Polystyrene-supported (R)-2-piperazino-1,1,2-triphenylethanol: A readily available supported ligand with unparalleled catalytic activity and enantioselectivity

Article abstract of DOI:10.1021/jo048310d

(Chemical Equation Presented) A very active and highly enantioselective catalytic resin, designed for minimal perturbation of the catalytic center by the polymer matrix, has been assembled in two steps from (S)-triphenylethylene oxide, piperazine, and Merrifield resin and tested in the enantioselective ethylation of aldehydes. 1-Arylpropanols of 94-95% ee are obtained in high yield by the use of only 2 mol % of catalytic resin at 0°C for 4 h.

Full text of DOI:10.1021/jo048310d

Polystyrene-Supported (R)-2-Piperazino-1,1,2-triphenylethanol: A
Readily Available Supported Ligand with Unparalleled Catalytic
Activity and Enantioselectivity
†
‡
‡
§
§
David Castellnou, Llu ´ı s Sol a` , Ciril Jimeno, Jos e´ M. Fraile, Jos e´ A. Mayoral,
†
,†,‡
Antoni Riera, and Miquel A. Peric a` s*
Institute of Chemical Research of Catalonia (ICIQ), 43007 Tarragona, Spain, Departament de Qu ´ı mica
Org a` nica and Parc Cient ı´ fic de Barcelona, Universitat de Barcelona, 08028 Barcelona, Spain, and
Instituto de Ciencia de Materiales de Arag o´ n, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
mapericas@iciq.es
Received September 22, 2004
A very active and highly enantioselective catalytic resin, designed for minimal perturbation of the
catalytic center by the polymer matrix, has been assembled in two steps from (S)-triphenylethylene
oxide, piperazine, and Merrifield resin and tested in the enantioselective ethylation of aldehydes.
1
-Arylpropanols of 94-95% ee are obtained in high yield by the use of only 2 mol % of catalytic
resin at 0 °C for 4 h.
Introduction
in catalytic activity and enantioselectivity with respect
to structurally referable, homogeneous ligands.
1
Long before the term green chemistry was coined,
substantial research effort had already been devoted to
the development of processes involving a rational use of
raw materials, the minimization of energy consumption,
and the avoidance of residue generation.
The venue of catalytic synthetic processes represented
a giant step toward these goals, and the introduction of
homogeneous catalysis paved the way for the clean and
efficient production of chiral compounds as single enan-
tiomers. Homogeneous catalytic processes, however, are
usually performed in a batch manner, and workup stages
required for product isolation and catalyst recovery are
detrimental to their overall sustainable characteristics.
Within this approach, the achievement of enantiocon-
trol in the alkylation or the arylation of aldehydes has
received considerable attention. The forementioned draw-
backs are not absent from this chemistry, and its solution
has been addressed by means of the introduction of
3
increasingly sophisticated ligands. Since synthetic com-
plexity in catalytic ligands severely hinders its practical
use, further work in this field is clearly warranted.
4
Since the early work by Fr e´ chet and Soai, different
polymer-supported amino alcohols such as 1-4 (Figure
1
) have been introduced for the ethylation of benzalde-
5
hydes. When their structures are analyzed, it becomes
To solve this problem, covalent anchoring of properly
functionalized ligands to polymeric supports has been
widely applied. While this method can ultimately allow
performing catalytic enantioselective reactions in a con-
tinuous mode, it is usually accompanied by a decrease
(
2) (a) Br a¨ se, S.; Lauterwasser, F.; Ziegert, R. E. Adv. Synth. Catal.
2
003, 345, 862-929. (b) Special Issue on Recoverable Catalysts and
2
Reagents; Gladisz, J. A., Ed. Chem. Rev. 2002, 102, 3215-3892. (c)
Chiral Catalyst Immobilization and Recycling; de Vos, D. E., Vankele-
kom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Weinheim, Germany,
2000.
(
3) For a successful, polymer-supported yet soluble ligand for
enantioselective phenylation of aldehydes, see: Bolm, C.; Hermanns,
N.; Classen, A.; Mu n˜ iz, K. Bioorg. Med. Chem. Lett. 2002, 12, 1795-
1798.
(4) (a) Itsuno, S.; Fr e´ chet, J. M. J. J. Org. Chem. 1987, 52, 4140-
4142. (b) Soai, K.; Niwa, S.; Watanabe, M. J. Org. Chem. 1988, 53,
927-928.
†
Universitat de Barcelona.
‡
Institute of Chemical Research of Catalonia.
§
Universidad de Zaragoza-CSIC.
(
1) Oldest hit in SciFinder for green chemistry: Pavel, D. Chem. Listy
1
991, 85, 1144-1149.
1
0.1021/jo048310d CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/21/2004
J. Org. Chem. 2005, 70, 433-438
433

Castellnou et al.
FIGURE 1. Some amino alcohol ligands anchored to poly-
meric matrixes through the nucleophilic nitrogen atom.
FIGURE 2. Tail-tied ligands 6 and 7, conceptually derived
from amino alcohol 5 by functionalization of the para positions
of the phenyl and piperidino rings, and model compound 12.
evident that taking advantage of the nucleophilic proper-
ties of the amino group has been the favorite anchoring
strategy.
SCHEME 1. Assembly of the Supported Ligand 7
by Sequential Nucleophilic Ring-Opening Plus
Alkylation with Piperazinea
Since the amino group critically participates in the
transition states (TS) leading to product formation in the
considered reaction, we reasoned that the close vicinity
of the polymeric backbone could perturb the geometry of
the TS’s and, hence, could be responsible for the de-
creases in catalytic activity and enantioselectivity gener-
ally observed with these ligands in comparison with their
homogeneous counterparts.6
In an attempt to solve these problems, we reasoned
that structural modification of homogeneous ligands
aimed at its conversion into supported ones should
preferably by done at positions remote from the atoms
involved in the catalytic event, so that a minimal
perturbation was introduced on the corresponding transi-
tion states. As an application of this idea, and basing our
7
design on (R)-2-piperidino-1,1,2-triphenylethanol (5), we
have developed polystyrene-supported amino alcohols 6,
and have introduced for their designation the term tail-
tied ligands. Gratifyingly enough, both the catalytic
a
Conditions A: LiClO4 (2 equiv), piperazine (32 equiv), 160 °C,
4
h. Conditions B: LiClO4 (2 equiv), piperazine (5 equiv), N,N-
dimethylacetamide, 160 °C, 3 h.
8
activity and the enantioselectivity exhibited by 6 are
among the highest ever recorded for supported ligands.
However, the price paid for efficiency was still high, since
the preparation of the ready-to-anchor ligand involved
up to five steps from commercial precursors (Figure 2).
We wish to report here the preparation of a second-
generation tail-tied ligand (7), available in enantiopure
form in only two steps from (S)-triphenylethylene oxide,
and exhibiting an optimal activity/enantioselectivity
profile.
Results and Discussion
Our strategy for the immediate availability of 7 from
commercial precursors involves the sequential participa-
tion of the two nitrogen atoms of piperazine in nucleo-
philic displacements. In the first place, and according to
our general strategy for the synthesis of modular amino
alcohols, (R)-2-piperazino-1,1,2-triphenylethanol (8) was
simply prepared by lithium perchlorate-induced ring-
9
opening of readily available enantiomerically pure (S)-
triphenylethylene oxide (9)10 with piperazine (Scheme 1).
Thanks to the sensitivity of these ring-opening pro-
cesses to the steric characteristics of the nucleophile, no
partial protection in piperazine was required, and prod-
uct arising from double ring-opening was never detected
in the reaction crudes. While the highest yielding reaction
conditions (Conditions A: 89% yield) involved the use of
excess piperazine as a solvent, workup was highly
simplified under Conditions B (70% yield), which re-
(
5) For 3, see: ten Holte, P.; Wijgergangs, J.-P.; Thijs, L.; Zwan-
nenburg, B. Org. Lett. 1999, 1, 1095-1097. For 4, see: Burguete, M.
I.; Garcia-Verdugo, E.; Vicent, M. J.; Luis, S. V.; Pennemann, H.; Graf
von Keyserling, N.; Martens, J. Org. Lett. 2002, 4, 3947-3950.
(6) (a) For insoluble, polymer-supported amino alcohol ligands whose
anchoring does not involve the amino moiety, see: Vidal-Ferran, A.;
Bampos, N.; Moyano, A.; Peric a` s, M. A.; Riera, A.; Sanders, J. K. M.
J. Org. Chem. 1998, 63, 6309-6318. (b) For soluble, polymer-supported
ligands with positive support effects, see: Fan, Q.-H.; Wang, R.; Chan,
A. S. C. Bioorg. Med. Chem. Lett. 2002, 12, 1867-1871 and references
therein.
(
7) (a) Sol a` , L.; Reddy, K. S.; Vidal-ferran, A.; Moyano, A.; Peric a` s,
M. A.; Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998,
6
3, 7078-7082. (b) Fontes, M.; Verdaguer, X.; Sol a` , L.; Peric a` s, M. A.;
(9) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J. Org. Chem. 1993, 58, 1221-1227.
(10) This epoxide can be routinely prepared at the molar scale in
>99.9% ee by Jacobsen epoxidation of triphenylethylene (Brandes, B.
D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378-4380) and recrys-
tallization from hexane.
Riera, A. J. Org. Chem. 2004, 69, 2532-2543. (c) Garc ´ı a-Delgado, N.;
Fontes, M.; Peric a` s, M. A.; Riera, A.; Verdaguer, X. Tetrahedron:
Asymmetry 2004, 15, 2085-2090.
(
8) Peric a` s, M. A.; Castellnou, D.; Rodr ´ı guez, I.; Riera, A.; Sol a` , L.
Adv. Synth. Catal. 2003, 345, 1305-1313.
434 J. Org. Chem., Vol. 70, No. 2, 2005

Immediately Available Chiral Supported Ligand
FIGURE 4. Bar chart showing the efficiency of ligand 7 in
the ethylation of aldehydes 10a-d at different loadings in
toluene at 0 °C, after 4 h.
FIGURE 3. Bar chart showing the efficiency of ligand 7 in
the ethylation of aldehydes 10a-d at different temperatures,
after 4 h.
less reactive, electron-rich substrates 10b-d required
SCHEME 2. Catalytic Enantioselective Ethylation
of Aldehydes Mediated by the Supported Ligand 7
13
extra reaction time with the considered catalyst loading.
For practical purposes the activity/enantioselectivity
profile exhibited by 7 at 0 °C was optimal. Next in the
optimization, we explored the possibility of reducing the
amount of catalyst at this temperature. In a series of
experiments with 10a-d, the amount of 7 was reduced
from 6 to 1 mol %. We were pleased to observe that, for
all substrates, enantioselectivities decreased by only 1%
with this change in catalyst amount. With respect to
conversion (Figure 4), the amount of catalyst exerted a
deeper influence, and only the highly reactive aldehyde
quired the use of only 3 equiv of piperazine in N,N-
dimethylacetamide as a solvent.
Anchoring of 8 to a Merrifield resin (2% DVB, f ) 0.84)
0
1
%
0a was completely consumed in the presence of 1 mol
was performed in a straightforward manner by shaking
under nitrogen a 1.2:1:2.4 mixture of 8, Merrifield resin,
and cesium carbonate in DMF for 72 h at room temper-
ature. A 97% yield could be calculated for the anchoring
stage by nitrogen elemental analysis of the functionalized
of 7 (0 °C, 4 h).
Since we were interested in determining practical
conditions14 for the use of 7 in enantioselective ethylation
reactions, two sets of reaction conditions (2 mol % of 7, 0
°C, 8 h and 4 mol % of 7, 0 °C, 6h) were tested with a
diverse and representative family of 15 aldehydes 10a-o
1
1
resin 7.
With ligand 7 in hand,12 optimal conditions for its use
(
Table 1). While for most aromatic aldehydes the first
in the selected benchmark (i.e., the catalytic enantio-
selective ethylation of aldehydes, Scheme 2) were studied.
conditions set would be sufficient, the second one ensures
complete conversion for all types of aromatic aldehydes
The optimization was performed in parallel on a set of
four aromatic aldehydes [o-fluorobenzaldehyde (10a),
m-anisaldehyde (10b), p-tolualdehyde (10c), o-tolualde-
hyde (10d)] comprising substitution in ortho, meta, and
para positions, with both electron-donating and electron-
withdrawing groups on the critical ortho position.
(
95% ee) and R-unsubstituted aliphatic (85-88% ee) or
R,â-unsaturated aldehydes (82% ee). For R-substituted
aldehydes (10n-o), higher enantioselectivities are re-
corded, but at an unaffordable low-activity price.
Although it is already clear from the results in Table
1
that the activity and enantioselectivity of 7 approach
For reaction temperature optimization, the reactions
were performed in toluene with 6 mol % of 7 at five
temperatures between -20 and +20 °C. Very interest-
ingly, all four alcohols 11a-d were obtained with excel-
lent enantioselectivity (96-95% ee) at -20 °C, 95-94%
ee at 0 °C, and 93-92% ee at +20 °C. With respect to
conversion (Figure 3), all substrates were completely
converted (>99%) after 4 h at 10 °C, and only traces of
the starting aldehydes remained after 4 h at 0 °C. By
further lowering the reaction temperature, conversion of
or even surpass those of many homogeneous ligands, a
direct comparison with a referable, soluble species would
be preferable. To this end, amino alcohol 12 (Figure 2)
was prepared either by simple benzylation of 8 (BnCl,
Cs
N-benzylpiperazine in the presence of lithium perchlorate
84%), and subsequently used for enantiocontrol in the
2 3
CO , DMF, rt, 77%) or by ring opening of 9 with
(
ethylation of benzaldehyde.
With respect to enantioselectivity, when 6 mol % of 12
was used in the alkylation reaction, a complete conver-
sion was recorded after 4 h at 0 °C in toluene, and alcohol
10a remained complete over the whole range, while the
(
11) Yield calculated as 100f/fmax, where f [mmol ligand/g resin] is
calculated from the nitrogen elemental analysis with the formula f )
.375(%N), and fmax [mmol ligand/g resin], the maximum ligand
substitution level, is calculated as described in ref 6.
(13) At -10 °C, all substrates reacted completely in 24 h. At -20
°C, over 90% conversion was recorded for all substrates in 24 h.
(14) In the context of this research, most practical conditions are
those involving the minimal catalyst amount leading to complete
conversion at the nearest to ambient temperature in the shortest
reaction time with an affordable decrease in enantioselectivity with
respect to its optimal value.
0
(
12) For the immobilization of 8 on silica by sol-gel synthesis and
grafting, see: Fraile, J. M.; Mayoral, J. A.; Serrano, J.; Peric a` s, M. A.;
Sol a` , L.; Castellnou, D. Org. Lett. 2003, 5, 4333-4335.
J. Org. Chem, Vol. 70, No. 2, 2005 435

Castellnou et al.
TABLE 1. Enantioselective Ethylation of Aldehydes
Mediated by 7
2
% of 7a
4% of 7b
conv
(%)
ee
(%)
conv
(%)
ee
(%)
starting aldehyde
o-fluorobenzaldehyde (10a)
m-methoxybenzaldehyde (10b)
p-tolualdehyde (10c)
>99
98
94
83
98
99
98
98
>99
75
97
96
98
27
52
94
95
94
94
95
94
94
95
94
94
80
85
88
86
91
>99
99
95
95
95
95
95
95
94
95
95
95
82
85
88
89
91
98
o-tolualdehyde (10d)
95
99
benzaldehyde (10e)
o-methoxybenzaldehyde (10f)
m-fluorobenzaldehyde (10g)
m-tolualdehyde (10h)
>99
>99
>99
>99
98
p-fluorobenzaldehyde (10i)
p-methoxybenzaldehyde (10j)
cinnamaldehyde (10k)
heptanal (10l)
98
97
FIGURE 5. Profiles of benzaldehyde conversion in the addi-
tion of diethylzinc to benzaldehyde mediated by resin 7 and
homogeneous ligand 12 (4 mol %) in toluene at 20 °C.
3
2
-phenylpropanal (10m)
-ethylbutanal (10n)
99
35
R-methylcinnamaldehyde (10o)
63
a
Reaction in toluene at 0 °C for 8 h. b Reaction in toluene at 0
studied here) for a 95% yield in the considered process
°
C for 4 h
(
10 mol % of ligand).
Even more remarkably, the heterogeneous ligand 7
16
11e was formed with >99% selectivity and 96% ee. As
compares favorably in catalytic activity with (-)-DAIB,
can be seen in Table 1, performing the reaction with 4
mol % of 7 under the same experimental conditions leads
to 11e of 95% ee. Thus, the enantioselectivity of the
homogeneous ligand 12 is not affected when this ligand
was incorporated to a polymer through a position remote
from the catalytic site.
the usual reference homogeneous ligand for carbonyl
additions. Thus, while for aromatic aldehydes such as 10e
and 10j the use of 2 mol % of (-)-DAIB in toluene at 0
°C for 6 h leads to essentially complete conversion, as
with 2 mol % of 7 in 8 h (see Table 1), for R,â-unsaturated
aldehydes such as 10k the use of (-)-DAIB under the
above conditions leads to incomplete conversion (81%
yield), and for aliphatic aldehydes such as 10m and 10l
a similar conversion is only achieved after 12 and 24 h,
respectively. As shown in Table 1, an essentially complete
conversion is achieved for all three last examples with 2
mol % of 7 at 0 °C for 8 h.17
To evaluate the effect of heterogenization on catalytic
activity, two parallel kinetic measurements on the di-
ethylzinc addition to benzaldehyde mediated by 7 and
1
2 were carried out in an Omnical reaction calorimeter.
The reactions were performed in toluene at 20 °C with a
mol % catalytic ligand. According to usual practice the
4
raw heat flow data, acquired every 3 s, were corrected
for the response time of the instrument (τ correction, see
Supporting Information) and, after confirming that the
ethylation of 10e takes place to completion in a strictly
selective manner under the employed reaction conditions,
transformed to conversion data.15 The corresponding
conversion vs time curves have been represented in
Figure 5.
As a final test on the performance of 7, the possibility
of its recovery and reuse was evaluated. Gratifyingly, the
supported ligand 7 could be recycled without any loss in
catalytic activity or in enantioselectivity. Thus, in five
consecutive batches of 1-phenylpropanol (11e) prepared
under standard conditions (4 mol % of 7, toluene, 0 °C, 6
h) with the same catalyst sample, conversion and selec-
tivity were complete (>99%) in all cases, with the
enantiomeric purity of the resulting alcohol keeping
constant within the limits of experimental error (95.2%,
94.9%, 95.1%, 95.0%, 95.1%).
It is clear from this plot that the homogeneous ligand
2 and the polymer-supported ligand 7 are practically
1
identical in terms of reaction rate and activity. At short
reaction times, 7 is even slightly more active than 12
(
8
83% conversion for the polymer-supported ligand and
0% for the homogeneous ligand after 30 min), but these
differences vanish as the reaction proceeds. Thus, after
0 min conversion was 96% (with 7) and 95% (with 12)
Conclusions
In summary, we have succeeded in developing an
immediately available, polymer-supported ligand for the
enantioselective alkylation of aldehydes which exhibits
the catalytic activity and enantioselectivity typical for a
homogeneous, low-molecular weight species, and the ease
for recovery and reuse characteristic of heterogeneous
catalysts. We are currently extending the use of 7 to other
processes with the aim of contributing to the establish-
ment of more sustainable practices in enantioselective
synthesis.
6
and after 80 min both reactions had reached 98%
conversion.
In addition to that, it is interesting to compare these
results with those reported for other supported ligands.
The poly(styrene) bonded analogue of DAIB,4a for in-
stance, requires 73 h in toluene at 0 °C for a 91% yield
in the same reaction (3.3 mol % of ligand), while a poly-
(
styrene) supported version of ephedrine4a,b requires 48
h in toluene at room temperature (the same conditions
(
16) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am. Chem.
(
15) For a discussion on the conversion of heat flow data into kinetic
Soc. 1986, 108, 6071-6072.
data see, for instance: Nielsen, L. P. C.; Stevenson, C. P.; Blackmond,
D. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360-1362, and
the Supporting Information.
(17) For the five examples where direct comparison is possible (10e,
10j, 10k, 10l, 10m) the mean enantiomeric excess recorded with (-)-
DAIB (2 mol %) is 87.6%, and that recorded with 7 (2 mol %) is 88.4%.
436 J. Org. Chem., Vol. 70, No. 2, 2005

Immediately Available Chiral Supported Ligand
Experimental Section
(CH
ppm. Elemental Anal. Calcd.: N, 1.85. Found: N, 1.79.
R)-2-(4-Benzylpiperazin-1-yl)-1,1,2-triphenylethanol
12). (a) From 8: To a flame-dried 10-mL round-bottom flask
prepared for magnetic stirring were added 50 mg (0.14 mmol)
of 8 and 91 mg (0.28 mmol) of Cs CO under nitrogen. DMF
0.5 mL) and benzyl chloride (16 µL, 0.14 mmol) were succes-
sively added, and the mixture was stirred under nitrogen for
4 h at room temperature. The solvent was removed under
vacuum, CH Cl (5 mL) and water (5 mL) were added to the
2 2 2 2
), 53.0 (CH ), 53.6 (CH ), 62.4 (CH ), 76.8 (CH), 78.6 (C)
(R)-1,1,2-Triphenyl-2-(piperazin-1-yl)ethanol (8). Con-
(
ditions A (excess piperazine as the solvent): To a flame-
dried 100-mL two-necked flask with reflux condenser and
nitrogen inlet were added 1.0 g (3.67 mmol) of epoxide 9
(
2
3
(
4
>99.9% ee), 1.0 g (9.4 mmol) of LiClO , and 10.0 g (0.116 mol)
(
of piperazine. The mixture was heated to 160 °C under
nitrogen for 4 h under stirring, cooled to room temperature,
and treated with dichloromethane and water (equal volumes)
until complete disolution of all precipitated matter. The
2
2
2
residue, and the organic layer was washed with water (2 × 5
4
aqueous phase, containing piperazine and LiClO , was dis-
mL). The combined aqueous phase was then extracted with
carded. To remove the remaining piperazine, the organic phase
was repeatedly washed with water (8 × 20 mL), and the
aqueous extracts were discarded. To remove impurities, the
product amino alcohol was transferred to an aqueous phase
by treating the organic extract with 100 mL of 1 N HCl, and
the remaining organic phase was discarded. The acidic solution
was then washed with dichloromethane (3 × 100 mL), and the
organic phases were again discarded. Finally, the pH of the
aqueous phase was adjusted to 10.5 by addition of aq 7.5 N
NaOH, and amino alcohol 8 was extracted with dichlo-
romethane (4 × 50 mL). The combined organic extracts were
dichloromethane (CH
2
Cl
2
) (3 × 5 mL), and the combined
organic extracts were dried (Na
2
SO ), filtered, and evaporated
4
to dryness to afford crude 12 (55 mg). Final purification was
achieved by column chromatography (2.5% v/v triethylamine:
2
pretreated SiO ), eluting with hexane ethyl acetate mixtures
of increasing polarity. Pure 12 (48 mg, 77% yield) was obtained
as a white solid. (b) From 9: To a flame-dried 50-mL two-
necked flask with reflux condenser and nitrogen inlet were
added 1.0 g (3.67 mmol) of epoxide 9 (>99.9% ee), 1.25 g (11.7
4
mmol) of LiClO , and 6.76 mL (6.88 g; 39.0 mmol) of N-
benzylpiperazine. The mixture was heated to 100 °C under
nitrogen for 22 h under stirring until the dissappearance of
the starting epoxide (TLC), cooled to room temperature, and
treated with 50 mL of dichloromethane and 50 mL of water.
The aqueous phase was extracted with dichloromethane (2 ×
2 4
dried (Na SO ), filtered, and evaporated to dryness to afford
pure 8 (1.16 g, 89% yield) as a white solid. Conditions B (in
N,N-dimethylacetamide): To a thick-walled pressure tube,
equipped with a Teflon screw-cap, and prepared for magnetic
stirring, were added 6.0 g (22.0 mmol) of epoxide 9 (>99.9%
5
2 4
0 mL), and the combined organic extracts were dried (Na SO )
4
ee), 4.7 g (44 mmol) of LiClO , 9.5 g (110 mmol) of piperazine
and evaporated. Final purification was achieved by column
and 11 mL of N,N-dimethylacetamide. The mixture was stirred
at 160 °C for 3 h, cooled to room temperature, and treated
with a 1:1 water:dichoromethane mixture (200 mL). Phases
were separated with the aqueous phase being discarded and
2
chromatography (2.5% v/v triethylamine:pretreated SiO ),
eluting with hexane ethyl acetate mixtures of increasing
polarity. Pure 12 (1.38 g, 84% yield) was obtained as a white
2
3
1
solid. Mp 162-163 °C. [R]
D 3
-105.2 (c 0.65, CHCl ). H NMR
the organic phase being washed with H
2
O (3 × 200 mL), the
(
300 MHz, CDCl
3
) δ 2.0-2.2 (m, 2H), 2.31 (br, 4H), 2.41-2.47
aqueous phases being discarded again. Hydrochloric acid (1
M, 200 mL) was next added, the organic phase was discarded,
2
2
(
m, 2H), 3.38 (AB, JHH ) 12.8 Hz, 1H), 3.43 (AB, JHH ) 12.8
Hz, 1H), 4.59 (s, 1H), 5.65 (br, 1H), 6.91-7.33 (m, 18H), 7.70-
7
and the aqueous phase was washed with CH
Cl
2 2
(3 × 200 mL),
1
3
.72 (m, 2H) ppm. C NMR (75.4 MHz, CDCl
3 2
) δ 53.8 (CH ),
the organic extracts being discarded again. Finally, the pH of
the aqueous phase was adjusted to 10.5 by addition of aq 7.5
M NaOH, and amino alcohol 8 was extracted with dichlo-
romethane (3 × 200 mL). The combined organic extracts were
6
2.9 (CH ), 76.8 (CH), 78.6 (C), 125.5 (CH), 125.6 (CH), 126.3
2
(
CH), 126.5 (CH), 127.0 (CH), 127.2 (CH), 127.5 (CH), 128.0
CH), 128.1 (CH), 129.1 (CH), 131.0 (CH), 137.4 (C), 138.0 (C),
(
1
45.8 (C), 149.2 (C) ppm. IR (film, NaCl) υmax 3027, 2930, 2807,
2 4
dried (Na SO ), filtered, and evaporated to dryness to afford
-
1
+
1
449, 740, 698 cm . MS (CI, NH
3
) m/e 450 ([M + 1] , 100%),
pure 8 (5.50 g, 70% yield) as a white solid. Mp 159-161 °C.
+
+
+
2
3
1
451 ([M + 2] , 40%). ES HRM m/z found 449.2574 (M + H) ,
[
D 3 3
R] -126.3 (c 0.51, CHCl ). H NMR (300 MHz, CDCl ) δ
calcd for C31
33 2
H N O 449.2593.
1
.50-1.80 (br, 1H), 1.90-2.10 (m, 2H), 2.30-2.50 (m, 2H),
.60-2.80 (m, 4H), 4.54 (s, 1H), 5.40-5.70 (br, 1H), 6.80-7.40
2
(
Kinetic Measurements. Reactions where carried out in a
reaction microcalorimeter. In a typical experiment, 62 mg of
resin 7 (f ) 0.641, 4 mol % of ligand) was weighed in a
calorimeter vessel and mixed with 0.25 mL of dry toluene for
30 min under argon atmosphere. After cooling at 0 °C,
diethylzinc 1.1 M (1.1 mL, 1.1 equiv) was added dropwise, and
the mixture was stirred for another 30 min. The vessel was
then allowed to warm to room temperature and placed into
the calorimeter. At the same time, a syringe containing 1 mmol
of benzaldehyde (120 µL, 1 equiv) in 0.5 mL of dry toluene
was placed in the addition port of the calorimeter. After 1 h of
equilibration at 20 °C, the solution in the syringe was quickly
added to the stirred reaction vessel, while monitoring the heat
flow every 3 s. Simultaneously, a blank reaction was carried
out in the twin vessel, which was identical to the previous
reaction except that only toluene, and no benzaldehyde, was
added in the final addition. ∆Hreaction ) 153.4 kJ/mol.
m, 13H), 7.60-7.80 (m, 2H) ppm. 13C NMR (75.4 MHz, CDCl
3
)
δ 46.6 (CH
2 2
), 54.3 (CH ), 77.3 (CH), 78.7 (C), 125.4 (CH), 125.5
(
(
CH), 126.2 (CH), 126.4 (CH), 126.9 (CH), 127.2 (CH), 127.4
CH), 127.9 (CH), 131.0 (CH), 137.1 (C), 145.6 (C), 149.0 (C)
ppm. IR (film, NaCl) υmax 3241, 2940, 2815, 1449, 1321, 702
-
1
+
+
cm . MS (CI, NH
3
) m/e 359 ([M + 1] , 100%), 360 ([M + 2] ,
2
7%). Elemental Anal. Calcd for C24H N O: C, 80.41; H, 7.31;
26 2
N, 7.81. Found: C, 80.19; H, 7.30; N, 7.51.
Anchoring of Amino Alcohol 8 to a Merrifield Resin
0.84 mmol Cl/g; 2% DVB). Preparation of supported
(
ligand 7: A solution of amino alcohol 8 (670 mg, 1.87 mmol)
in DMF (6.7 mL) under N was added via cannula to a
suspension of Merrifield resin (1.72 g, 1.44 mmol of active Cl)
and Cs CO (1.22 g, 3.74 mmol) in DMF (12.6 mL), previously
2
2
3
stirred at 25 °C for 45 min, and the resulting mixture was
stirred at room temperature under nitrogen for 24 h. Solvent
and excess reagents were separated by filtration, and the
resulting resin was successively washed with DMF (2 × 10
mL), 1:1 DMF-water (4 × 10 mL), water (4 × 10 mL), pH 9
The calorimetric experiment with the homogeneous ligand
was identical except that 18 mg (4 mol %) of amino alcohol 12
was used. ∆Hreaction ) 144.4 kJ/mol.
Na
2
CO
3
/NaHCO
3
buffer (4 × 10 mL), water (8 × 10 mL),
2 2
MeOH (4 × 10 mL), toluene (4 × 10 mL), and CH
Cl
(4 × 10
Acknowledgment. We thank DGI-MCYT (Grants
BQU2002-02459 and PPQ2002-04012), DURSI (Grant
mL). After drying under vacuum until constant weight, 1.94
g of functionalized resin 7 (2% DVB, f ) 0.641) was obtained.
A 97% yield of functionalization is calculated on the basis of
nitrogen elemental analysis [see below, %Nfound/%Ncalcd ) 1.79/
2
001SGR50), Fundaci o´ n Ramon Areces, and ICIQ Foun-
dation for financial support. D.C. thanks MECyD for a
fellowship. C.J. thanks MCYT for a Torres Quevedo
1
3
3
1.85 ) 0.97]. C NMR (gel, 75 MHz, CDCl ) δ 40.3 (CH), 43.9
J. Org. Chem, Vol. 70, No. 2, 2005 437

Castellnou et al.
research position. We also thank Dr. Gisela Colet for
his assistance with the kinetic/calorimetric measure-
ments.
of enantiomeric composition, NMR spectra of new compounds,
and details on the calorimetric-kinetic measurements. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: General experimen-
tal methods, conditions for GC analysis in the determination
JO048310D
438 J. Org. Chem., Vol. 70, No. 2, 2005