group is crucial to separate
in parentheses.
d
Determined by chiral HPLC analysis for anti product.
(
the bulky group P-Ph and P-Prol, while the P-Ph group is necessary
to increase the hydrophobicity of solid surface.
In order to increase the catalytic activity of solid CAT3, we eval-
uate the effect of temperature and concentration of reagents on the
reactivity and selectivity (Table 4, Entries 9–12). In particular,
4, Entry 8). We also studied in aqueous medium the pH effect on
the reactivity and selectivity. Starting from the initial pH value of
1.9 obtained by simply mixing the reactants, a moderate increasing
to pH 3.5 (achieved by adding NaOH 0.2 M) leads to an increase of
reactivity (conv. 71%) with still a good selectivity (ee 91%, Table 5,
Entry 5), while at pH 6.0, a good stereoselectivity was observed but
the reactivity decreased (Table 5, Entry 6).
reducing by half the volume of reaction medium (from 200
lL to
1
00 L per 0.125 mmol of p-nitrobenzaldehyde; Table 4, Entry 9
l
vs. 8), we observed a significantly higher conversion (75%) with a
slight decrease of selectivity (anti/syn = 91:9, ee 93%), while dou-
0
In all cases, the major product of aldol addition had (2S,1 R)
bling the volume of reaction medium (from 200
lL to 400
l
L per
absolute stereochemistry [13e,21b]. Therefore, the enamine inter-
0
.125 mmol of p-nitrobenzaldehyde; Table 4, Entry 10 vs. 8), we
mediate of
L-proline supported zirconium phosphate/phospho-
observed poorer reactivity and selectivity. Lowering the reaction
temperature to 25 °C (Table 4, Entry 11 vs. 8) the reactivity de-
creased but the selectivity was higher (ee 97%). The best result
nates favored a re-facial attack on the arylaldehyde in agreement
with the homogeneous
[13b,13e].
L-proline-catalyzed aldol reactions
was obtained at 25 °C with 100
l
L of DMF/H
2
O 9:1 per 0.125 mmol
Ultimately, we have compared the reactivity and selectivity of
heterogeneous catalyst CAT3 with that of the corresponding homo-
geneous catalysts (Table 6). We obtained surprising and interesting
of p-nitrobenzaldehyde (Table 4, Entry 12) where a good conver-
sion was still observed (70%) and a high stereoselectivity was
achieved (anti/syn 93:7; ee 96%).
2
results. In DMF/H O 9:1, the heterogeneous catalyst CAT3 gave
In order to realize more eco-friendly processes, the catalytic
activity of solid CAT3 was also investigated in aqueous medium
similar results to that of homogeneous (4R)-4-(phosphonooxy)-
L
-proline (Table 6, Entry 4 vs. Entry 3) while the homogeneous
-proline and trans-4-hydroxy- -proline gave higher reactivity but
(Table 5). Under solvent-free conditions, at 30 °C, we observed a
L
L
low reactivity and selectivity (Table 5, Entry 1), while in sole water,
we obtained good results (Table 5, Entries 2–4) comparable with
that obtained in DMF/H O 9:1 at 30 °C (Table 5, Entry 4 vs. Table
2
lower selectivity (Table 6, Entries 1 and 2). In water, the homoge-
neous catalyst (4R)-4-(phosphonooxy)- -proline gave only traces
of products (Table 6, Entry 7) while the heterogeneous catalyst
L

S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
117
Table 6
The reactivity and selectivity of homogeneous catalysts and heterogeneous catalyst CAT3.
Entrya
1
Catalyst
-Proline
Medium
Conv.b,c (%)
99
anti/sync
eed (%)
L
DMF/H
2
O (9:1)
66/34
79
2
3
4
trans-4-Hydroxy-
(4R)-4-(Phosphonooxy)-L-proline
CAT3
L
-Proline
DMF/H
DMF/H
DMF/H
2
O (9:1)
2
O (9:1)
2
O (9:1)
98
62
54
91/9
93/7
94/6
85
96
96
5
L-Proline
H
2
O
24
91/9
94
6
7
8
trans-4-Hydroxy-
(4R)-4-(Phosphonooxy)-L-proline
CAT3
L
-proline
H
H
H
2
O
2
O
2
O
12
<2
51
75/25
–
89/11
84
–
93
a
Reaction conditions: p-nitrobenzaldehyde 0.125 mmol, cyclohexanone 5 equiv., medium: DMF/H
for 4 days.
2
O (9:1) 200
lL or H
2
O 150
l
L, catalyst 30 mol% in P-Prol groups, at 30 °C
b
The complement to 100% is unreacted p-nitrobenzaldehyde.
c
Determined by 1H NMR of crude product.
d
Determined by chiral HPLC analysis for anti product.
Table 7
Recycling of solid catalyst CAT3 in DMF/H
2
O 9:1 and in aqueous medium.
Entrya
Medium
Run
Conv.b (%)
anti/sync
eed (%)
% of hydrolyzed P-Prol groupe
1
2
3
4
5
DMF/H
DMF/H
DMF/H
2
2
2
O (9:1)
O (9:1)
O (9:1)
Cycle 1
Cycle 2
Cycle 3
Cycle 1
Cycle 2
75
64
51
71
77
91/9
93
72
49
91
62
7
19
30
5
61/39
46/54
85/15
55/45
H
H
2
O (pH = 3.5)
O (pH = 3.5)
2
25
a
Reaction conditions: p-nitrobenzaldehyde 0.5 mmol, cyclohexanone 5 equiv., medium: DMF/H
2
O (9:1) 400
l
2
L or H O (pH = 3.5) 600 lL, catalyst CAT3 (30 mol% in P-Prol
groups), at 30 °C, 4 days.
b
The complement to 100% is unreacted p-nitrobenzaldehyde.
c
Determined by 1H NMR of crude product.
d
Determined by chiral HPLC analysis for anti product.
e
31
Determined by P NMR analysis of recovered solid catalyst.
CAT3 induced higher reactivity than that of
L
-proline (51% vs. 24%)
4. Conclusion
with comparable stereoselectivity (Table 6, Entry 8 vs. Entry 5).
When a solid catalyst is used, its reusability is an important is-
sue [21g]. The recycling of catalyst CAT3, used in the reaction in
The results presented in this paper are encouraging and pave
the way toward the development of new supports for chiral heter-
DMF/H
2
O 9:1 and in aqueous medium at pH 3.5, has been investi-
ogeneous catalysts. Several L-proline functionalized zirconium
gated (Table 7). At the end of reaction, the solid catalyst CAT3 was
recovered after removing of the reaction products by extraction
with ethyl acetate followed by centrifugation. The solid was
washed with water and dried at 80 °C for 15 h and reused. After
phosphates/phosphonates have been prepared, and their catalytic
activity was tested in the asymmetric aldol addition of p-nitro-
benzaldehyde to cyclohexanone.
The catalyst CAT3 where both P-Me and P-Ph group are present
together with the L-proline group was the best catalyst. The pres-
the first cycle in DMF/H
2
O 9:1 (Table 7, Entry 1), the 31P NMR anal-
ysis of recovered catalyst evidenced the presence of the P-OH
group on the catalyst surface of solid (7%), which was obtained
by hydrolysis of P-Prol group. The decrease of stereoselectivity in
the second cycle was therefore expected (ee 72% vs. 92%) (Table
ence of P-Me group is crucial to separate the bulky group P-Ph
and P-Prol, while the P-Ph group is necessary to increase the
hydrophobicity of solid surface.
This system was thought to mime the behavior of enzymes,
which catalyze reactions in soft conditions, especially in water,
using hydrophobic tasks. In fact, we obtained good results in both
7, Entry 2) because the P-OH group catalyzes the reaction via the
formation of an achiral enol. At the end of second cycle, the per-
centage of hydrolyzed P-Prol group increases to 17% and in the
third cycle, the selectivity decreases further (Table 7, Entry 3, ee
DMF/H O 9:1 (conv. 70%, ee 96%) and water (conv. 71%, ee 91%).
2
Also, it was found that in water, the heterogeneous catalyst CAT3
4
9%). The result of the catalyst recovery and reuse was also unsat-
was a better catalytic system than the analogous homogeneous
one.
However, the recover and the recycling of CAT3 were unsatis-
factory because of the hydrolysis of phosphate ester bond that
isfactory in the case of the reaction performed in water (Table 7,
Entries 4 and 5). To confirm our hypothesis, we performed the
aldol addition in the presence of 30 mol% in P-OH groups of
Zr(PO
work [8d]. The solid acid catalyzed the non-stereoselective aldol
addition both in DMF/H O 9:1, where we observe a 32% of conver-
sion with a 43:57 anti/syn ratio, and in sole water with a conver-
sion of 60% and a 39:64 anti/syn ratio.
3
OH)0.37(PO
3
Me)0.65(PO
3
Ph)0.98 prepared by us in a previous
links the
L-proline group to the inorganic layer. Further efforts
are currently directed to improve this aspect, and efficient and
recyclable catalyst will be prepared in order to have
phonates more stable than phosphates.
2
L-proline phos-
The L-proline group is linked to inorganic layer by a phosphate
ester bond; it is acid sensitive and easily hydrolyzable under the
reaction conditions and this not permit the recycling of solid cata-
Acknowledgments
lyst. The substitution of phosphate
stable phosphonate -proline group should lead to a recoverable
and recyclable catalysts.
L
-proline group with a more
We gratefully acknowledge the Ministero dell’Istruzione,
dell’Università e della Ricerca (MIUR) within the financing pro-
grams PRIN 2008 and ‘‘Firb-Futuro in Ricerca’’ and the Università
L

1
18
S. Calogero et al. / Journal of Catalysis 282 (2011) 112–119
degli Studi di Perugia for financial support. Dr. Fabio Marmottini
and Dr. Morena Nocchetti are thanked for TG DTA, ICP-OES and
B.E.T. surface area analysis.
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