Synthesis of Zirconium Phosphonate Supported L -Proline as an Effective Organocatalyst for Direct Asymmetric Aldol Addition

Article abstract of DOI:10.1002/ejoc.201301673

Stable L-proline-functionalized zirconium methyl- and/or phenylphosphonates have been prepared as amorphous solids by the precipitation of (4R)-4-[(4′-phosphonobenzyl)oxy]-L-proline and methyl- and/or phenylphosphonic acid with ZrOCl₂. The supp

Full text of DOI:10.1002/ejoc.201301673

FULL PAPER
DOI: 10.1002/ejoc.201301673
Synthesis of Zirconium Phosphonate Supported -Proline as an Effective
L
Organocatalyst for Direct Asymmetric Aldol Addition
Marco Angeloni,[a] Oriana Piermatti,*[a] Ferdinando Pizzo,[a] and Luigi Vaccaro[a]
Keywords: Heterogeneous catalysis / Supported catalysts / Organocatalysis / Aldol reactions / Zirconium phosphonates
Stable
L
-proline-functionalized zirconium methyl- and/or
(up to 99%ee) have been achieved. Moreover, an easy proto-
col for the efficient recovery of the catalytic system by simple
centrifugation has been defined, and the effective reuse of
the catalyst has been reported in the representative aldol ad-
dition of cyclohexanone with p-nitrobenzaldehyde. This
phenylphosphonates have been prepared as amorphous sol-
ids by the precipitation of (4R)-4-[(4Ј-phosphonobenzyl)oxy]-
L
-proline and methyl- and/or phenylphosphonic acid with
ZrOCl2. The supported -proline catalysts were tested in the
direct asymmetric aldol addition between several ketones
and p-substituted benzaldehydes. High yields, diastereo- systems can be used at least six times without loss of activity
L
study has shown that these L-proline immobilized catalytic
selectivities (anti/syn up to 92:8) and enantiomeric excesses
and with reproducible anti/syn and ee values.
usually considered for the immobilization of l-proline and
its derivatives. Alternative strategies involve the simple phy-
sisorption of l-proline on γ-Al2O3 or graphene oxide[15] and
ion-exchange methods. l-Proline has been intercalated into
layered materials such as layered double hydroxides
(LDHs),[16] hydrotalcite clays[17] or layered montmorillon-
ites (MMTs).[18]
Introduction
According to the urgent need for more environmentally
responsible chemistry, heterogeneous organocatalysis is cur-
rently taking a leading role in the development of efficient
and cleaner organic chemistry.[1]
Organic catalysts have attracted the interest of chemists
as they are water- and air-tolerant and give access to mild,
practical and generally simple synthetic methods without
the need for any metal.[2] In this context, l-proline and its
derivatives have been widely used as organic catalysts for a
wide range of enantioselective transformations, in particu-
lar asymmetric aldol,[3] Michael,[4] Mannich,[5] α-amin-
ation,[6] Diels–Alder[7] and Baylis–Hillman[8] reactions.
In recent years, methods for the preparation, use and re-
cycling of immobilized l-proline catalysts have received
considerable attention.[9] Although l-proline is not very ex-
pensive, an improved l-proline immobilization strategy may
be then applied to more expensive organocatalysts for
which the recovery and reuse is of still higher value and
would increase the greenness of the process. Moreover, as
the support plays an important role in determining the ac-
cessibility to the active sites and, therefore, crucially influ-
ences the course of an enantioselective transformation,[1,10]
the immobilization of l-proline gives the possibility to ex-
plore modifications of the properties of the supported cata-
lysts by employing specific characteristics of the supports.
Several types of supports such as organic polymers,[11,12]
mesoporous materials[13] and supported ionic liquids[14] are
Recently, a new class of hybrid organic–inorganic materi-
als prepared from organic linkers and metal nodes have re-
ceived a great deal of attention as they are synthesized un-
der mild conditions and in principle allow the incorporation
and fine-tuning of the desired chemical and physical prop-
erties by a judicious choice of the building blocks.[19]
In addition, the application of inorganic materials as
heterogeneous supports offers a numbers of advantages, for
example, their rigid structure does not allow the aggrega-
tion of active catalysts, they do not swell and they are insol-
uble in organic solvents and water.[20] In addition, inorganic
supports possess better thermal and mechanical stability
under catalytic conditions. Among these, the class of zirco-
nium phosphates and phosphonates represent a valid choice
thanks to their interesting physicochemical properties and
high versatility.[21] The layered inorganic backbone of these
compounds may be considered as a hook onto which or-
ganic groups with different functionalities may be attached
(e.g., acidic, basic, polar or hydrophobic) to allow the con-
trol of both the activity and the selectivity of an organic
process.[21,22] These materials can be easily prepared by a
self-assembly approach, and as they are insoluble in water
and organic solvents, they can be easily recovered and re-
used.[21–23] Only a few papers report the use of zirconium
phosphates or phosphonates as solid supports for the prep-
aration of heterogeneous chiral catalysts.[22a,24] Zirconium
phosphonates containing chiral functionalities such as 1,1Ј-
[a] Laboratory of Green Synthetic Organic Chemistry, CEMIN –
Dipartimento di Chimica, Università di Perugia,
Via Elce di Sotto 8, 06123 Perugia, Italy
E-mail: oriana.piermatti@unipg.it
http://www.unipg.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301673.
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Supported l-Proline as Organocatalyst
bi-2-naphthol (BINOL) or 2,2Ј-bis(diphenylphosphino)- phonates as supports for the immobilization of covalently
1,1Ј-binaphthyl (BINAP) have been prepared as amorphous linked chiral organic catalysts based on the l-proline moie-
materials and efficiently used as heterogeneous catalysts in ty.[22e] Several l-proline-functionalized zirconium phos-
the stereoselective addition of diethylzinc to benzaldehyde, phate methyl- and/or phenylphosphonates have been pre-
aldol condensation and the hydrogenation of aromatic pared, and their catalytic activities were tested in the asym-
ketones and β-keto esters.[24a–24c] Cinchonidine with dif- metric aldol addition of p-nitrobenzaldehyde to cyclohex-
ferent arm lengths has been covalently immobilized onto anone.[22e] High diastereoselectivities (anti/syn up to 94:6)
the backbone of zirconium phosphonate to afford mesopo- and enantiomeric excesses (up to 97%ee) have been ob-
rous materials, which have been used in the stereoselective tained. However, we highlighted a critical issue related to
addition of diethylzinc to aldehydes.[24d] Zirconium phos- the recovery and reuse of the solid catalyst: this was unsatis-
phonates have been used for the preparation of supported factory owing to the hydrolysis of the phosphate ester bond
oxidation catalysts by the immobilization of MnIII porphyr- used to link the l-proline moiety to the inorganic layer.
ins[24e] and chiral salen MnIII complexes.[24f] Organosoluble
In this contribution, we report our investigations aimed
zirconium phosphonate supported palladium and ruth- at the solution of this issue to define an efficient, recovera-
enium catalysts have been prepared and used in Suzuki cou- ble and reusable catalytic system based on the immobiliza-
pling and asymmetric hydrogenation, respectively.[24g–24i]
A
tion of l-proline by a phosphonate link, which is more
chiral borane of layered α-zirconium-N-(m-sulfophenyl)-l- stable than a phosphate one.
valinephosphonate methanephosphonate has been used in
We report the preparation of new solid catalysts based on
l-proline supported on zirconium phosphonates and their
the asymmetric Mukaiyama aldol reaction.[22a]
Recently, we have been involved in the development of catalytic performances in the aldol addition of various
solid catalysts to be used in benign reaction media for ketones to p-substituted benzaldehydes.
chemically and environmentally efficient organic process-
es.[25,26,22b–22e] We reported the preparation and characteri-
Results and Discussion
zation of new amorphous zirconium hydrogen phosphate
alkyl- and arylphosphonates of general formula
Zr(PO3OH)2–(x+y)(PO3R)x(PO3R1)y (with R = R1 = Me,
Ph, Pr or R = Me R1 = Ph).[22d] The presence of hydro-
Catalysts Preparation and Characterization
To obtain new and efficient chiral heterogeneous cata-
phobic groups such as Me, Ph and Pr is associated with lysts and to understand the role of the support on the
a high micro- and mesopore volume and an extraordinary stereoselectivity of the aldol addition, we have prepared
specific surface area (200–380 m2/g). They have been ef- new zirconium phosphonate supported l-proline by direct
ficiently used to promote (conversion up 99%) the direct amorphous precipitation of a suitable phosphonic acid with
aza-Diels–Alder reaction of 2-cyclohexen-1-one with N- ZrClO2 (P/ZrIV = 2.5).
PMP-pCl-benzaldimine (PMP = p-methoxyphenyl) in water
The alkyl phosphonic acid chosen for the preparation of
zirconium phosphonate supported l-proline was (4R)-4-
without any additive.[22d]
On the basis of these excellent results, we have further [(4Ј-phosphonobenzyl)oxy]-l-proline (6), which was synthe-
investigated the use of zirconium phosphates and phos- sized from trans-N-Boc-4-hydroxy-l-proline (1, Boc = tert-
Scheme 1. Synthesis of (4R)-4-[(4Ј-phosphonobenzyl)oxy]-l-proline 6.
Eur. J. Org. Chem. 2014, 1716–1726
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Angeloni, O. Piermatti, F. Pizzo, L. Vaccaro
FULL PAPER
butyloxycarbonyl; Scheme 1). The sodium salt of 1, pre-
pared by reaction with 2 equiv. of NaH in a mixture of
tetrahydrofuran/N,N-dimethylformamide (THF/DMF 4:1),
was treated with 4-bromobenzyl chloride at room temp. for
20 h to afford (4R)-4-[(4Ј-bromobenzyl)oxy]-N-Boc-l-
proline (2). The esterification of the carboxylic acid group
with CH2N2 gave the corresponding methyl ester derivative
3, which was reacted with diethyl phosphite in toluene at
110 °C for 20 h in the presence of tetrakis(triphenyl-
phosphine)palladium(0) and triethylamine. The diethoxy-
phosphoryl and ethoxy(hydroxy)phosphoryl derivatives 4a
and 4b, obtained in an 80:20 ratio, were hydrolyzed by treat-
ment with trimethylsilyl bromide followed by MeOH to give
(4R)-4-[(4Ј-phosphonobenzyl)oxy]-l-proline methyl ester
(5), which was treated with aqueous 3 m HCl to yield the
desired (4R)-4-[(4Ј-phosphonobenzyl)oxy]-l-proline (6) in
ca. 62% overall yield from 1.
Four different zirconium methyl- and/or phenylphos-
phonates functionalized with (4R)-4-[4Ј-(phosphonatobenz-
yl)oxy]-l-proline (PB-Prol) groups have been prepared from
6 and methylphosphonic acid (1:1; ZrPB-Pro 1) or 6, meth-
ylphosphonic acid and phenylphosphonic acid (1:1:1,
0.5:1:1 and 0.35:1:1 to yield ZrPB-Pro 2, ZrPB-Pro 3 and
ZrPB-Pro 4, respectively).
Figure 1. Schematic arrangement of phosphonate groups on the
layer of l-proline-functionalized zirconium phosphonates.
The obtained solids ZrPB-Pro 1– ZrPB-Pro 4 have been
1
characterized by H, 13C and 31P NMR spectroscopy, ther- and 1200 °C correspond to the loss of 33.9% of the initial
mogravimetric/differential thermal analysis (TG-DTA), in- weight owing to the oxidation of the organic groups. At
ductively coupled plasma optical emission spectroscopy 1200 °C, the formation of cubic ZrP2O7 is considered, as
(ICP-OES) and nitrogen adsorption–desorption at 77 K.
shown by the X-ray powder diffraction (XRPD) spectrum
The molar ratio of phosphonic acids used during the of a sample heated at 1200 °C (data not shown). These data
preparation, molar ratio between the PB-Prol and methyl/ together with the PB-Prol/P–Ph/P–Me molar ratio
phenylphosphonate groups (P–R, R = Me and/or Ph) in the (1:2.7:2.8) allow the determination of the molecular for-
solid, molecular formulas, molecular weights, Zr/P molar mula of solid ZrPB-Pro 4 (Table 1).
ratio and the calculated Brunauer–Emmett–Teller (BET)
The chemical compositions of the solids are in good
surface area are reported in Table 1. Figure 1 shows the agreement with those obtained by P and Zr analyses per-
schematic arrangement of phosphonate groups on the layer formed by ICP and C, H, N elemental analyses (Table 2).
of l-proline-functionalized zirconium methyl- and/or phen-
ylphosphonates.
As observed in our previous work,[22d] the surface prop-
erties of the prepared solids are highly dependent on both
The molecular formulas were obtained from thermograv- the nature and the percentage of the alkyl phosphonic acids
imetric (TG) and differential thermal analysis (DTA) used during the amorphous precipitation. The solids ZrPB-
curves, and the PB-Prol/P–R molar ratios were determined Pro 1 – ZrPB-Pro 3, which have a high percentage of PB-
by 31P NMR analysis. As a representative example, the TG- Prol groups, have low specific surface areas (BET surface
DTA curves of catalyst ZrPB-Pro 4 is shown in Figure 2. area 2–5 m2/g) and are not micro- or mesoporous (Vmicro
Thermal decomposition occurs in four steps: the first, be- and Vmeso Ͻ 0.01 cm3/g). The solid ZrPB-Pro 4, which has
tween 50 and 180 °C, corresponds to the loss of 5.1% of a very low percentage of PB-Prol groups, has a higher spe-
the initial weight and is attributed to loss of the water of cific surface area (BET surface area 68 m2/g), it is not
crystallization. The second between 180 and 350 °C, the microporous (Vmicro Ͻ 0.01 cm3/g) but it is mesoporous
third between 350 and 900 °C and the fourth between 900 (Vmeso = 0.05 cm3/g; Table 1).
Table 1. Chemical and surface properties of ZrPB-Pro 1– ZrPB-Pro 4.
Solid
R
PB-Prol/P– R PB-Prol/P– R
solution molar solid molar
Molecular formula
P/Zr
molar
ratio
MW [u] BET sur-
face area
ratio
ratio
[m2/g]
ZrPB-Pro 1
ZrPB-Pro 2
ZrPB-Pro 3
ZrPB-Pro 4
Me
1:1
1:1.3
Zr(PO3–C6H4–CH2O–C5H8O2N)0.91(PO3Me)1.21·1.7H2O
2.12
2.17
2.14
2.10
507.6
450.4
527.9
429.7
2[a]
5[a]
Ph, Me 0.5:1:1
Ph, Me 1:1:1
Ph, Me 0.35:1:1
1:2.3:2.1
1:1:0.8
1:2.7:2.8
Zr(PO3–C6H4–CH2O–C5H8O2N)0.40(PO3Ph)0.92(PO3Me)0.85·0.9H2O
Zr(PO3–C6H4–CH2O–C5H8O2N)0.79(PO3Ph)0.78(PO3Me)0.57·1.4H2O
Zr(PO3–C6H4–CH2O–C5H8O2N)0.32(PO3Ph)0.87(PO3Me)0.91·1.2H2O
2[a]
68[b]
[a] Vmicro and Vmeso Ͻ0.01 cm3/g. [b] Vmicro Ͻ0.01 cm3/g and Vmeso = 0.05 cm3/g.
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Supported l-Proline as Organocatalyst
bond-formation.[27] l-Proline-mediated aldol additions are
typically performed in organic solvents such as dimethyl
sulfoxide (DMSO), DMF or chloroform, and although the
addition of a small amount of water often accelerates the
reactions and/or improves enantioselectivities, the addition
of a large amount of water as reaction solvent has typically
resulted in low yields with low or no enantioselectivity.[3e,28]
Recently, several papers have described the role of water
from substoichiometric amounts to a large excess in pro-
line-mediated aldol reactions.[29]
In our previous work,[22e] three different l-proline-func-
tionalized zirconium phosphate methyl- and/or phenylphos-
phonates CAT1–CAT3 were prepared from (4R)-4-(phos-
phonooxy)-l-proline (P-Prol), methylphosphonic acid and/
or phenylphosphonic acid, and their catalytic activities were
tested for the asymmetric aldol addition of cyclohexanone
to p-nitrobenzaldehyde in DMF/H2O (9:1) in the presence
of 30 mol-% of P-Prol groups (Scheme 2). When the P–Me
group was present as spacer for the bulky P-Prol groups
(CAT1: P-Prol/P–Me = 1:1.2), we observed a low conver-
sion but good diastereoselectivity and enantioselectivity
(Scheme 2). The presence of P–Ph groups as spacer (CAT2:
P-Prol/P–Ph = 1:1.2) increased the hydrophobicity of the
solid surface but made the system very rigid; we observed
an increase of conversion, but the selectivity decreased in
comparison to that of CAT1 (Scheme 2). When both P–Me
and P–Ph groups were present together with the l-proline
group (CAT3: P-Prol/P–Ph/P–Me = 1:1.5:1.1), we obtained
the best results with a conversion of 54%, an anti/syn ratio
of 94:6 and 96%ee of the anti product (Scheme 2). The
presence of P–Me groups is crucial to separate the bulky P–
Ph and P-Prol groups, whereas the P–Ph group is necessary
to increase the hydrophobicity of the solid surface.
Figure 2. Thermogravimetric (TG) and differential analysis (DTA)
curves of ZrPB-Pro 4 obtained at a heating rate of 10 °C/min under
air.
Table 2. Elemental analysis of ZrPB-Pro 1, ZrPB-Pro 2, ZrPB-Pro
3, and ZrPB-Pro 4.
% Zr
% P
% C
% H
% N
ZrPB-Pro 1
ZrPB-Pro 2
ZrPB-Pro 3
ZrPB-Pro 4
calcd.
found
calcd.
found
calcd.
found
calcd.
found
17.97
17.71
20.25
19.79
17.25
16.86
21.22
20.85
12.95
12.68
14.93
14.64
12.54
12.33
15.14
14.87
28.67
28.04
29.76
30.73
33.42
33.75
27.84
28.14
3.89
3.62
3.23
3.08
3.70
3.53
3.25
3.39
2.51
2.27
1.43
1.31
2.09
1.94
1.04
1.07
Catalytic Activity
Among the l-proline-mediated organic reactions, the
aldol addition has been deeply investigated as it is one of
However, the recovery and the reuse of CAT3 were unsat-
the most important tools in organic synthesis for C–C isfactory because of the hydrolysis of the phosphate ester
Scheme 2. Aldol addition of cyclohexanone to p-nitrobenzaldehyde catalyzed by the l-proline-functionalized zirconium phosphates
CAT1–CAT3.[22e]
Eur. J. Org. Chem. 2014, 1716–1726
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M. Angeloni, O. Piermatti, F. Pizzo, L. Vaccaro
FULL PAPER
bond used to link the l-proline moiety to the inorganic Table 3. Aldol addition of cyclohexanone to p-nitrobenzaldehyde
catalyzed by the l-proline-functionalized zirconium phosphonates
ZrPB-Pro 1, ZrPB-Pro 2 and ZrPB-Pro 3.
layer.
With the present work, we intend to improve this aspect,
and efficient and recyclable catalysts will be prepared with
l-proline phosphonates, which are more stable than phos-
phates. The use of 6 as a building block allows the prepara-
tion of l-proline-functionalized zirconium phosphonates
with both high chemical stability, which allows a high re-
cyclability, and high catalytic activity.
Entry[a] Catalyst
T [°C] t [d] Conv. [%][b,c] anti/syn[c] ee [%][d]
1[e]
2
ZrPB-Pro 1[f]
30
30
30
30
25
30
30
30
30
4
4
4
4
4
4
2
2
2
66
96
68
95 (90)
65
96 (92)
37
92:8
92:8
92:8
92:8
92:8
90:10
91:9
91:9
81:19
91
92
91
92
94
92
92
93
90
The aldol addition of cyclohexanone to p-nitrobenzalde-
hyde to give anti and syn diastereomers of 2-[hydroxy(p-
nitrophenyl)methyl]cyclohexanone was chosen as the test
reaction to evaluate the catalytic activity of the solids
ZrPB-Pro 1 – ZrPB-Pro 4.
We started the study with ZrPB-Pro 1, which has a
methyl group spacer between the bulky phosphonatobenz-
yloxy-l-proline groups (Table 3). The aldol addition was
performed under the best conditions for CAT1–CAT3
ZrPB-Pro 1[f]
ZrPB-Pro 1
ZrPB-Pro 1
ZrPB-Pro 1
ZrPB-Pro 2
ZrPB-Pro 1
ZrPB-Pro 2
ZrPB-Pro 3
3[e]
4
5
6
7
8
75 (73)
45
9
[a] Reaction conditions: p-nitrobenzaldehyde (0.125 mmol), cyclo-
hexanone (5 equiv.), DMF/H2O (9:1, 100 μL), catalyst 20 mol-%
(DMF/H2O 9:1, 200 μL per 0.125 mmol of p-nitrobenzalde- in PB-Prol groups. [b] The complement to 100% is unreacted p-
nitrobenzaldehyde. [c] Determined by 1H NMR spectroscopy of the
hyde; catalyst 30 mol-% in PB-Prol groups for 4 d). We ob-
crude product. The yield of isolated products is given in parenthe-
served a significant increase of catalytic activity (66% con-
ses. [d] Determined by chiral HPLC analysis for the anti product.
version) relative to those of CAT1–CAT3 (16–54% conver-
[e] Medium 200 μL. [f] Catalyst 30 mol-% in PB-Prol groups.
sion, Scheme 2), and the high diastereoselectivity and
enantioselectivity was maintained (Table 3, Entry 1). We re-
duced the volume of the reaction medium by half (from 200
Solvents make a large contribution to the environmental
impact of manufacturing processes and also play an impor-
to 100 μL per 0.125 mmol of p-nitrobenzaldehyde; Table 3,
Entry 2) and observed a significantly higher conversion
tant role in the catalytic activity of heterogeneous cata-
(96%). When the percentage of solid catalyst was reduced
lysts.[30] Therefore, the reaction conditions were further op-
timized by evaluating the catalytic activity of solid ZrPB-
Pro 2 in different reaction media (Table 4). As shown in
Table 4, in only water we observed a low conversion and
from 30 to 20 mol-% in PB-Prol groups, we did not observe
any change in the catalytic activity (Table 3, Entries 3 and
4 vs. 1 and 2). The presence of the benzyloxy spacer be-
tween the inorganic layer and the l-proline moiety increases
both the hydrophobicity of the catalyst surface and the con-
formational freedom of the l-proline groups, which leads to
an increase in the catalytic activity of the new solid catalysts
stereoselectivity (Table 4, Entry 9), but the presence of
water as cosolvent is essential to obtain a high catalytic ac-
tivity.[28,29] The best result was obtained with DMSO/H2O
(9:1) as the reaction medium, and a conversion of 86%, a
92:8 anti/syn ratio and 94%ee of the major anti product
were obtained (Table 4, Entry 8).
relative to those prepared in our previous work.[22e]
At a lower reaction temperature of 25 °C (Table 3, En-
try 5 vs. 4), a comparable stereoselectivity was observed
(anti/syn 92:8; 94%ee), but the conversion decreased (65%).
As already observed in our previous work,[22e] we sup-
posed that the insertion of more hydrophobic groups on the
surface of l-proline-functionalized zirconium phosphonate
should lead to increased catalytic activity.
To this aim, the catalyst ZrPB-Pro 2 (PB-Prol/P–Ph/P–
Me = 1:2.3:2.1) was prepared and tested under the best con-
ditions for ZrPB-Pro 1 (Table 3, Entry 6 vs. 4). A high con-
version (96%) and good stereoselectivity were also observed
in this case (anti/syn 90:10; 92%ee). To compare the activity
of the two catalysts, the reaction time was reduced to 2 d
(Table 3, Entries 7 and 8). In presence of ZrPB-Pro 1, we
observed a conversion of only 37%, whereas in the presence
of ZrPB-Pro 2, as expected, the conversion was higher
(75%).
To study the effect of the PB-Prol loading on the catalytic
activity, ZrPB-Pro 3 (PB-Prol/P–Ph/P–Me = 1:1:0.8) was
prepared. An increased loading led to a decrease of the
BET specific surface area (Table 1) and consequently, simi-
larly to ZrPB-Pro 1, to a lower activity (Table 3, Entry 9).
Table 4. Effect of the reaction medium on the aldol addition of
cyclohexanone to p-nitrobenzaldehyde catalyzed by ZrPB-Pro 2.
Entry[a] Medium
Conv.
[%][b,c]
anti/syn[c] ee
[%][d]
1
2
3
4
5
6
7
8
9
DMF/H2O (9:1)
75 (73) 91:9
93
tert-amyl methyl ether
tert-amyl methyl ether/H2O (9:1)
cyclopentyl methyl ether
12
76
20
67:33
77:23
61:39
70:30
75:25
88:12
–
90
–
86
90
94
94
85
cyclopentyl methyl ether/H2O (9:1) 73
2-methylTHF/H2O (9:1)
ethylene carbonate/H2O (9:1)
DMSO/H2O (9:1)
H2O
73
42
86 (84) 92:8
38 82:18
[a] Reaction conditions: p-nitrobenzaldehyde (0.125 mmol), cyclo-
hexanone (5 equiv.), medium (100 μL), ZrPB-Pro 2 (20 mol-% in
PB-Prol groups), 30 °C, 2 d. [b] The complement to 100% is unre-
acted p-nitrobenzaldehyde. [c] Determined by 1H NMR spec-
troscopy of the crude product. The yield of isolated products is
given in parentheses. [d] Determined by chiral HPLC analysis for
the anti product.
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Supported l-Proline as Organocatalyst
Table 5. Aldol addition of cyclohexanone to p-nitrobenzaldehyde catalyzed by the l-proline-functionalized zirconium phosphonates ZrPB-
Pro 4 and ZrPB-Pro 2.
Entry[a]
Catalyst
Medium
t [d]
Conv. [%][b,c]
anti/syn[c]
ee [%][d]
1
2
3
4
5
6
7
ZrPB-Pro 2
ZrPB-Pro 2
ZrPB-Pro 4
ZrPB-Pro 4
ZrPB-Pro 4
ZrPB-Pro 4[e]
ZrPB-Pro 4[e]
DMF/H2O (9:1)
DMSO/H2O (9:1)
DMF/H2O (9:1)
DMSO/H2O (9:1)
DMSO/H2O (9:1)
DMSO/H2O (9:1)
DMSO/H2O (9:1)
2
2
2
2
1
1
2
75
86 (84)
97
99 (93)
94 (88)
70
91:9
92:8
75:25
88:12
91:9
90:10
91:9
93
94
91
95
96
94
94
92
[a] Reaction conditions: p-nitrobenzaldehyde (0.125 mmol), cyclohexanone (5 equiv.), medium 100 μL, catalyst (20 mol-% in PB-Prol
1
groups), 30 °C. [b] The complement to 100% is unreacted p-nitrobenzaldehyde. [c] Determined by H NMR spectroscopy of the crude
product. The yield of isolated products is given in parentheses. [d] Determined by chiral HPLC analysis for the anti product. [e] Catalyst
10 mol-%.
To obtain more efficient solid catalysts, we prepared Table 6. Recycling of solid catalyst ZrPB-Pro 4 in DMSO/H2O
(9:1).
ZrPB-Pro 4 (PB-Prol/P–Ph/P–Me = 1:2.8:2.9), an l-pro-
Run[a]
Conv. [%][b] anti/syn[c] ee [%][d] Recovered catalyst [%][e]
line-functionalized zirconium phosphonate with a lower
loading of PB-Prol groups. The nitrogen adsorption–de-
sorption isotherm of solid ZrPB-Pro 4 at 77 K showed that
Cycle 1
Cycle 2
94
92
88
91
90
88
91:9
92:8
91:9
90:10
90:10
90:10
96
96
96
96
96
96
92
93
92
94
92
92
the solid is mesoporous (Vmeso = 0.05 m3/g) and has a high Cycle 3
BET surface area (68 m2/g). We tested the catalytic activity
Cycle 4
Cycle 5
of ZrPB-Pro 4 in the aldol addition of cyclohexanone to p-
Cycle 6
nitrobenzaldehyde and observed a considerable increase of
[a] First cycle: p-nitrobenzaldehyde (0.625 mmol), cyclohexanone
(5 equiv.), DMSO/H2O (9:1; 500 μL), ZrPB-Pro 4 (20 mol-% in
PB-Prol groups), 30 °C, 1 d. Successive cycles: the amount of rea-
gents and medium were calculated on the basis of the amount of
recovered catalyst. [b] The complement to 100% is unreacted p-
nitrobenzaldehyde. [c] Determined by 1H NMR spectroscopy of the
crude product. [d] Determined by chiral HPLC analysis for the anti
product. [e] 31P NMR spectroscopy of the recovered catalyst shows
that the solid composition is unchanged.
conversion (97–99%) with high selectivity maintained
(Table 5, Entries 1–4). The increased catalytic activity has
been related to the high specific surface area of the mesopo-
rous solid ZrPB-Pro 4. We reduced the reaction time by
half and still obtained a high conversion (94%) with a 91:9
anti/syn ratio and a 96%ee of the anti product (Table 5,
Entry 5). We observe a significant decrease of conversion
(Table 5, Entries 6 and 7) when the percentage of PB-Prol
groups in the solid catalyst was decreased to 10 mol-%.
When an immobilized catalyst is used, its reusability is conversions for electron-withdrawing p-substituted benzal-
an important issue.[12g] The recycling of catalyst ZrPB-Pro dehydes were very good (Table 7, Entries 1–4), moderate or
4 in DMSO/H2O (9:1) has been investigated (Table 6). At low conversions were observed for the less reactive benzal-
the end of reaction, the solid catalyst ZrPB-Pro 4 was reco- dehyde and p-tolualdehyde, respectively (Table 7, Entries 5–
vered after removal of the reaction products by extraction 7). Good-to-excellent enantioselectivities were observed in
with ethyl acetate followed by centrifugation. The solid was all cases (89–99%ee).
dried at 80 °C for 2 h and reused. The solid catalyst was
Finally, we examined the reactions between different
used six times without loss of activity and each cycle gave ketones with p-nitrobenzaldehyde (Table 7, Entries 8–13).
reproducible anti/syn and ee values (Table 6). The 31P NMR Cyclopentanone gave excellent conversions with a low
analysis of the recovered catalyst showed no structural anti/syn ratio, comparable to those observed with unsup-
changes to the composition of the solid. This study showed ported l-proline,[3b,3e] but with a very high enantiomeric ex-
that the substitution of a phosphate-l-proline group (P- cess of the anti product (99%ee; Table 7, Entry 8).
Prol, CAT1–CAT3, Scheme 2) with a more stable phospho-
The reaction of acetone in DMSO/H2O (9:1) provided
natobenzyloxy-l-proline group (PB-Prol, ZrPB-Pro 1– moderate conversion with low enantioselectivity (62%ee;
ZrPB-Pro 4, Figure 1) led to recoverable and recyclable cat- Table 7, Entry 9), comparable with those observed pre-
alysts.
viously.[3b,3e,12c] When the reaction was performed in acet-
As a further development of the work, a representative one/H2O (9:1), only traces of product were observed
set of p-substituted benzaldehydes were examined with (Table 7, Entry 10). Hydroxyacetone gave anti/syn dia-
DMSO/H2O (9:1) as the reaction medium in the presence stereomers in high yield, and we did not observe the forma-
of 20 mol-% of solid ZrPB-Pro 4 (Table 7, Entries 1–7). The tion of any iso-regioisomeric compound (Table 7, En-
reaction times ranged between 1 and 5 d and, although the try 11).[31] The diastereoselectivity (anti/syn 62:38) and the
Eur. J. Org. Chem. 2014, 1716–1726
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1721

M. Angeloni, O. Piermatti, F. Pizzo, L. Vaccaro
FULL PAPER
Table 7. Aldol addition of various ketones to p-substituted benzal- ferent methodologies are known to improve the mesopore
dehydes catalyzed by l-proline-functionalized zirconium phos-
phonate ZrPB-Pro 4.
volume and BET specific surface area, including hydrother-
mal and surfactant-assisted methods,[32] it should be pos-
sible to further increase the catalytic activity of zirconium
phosphonate supported l-proline.
Conclusions
Several l-proline-functionalized zirconium phosphonates
have been prepared by simple amorphous precipitation of
(4R)-4-[(4Ј-phosphonobenzyl)oxy]-l-proline and methyl-
and/or phenylphosphonic acid with ZrOCl2, and their cata-
lytic activity has been tested in the asymmetric aldol ad-
dition between several ketones and p-substituted benzalde-
hydes. High yields, diastereoselectivities (anti/syn up to
92:8) and enantiomeric excesses (up to 99%ee) have been
obtained.
The presence of a benzyloxy spacer between the inor-
ganic layer and the l-proline moiety together with the pres-
ence of P–Ph and P–Me groups increases both the hydro-
phobicity of the solid catalyst surface and the conforma-
tional freedom of the reactive intermediate, which leads to
an increase in the catalytic activity of the new l-proline-
immobilized catalysts.
The solid ZrPB-Pro 4, which has the lowest loading of
PB-Prol groups, is the best catalyst. The high catalytic effi-
ciency can be related to its surface properties, particularly,
its high mesopore volume and BET surface area.
Moreover, the catalyst ZrPB-Pro 4 has been easily reco-
vered by simple centrifugation and reused in the representa-
tive aldol addition of cyclohexanone to p-nitrobenzalde-
hyde. This study showed that this material is a stable and
highly recyclable solid catalyst that can be used at least six
times without loss of activity and with reproducible anti/syn
and ee values.
The use of zirconium phosphonates as supports for the
immobilization of ligands represents a valid tool for the
preparation of heterogeneous catalysts.
[a] Reaction conditions: p-substituted benzaldehyde (0.125 mmol),
ketone (5 equiv.), DMSO/H2O (9:1; 100 μL), catalyst 20 mol-% in
Experimental Section
PB-Prol groups. [b] The complement to 100% is unreacted p-substi-
tuted benzaldehyde. [c] Determined by 1H NMR spectroscopy of
the crude product. The isolated product yields are given in paren-
theses. [d] Determined by chiral HPLC analysis for the anti prod-
uct. [e] Medium: acetone (100 μL).
General Remarks: All chemicals were purchased and used without
any further purification. 1H, 13C and 31P spectra were recorded
with Bruker AMX-400 and Bruker AC-200 instruments. The
liquid-state NMR analyses of solid catalysts were performed by
dissolving 30 mg of solid in a small volume of HF (ca. 0.05 mL)
with D2O as solvent (ca. 0.6 mL). TG and DTA analyses were per-
formed with an STA 449 C Jupiter thermal analyzer. P and Zr
elemental analyses were performed with inductively coupled
plasma optical emission spectrometers (ICP-OES). C, H, N ele-
mentary analyses were performed with an EA1108 CHN analyzer
(Fison Instruments). Nitrogen adsorption–desorption isotherms[33]
were determined with a Micromeritics ASAP 2010 instrument at
77 K with samples outgassed overnight at 373 K. The specific sur-
face areas were calculated by the BET method.[34] The micropore
volumes and external surface areas were evaluated by the t-plot
method[35] with nonporous α-ZrP as the reference material.[36] Me-
enantiomeric excess of the anti product (87%ee) are com-
parable with the results obtained with unsupported l-pro-
line.[31b]
As expected, the reactions between butanone and cyclo-
heptanone with p-nitrobenzaldehyde gave no conversion
(Table 7, Entries 12 and 13).[12c]
The surface properties are crucial for the catalytic ac-
tivity of solid catalysts. The catalyst ZrPB-Pro 4, prepared
simply by direct amorphous precipitation, presents relevant
surface properties that allow good catalytic activity. As dif- sopore characterizations were performed by the Barrett–Joyner–
1722
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1716–1726

Supported l-Proline as Organocatalyst
Halenda method.[37] Centrifugation was performed at 12000 rpm
for 15 min. Thin layer chromatography analyses were performed
with silica gel on aluminium plates (silica gel 60 F254, Fluka). Col-
umn chromatography to purify the aldol reaction products was per-
formed by using silica gel 230–400 mesh (silica gel 60, Merck)
eluted with petroleum ether/ethyl acetate (85:15 to 50:50).
(5 mL) was stirred at 110 °C under a slight N2 stream for 20 h. The
final mixture was cooled and concentrated under reduced pressure.
The crude product was purified by column chromatography eluted
with ethyl acetate/chloroform/benzene (5:4:1) to afford 4a (1.75 g,
77% yield) and then with ethyl acetate/MeOH (7:3) to give 4b
(0.38 g, 18% yield). 4a: Viscous oil. [α]D = –22.8 (c = 1.04, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.31 (t, 6 H, 2 CH3CH2O), 1.40,
1.45 (2 s, 9 H, Boc), 2.04–2.13 [m, 1 H, 3-H], 2.32–2.46 [m, 1 H,
3-H], 3.51–3.75 [m, 2 H, 5-H], 3.72, 3.74 (2 s, 3 H, OCH3), 4.00–
4.23 [m, 5 H, 2-H, 2ϫCH3CH2O], 4.33–4.46 [m, 1 H, 4-H], 4.55
(m, 2 H, CH2O), 7.40 (dd, J = 8.0, 3.9 Hz, 2 H, 2Ј-H, 6Ј-H), 7.78
(dd, J = 13.1, 8.0 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 16.2 (d, J = 6.4 Hz, 2 C, CH3CH2O),
28.2, 28.3 [(CH3)3C, Boc], 35.5, 36.6 (C-3), 51.2, 51.8 (C-5), 52.0,
52.2 (OMe), 57.5, 57.9 (C-2), 62.0 (d, J = 5.2 Hz, 2 C, CH3CH2O),
70.3, 70.4 (OCH2), 76.5, 77.2 (C-4), 80.2 [C(CH3)3, Boc], 127.2 (d,
J = 15.3 Hz, C-2Ј, C-6Ј), 127.6 (d, J = 189.1 Hz, C-4Ј), 131.9 (J =
10.2 Hz, d, C-3Ј, C-5Ј), 142.4 (C-1Ј), 153.7, 154.3 (C=O, Boc),
173.2, 173.5 (COOMe) ppm. 31P NMR (161.9 MHz, CDCl3): δ =
18.9 ppm. C22H34NO8P (471.48): calcd. C 56.04, H 7.27, N 2.97;
found C 56.31, H 7.13, N 2.84.
1
The anti/syn ratios were determined by H NMR spectroscopy of
the crude product in CDCl3; the enantiomeric excesses were deter-
mined by chiral HPLC analysis with CHIRALPACK AD-H; eluted
with n-hexane/2-propanol, flow rate 0.5 mL/min, UV detector. The
aldol reaction products are known compounds and showed spec-
troscopic and analytical data in agreement with their structures.
Product configurations were assigned by comparison with literature
data.[3,12c]
(4R)-4-[(4Ј-Bromobenzyl)oxy]-N-Boc-L-proline (2): A solution of
trans-N-Boc-4-hydroxy-l-proline (1) (2.0 g, 8.65 mmol) in anhy-
drous THF (30 mL) was added dropwise under N2 at room temp.
to a suspension of NaH (60% mineral oil, 0.88 g, 22 mmol, washed
with petroleum ether) in an anhydrous solution of THF/DMF (4:1,
25 mL). After 30 min, 4-bromobenzyl chloride (4.1 g, 20 mmol)
was added, and the mixture was stirred at room temp. for 20 h.
Water was added (40 mL), and the mixture was extracted with di-
ethyl ether (3ϫ 40 mL) to remove the unreacted 4-bromobenzyl
chloride. The aqueous phase was acidified at pH 2 by adding a 2m
solution of KHSO4 and then extracted with ethyl acetate (3ϫ
60 mL). The combined organic extracts were dried (Na2SO4) and
concentrated under reduced pressure to afford 2 (2.9 g, 84%).
White solid, m.p. 108–109 °C (hexane/ethyl acetate). [α]D = –37.9
(4R)-4-({4Ј-[Ethoxy(hydroxy)phosphoryl]benzyl}oxy)-N-Boc-L-prol-
1
ine Methyl Ester (4b): Viscous oil. H NMR (200 MHz, D2O): δ =
1.00 (t, 3 H, CH3CH2O), 1.21, 1.25 (2 s, 9 H, Boc), 1.84–2.04 [m,
1 H, 3-H], 2.26–2.44 [m, 1 H, 3-H], 3.35 [m, 1 H, 5-H], 3.52 [m, 1
H, 5-H], 3.59, 3.61 (2 s, 3 H, OCH3), 3.54–3.83 (m, 2 H,
CH3CH2O), 4.13–4.32 [m, 1 H, 4-H], 4.46 (m, 2 H, CH2O), 7.28
(dd, J = 7.9, 3.0 Hz, 2 H, 2Ј-H, 6Ј-H), 7.53 (dd, J = 12.2, 7.9 Hz,
2 H, 3Ј-H, 5Ј-H) ppm. 31P NMR (161.9 MHz, D2O): δ = 15.6 ppm.
1
(c = 1.01, MeOH). H NMR (400 MHz, CD3OD): δ = 1.41, 1.43
(4R)-4-[(4Ј-Phosphonobenzyl)oxy]-L-proline (6): A mixture of 4a
(2 s, 9 H, Boc), 2.02–2.11 [m, 1 H, 3-H], 2.38–250 [m, 1 H, 3-H],
3.47–3.65 [m, 2 H, 5-H], 4.20 [m, 1 H, 2-H], 4.23–4.34 [m, 1 H, 4-
H], 4.48 (m, 2 H, CH2O), 7.24 (d, J = 8.4 Hz, 2 H, 2Ј-H, 6Ј-H),
7.47 (d, J = 8.4 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR (100.6 MHz,
CD3OD): δ = 28.5, 28.7 [(CH3)3C, Boc], 36.7, 37.4 (C-3), 52.6, 53.2
(C-5), 58.9, 59.4 (C-2), 71.1, 71.2 (OCH2), 77.8, 78.5 (C-4), 81.6,
81.9 [C(CH3)3, Boc], 122.4 (C-4Ј), 130.5 (C-2Ј, C-6Ј), 132.5 (C-3Ј,
C-5Ј), 138.7, 138.9 (C-1Ј), 155.9, 156.3 (C=O, Boc), 176.2, 176.6
(COOH) ppm. C17H22BrNO5 (400.26): calcd. C 51.01, H 5.54, N
3.50; found C 51.36, H 5.58, N 3.49.
(1.75g, 3.71 mmol) and 4b (0.38 g, 0.86 mmol) and trimethylsilyl
bromide (2.8 g, 18.3 mmol) in anhydrous CH2Cl2 (25 mL) was
stirred at room temp. for 20 h. Methanol (45 mL) was then added,
and the mixture was stirred at room temperature for an additional
30 min. The solvent was removed under reduced pressure to yield
5.
The crude product 5 (1.42 g) was dissolved in aqueous 3 M HCl
(25 mL), and the solution was heated to reflux for 4 h. The mixture
was cooled, and the water was evaporated under reduced pressure.
The residue was dissolved in water (15 mL), and the solution was
evaporated again; this operation was repeated three times. The final
residue was dissolved in ethanol, and 1,2-epoxypropane was pro-
gressively added until complete precipitation occurred. The super-
natant was removed by decantation, and the solid 6 was washed
with ethanol/water (30:1, 20 mL) and finally dried under reduced
pressure (1.15 g, 84% yield).
(4R)-4-[(4Ј-Bromobenzyl)oxy]-N-Boc-L-proline Methyl Ester (3):
The crude product 2 (2.9 g, 7.25 mmol) was dissolved in diethyl
ether and treated with CH2N2 (freshly distilled) until the complete
esterification of proline carboxylic acid group was achieved. The
ethereal solution was concentrated under reduced pressure, and the
residue was purified by column chromatography eluted with petro-
leum ether/ethyl acetate (70:30) to afford 3 (2.8 g, 93%). White so-
lid, m.p. 60–62 °C. [α]D = –27.6 (c = 1.03, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 1.40, 1.44 (2 s, 9 H, Boc), 1.98–2.09 [m,
1 H, 3-H], 2.36–2.48 [m, 1 H, 3-H], 3.47–3.68 [m, 2 H, 5-H], 3.71,
3.73 (2 s, 3 H, OCH3), 4.19 [m, 1 H, 2-H], 4.27–4.37 [m, 1 H, 4-
H], 4.48 (m, 2 H, CH2O), 7.24 (d, J = 8.3 Hz, 2 H, 2Ј-H, 6Ј-H),
7.47 (d, J = 8,3 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR (100.6 MHz,
CD3OD): δ = 28.5, 28.7 [(CH3)3C, Boc], 36.6, 37.4 (C-3), 52.7, 53.2
(C-5), 52.7 (OMe), 59.0, 59.4 (C-2), 71.1, 71.2 (OCH2), 77.7, 78.5
(C-4), 81.7, 81.8 [C(CH3)3, Boc], 122.4 (C-4Ј), 130.5 [C-2Ј, C-6Ј],
132.5 (C-3Ј, C-5Ј), 138.8, 138.9 (C-1Ј), 155.7, 156.2 (C=O, Boc),
174.8, 175.1 (COOMe) ppm. C18H24BrNO5 (414.29): calcd. C
52.18, H 5.84, N 3.38; found C 52.39, H 5.97, N 3.44.
(4R)-4-[(4Ј-Phosphonobenzyl)oxy]-L-proline Methyl Ester (5): White
solid, m.p. 148–150 °C. [α]D = –4.8 (c = 1.05, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 2.23 (ddd, J = 14.0, 10.6, 4.3 Hz, 1 H, 3-
H), 2.68 [br. dd, J = 14.0, 7.4 Hz, 1 H, 3-H], 3.49 [dd, J = 12.6,
3.5 Hz, 1 H, 5-H], 3.58 [br. d, J = 12.6 Hz, 1 H, 5-H], 3.85 (s, 3 H,
OMe), 4.44 [br. s, 1 H, 4-H], 4.60 [dd, J = 10.5, 7.7 Hz, 1 H, 2-H],
4.63 (s, 2 H, CH2O), 7.46 (dd, J = 7.9, 3.6 Hz, 2 H, 2Ј-H, 6Ј-H),
7.78 (dd, J = 12.8, 7.9 Hz, 2 H, 5Ј-H, 3Ј-H) ppm. 13C NMR
(100.6 MHz, CD3OD): δ = 35.6 (C-3), 52.4 (C-5), 54.0 (OMe), 59.4
(C-2), 71.5 (CH2O), 78.4 (C-4), 128.4 (d, J = 14.9 Hz, C-2Ј, C-6Ј),
132.0 (d, J = 9.8 Hz, C-3Ј, C-5Ј), 133.6 (d, J = 186.8 Hz, C-4Ј),
142.4 (C-1Ј), 170.2 (COOMe) ppm. 31P NMR (161.9 MHz,
CDCl3): δ = 15.2 ppm. C13H18NO6P (315.26): calcd. C 49.53, H
5.75, N 4.44; found C 49.27, H 5.61, N 4.63.
(4R)-4-{[4Ј-(Diethoxyphosphoryl)benzyl]oxy}-N-Boc-L-proline Methyl
Ester (4a): A mixture of 3 (2.0 g, 4.8 mmol), diethyl phosphite
(0.73 g, 5.3 mmol), triethylamine (0.54 g, 5.3 mmol) and tetrakis-
(triphenylphosphine)palladium(0) (0.55 g, 0.48 mmol) in toluene
(4R)-4-[(4Ј-Phosphonobenzyl)oxy]-
L-proline (6): White solid, m.p.
230–240 °C. [α]D = –16.4 (c = 0.6, H2O). 1H NMR (400 MHz,
Eur. J. Org. Chem. 2014, 1716–1726
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1723

M. Angeloni, O. Piermatti, F. Pizzo, L. Vaccaro
FULL PAPER
1
Table 8. The H, 13C and 31P NMR spectroscopic data of ZrPB-Pro 1–4.[a]
1H NMR
13C NMR
31P NMR
δ [ppm]
H
Mult.
δ [ppm]
J [Hz]
C
Mult.
δ [ppm]
J [Hz]
PB-Prol
3-H
3-H
5-H
5-H
4-H
2-H
CH2O
ddd
br. dd
dd
br. d
m
dd
s
1.93
2.35
3.18
3.27
4.16
4.25
4.30
7.17
7.43
14.4, 10.5, 4.5
14.4, 7.8
13.0, 3.9
13.0
C-3
C-5
C-2
CH2O
C-4
C-2Ј, C-6Ј
C-3Ј, C-5Ј
C-4Ј
C-1Ј
COOH
s
s
s
34.2
50.8
58.2
70.1
–
–
–
–
16.7
–
77.1
–
10.5, 7.8
–
8.0, 3.6
13.3, 8.1
d
d
d
s
128.0
130.7
130.2
141.2
171.2
15.1
10.9
183.7
–
2Ј-H, 6Ј-H dd
3Ј-H, 5Ј-H dd
s
–
P-C6H5
P-Me
3-H, 5-H
4-H
2-H, 6-H
m
t
dd
7.19
7.27
7.43
–
7.4
13.6, 8.0
C-3, C-5
C-2, C-6
C-4
d
d
d
d
128.3
130.1
132.1
129.8
15.0
10.6
2.9
17.3
30.8
C-1
183.8
1-H
d
1.15
17.4
C-1
d
11.2
134.4
[a] The liquid-state NMR analyses were performed in D2O/HF solution.
D2O): δ = 2.04 (ddd, J = 14.4, 10.5, 4.4 Hz, 1 H, 3-H), 2.49 [br.
dd, J = 14.4, 7.8 Hz, 1 H, 3-H], 3.30 [dd, J = 12.9, 3.9 Hz, 1 H, 5-
H], 3.39 [br. d, J = 12.9 Hz, 1 H, 5-H], 4.30 [br. s, 1 H, 4-H], 4.35
[br. t, J = 8.6 Hz, 1 H, 2-H], 4.43 (s, 2 H, CH2O), 7.29 (dd, J =
0.625 mmol, 5 equiv.) was added. The resulting mixture was stirred
at 30 °C for 24 h and then diluted with ethyl acetate (2 mL). The
organic phase was separated by centrifugation, and the solid cata-
lyst was washed again with ethyl acetate (2ϫ 1 mL) and separated
8.0, 3.3 Hz, 2 H, 2Ј-H, 6Ј-H), 7.55 (dd, J = 13.0, 8.0 Hz, 2 H, 5Ј- by centrifugation. The combined organic layers were washed with
H, 3Ј-H) ppm. 13C NMR (100.6 MHz, D2O): δ = 34.2 (C-3), 50.9
water (2ϫ 3 mL), dried (Na2SO4) and evaporated under reduced
(C-5), 58.2 (C-2), 70.2 (CH2O), 77.1 (C-4), 128.0 (d, J = 15.0 Hz, pressure. The crude products were purified by column chromatog-
C-2Ј, C-6Ј), 130.3 (d, J = 187.5 Hz, C-4Ј), 130.7 (d, J = 10.8 Hz, C- raphy eluted with petroleum ether/ethyl acetate (80:20). The solid
3Ј, C-5Ј), 141.1 (C-1Ј), 171.2 (COOH) ppm. 31P NMR (161.9 MHz,
CDCl3): δ = 16.7 ppm. C12H16NO6P (301.23): calcd. C 47.85, H
5.35, N 4.65; found C 47.59, H 5.28, N 4.72.
catalyst was dried at 80 °C for 2 h and reused.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H, 13C and 31P NMR spectra.
General Procedure for the Preparation of Zirconium (4R)-4-[4Ј-
(Phosphonatobenzyl)oxy]-L-proline Methyl- and/or Phenylphos-
Acknowledgments
phonates (ZrPB-Pro 1–4): An aqueous ZrOCl2 solution (2 mmol in
4 mL of water) was slowly added at room temp. to a stirred aque-
ous solution of 6 and methyl- and/or phenylphosphonic acid
(6 mmol in 18 mL of water). The molar ratios between the phos-
phonic acids used during the preparation are reported in Table 1.
The authors gratefully acknowledge the Ministero dell’Istruzione,
dell’Università e della Ricerca (MIUR) within the financing pro-
grams PRIN and “Firb-Futuro in Ricerca” and the Università de-
gli Studi di Perugia for financial support. Dr. Andrea Capocci and
Dr. Serena Mantenuto are thanked for the contribution given with
their thesis. Dr. Fabio Marmottini and Dr. Morena Nocchetti are
thanked for TG-DTA, ICP-OES and BET surface area analysis.
The preparation conditions were as follows: molar ratio P/ZrIV
=
2.5, precipitation temperature 25 °C, precipitation time 4 h. The
obtained l-proline-functionalized zirconium phosphonates were
separated from the aqueous medium by centrifugation, washed
with water (4ϫ 100 mL) and finally dried at 80 °C for 24 h.
The 1H, 13C and 31P NMR spectroscopic data of the l-proline-
based solid catalysts are reported in Table 8.
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Published Online: January 17, 2014
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