Chiroptical properties and applications in PTC of new dendritic cinchonidine-derived ammonium salts

Article abstract of DOI:10.1016/j.tetasy.2003.08.030

Chiral nanosize molecules, derived from cinchonidine and Frechet dendritic wedges up to generation three, have been synthesized. The chiroptical properties, optical rotation and circular dichroism of these systems have been studied. These chiral dendritic molecules have been used as phase transfer catalysts in the alkylation of a glycine imine ester, showing a promising level of asymmetric induction.

Full text of DOI:10.1016/j.tetasy.2003.08.030

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3705–3712
Chiroptical properties and applications in PTC of new dendritic
cinchonidine-derived ammonium salts
Gabriela Guillena,a Robert Kreiter,a Rob van de Coevering,a Robertus J. M. Klein Gebbink,a
Gerard van Koten,a,* Patricia Mazo´n,b Rafael Chinchillab and Carmen Na´jerab,*
aDebye Institute, Department of Metal-Mediated Synthesis, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
bDepartamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo 99, E-03080 Alicante, Spain
Received 25 July 2003; accepted 27 August 2003
Abstract—Chiral nanosize molecules, derived from cinchonidine and Fre´chet dendritic wedges up to generation three, have been
synthesized. The chiroptical properties, optical rotation and circular dichroism of these systems have been studied. These chiral
dendritic molecules have been used as phase transfer catalysts in the alkylation of a glycine imine ester, showing a promising level
of asymmetric induction.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
dendritic wedges, while the catalysts become recover-
able by means of (nano)filtration or dialysis techniques.
Phase transfer catalysis (PTC) processes offer another
possibility for continuous separation of catalytic den-
drimers from product streams.
Dendrimers are three-dimensional macromolecules
characterized by a well-defined structure of nanoscopic
dimensions and ideally with a globular shape.1 The
potential application of these macromolecules, which
resemble in size biomolecules such as proteins or
enzymes, in (bio)chemical and material science have
been envisaged.2 A promising development has been the
use of (metallo)dendrimers as homogeneous catalysts,
providing systems large enough to be recovered by
means of ultra- or nano-filtration or size exclusion
techniques.3 In this research field, the use of chiral
dendrimers for asymmetric catalytic transformations
has already been reported.4 However, only in a few
examples has a high level of chiral induction been
achieved.5 In most cases, the chiral dendritic species
were part of the ligands of catalytically active metal
complexes. So far, metal-free, chiral dendrimers have
rarely been used in asymmetric catalysis.6 There are
various possibilities of rendering a dendritic species
chiral; (i) by introducing chiral peripheral units; (ii) by
employing chiral building blocks or (iii) by using a
chiral core. Following the last strategy, the chiral infor-
mation of the core might even be enhanced by the steric
congestion created by using higher generations of the
In PTC processes, impressive improvements in the level
of asymmetric induction have been achieved by using
Cinchona derived ammonium salts.7 For instance, N-
aryl methyl substituted Cinchona alkaloids have shown
to be highly efficient for the practical asymmetric syn-
thesis of a-amino acids.8 Several attempts to recover
and re-use these chiral alkaloid-derived ammonium
salts by anchoring them to a solid support have been
also described.9
* Corresponding authors. Tel.: +31-30-2533120; fax: +31-30-2523615
(G.v.K.); tel.: +34-96-5903728; fax: +34-96-5903549 (C.N.); e-mail:
g.vankoten@chem.uu.nl; cnajera@ua.es
Recently, we have reported the synthesis and use as
catalysts of new cinchonidinium salts bearing 3,5-
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.08.030

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G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
dialkoxybenzyl groups 1.10 Unexpectedly, these cata-
lysts have shown a metal base-dependent inversion in
the enantioselectivity in the asymmetric synthesis of
a-amino acids. These unexpected results prompted us to
investigate the synthesis, as well as the study of the
chiroptical properties, of phase transfer catalysts
derived from cinchonidine as a chiral core and having
N-bound Fre´chet dendritic wedges of higher
generations.
As under the reaction conditions employed in PTC
processes, the hydroxyl group of the ammonium salts
can be converted to the corresponding ethers, species
1a–3a were transformed into the corresponding allyl
ethers by reaction with allyl bromide in a biphasic
mixture of CH2Cl2/KOH (50%), to give compounds
1b–3b in about 70% yield. All compounds were charac-
1
terized and identified by H, and 13C NMR, MALDI-
TOF or ESI mass spectrometry as well as elemental
analysis, the results being in full agreement with the
proposed structures (Scheme 1).
2. Results and discussion
(−)-Cinchonidine was derivatized with Fre´chet dendritic
wedges up to generation three. These wedges were
prepared using a convergent approach, involving stan-
dard K2CO3/18-crown-6 mediated ether formation
steps and alcohol to bromide conversions using PBr3.11
In addition, N-benzylcinchonidinium bromide 4 (G0-
cinchonidine) was prepared according to the litera-
ture.12 The quaternization of the nitrogen of the
quinuclidine moiety was performed by refluxing the
corresponding dendritic wedges (as the bromide), with
cinchonidine in acetone (Scheme 1).13 The resulting
salts were purified by precipitation (CH2Cl2/Et2O) and
centrifugation, rendering derivatives 1a and 2a in about
65% yield. This purification method was not suitable
for G3-cinchonidine salt 3a due to the high solubility of
this compound in common solvents. However, in this
case, due to the high molecular weight of the salt,
dialysis techniques can be used as a convenient and
efficient purification method. Thus, 3a was dissolved in
a minimum quantity of acetone and submitted to dialy-
sis for 48 h,14 giving pure 3a in 84% yield.
2.1. Chiroptical properties
Measurements of the optical activity of 1a–3a and
1b–3b showed that the [h]D value decreases with
increasing generation number. This is in concert with
earlier findings5e showing that attachment of achiral
branches to a chiral core leads to a kind of dilution
effect of the optical activity. The molar rotation ([b]D)
values were similar for G1- and G2-cinchonidine com-
pounds 1a and 2a, respectively. However, a lower
value, was observed for 3a. For the allylic ethers 1b and
3b, an different behavior was observed as they show a
similar [b]D value, whereas the G2-cinchonidine allyl
ether salt 2b has a higher value for both [h]D and [b]D
rotation (Fig. 1).
CD spectra of 10−5 M solutions of 1–4 in CH2Cl2 were
recorded in order to study the influence of dendritic
wedges on the spectroscopic properties. To avoid dis-
tortion of the dichroic absorption caused by the pres-
ence of an increasing number of benzene chromophores
Scheme 1. Reagents and conditions: (a) GnBr, acetone, D; (b) allyl bromide, KOH (50%), CH2Cl2, rt.
Figure 1. Comparison between the specific and molar rotation for dendrimers 1a–4 and 1b–3b.

G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
3707
in the dendrimer, the obtained Dm values were divided
by the number of benzylic rings present in each den-
drimer, i.e. one for 4, three for 1a, etc. All compounds
show a negative Cotton effect in the region of 315 and
305 nm which corresponds to adsorption of the chiral
cinchonidine moiety, i.e. these absorptions decrease as
the generation increases. A positive Cotton effect was
observed when the benzylic moiety was introduced in
the molecule. Thus, for the G0-cinchonidine 4 a maxi-
mum at ca. 275 nm was observed, while this effect
decreases with the increasing generation number as
expected. The same trend was observed for the CD
spectra of the allyl ether derivatives 1b–3b (Fig. 2).
2.2. Use as catalysts
In order to check if these chiroptical properties would
correlate with the enantioselectivities when the chiral
dendritic compounds would be applied in catalysis,
compounds 1–3 were tested in the biphasic alkylation
reaction of N-(diphenylmethylene)glycine isopropyl
ester 5 with benzyl bromide under different reaction
conditions (Table 1). The ee’s were determined by chiral
GLC analysis15 of the corresponding N-trifluoroac-
etamide amido esters.16
A study of the influence of base, temperature and
solvent on the catalytic reaction was performed using
Figure 2. CD spectra of compounds 1–4.
Table 1. Optimization of conditions on the alkylation of N(diphenyliminemethylene)glycine 5 with catalyst 1
Entry
Cat.
Solvent
Base
T (°C)
tR (h)a
Yield (%)b
Ee (%)c
Abs. conf.c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
CsOH·H2O
50% KOH
50% NaOH
50% KOH
50% NaOH
25% NaOH
25% KOH
50% KOH
25% NaOH
50% KOH
50% KOH
50% NaOH
50% NaOH
50% NaOH
50% NaOH
50% KOH
50% NaOH
50% CsOH
(−78)–(−50)
0
0
0
0
0
0
rt
1
2
2.5
0.75
3
7
2
1
2
3
7
7
15
2.5
1
1
6
85
96
98
96
93
76
88
88
84
80
91
96
93
94
83
84
85
76
26
34
36
44
8
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
46
40
35
38
58
66
40
40
26
43
76
30
76
9
PhMe
rt
10
11
12
13
14
15
16
17
18
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
−20
−40
−20
−40
0
rt
−20
−20
−20
5.5
a The reaction was monitored by GLC and quenched when the conversion was more than 90%.
b Isolated crude yield determined by 1H NMR (300 MHz).
c Determined by chiral GLC15 of the corresponding N-trifluoroacetamide amido esters.16

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G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
Table 2. Influence of the generation of the catalysts in the alkylation process of 5 with benzyl bromide
Entry
Cat.
Solvent
Base
T (°C)
tR (h)a
Yield (%)b
Ee (%)c
Abs. conf.c
1
2
3
4
5
6
7
8
9
1a
1b
2a
2b
3a
3b
2a
2b
2a
2b
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
PhMe/CHCl3
25% NaOH
25% NaOH
25% NaOH
25% NaOH
25% NaOH
25% NaOH
50% KOH
50% KOH
50% NaOH
50% NaOH
0
0
0
0
0
7
4
4
4
5
8.5
3.5
3
7
15
76
80
88
80
85
80
94
89
88
78
46
58
76
54
40
44
72
76
24
54
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
0
−20
−20
−20
−20
10
a The reaction was monitored by GLC and quenched when the conversion was more than 90%.
b Isolated crude yield determined by 1H NMR (300 MHz).
c Determined by chiral GLC15 of the corresponding N-trifluoroacetamide amido esters.16
sion of enantioselectivity using aq. 50% NaOH was
studied, being all results collected in Table 2.
derivative 1a as catalyst, the results being summarised
in Table 1. When CH2Cl2 was used as solvent, the best
results were achieved using aq. KOH or NaOH as base
at 0°C (Table 1, entries 1–3). Changing the solvent to
toluene, a dramatic effect on the enantioselectivity of
the reaction was observed, especially when aq. NaOH
was used as base. In this case (Table 1, entry 5) a poor
8% ee was obtained for 6a, the enantioselection being
recovered when aq. 25% NaOH at 0°C was used (Table
1, entry 6). However, the same increase of the enan-
tioselection was not observed when aq. 25% KOH was
used as base (Table 1, entry 7). Next, using aq. 25%
NaOH or 50% KOH as base for the alkylation process,
the temperature was raised to rt, leading to a decrease
on the enantioselection (Table 1 compare entries 4 and
6 with 8 and 9). The use of a mixture of toluene/CHCl3
(7/3 v/v) as solvent for the alkylation reaction would
allow to decrease the temperature below 0°C. There-
fore, the reaction was carried out using aq. 50% KOH
as base at −20 and −40°C. As expected the best enan-
tioselection for the alkylated product was obtained at
the lower temperature (Table 1, entries 10 and 11).
Surprisingly, when the base was changed to aq. 50%
NaOH the opposite (R)-enantiomer was obtained at
−40, −20 and 0°C, with higher enantioselection as the
temperature decreases. This effect of reversal of the
enantioselectivity was not observed at rt (Table 1,
entries 12–16). To the best of our knowledge this
base-dependent stereoselectivity was not shown before
at PTC reactions using ammonium salts as catalyst.
The inversion of enantioselectivity was also not
observed for the related allylated catalysts. Thus, 1b
gave the best results when aq. 50% KOH or 50% CsOH
was used as base in toluene/CHCl3 achieving 76% ee of
6a, the enantioselectivity was only 30% for the (S)-
enantiomer with aq. 50% NaOH (Table 1, entries 16–
18).
Comparing the results obtained with the three different
generation catalysts, best enantioselections (76% ee)
were achieved using second generation catalysts 2a or
2b and aq. 25% NaOH or aq. 50% KOH, respectively
(Table 2, entries 3 and 8), the enantioselectivity
achieved with third generation catalysts 3a being simi-
lar to that obtained with first generation salt 1a (Table
2, compare entries 1 and 5). Therefore, the increment of
the sterical hindrance due to the bulkiness of the den-
drimer seems to have little effect in the enantioselection,
being the results of the catalytic experiments not easily
correlated with the optical activities and CD values of
the dendritic salts 1–3. When aq. 50% NaOH and
catalysts 2a was used as a base for the alkylation
process a reversal on the enantioselection was not
observed. However, the use of this conditions led to
low enantioselectivities of the (S)-isomer (Table 2,
entries 7 and 9).
Finally, other alkyl halides were used as electrophiles
for the alkylation process catalyzed by 1a or 2a. In all
cases the enantioselectivity achieved with aq. 50% KOH
was much higher than the obtained with aq. 50%
NaOH, being in both cases the (S)-stereoisomer prefer-
entially formed (Table 3).The high molecular weight of
the catalysts of higher generations would allow their
retention by dialysis membranes commonly used to
purify proteins.17 With this idea in mind, the dendritic
catalysts could be dissolved and placed into a dialysis
membrane tube, which then can be submerged as a ‘tea
bag’18 in the reaction media. Reactants would flow
through the membrane pores and the catalyst contained
in the membrane could be recovered and reused in a
next catalytic run. Therefore, we tried this concept
using catalysts 2a and 3a contained in a dialysis mem-
brane to perform the alkylation reaction of 5 with aq.
25% NaOH as a base.
Then, the influence of the catalysts generation on the
enantioselection of the reaction was considered. For
this process, benzyl bromide was chosen as standard
electrophile and the reaction was performed using aq.
25% NaOH in toluene as solvent or aq. 50% KOH in a
mixture of toluene/CHCl3 (7/3 v/v). Finally, the inver-
Similar results were obtained at the first and second run
for both catalytic salts 2 and 3 (Table 4, entries 1–2 and
4–5) although for catalysts 2 a dramatic increase of the
reaction time was need to complete the reaction. This

G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
3709
Table 3. Alkylation of (diphenyliminemethylene)glycine 5 with different electrophiles. Preparation of compounds 6
Entry
Cat.
RX
Base
tR (h)a
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
4-CNC6H4CH2Br
2-NaphCH2Br
2-NaphCH2Br
CH3CH2CH2CH2I
CH3CH2CH2CH2I
3,5-(CH3O)2C6H3CH2Br
3,5-(CH3O)2C6H3CH2Br
4-CNC6H4CH2Br
KOH
KOH
NaOH
KOH
NaOH
KOH
NaOH
KOH
KOH
NaOH
3
4
30
18
20
3
24
4
6.5
2.5
90
95
95
65
78
85
83
87
91
86
62 (S)
60 (S)
28 (S)
44 (S)
32 (S)
72 (S)
18 (S)
70 (S)
68 (S)
18 (S)
3,5-(CH3O)2C6H3CH2Br
3,5-(CH3O)2C6H3CH2Br
10
a The reaction was monitored by GLC and quenched when the conversion was more than 90%.
b Isolated crude yield determined by 1H NMR (300 MHz).
c Determined by chiral GLC15 of the corresponding N-trifluoroacetamide amido esters.16 In parenthesis, absolute configuration of the major
enantiomer.
Table 4. Alkylation of N(diphenyliminemethylene)glycine
5 using catalyst-dialysis membrane processa
4. Experimental
4.1. General
Entry
Catalysts
Run tR (h)
Yield (%)
Ee (%)
All reagents were obtained commercially and used
without further purification. Benzoylated dialysis tub-
ing (Sigma D-7884, cut-off mass=1500 gmol−1) was
stored in methanol or acetone prior to use. The 1H
and 13C NMR spectra were recorded on a Varian
Inova 300 at 300 and 75 MHz, respectively, at 25°C
and were referenced to external SiMe4 (l=0.00, J in
Hz). Elemental analyses were performed by Kolbe,
Mikroanalytisches Laboratorium (Mu¨lheim, Ger-
many). ESI-MS were obtained from the Biomolecular
Mass Spectrometry Department of the Utrecht Uni-
versity. MALDI-TOF-MS spectra were acquired using
a Voyager-DE BioSpectrometry Workstation (PerSep-
tive Biosystems Inc., Framingham, MA) mass spec-
trometer equipped with a nitrogen laser emitting at
337 nm. The instrument was operated in the linear
mode at an accelerating voltage in the range 22000 V.
External calibration was performed using C60/C70, and
detection was performed by means of a linear detector
and digitizing oscilloscope operating at 500 MHz.
Sample solutions of ꢀ10 mg/mL in THF were used,
and the matrix was 3,5-dihydroxybenzoic acid in THF
(10 mg/mL). A solution of silver(I) trifluoroacetate in
THF was added to the sample in order to improve the
peak resolution. The sample solution (0.2 mL) and the
matrix solution (0.2 mL) were combined and placed on
a gold MALDI target and analyzed after evaporation
of the solvents. CD spectra were recorded on a Jasco
J-810 spectropolarimeter. Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter. HRMS
spectra were measured on a Finnigan MAT 95S spec-
trometer at the Research Technical Services in the
University of Alicante.
1
2
3
4
5
2a
2a
1
2
3
1
2
72
96
120
24
45
90
78
65
65
64
60
40
40
39
2a
3ab
3ab
25
a The reaction was conducted using benzyl bromide as electrophile,
aq. 25% NaOH as base in toluene at 0°C.
b The reaction was carried out at rt.
behaviour could be attributed to leaching of the cata-
lyst out of the dialysis tube or decomposition of the
membrane under the reaction conditions. However, for
catalyst 3, the yields, ee and reaction times were the
same for both catalytic runs. Probably the higher
molecular weight of these catalysts prevent leaching of
the salt out of the membrane allowing the use of this
type of catalysts in a membrane reactor.
3. Conclusions
We have demonstrated that dendritic cinchonidine
ammonium salts can be applied as phase transfer cata-
lysts. These systems show to be good PTC catalysts
reaching a moderate level of asymmetric induction,
while the chiroptical properties are independent of the
enantioselection achieved. Furthermore, for first gener-
ation catalysts a reversal on the stereoselectivity can
be achieved changing the nature of the inorganic base
from KOH to NaOH. Promising results have been
obtained in the recovery and reuse of higher genera-
tion salts by dialysis membranes. Current research
aims at in the variation of the molecular structure to
improve enantioselectivity in this and other organic
transformation.
4.2. Synthesis of dendritic ammonium salts 1–3a
To a solution of cinchonidine (2.94 g, 10 mmol) in
acetone (40 mL) was added the corresponding
Frechet’s bromide (10 mmol). The mixture was

3710
G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
refluxed for 3 h. After this time the solvent was
removed and the residue was dissolved in CH2Cl2 and
Et2O was slowly added until the solution appeared to
be cloudy. Then, the flask was kept at −20°C until the
crystallization was completed. The purification of 3a
was achieved by dialyzing the salt in a membrane
tubing for 24 h in acetone.
4.3. Synthesis of dendritic ammonium salts 1–3b
To a solution of the corresponding ammonium salt (1
mmol) in CH2Cl2 (40 mL) was added allyl bromide (3
mmol) and 0.6 mL of a 50% soln. of KOH. The
mixture was stirred for 4 h. Then, the organic layer was
washed with water and brine, dried, filtered and sol-
vents removed. The resulting orange solid was recrys-
tallized from CH2Cl2 and Et2O. The purification of 3b
was achieved by dialysing the salt in a membrane
tubing for 24 h in acetone.
4.2.1. N-3,5-Di(benzyloxy)benzylcinchonidinium bromide
1a. Mp 215°C. IR (KBr) w 3187, 2939, 2878, 1602,
1
1454, 1381, 1320, 1152, 1058, 858, 754, 696 cm−1. H
NMR l 8.78 (d, J=4.6, 1H), 8.15 (m, 1H), 7.83 (d,
J=4.6, 1H), 7.61 (m, 1H), 7.49 (d, J=7.3, 4H), 7.28
(m, 6H), 7.05 (m, 2H), 6.88 (s, 2H), 6.68 (d, J=5.5,
1H), 6.49 (s, 1H), 6.42 (br.s 1H), 5.89 (d, J=11.6, 1H),
5.37 (d, J=11.6, 1H), 5.31 (d, J=4.3, 2H), 5.08 (dd,
J=12.2, 17.7, 4H), 4.89 (app.t, 1H), 4.38 (m, 1H), 4.08
(m, 1H), 3.78 (bd, J=12.8, 1H), 2.94 (bt, J=10.5, 1H),
2.56 (app.t, J=11.5, 1H), 2.23 (m, 1H), 1.80 (m, 1H),
1.41 (m, 1H), 0.90 (m, 1H). 13C NMR l 159.3, 149.0,
137.0, 136.2, 129.1, 128.9, 128.7, 128.0, 127.95, 127.7,
123.7, 123.2, 119.9, 118.0, 112.9, 104.7, 70.0, 66.7, 65.5,
62.2, 60.0, 50.2, 37.9, 26.4, 25.3, 22.7. MS MALDITOF
[M+−Br] 598.8. Anal. calcd for C40H41BrN2O3: C,
70.89; H, 6.10; Br, 11.79; N, 4.13; found C, 70.74; H,
5.98; Br, 11.63; N, 4.08. [h]2D5=−160 (c 1, CHCl3).
4.3.1. O-Allyl N-3,5-di(benzyloxy)benzylcinchonidinium
bromide 1b. Mp 164°C. IR (KBr) w 3409, 3040, 2939,
2878, 1596, 1454, 1381, 1347, 1300, 1158, 1072, 937,
1
857, 743, 696 cm−1. H NMR l 8.95 (d, J=4.4, 1H),
8.81 (d, J=8.4, 1H), 8.13 (d, J=8.4, 1H), 7.94 (m, 1H),
7.78 (t, J=7.6, 1H), 7.49 (m, 4H), 7.25–7.36 (m, 6H),
7.15 (m, 2H), 6.75 (s, 1H), 6.39 (d, J=11.6, 1H), 6.15
(s, 1H), 6.05 (m, 1H), 5.66 (m, 1H), 5.38 (m, 3H), 5.20
(d, J=11.9, 1H), 5.14 (d, J=11.8, 1H), 5.02 (d, J=
10.4, 1H), 4.77 (m, 1H), 4.58 (m, 1H), 4.43 (d, J=11.7,
1H), 4.22 (dd, J=12.5, 5.1, 1H), 4.15 (m, 2H), 3.98 (dd,
J=12.5, 6.7, 1H), 3.25 (m, 1H), 2.94 (t, J=11.7, 1H),
2.41 (m, 1H), 2.00–2.23 (m, 5H), 1.65 (m, 1H), 1.36 (m,
1H). 13C NMR l 159.7, 149.3, 148.4, 139.8, 136.4,
136.1, 132.4, 130.2, 129.8, 129.1, 128.4, 127.9, 127.8,
125.1, 124.5, 119.8, 118.3, 113.0, 104.2, 70.2, 66.1, 62.1,
59.6, 51.21, 37.7, 26.7, 25.1, 22.6. MS MALDITOF
[M+−Br] 638.5. Anal. calcd for C43H45BrN2O3: C,
71.96; H, 6.32; N, 3.90; found: C, 71.85; H, 6.27; N,
3.81. [h]2D5=−48 (c 1, CHCl3).
4.2.2.
N-Bis-3,5-[(3%,5%-di(benzyloxy)phenylmethoxy]-
benzylcinchonidinium bromide 2a. Mp 164°C. IR (KBr)
w 3409, 3040, 2939, 2878, 1596, 1454, 1381, 1347, 1300,
1159, 1072, 937, 857, 743, 696 cm−1. 1H NMR l 8.76 (d,
J=3.1, 1H), 8.17 (m, 1H), 7.78 (m, 1H), 7.67 (m, 1H),
7.32 (m, 20H), 7.13 (m, 1H), 6.88 (m, 1H), 6.79 (s, 6H),
6.47 (s, 3H), 6.42 (br.s, 1H), 5.84 (d, J=11.0, 1H), 5.38
(d, J=11.6, 2H), 5.03 (s, 14H), 4.89 (app.dd, 1H), 4.33
(m, 1H), 4.00 (m, 1H), 3.55 (m, 1H), 2.70 (m, 2H), 2.19
(m, 1H), 1.86 (m, 2H), 1.42 (m, 1H), 1.23 (m, 1H), 0.89
(m, 1H). 13C NMR l 159.6, 158.6, 148.9, 146.5, 144.1,
140.0, 136.4, 135.5, 128.9, 128.1, 127.5, 127.4, 127.2,
122.9, 122.5, 119.3, 117.0, 112.3, 105.9, 104.0, 101.3,
69.5, 69.4, 66.1, 61.4, 59.4, 49.6, 37.0, 29.2, 25.6, 24.5,
22.0. MS ES [M+−Br] 1022.8. Anal. calcd for
C68H65BrN2O7: C, 74.10; H, 5.94; Br, 7.25; N, 2.54;
found: C, 74.25; H, 5.90; N, 2.03. [h]2D5=−98 (c 1,
CHCl3).
4.3.2.
O-Allyl-N-bis-3,5-[(3%,5%di(benzyloxy)phenyl-
methoxy]benzylcinchonidinium bromide 2b. Mp 91°C. IR
(KBr) w 3409, 3066, 3033, 2932, 2878, 1596, 1454, 1381,
1
1300, 1159, 1051, 843, 743, 696 cm−1. H NMR l 8.95
(d, J=4.4, 1H), 8.78 (app t, J=9.5, 1H), 8.14 (d,
J=8.4, 1H), 1H), 7.93 (m, 1H), 7.79 (m, 1H), 7.12–7.51
(m, 21H), 6.73 (m, 5H), 6.54 (s, 2H), 6.36 (app t,
J=13.0, 1H), 6.15 (s, 1H), 6.03 (m, 1H), 5.64 (m, 1H),
5.26–5.42 (m, 4H), 4.92–5.22 (m, 12H), 4.58 (m, 1H),
4.43 (app. t, J=12.8, 1H), 4.08–4.23 (m, 2H), 3.95 (m,
1H), 3.30 (m, 1H), 2.84–3.03 (m, 1H), 2.43 (m, 1H),
2.02 (m, 6H), 1.67 (m, 1H), 1.38 (m, 1H). 13C NMR l
160.1, 159.8, 149.4, 148.5, 139.9, 139.0, 136.7, 136.5,
136.2, 136.0, 132.4, 130.4, 129.9, 128.9, 128.5, 128.4,
128.3, 128.0, 127.6, 127.1, 124.5, 120.0, 119.8, 118.4,
113.0, 112.9, 106.5, 104.3, 101.6, 72.3, 72.2, 70.1, 62.4,
59.8, 59.7, 51.2, 51.1, 37.8, 37.7, 26.8, 26.7, 25.2, 22.7.
MS ES [M+−Br] 1061.7. Anal. calcd for C71H69BrN2O7:
C, 74.66; H, 6.09; N, 2.45; found: C, 74.57; H, 6.16; N,
2.53. [h]D=−73 (c 1, CHCl3).
4.2.3. N-Tris-{3,5-[bis-3%,5%-(3¦,5¦-di(benzyloxy)-phenyl-
methoxy]}benzylcinchonidinium bromide 3a. IR (KBr)
3409, 3040, 2939, 2878, 1596, 1454, 1381, 1347, 1300,
1159, 1072, 937, 857, 743, 696 cm−1. 1H NMR l 8.66 (d,
J=3.5, 1H), 8.09 (m, 1H), 7.73 (m, 1H), 7.55 (m, 1H),
7.32 (m, 41H), 7.13 (m, 2H), 7.06 (m, 2H), 6.97 (m,
4H), 6.68 (s, 9H), 6.54 (m, 8H), 5.84 (d, J=10.2, 1H),
5.42–4.79 (m, 32H), 4.31 (m, 1H), 4.00 (m, 1H), 3.50
(m, 1H), 2.78 (m, 2H), 2.19 (m, 1H), 1.86 (m, 2H), 1.42
(m, 1H), 1.23 (m, 4H), 0.89 (m, 1H). 13C NMR l 160.4,
160.35, 159.4, 158.6, 149.6, 147.2, 144.8, 149.7, 137.1,
136.2, 129.6, 128.8, 128.3, 127.8, 123.6, 123.1, 120.0,
117.9, 113.1, 106.7, 104.7, 102.6, 101.8, 100.2, 70.3,
66.9, 65.5, 60.2, 50.5, 37.8, 32.5, 30.0, 26.4, 25.3, 22.7.
MS ES [M+−Br] 1871.4. Anal. calcd for
C124H113BrN2O15: C, 76.33; H, 5.84; N, 1.44; found: C,
76.26; H, 5.95; N, 1.44. [h]D=−29 (c 1, CHCl3).
4.3.3.
O-Allyl-N-tris-3,5-[bis-3%,5%-(3¦,5¦-di(benzyl-
oxy)phenylmethoxy]benzylcinchonidinium bromide 3b. IR
(KBr) w 3409, 3040, 2939, 2878, 1596, 1454, 1381, 1347,
1300, 1159, 1072, 937, 857, 743, 696 cm−1. H NMR l
1
8.95 (d, J=3.6, 1H), 8.88 (m, 1H), 8.27 (m, 1H), 8.14
(d, J=7.6, 1H), 8.05 (m, 1H), 7.88–7.21 (m, 40H), 6.79
(m, 4H), 6.71 (s, 15H), 6.59 (m, 10H), 6.03 (m, 2H),
5.37–4.88 (m, 35H), 4.62 (m, 1H), 4.40 (m, 1H), 4.17
(m, 1H), 3.93 (m, 2H), 3.42 (m, 2H), 2.98 (m, 2H), 2.43

G. Guillena et al. / Tetrahedron: Asymmetry 14 (2003) 3705–3712
3711
(m, 2H), 1.95 (m, 2H), 1.30 (m, 2H), 0.96 (m, 1H). 13C
NMR l 160.0, 159.8, 159.6, 150.0, 149.3, 148.4, 139.7,
139.3, 139.2, 139.1, 138.9, 135.9, 133.7, 132.3, 130.3,
129.8, 129.3, 129.1, 128.8, 128.4, 128.1, 127.8, 127.4,
126.8, 125.5, 124.6, 121.1, 119.9, 112.9, 106.3, 105.6,
104.0, 101.4, 100.5, 70.1, 66.9, 65.9, 62.2, 51.2, 37.6,
29.6, 26.6, 25.2, 22.7. MS ES [M+−Br] 1911.2. Anal.
calcd for C127H117BrN2O15: C, 76.61; H, 5.92; N, 1.41;
found: C, 76.69; H, 5.87; N, 1.43. [h]D=−16 (c 1,
CHCl3).
NMR l 7.66–7.51 (m, 3H), 7.81 (m, 1H), 7.48–7.29 (m,
5H), 7.17 (m, 1H), 5.06 (m, 1H), 3.98 (m, 1H), 1.89 (m,
2H), 1.34 (m, 2H), 1.25 (m, 8H), 0.8 (t, J=7.2, 3H). 13
C
NMR l 171.2, 171.6, 137.7, 132.4, 130.1, 128.3, 69.8,
60.4, 29.7, 22.2, 21.7, 13.6. MS m/z [M+], 337. HRMS
calcd for C22H27NO2: 337.2042. Found 337.2077.
4.4.5. Isopropyl 3-(3,5-dimethoxyphenyl)-2-diphenyl-
methyleneaminopropanoate 6e. IR (film) w 3062, 2979,
1
2941, 2839, 1741, 1606, 1209, 1156 cm−1. H NMR l
7.80 (d, J=7.0, 1H), 7.58 (m, 2H), 7.48 (t, J=7.3, 1H),
7.39–7.23 (m, 4H), 7.17 (d, J=7.4, 1H), 6.66 (d, J=7.4,
1H), 6.28 (t, J=2.3, 1H), 6.20 (d, J=2.3, 2H), 5.05
(hept, J=6.2, 1H), 4.19 (dd, J=9.3, 4.3, 1H), 3.63 (s,
6H), 3.11, 3.20 (2dd, J=13.2, 9.3, 4.3, 2H), 1.24 (2d,
J=6.2, 6H). 13C NMR l 171.2, 170.6, 160.4, 140.3,
139.4, 136.1, 132.4, 130.2, 130.1, 129.0, 128.7, 128.25,
128.2, 128.15, 128.0, 127.9, 125.7, 125.3, 107.4, 99.1,
68.4, 67.2, 55.1, 39.9, 21.8. MS m/z [M+], 431. HRMS
calcd for C27H29NO4: 431.2097. Found 431.2057.
4.4. Alkylation general procedure. Synthesis of 6
A mixture of 5 (0.5 mmol, 140 mg), benzyl bromide (2.5
mmol, 425 mL) and the catalyst (0.05 mmol) in toluene/
CHCl3 (7/3 v/v, 2.5 mL) was cooled and an aq. 50%
solution of KOH (0.75 mL) or NaOH (0.55 mL) was
added. The mixture was vigorously stirred and moni-
tored by GLC. When the reaction was finished, water
(15 mL) was added and the mixture was extracted with
AcOEt (3×15 mL). The organics extracts were com-
bined and dried (Na2SO4) then evaporated to dryness in
vacuo.
Acknowledgements
4.4.1. Isopropyl 2-diphenylmethyleneamino-3-phenyl-pro-
pionate 6a. IR (film) w 3063, 3032, 2976, 2935, 1742,
1
This work was supported by the Council for Chemical
Sciences from the Dutch Organisation for Scientific
Research (CW-NOW), the Netherlands Research
School Combination Catalysis (NRSC-C), University
of Utrecht, the Ministerio de Ciencia y Tecnolog´ıa
(MCyT) of Spain (DG, research project BQU2001-
0724-C02-01), Generalitat Valenciana (CTIOIB/2002/
320) and the University of Alicante. G.G. thanks the
European Commission for a Marie Curie fellowship
(Contract No. HPMF-CT-2000-00472).
1629 cm−1. H NMR l 7.79 (d, J=7.9, 1H), 7.03–7.60
(m, 13H), 6.62 (m, 1H), 5.04 (hept, J=6.1, 1H), 4.19
(dd, J=9.2, 4.3, 1H), 3.17, 3.27 (2dd, J=13.1, 9.2, 4.3,
2H), 1.21 (2d, J=6.5, 6H). 13C NMR l 171.1, 170.5,
139.4, 138.0, 136.1, 132.3, 130.1, 130.0, 129.7, 128.6,
128.1, 128.0, 127.8, 127.5, 126.1, 68.2, 67.3, 39.5, 21.7.
MS m/z [M+], 371. HRMS calcd for C22H25NO2:
371.1885. Found 371.1847.
4.4.2. Isopropyl 3-(4-cyanophenyl)-2-diphenylmethyl-
eneaminopropanoate 6b. Mp 145°C. IR (KBr) w 3066,
1
2979, 2932, 2905, 2227, 1737, 1622 cm−1. H NMR l
7.80 (d, J=8.4, 1H), 7.66 (d, J=6.7, 1H), 7.26–7.62 (m,
10H), 7.18 (d, J=8.3, 2H), 6.70 (m, 1H), 5.04 (hept,
J=6.3, 1H), 4.20 (dd, J=8.6, 4.8, 1H), 3.24, 3.31 (2dd,
J=13.3, 8.6, 4.8, 2H), 1.22 (2d, J=6.3, 6H). 13C NMR
l 171.1, 170.5, 144.0, 139.0, 135.9, 132.6, 132.3, 131.8,
130.5, 130.0, 128.7, 128.6, 128.3, 128.2, 128.0, 127.7,
127.5, 127.0, 119.0, 110.1, 68.8, 64.6, 39.6, 21.7. MS
m/z [M+], 396 HRMS calcd for C22H17N2: 309.1384.
Found 309,1392.
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