New enantiopure imidazolinium carbene ligands incorporating two hydroxy groups for Lewis acid-catalyzed diethyl zinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2008.10.011

New enantiopure imidazolinium carbene ligands incorporating two hydroxy functions have been synthesized from commercially available chiral amino alcohols and diamines. These ligands in combination with different metallic salts have been investigated in th

Full text of DOI:10.1016/j.tetasy.2008.10.011

Tetrahedron: Asymmetry 19 (2008) 2346–2352
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Tetrahedron: Asymmetry
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New enantiopure imidazolinium carbene ligands incorporating two
hydroxy groups for Lewis acid-catalyzed diethyl zinc addition to aldehydes
*
Mazhar Gilani, René Wilhelm
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, 38678, Clausthal-Zellerfeld, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
New enantiopure imidazolinium carbene ligands incorporating two hydroxy functions have been synthe-
sized from commercially available chiral amino alcohols and diamines. These ligands in combination
with different metallic salts have been investigated in the diethylzinc addition to aldehydes with good
yields and enantioselectivity.
Received 30 July 2008
Revised 6 October 2008
Accepted 14 October 2008
Available online 5 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
N
N
Mes
Cl
The family of enantiopure N-heterocyclic carbenes has emerged
as an important class of ligands with many applications in organo-
metallic chemistry1 and as organocatalysts.2 In general the carb-
enes are mainly prepared from the corresponding salts via
deprotonation. The latter can also be considered to be part of the
class of chiral ionic liquids3 depending on their melting points.
For example, chiral imidazolinium-based ionic liquids have re-
cently been reported.3b,4 The number of highly selective enantio-
pure carbene ligands in a few reactions is increased, but remains
small compared to the many other applications of chiral phosphine
ligands, this makes it desirable to expand upon the library of chiral
carbene ligands.1f
N
N
OH
tBu
BF4
HO
1
2
iPr
tBu
N
N
N
N
Mes
HO
PF6
A limited number of chiral imidazol(in)ium salts incorporating
hydroxy groups have been reported. The salts are precursors for
bidentate ligands and for example salt 3 has also been used as an
ionic liquids.4a A very successful bidentate hydroxy-carbene ligand
prepared from salt 1 was described by Hoveyda et al.5 giving up to
96% ee in an asymmetric olefin metathesis and 98% ee in a copper-
catalyzed allylic alkylation. Arnold et al. prepared from salt 2 a CuI
complex for the diethylzinc conjugate addition to cyclohexenone,
resulting in up to 51% ee.6 Mauduit et al. used various analogues
of salt 4 in the CuII-catalyzed addition of diethylzinc to cyclohexe-
none obtaining ees of up to 93% (Fig. 1).7
HO
PF6
3
4
BF4
N
N
OHHO
5
Figure 1. Hydroxy-containing imidazol(in)ium salts.
In addition, Alexakis and Mauduit also used analogues of 4 and
other chiral imidazolinium salts as carbene precursors in a copper-
catalyzed conjugate Grignard addition to 3-substituted cyclohexe-
nones to obtain quaternary chiral centers in up to 96% ee.8
Recently, we explored the behavior of a few new imidazolinium
salts of type 5 with two hydroxy groups as potential tridentate li-
gands in the diethyl zinc addition to aldehydes giving up to 66% ee
and 67% yield without the addition of an additional metal salt.4c In
order to explore this group of ligands further, we herein report an
expansion of the library of these ligands and a study of the influ-
ence of various Lewis acidic metals. In particular oxophilic metals,
related to zinc, were explored with these carbene ligands in the
diethyl zinc addition9 to aldehydes in order to prepare optically ac-
tive secondary alcohols, which are important intermediates in
synthesis.
* Corresponding author. Tel.: +49 5323 723886; fax: +49 5323 722834.
E-mail address: rene.wilhelm@tu-clausthal.de (R. Wilhelm).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.011

M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
2347
The salts were then prepared by the direct reaction of the dia-
mines and triethyl orthoformate in the presence of ammonium
salts according to a literature procedure.11 The latter were used
as a Brønsted acid source for the activation of the orthoester. These
ammonium salts also acted as a source of the anion for the corre-
sponding imidazolinium salts (Scheme 3).
2. Results and discussion
2.1. Preparation of the salts
The synthesis started with the preparation of C2 symmetric dia-
mines. Two routes were employed for their synthesis. First, dia-
mines bearing hydroxy groups were prepared by simple
alkylation of the corresponding amino alcohols with 1,2-dibromo-
ethane via a literature procedure.10 The reaction was neat and gave
excellent yields of the diamines (Scheme 1). The HBr salt of the cor-
responding diamine was precipitated as a yellow solid in the reac-
tion mixture, which was dissolved in water. After removal of
impurities by solvent extraction with chloroform, the aqueous
phase was basified with NaOH to obtain pure bis-amino alcohol
which was free of acid contents.
R2
N
R2
R2
R2
(EtO)3CH, NH4X
120 °C
R1
X
N
R1
R1 NH HN R1
Scheme 3. Synthesis of imidazolinium salts.
Salt 12 has been synthesized from amino alcohol 6 with a yield
of 74%.4c Salts 13, 14, and 15 have the same cation but different an-
ions. Chloride, bromide, and iodide salts were synthesized in order
to investigate the influence of harder anions in the diethylzinc
addition to aldehydes. Salts 18 and 19 have additional steric infor-
mation in their backbone, and have been synthesized in excellent
yields of 80% and 90%, respectively. The results are summarized
in Table 1.
i) 100 ºC, 16 h
R1 NH2
+
Br
Br
R1 NH HN R1
Ph
ii) NaOH
Ph
NH HN
NH HN
Ph
Ph
OH
HO
OH HO
6
, 98%
7
, 93%
Ph
Ph
NH HN
OH HO
Table 1
Preparation of salts
Entry
Diamine
Cation
Anion
Salt
Yield (%)
8
, 92%
ꢀ
1
2
3
4
BF4
12
13
14
15
74
42
66
67
6
Clꢀ
Brꢀ
Iꢀ
Scheme 1. Alkylation of amino alcohols.
N
N
Ph
Ph
Ph
In addition C2 symmetric amino alcohols were also synthesized
by the ring opening of epoxides. Here, chiral diamine 9 was reacted
with chiral and achiral epoxides giving rise to b-amino alcohols
(Scheme 2). The mixture was refluxed in EtOH for 72 h. The solvent
was removed, after which the solid was dissolved in water and
acidified to pH 2 with 2 M hydrochloric acid. The aqueous layer
was extracted with chloroform which was discarded. The aqueous
layer was then basified to pH 11 with 2 M NaOH solution and the
product was obtained by extracting the aqueous layer with chloro-
form. The amino alcohols 10 and 11 were obtained in excellent
yields with high purity.
HO
OH
ꢀ
5
6
7
7
BF4
16
17
18
57
66
80
Ph
N
N
HO
OH
ꢀ
8
BF4
Ph
Ph
N
N
HO
OH
ꢀ
O
10
BF4
Ph
Ph
Ph
Ph
N
Ph
Ph
NH HN
N
H2N
NH2
EtOH, 72 h, 90 ºC
O
OH
OH
HO
, 92%
9
10
OH HO
ꢀ
8
11
BF4
19
90
Ph
Ph
Ph
Ph
NH HN
N
N
HO
OH
HO
11, 90%
Scheme 2. Ring opening of epoxides.

2348
M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
attributed to the fact that these anions also take part in the transi-
tion state formed, depending on their binding strength to the metal
cation. Calcium chloride proved to be a better Lewis acid as com-
pared to MgBr2, as can be seen from entries 9 and 10 of Table 3.
The results obtained with calcium are remarkable as this metal
has not often been used in such a type of catalysis, and is an envi-
ronmentally friendly cation.
Et
OH
O
*
Et2Zn
21
20
Scandium triflate gave a poor yield of 8% with an ee of 57%.
Ni(acac)2 and silver oxide led to an ee of 18% and 10%, respectively.
The best yield was 70%, obtained by using zinc triflate with an ee of
63%. Fe+2 proved to be superior to Fe+3 as the former gave 53% yield
with an ee of 63%, while the latter gave 32% yield and 49% ee. It can
be seen that the ligand based on salt 12 has a wide range of inter-
action with several metallic cations.
Scheme 4. Diethylzinc addition to aldehydes.
Table 2
Investigation of the salts: 2.5 mol % Cu(OTf)2, 5 mol % salt, 15 mol % KOtBu, 46 h, rt,
toluene
Entry
Salt
Yield (%)
ee (%)
Conf.
1
12
13
14
15
16
17
18
19
42
37
43
31
16
13
62
55
84
44
42
22
0
0
12
34
(R)
(R)
(R)
(R)
—
—
(S)
(R)
2a
3
Table 4
4a
5
6
7
8
Investigation of salt 12 with different metals concentrations: (metal salt:salt
12:KOtBu) (1:1:3), 46 h, rt, toluene
Entry
Metal salt
CuI
Ligand (mol %)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
20
10
5
3
1
10
5
3
21
22
53
55
51
12
42
44
24
80
80
84
82
63
80
84
77
6
a
5 mol % Cu(OTf)2, 10 mol % salt, 30 mol % KOtBu.
2.2. Investigation in catalysis
Cu(OTf)2
The imidazolinium salts were applied in the diethylzinc addi-
tion to 1-naphthaldehyde 20 as shown in Scheme 4 in order to
evaluate their efficiency in terms of yield and stereoselectivity.
Therefore, the carbene ligands were employed along with cop-
per(II) triflate (Table 2). It was found that ligand 12 gave the high-
est ee of 84% with a moderate yield of 42%. Among the other
ligands, 18 gave a higher yield of 62% but with a lower ee of 12%.
The large influence of the counter-anion on the ee can be attrib-
uted to the fact that BF4, at least in comparison to Cl, Br, and I, is
a non-coordinating anion. The halide anions could co-ordinate a
metal center and therefore change the catalytic species.
Since the carbene based on salt 12 gave the best results, further
optimization was performed with this ligand. Since different metal
cations can influence the reaction due to their size, co-ordination
sphere, and charge density, several metal salts were investigated
in the reaction. The results are summarized in Table 3. Cu(OTf)2
was found to give the highest enantiomeric excess of 84%, but with
a moderate yield of 42%. Cupric ions with different counter-anions
such as chloride gave 80% ee. However, the yield decreased to 32%
indicating the influence of the metallic halide counter-anion,
which coordinates to the metal in the catalytic species.
1
In these experiments, three parts of KOtBu were added to one
part of the imidazolinium salt in toluene. As shown in Table 5, this
was important in order to deprotonate the C2 position and both
hydroxyl groups. After 30 min, metallic salt was added and the
mixture left to stir for 1 h. Next 1-naphthaldehyde 20 was added,
followed by the addition of Et2Zn (1.1 equiv). The reaction was stir-
red for 46 h at rt and then quenched with 1 M HCl. Considering the
fact that the ligand contains two hard oxygen ligator atoms and
one soft carbene moiety, one could explain why these metals
(being in the middle of the hard-soft scale) gave the best results.
As catalytic active species, a tridentate ligand arrangement can
be assumed, as has been reported for tris-oxazoline ligands,12
which were able to coordinate to a copper center to give a hexaco-
ordinated stereo-discriminating complex containing the tridentate
ligand, and one water molecule, leaving two co-ordination sites for
the substrate.
Table 5
Titanium(IV)chloride gave an ee of 15% while titanium(IV)tetra-
isopropoxide resulted in 51% ee. This marked difference can be
Investigation of base: (metal salt:salt 12) (1:1), 46 h, rt, toluene
Entry
Base
Base (equiv)
Yield (%)
Ee (%)
Table 3
Investigation of salt 12 with different metals: (metal salt:salt 12:KOtBu) (1:1:3), 46 h,
rt, toluene
1
2
3
4
5
6
KOtBu
0.3
0.2
0.1
0.3
0.2
0.1
42
26
Traces
44
31
Traces
80
80
—
28
5
Entry
Metal salt
Ligand (mol %)
Yield (%)
ee (%)
KHMDS
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
CuI
CuCl2
Cu(OTf)2
Cu(acac)2
FeCl2
FeCl3
Ti(iPrO)4
TiCl4
5
3
5
10
2
2
3
3
5
5
53
32
42
15
53
32
41
34
60
52
8
80
80
84
28
63
49
51
15
43
25
57
18
10
63
86
—
The concentration of the catalyst in the diethyl zinc addition to
1-naphthaldehyde could play a pivotal role on the yield and enan-
tiomeric excess of the product. In order to evaluate the effect of
concentration of catalyst, CuI and Cu(OTf)2 were employed as these
catalysts prove the best candidates for further investigation as
shown in Table 4. When the salt to ligand ratio was 1:1, CuI with
20 mol % of ligand gave 21% yield with 80% ee. Moreover,
10 mol % of ligand gave 22% yield and 80% ee, while 5 mol % of
ligand gave 53% yield and 84% ee. A yield of 55% and 82% ee was
CaCl2
MgBr2
Sc(OTf)3
Ni(acac)2
Ag2O
Zn(OTf)2
CrCl3
5
10
10
5
52
14
70
45
5

M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
2349
found when 3 mol % of the ligand was used. With Cu(OTf)2, 5 mol %
of ligand was the best concentration as it gave 42% yield and 84%
ee. It is rare but not unknown that lower catalyst loading gives bet-
ter yield and higher ee.13 In the present case the drop of ee at lower
catalyst loading and therefore lower concentration can be ex-
plained by a competitive, ligand-free background reaction. On
the other hand, at a higher catalyst loading and therefore higher
concentration, it may be possible that an inactive dimer with
two copper atoms and two ligands could be formed.
In addition, the influence of the bases KHMDS and KOtBu to
generate the carbenes was investigated. The latter gave the best re-
sults. KHMDS resulted in 28% ee when 3 equiv was used with a
yield of 44% (Table 5, entry 4), while 31% yield was obtained with
a low ee of 5%, when 2 equiv of base was applied. KOtBu proved to
be the best choice. It can also be concluded from entries 1–3 of Ta-
ble 5 that 3 equiv of KOtBu is necessary in order to achieve a yield
of 42% and an ee of 84%. For all these reactions, Cu(OTf)2 was used
and the ligand to salt ratio was 1:1. The need for 3 equiv of KOtBu
strongly supports that a tridentate ligand is present in the active
catalyst. In addition the enhanced ee resulting in KOtBu can be
attributed to the fact that the released tBuOH is also participating
in the formation of the catalytically active species and could coor-
dinate the metal center. That the alcohol plays such a role is also
shown later, when the sterically less hindered ethanol was added,
which increased the ee.
It is known that the salt to ligand ratio can play a crucial role in
controlling the outcome of the reaction particularly in terms of
yield. In the case of Cu(OTf)2 the yield of the product was maxi-
mized to 76% from 42% as the salt to ligand ratio was changed from
1:1 to 1:2. The enantiomeric excess experienced a slight drop from
84% to 73% (Table 7, entries 1 and 2). The reversal of this optimized
M:L ratio gave 35% yield and 11% ee (Table 7, entry 3). This can be
explained by a ligand-free background reaction. In case of Ti(iPrO)4,
when the salt to ligand ratio was changed from 1:1 to 1:2, the yield
improved from 41% to 54% and the ee rose from 51% to 75%.
The catalytic system was then examined to determine if a non-
linear effect was present, since the best results were obtained with
a metal:ligand ratio of 1:2. Both enantiomers of norephedrine-
based imidazolinium salt 12 were mixed in different ratios. The
graph obtained shows a slight deviation from linearity, as can be
seen from the following graph (Fig. 2). However, taking the error
range into consideration no nonlinear effect is present, and the
benefit of using a larger amount of ligand is in order to suppress
a ligand-free catalyzed background reaction.
In order to further optimize the diethylzinc addition to 1-naph-
thaldehyde, the reaction was carried out at different temperatures.
It was found that by lowering the temperature to 0 °C, the yield de-
creased markedly to 8% and also a slightly lower ee of 73% was ob-
served (Table 6, entry 5). A further decrease in temperature also
decreased the ee to 9% (Table 6, entry 4). For this experiment, n-
BuLi was used as a base instead of KOtBu, showing again the
importance of the presence of tBuOH for the enantioselective reac-
tion. When the reaction was carried out at 40 °C, the results were
almost similar to those obtained when the reaction was performed
at rt (Table 6, entries 1 and 2). Increasing the temperature to 60 °C
led to a decrease in yield and in ee of the product, respectively (Ta-
ble 6, entry 3). The decrease of the ee at higher temperature is
obvious since an enantioselective-catalyzed reaction is kinetically
controlled. The decrease of the yield and more important the ee
at lower temperatures could be explained by the formation of dif-
ferent catalytic copper species and clusters. Similarly, unusual rela-
tionships have been observed by Hoveyda14 and Leighton15 in the
copper-catalyzed enantioselective conjugate addition with chiral
phosphine ligands.
Figure 2. Absence of a nonlinear effect.
The influence of ethanol, as an additive, was also explored. It
was seen that addition of ethanol as an additive in the diethylzinc
addition to 1-naphthaldehyde showed a marked increase in the ee
of the product, that is, 85% as compared with 73% ee, which was
obtained without the addition of any additive. However, the yield
decreased slightly from 76% to 65%. Furthermore, exploring other
solvents revealed that toluene is the best solvent for this system.
In addition, the new bis-amino alcohols ent-10 and 11 were also
evaluated as ligands in the diethyl zinc addition to 1-naphthalde-
hyde. The product was obtained in 77% and 90% yield with an ee
of 53 (S) and 43% (R), respectively.
Table 6
Investigation of temperature: (metal salt:salt 12) (1:1), 46 h, rt, toluene
Entry
Salt
CuI
t (°C)
Yield (%)
ee (%)
1
2
rt
40
60
53
43
29
47
8
80
83
56
9
3
4a
5
Cu(OTf)2
ꢀ50
0
73
Finally, different aldehydes were used under the optimized con-
ditions as shown in Table 8. The results were comparable to those
of 1-naphthaldehyde.
a
n-BuLi was used as a base.
Table 7
Effect of salt to ligand ratio
Table 8
Enantioselective diethylzinc addition to aldehydesa
Entry
Metal salt
Cu(OTf)2
Metal:ligand
Yield (%)
ee (%)
Entry
Aldehyde
Yield (%)
ee (%)
Conf.
1
2
3
4
5
6
1:1
1:2
2:1
1:4
1:1
1:2
42
76
35
60
41
54
84
73
11
70
51
75
1
2
3
4
2-Naphthaldehyde
Benzaldehyde
p-Chlorobenzaldehyde
p-Methylbenzaldehyde
57
59
60
50
50
75
78
71
(R)
(R)
(R)
(R)
Ti(iPrO)4
a
Cu(OTf)2:12:KOtBu/1:2:3, 46 h, rt, toluene.

2350
M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
Table 9
tra were recorded with a Bruker Vektor 22 FTIR spectrometer, as
KBr pellets in case of solid compounds and as thin films between
NaCl plates in cases of oils and liquids. Melting points were taken
with a Dr. Tottoli apparatus and are uncorrected.
Chemical shifts d of Mosher’s carboxylate in ppm and
D
d values in Hz (400 MHz 1H
NMR, 375 MHz 19F NMR)
Entry
Salt
d(1H) (S)/(R)
d(19F) (S)/(R)
D
d(1H)
D
d(19F)
1
2
3
4
5
6
7
8
—
3.57/3.57
3.56/3.56
3.57/3.54
3.56/3.53
3.56/3.56
3.60/3.61
3.60/3.60
3.62/3.62
ꢀ71.19/ꢀ71.19
ꢀ70.75/ꢀ70.75
ꢀ70.73/ꢀ71.04
ꢀ70.68/ꢀ70.99
ꢀ71.06/ꢀ71.06
ꢀ71.17/ꢀ71.17
ꢀ70.97/ꢀ71.03
ꢀ71.07/ꢀ71.07
0
0
0
117
117
0
0
22
0
13
14
15
16
17
18
19
0
12
12
0
4
0
4.2. Preparation of C2 symmetric diamines
4.2.1. General procedure for the preparation of diamines by
alkylation with dibromoethane
An amino alcohol (1.00 mmol) was added in to a dried flask un-
der nitrogen. Dibromoethane (43 lL, 0.50 mmol) was added via
0
syringe under nitrogen. The reaction mixture was heated at
100 °C for 16 h. The mixture was then cooled to room temperature.
After dissolving the solid in water, the aqueous phase was washed
with chloroform. The aqueous phase was basified with 2 M NaOH
and the diamine was extracted with chloroform (3 ꢁ 5 mL). The
combined organic fractions were dried (Na2SO4) and the solvent
was evaporated under reduced pressure to give the bis-amino
alcohol.
2.3. Use as a shift reagent
The newly synthesized salts were investigated for their ability
to interact with Mosher’s carboxylate, by examining the differ-
ences in the chemical shifts of the MeO group and the CF3 group
of the two enantiomers of Mosher’s carboxylate. In order to assign
the signals of the corresponding enantiomers, enantioenriched
(12% ee) Mosher’s carboxylate was mixed with the chiral imidazo-
linium salts in a 1:1 ratio. The mixture was dissolved in acetone-d6
and 1H and 19F NMR spectra were recorded. The results are sum-
marized in Table 9.
4.2.2. (ꢀ)-(1R,10R,2S,20S)-2,20-(Ethane-1,2-
diylbis(azanediyl))bis(1-phenylpropan-1-ol) 6
This compound was prepared from (ꢀ)-norephedrine (3.00 g,
19.84 mmol) and dibromoethane (0.85 mL, 9.92 mmol), after basi-
fication with NaOH as a yellow solid (3.18 g, 98%). Spectroscopic
data are consistent with literature values.16
Salt 13 showed no splitting in either the 1H or 19F spectra. When
the anion was changed from chloride to bromide and iodide, a
splitting of 12 Hz in 1H NMR and 117 Hz in 19F NMR was observed
in each case (Table 9, entries 3 and 4). Salts 16 and 19 showed no
splitting at all, while salt 18 showed a splitting of 22 Hz in 19F NMR
and salt 17 displayed a splitting of 4 Hz in 1H NMR.
4.2.3. (ꢀ)-(2S,20S)-2,20-(Ethane-1,2-diylbis(azanediyl))bis(3-
phenylpropan-1-ol) 7
This compound was prepared from (ꢀ)-(S)-2-amino-3-phenyl-
1-propanol (0.30 g, 1.98 mmol) and dibromoethane (86.0
lL,
3. Conclusion
0.99 mmol), after basification with NaOH as
a yellow solid
(0.30 g, 93%). Spectroscopic data are consistent with literature
In conclusion, enantiomerically pure imidazolinium-based li-
gands incorporating two hydroxy groups have been synthesized
in moderate to excellent yields by following a simple two-step pro-
cedure. The ligands have been employed in the diethylzinc addi-
tion to 1-naphthaldehyde, and an ee of up to 84% has been
achieved. Moreover, extensive optimization allowed us to under-
stand the behavior of the ligands under different reaction condi-
tions, indicating a tridentate ligand and tBuOH coordinating to
the metal cation. It was found that copper gave the highest ee in
the reaction, which is remarkable since it is normally used for
the 1,4 addition of diethyl zinc to unsaturated carbonyl
compounds.
values.17
4.2.4. (+)-(2S,20S)-2,20-(Ethane-1,2-diylbis(azanediyl))bis(2-
phenylethanol) 8
This compound was prepared from (+)-(S)-phenylglycinol
(0.30 g, 2.19 mmol) and dibromoethane (95.0 lL, 1.09 mmol), after
basification with NaOH as a yellow oil (0.30 g, 92%). Spectroscopic
data are consistent with literature values.18
4.2.5. General procedure for the preparation of diamines by
ring opening of epoxides
To a stirred solution of chiral 1,2-diphenyl-1,2-ethanediamine
(0.21 g, 1.0 mmol) in anhydrous ethanol (5 mL) was added epoxide
(3.0 mmol) via a syringe dropwise under an inert atmosphere at
room temperature. Upon complete addition, the mixture was
heated at reflux for 46 h. After refluxing, the mixture was cooled
to room temperature whereupon the solvent was evaporated to
give a white solid. The solid was dissolved in water that was acid-
ified to pH 2 with 2 M hydrochloric acid and the aqueous layer ex-
tracted with chloroform (3 ꢁ 5 mL) which was discarded. The
aqueous layer was then basified to pH 11 with 2 M aqueous so-
dium hydroxide and the aqueous layer was again extracted with
chloroform (3 ꢁ 5 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated, resulting in a white crystal-
line solid.
4. Experimental
4.1. General experimental
All reactions were carried out in anhydrous solvents under
nitrogen. All solvents were dried by standard procedures before
being used in the reactions. 1H NMR spectra were acquired with
Bruker AC 200F (200 MHz) at ambient temperature. Chemical 13C
NMR spectra were recorded at ambient temperature with AC
200F (50 MHz) instruments and 19F NMR spectra were recorded
at ambient temperature with a Bruker AMX 400 (378 MHz) instru-
ment. Chemical shifts are reported in ppm relative to tetramethyl-
silane as an internal standard. Mass spectra (ESI) were recorded
with a Hewlett–Packard MS LC/MSD Series 1100 MSD instrument,
while high-resolution mass spectra were measured with a Bruker
Daltonik Tesla–Fourier Transform-Ion Cyclotron Resonance Mass
Spectrometer. Elemental analyses were carried out by the Micro-
analytical Laboratory of the Institut für Pharmazeutische Chemie
der Technische Universität Braunschweig with an Elemental Ana-
lyzer Model 1106 from Carlo Erba Instrumentazione. Infrared spec-
4.2.6. (ꢀ)-(R,R)-1,2-Diphenyl-N,N0-bis((R)-2-hydroxyethyl)-3-
methyl)ethylenediamine 10
This amino alcohol was synthesized from (+)-(1R,2R)-1,2-diphe-
nyl-1,2-ethanediamine (0.20 g, 0.94 mmol) and (+)-(R)-propylene
oxide (0.20 mL, 2.83 mmol) by following the general procedure
as a white crystalline solid (0.287 g, 93%). mp 119 °C. ½a D22
¼ ꢀ30
ꢂ

M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
2351
(c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) d 7.07–6.94 (m, 10H),
3.80–3.70 (m, 2H), 3.63 (s, 2H) 2.43–2.16 (m, 4H), 0.98 (d,
J = 5.4 Hz, 6H) 13C NMR (50 MHz, CDCl3) d 140.7, 128.0, 127.7,
127.0, 68.3, 65.9, 54.3, 20.5. IR (KBr): 3303, 2961, 2909, 1646,
1454, 1126, 1051, 864, 772, 700, 625, 575 cm–1. MS (ESI = 0 V):
m/z = 351 [M+Na]. HRMS (ESI): calcd for C21H29N2O2 [M+H]:
329.2229; found 329.2229.
5.68 (d, J = 4.0 Hz, 2H), 5.10 (br s, 2H) 4.09–3.86 (m, 6H), 0.85 (d,
J = 7.0 Hz, 6H). 13C NMR (50 MHz, (CD3)2CO) d 157.2, 142.3,
128.9, 127.7, 126.8, 72.3, 60.3, 48.8, 11.1. IR (KBr) 3344, 1647,
1266, 1151, 753, 704 cm–1: MS (ESI = 0 V): m/z (%) = 339 [M].
þ
HRMS (ESI): calcd for C21H27N2O2 339.2073; found 339.2070.
4.2.12. (ꢀ)-3-Bis-[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl]-
imidazolinium iodide 15
This compound was prepared from 6 (200 mg, 0.61 mmol), NH4I
(88.3 mg, 0.61 mmol), and CH(OEt)3 (100 lL, 0.61 mmol). The reac-
4.2.7. (+)-(R,R)-1,2-Diphenyl-N,N0-bis(2-hydroxy-2-methyl-
propyl)ethylenediamine 11
This amino alcohol was synthesized from (+)-(1R,2R)-1,2-diphe-
nyl-1,2-ethanediamine (0.10 g, 0.47 mmol) and isobutylene oxide
(0.13 mL, 1.41 mmol) by following the general procedure as a
tion mixture was heated to 120 °C in a sealed vessel for 5 h. After
the removal of the solvent, the crude was washed with hexane
and diethyl ether giving the title compound as a white crystalline
solid (189 mg, 67%). Compound 15 was recrystallized in acetone
white crystalline solid (0.148 g, 90%). mp 123 °C. ½a D22
¼ þ13 (c
ꢂ
0.5, MeOH); 1H NMR (200 MHz, CDCl3) d 7.26–6.98 (m, 10H),
3.69 (s, 2H) 2.36 (s, 6H), 1.17 (s, 6H), 1.13 (s, 6H). 13C NMR
(50 MHz, CDCl3) d 141.0, 128.0, 127.6, 127.0, 69.9, 69.6, 58.1,
27.4, 27.3. IR (KBr): 3302, 2962, 2907, 1455, 1405, 1164, 1127,
896, 845, 764, 699, 580 cm–1. MS (ESI = 0 V): m/z (%) = 379 (70%)
[M+Na], 357 (60) [M+H]. HRMS (ESI): calcd for C21H33N2O2
[M+H]: 357.2542; found 357.2542.
for X-ray crystallography. mp 184 °C. ½a D22
¼ ꢀ4 (c 0.3, MeOH);
ꢂ
1H NMR (200 MHz, CD3OD) d 7.90 (s, 1H), 7.16–7.08 (m, 10H),
4.61 (s, 2H), 3.72–3.60 (m, 6H), 1.00 (d, J = 7.0 Hz, 6H). 13C NMR
(50 MHz, CD3OD) d 157.8, 142.1, 129.6, 129.1, 127.5, 75.2, 60.9,
47.2, 13.5. IR (KBr): 3438, 3236, 1650, 1496, 1262, 1138, 1029,
1016, 753, 704 cm–1. MS (ESI = 0 V): m/z = 339 [M]. HRMS (ESI):
þ
calcd for C21H27N2O2 339.2073; found 339.2072.
4.2.8. General procedure for preparation of imidazolinium salts
A bis-amino alcohol (1.00 mmol) was placed in a flask, and the
counteranion source (typically NH4BF4, 1.00 mmol) and triethyl
4.2.13. (ꢀ)-1,3-Bis[(S)-1-(hydroxymethyl)-2-methylbenzyl]-
imidazolinium tetrafluoroborate 16
This compound was prepared from 7 (200 mg, 0.61 mmol),
NH4BF4 (68.6 mg, 0.67 mmol), and CH(OEt)3 (109 lL, 0.67 mmol).
The reaction mixture was heated to 120 °C in a sealed vessel for
5 h. After removal of the solvent, the crude was washed with hex-
ane and diethyl ether giving the title yellow gummy compound
orthoformate (148 mg, 165 lL, 1.00 mmol) was added. The reac-
tion vessel was flushed with nitrogen and sealed, and the mixture
was heated to 120 °C for 5 h. After cooling, the mixture was dried
under vacuum, in order to remove ethanol, formed during the reac-
tion, to give the crude salt in high purity.
(147 mg, 57%). ½a D22
ꢂ
¼ ꢀ71 (c 1.0, CHCl3); 1H NMR (200 MHz,
(CD3)2CO) d 8.16 (s, 1H), 7.20–7.14 (m, 10H), 3.57–3.95 (m, 12H),
2.84 (m, 4H). 13C NMR (50 MHz, (CD3)2CO) d 158.6, 137.9, 129.9,
129.6, 127.7, 62.8, 61.3, 46.9, 35.6. IR (NaCl): 3054, 2987, 1422,
1265, 896, 739 cm–1. MS (ESI = 0 V): m/z = 339 [M]. HRMS (ESI):
4.2.9. (ꢀ)-1,3-Bis[(1S,2R)-2-hydroxy-1-methyl-2-
phenylethyl]imidazolinium tetrafluoroborate 12
This compound was prepared from 6 (500 mg, 1.52 mmol),
NH4BF4 (156 mg, 1.52 mmol), and CH(OEt)3 (250 lL, 1.52 mmol).
þ
calcd for C21H27N2O2 339.2073; found 339.2075.
The reaction mixture was heated to 120 °C in a sealed vessel for
5 h. After removing the ethanol, the crude was washed with hex-
ane, diethyl ether, and dichloromethane giving the title compound
as a white solid (481 mg, 74%). Spectroscopic data are consistent
with literature values.4c
4.2.14. (+)-1,3-Bis[(S)-1-(hydroxymethyl)-2-methylphenyl]-
imidazolinium tetrafluoroborate 17
This compound was prepared from 8 (100 mg, 0.33 mmol),
NH4BF4 (53.8 mg, 0.49 mmol), and CH(OEt)3 (83 lL, 0.49 mmol).
The reaction mixture was heated to 120 °C in a sealed vessel for
16 h. After the removal of the solvent, the crude was washed with
hexane and diethyl ether giving a yellow oil (87 mg, 66%).
4.2.10. (ꢀ)-3-Bis-[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl]-
imidazolinium chloride 13
This compound was prepared from 6 (300 mg, 0.91 mmol),
NH4Cl (48.8 mg, 0.91 mmol), and CH(OEt)3 (148 lL, 0.91 mmol).
The reaction mixture was heated to 120 °C in a sealed vessel for
16 h. After removal of the solvent, the crude was washed with
hexane, diethyl ether, and chloroform giving the title compound
½
a 2D2
ꢂ
¼ þ65 (c 0.65, MeOH); 1H NMR (200 MHz, (CD3)2CO) d 8.74
(s, 1H), 7.33–7.24 (m, 10H), 4.97–4.91 (m, 2H), 4.54 (s, br, 2H),
3.90–3.82 (m, 8H). 13C NMR (50 MHz, (CD3)2CO) d 158.5, 135.5,
129.9, 129.7, 128.7, 64.9, 62.1, 47.4. IR (NaCl): 3054, 2987, 1422,
1265, 896, 739 cm–1. MS (ESI = 0 V): m/z = 311 [M]. HRMS (ESI):
as
a
white crystalline solid (143 mg, 42%); mp 199 °C.
þ
½
a 2D2
ꢂ
¼ ꢀ16 (c 0.4, MeOH); 1H NMR (200 MHz, CD3OD) d 7.90 (s,
calcd for C19H23N2O2 311.1760; found 311.1761.
1H), 7.17–7.08 (m, 10H), 4.61 (d, J = 4.4 Hz, 2H), 3.71–3.59 (m,
6H), 1.07 (d, J = 7.0 Hz, 6H). 13C NMR (50 MHz, CD3OD) d 156.3,
140.6, 128.1, 127.6, 126.0, 73.7, 59.4, 47.0, 11.9; IR (KBr) 3298,
3223, 1246, 1148, 1050, 995, 744, 698 cm–1. MS (ESI = 0 V): m/z
4.2.15. (+)-(4R,5R)-Diphenyl-1,3-bis((R)-2-hydroxyethyl)-3-
methyl)-imidazolinium tetrafluoroborate 18
This compound was prepared from 10 (104 mg, 0.32 mmol),
NH4BF4 (35.8 mg, 0.35 mmol), and CH(OEt)3 (58 lL, 0.35 mmol).
þ
(%) = 339 [M]. HRMS (ESI): calcd for C21H27N2O2 339.2073; found
The reaction mixture was heated to 120 °C in a sealed vessel for
5 h. After the removal of solvent, the crude was washed with hex-
ane and diethyl ether giving the white crystalline compound
339.2073.
4.2.11. (ꢀ)-1,3-Bis-[(1S,2R)-2-hydroxy-1-methyl-2-phenyl-
ethyl]-imidazolinium bromide 14
This compound was prepared from 6 (100 mg, 0.30 mmol),
NH4Br (32.2 mg, 0.33 mmol), and CH(OEt)3 (56 lL, 0.34 mmol).
(143 mg, 80%). mp 118 °C. ½a D22
ꢂ
¼ ꢀ51 (c 1.2, CHCl3); 1H NMR
(200 MHz, (CD3)2CO) d 8.72 (s, 1H), 7.44–7.33 (m, 10H), 4.48 (d,
J = 5.6Hz, 2H), 4.01 (s, br, 2H), 3.52–3.06 (m, 4H), 1.03 (d,
J = 6.2 Hz, 6H). 13C NMR (50 MHz, (CD3)2CO) d 160.1, 136.9,
130.4, 128.6, 73.4, 63.2, 53.5, 20.9. IR (KBr): 3346, 2971, 1640,
1458, 1211, 1083, 763, 702, 625, 522 cm–1. MS (ESI = 0 V): m/
The reaction mixture was heated to 120 °C in a sealed vessel for
12 h. After the removal of solvent, the crude was washed with hex-
ane and diethyl ether giving the title compound as a yellow crys-
talline solid (84 mg, 66%); mp 148 °C. ½a D22
¼ ꢀ17 (c 1.0, MeOH);
ꢂ
þ
z = 339 [M]. HRMS (ESI): calcd for C21H27N2O2 339.2073; found
1H NMR (200 MHz, (CD3)2CO) d 8.51 (s, 1H), 7.28–7.04 (m, 10H),
339.2064.

2352
M. Gilani, R. Wilhelm / Tetrahedron: Asymmetry 19 (2008) 2346–2352
4.2.16. (+)-(4R,5R)-Diphenyl-1,3-bis(2-hydroxy-2-
methylpropyl)-imidazolinium tetrafluoroborate 19
This compound was prepared from 11 (150 mg, 0.42 mmol),
was further dried under high vacuum to give the potassium
Mosher’s carboxylate salt as a white solid (351 mg, quant).
NH4BF4 (47.5 mg, 0.46 mmol), and CH(OEt)3 (78
l
L, 0.46 mmol).
4.3.2. NMR experiment with the racemic Mosher’s acid salt
The Mosher’s acid salt (1 mmol) and the corresponding imidaz-
olinium salt (1 mmol) were dissolved in acetone-d6 and the 1H
NMR and 19F NMR spectra were recorded at rt. For results see
Table 8.
The reaction mixture was heated to 120 °C in a sealed vessel for
12 h. After removal of the solvent, the crude was washed with hex-
ane and diethyl ether to give a white crystalline compound
(170 mg, 90%). mp 108 °C. ½a D22
ꢂ
¼ þ150 (c 1.1, MeOH); 1H NMR
(200 MHz, (CD3)2CO) d 8.84 (s, 1H), 7.44–7.33 (m, 10H), 5.43 (s,
2H), 3.68–3.61 (m, 4H) 3.14 (s, 1H), 3.07 (s, 1H) 1.18 (s, 6H), 1.10
(s, 6H) 13C NMR (50 MHz, (CD3)2CO) d 157.2, 142.3, 128.9, 127.7,
126.8, 72.3, 60.3, 48.8, 11.1. IR (KBr): 3355, 2976, 1638, 1457,
1379, 1159, 1061, 763, 702, 625 cm–1. MS (ESI = 0 V): m/z = 367
Acknowledgments
Financial support by Fonds der Chemischen Industrie is grate-
fully acknowledged. In addition the author would like to thank
Dr. Dräger from the University of Hannover for HRMS measure-
ments and Dr. Namyslo for F NMR measurements. M.G. would like
to thank the HEC for a scholarship.
þ
[M]. HRMS (ESI): calcd for C23H31N2O2 367.2386; found 367.2383.
4.2.17. General procedure for Et2Zn addition to aldehydes
An imidazolinium salt (0.017 mmol) and KOtBu (6.1 mg,
0.051 mmol) were placed in a dry Schlenk flask and dry toluene
(1 mL) was added. After stirring the mixture for 30 min, Cu(OTf)2
(3.2 mg, 0.009) mmol) was added and left to stir for 1 h. Aldehyde
(0.35 mmol) was added and the mixture was stirred for 5 min.
Then Et2Zn (0.5 mL of a 1 0 M solution in hexane) was added drop-
wise. The mixture was stirred at rt for 46 h, quenched by the addi-
tion of 1 M HCl (1 mL), and extracted with Et2O (3 ꢁ 5 mL). The
combined organic phases were dried over Na2SO4 and the solvent
was removed under reduced pressure to give the crude product,
which was purified by flash column chromatography (petroleum
ether/ethyl acetate, 9:1) to give the corresponding alcohol 21.
References
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4.2.18. (R)-1-(1-Naphthyl)-propan-1-ol 21
½
a 2D2
ꢂ
¼ þ35 (c 0.30, CHCl3). For catalysts, bases, yields, and ee
see Tables 1–7. Spectroscopic data were consistent with literature
values.4 73% ee (R) by HPLC analysis [OD–H; iPrOH/hexane, 5:95;
0.4 mL min–1; t1(S) = 35.7 min, t2(R) = 67.6 min].
4. (a) Clavier, H.; Boulanger, L.; Audic, N.; Toupet, L.; Mauduit, M.; Guillemin, J. C.
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Chem. Commun. 2004, 1224; (b) Jurcík, V.; Wilhelm, R. Tetrahedron: Asymmetry
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Am. Chem. Soc. 2006, 128, 8416.
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Hayasaka, T. J. Org. Chem. 1991, 56, 4264; (f) Gadenne, B.; Hesemann, P.;
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R.; Schneider, P. H.; Silveira, C. C.; Wessjohann, L. A. A. Tetrahedron: Asymmetry
1999, 10, 1733; (l) Okamoto, K.; Kimachi, T.; Ibuka, T.; Takemoto, Y.
Tetrahedron: Asymmetry 2001, 12, 463; (m) Ohga, T.; Umeda, S.; Kawanami,
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Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, 1207.
4.2.19. (R)-1-(2-Naphthyl)-propan-1-ol
Yield = 57%; ½a 2D2
ꢂ
¼ þ29 (c 0.50, CHCl3). 50% ee (R) by HPLC
analysis
[OD-H;
iPrOH/hexane, 10:90;
1.0 mL minꢀ1
;
t1(S) = 10.0 min, t2(R) = 11.0 min]. Spectroscopic data were consis-
tent with literature values.4
4.2.20. (R)-1-Phenyl-1-propanol
Yield = 39%; ½a 2D2
¼ þ36 (c 0.50, CHCl3). 75% ee (R) by HPLC
ꢂ
analysis [OD-H; iPrOH/hexane, 5:95; 1.0 mL minꢀ1; t1(R) = 8.0 min,
t2(S) = 9.0 min]. Spectroscopic data were consistent with literature
values.4
4.2.21. (R)-1-(4-Chlorophenyl)-1-propanol
Yield = 60%; ½a 2D2
ꢂ
¼ þ28 (c 1.33, CHCl3). 78% ee (R) by HPLC
analysis
[OD-H;
iPrOH/hexane, 2.5:97.5;
1.0 mL minꢀ1
;
t1(S) = 11.8 min, t2(R) = 12.5 min]. Spectroscopic data were consis-
tent with literature values.4
4.2.22. (R)-1-(4-Methylphenyl)-1-propanol
10. Santes, V.; Gomez, E.; Santiallan, R.; Farfan, N. Synthesis 2001, 235.
11. Saba, S.; Brescia, A.; Kaloustain, M. K. Tetrahedron Lett. 1991, 32, 5031.
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Y. J. Comb. Chem. 2004, 6, 301; (d) Ye, M.-C.; Li, B.; Zhou, J.; Sun, X.-L.; Tang, Y. J.
Org. Chem. 2005, 70, 6108.
Yield = 50%; ½a 2D2
ꢂ
¼ þ32 (c 1.0, CHCl3). 71% ee (R) by HPLC anal-
ysis
[OD–H;
iPrOH/hexane, 0.1:99.9;
1.0 mL minꢀ1
;
t1(R) = 67.7 min, t2(S) = 85.0 min]. Spectroscopic data were consis-
tent with literature values.4
13. Chi, Y.; Gellaman, S. H. Org. Lett. 2005, 7, 4253.
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15. Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201.
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Tetrahedron: Asymmetry 1999, 10, 799.
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5169.
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Tetrahedron: Asymmetry 2001, 12, 241.
4.3. NMR Experiments with Mosher’s acid salt
4.3.1. Preparation of racemic potassium Mosher’s carboxylate
Racemic Mosher’s acid (302 mg, 1.29 mmol) was dissolved in
water (1 mL) and a solution of KOH (72 mg, 1.29 mmol) in water
(3 mL) was added. The mixture was stirred at rt for 15 min and
water was removed under reduced pressure. The remaining solid