Enantioselective diethylzinc additions to aldehydes catalyzed by chiral relay ligands

Article abstract of DOI:10.1016/j.tetasy.2004.09.006

A new pyrazole ligand system incorporating fluxional chirality was found to catalyze the addition of diethylzinc to aldehydes giving rise to the corresponding secondary alcohol products in excellent yields (74-99%) with moderate to high enantioselectivities (46-93%). The size of the fluxional group on the ligand correlated with the level of enantioselectivity of the product.

Full text of DOI:10.1016/j.tetasy.2004.09.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3353–3356
Enantioselective diethylzinc additions to aldehydes catalyzed by
chiral relay ligands
Mukund P. Sibi* and Levi M. Stanley
Department of Chemistry, North Dakota State University, Ladd Hall, Fargo, ND 58105, USA
Received 9 August 2004; accepted 9 September 2004
Available online 18 October 2004
Abstract—A new pyrazole ligand system incorporating fluxional chirality was found to catalyze the addition of diethylzinc to alde-
hydes giving rise to the corresponding secondary alcohol products in excellent yields (74–99%) with moderate to high enantioselec-
tivities (46–93%). The size of the fluxional group on the ligand correlated with the level of enantioselectivity of the product.
Ó 2004 Elsevier Ltd. All rights reserved.
3
3
3
*
*
*
1. Introduction
2
2
2
R
N
R
N
R
N
R
2
R
2
R
2
4
5
4
5
4
5
R
R
R
R
R
R
R
R
R
N
N
N
N
N
N
Development of modular ligand systems that are appli-
cable in a broad set of enantioselective transformations
is important.1 We have recently introduced a new class
of ligands containing fluxional groups2,3 that show
promise in Diels–Alder cycloadditions4 and radical reac-
tions.5 Addition of dialkyl zinc reagents to aldehydes
has become a primary reaction sequence to evaluate
the efficiency of new ligand systems.6,7 In the previous
Diels–Alder study using chiral relay ligands, zinc Lewis
acids were found to be optimal for selectivity. Herein we
report the utility of chiral relay ligands in diethylzinc
addition to aldehydes and show that the size of the flux-
ional group on the ligand correlates with the level of
enantioselectivity of the product.
M
M
1
1
1
R
HO
O
O
R
R
1
2
3
Figure 1.
shielding. The permanent stereogenic center need not
necessarily serve a face-shielding role, as long as it dic-
tates the conformation of R1 (2 or 3); (4) the stereocon-
trol element R1 can be varied simply by alkylation; (5)
the chiral portion of the molecule is derived from vari-
ous chiral amines, which can be obtained commercially
or synthesized independently, and (6) when an amino
alcohol is used as the chiral source, the ligands are
potentially tridentate. One advantage inherent to these
ligands is the presence of multiple sites for facile diversi-
fication. Of particular interest to the current study is
the effect of the size of the fluxional group on
enantioselectivity.
2. Results and discussion
The chiral relay ligand system contains a dihydropyraz-
ole moiety with chirality residing remotely to the flux-
ional group R1 as shown in Figure 1. The ligand
design incorporates the following features: (1) it has
two nitrogen atoms, which can form a five-membered
chelate with Lewis acids; (2) the permanent stereogenic
center could indirectly control the orientation of the
fluxional N1 substituent in a metal complex; (3) the
fluxional N1 substituent R1 plays a major role in face
The chiral relay ligands 7a–g were synthesized as shown
in Scheme 1. Mesityl oxide was converted to the bro-
mide 4 using a literature procedure.8 N-Alkylation of
(1R,2R)-(À)-pseudoephedrine 5 with bromide 4 gave
amino ketone 6 in good yield. Reaction of 6 with hydra-
zine followed by alkylation with the corresponding alkyl
bromide provided ligands 7a–g. The overall yields for
the ligand synthesis ranged from 24% to 72% over three
steps.
*
Corresponding author. Tel.: +1 701 231 8251; fax: +1 701 231
1057; e-mail: mukund.sibi@ndsu.nodak.edu
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.006

3354
M. P. Sibi, L. M. Stanley / Tetrahedron: Asymmetry 15 (2004) 3353–3356
O
enantioselectivity. The above results demonstrate that
O
NEt , CH Cl ,
MeCN, rt
HN
HO
3
2
2
N
enantioselectivity is highly dependent on the size of the
fluxional group R on the N1 nitrogen with large groups
producing the highest enantioselectivity.
Br
HO
80%
6
4
5
We then undertook a breadth and scope study using the
best ligand 7f (Table 2). Ligand 7f catalyzed diethylzinc
addition to a variety of aromatic aldehydes in moderate
to good enantioselectivities and excellent yields (entries
1–7).10 One exception was the addition to o-anisalde-
hyde (entry 4). The lower selectivity observed in this
reaction is likely due to steric crowding due to the ortho
substitution. Reactions with aliphatic aldehydes pro-
ceeded in high yields and the products obtained in good
selectivities (entries 8–10). This is encouraging as a num-
ber of ligand systems suffer from poor yields in the addi-
tion of diethylzinc to aliphatic aldehydes. As is common
with many other ligand systems, 9f catalyzed the addi-
tion of diethylzinc to trans-cinnamaldehyde in moderate
yield and poor enantioselectivity (entry 11).
R
7a Methyl
7b Phenyl
7c Mesityl
7d Benzhydryl
7e 2-Naphthyl
7f 1-Naphthyl
7g 9-Anthracenyl
N
1) hydrazine, EtOH,
reflux
N
N
HO
2) RCH Br, K CO ,
2
2
3
R
MeCN, rt.
7a-g
30-90% over
2 steps
Scheme 1.
With ligands 7a–g in hand, diethylzinc addition to benz-
aldehyde was examined as shown in Scheme 2. A cata-
lytic loading of 10mol% of the ligand and reaction at
0°C was used as the standard conditions.9 Our initial
goal was to evaluate the effect of the size of the N1-flux-
ional group on the level of enantioselectivity. The results
from these experiments are shown in Table 1. From
these results it is evident that ethyl group addition pro-
ceeds in high yield using all the different ligands (entries
1–7). Furthermore, the size of the group on the fluxional
nitrogen plays an important role in determining the lev-
els of enantioselectivity. For example, reaction with lig-
and 7a with a small ethyl substituent is less selective
(entry 1, 50% ee) than with 7b containing a benzyl group
(entry 2, 77% ee). This trend holds true for all the lig-
ands except for 7d (entry 4) with a benzhydryl group.
Ligand 7g with a bulky 9-anthracenyl substituent gave
the highest selectivity (entry 7, 93% ee, reaction at
25°C). Lowering the reaction temperature or increasing
the ligand loading did not lead to substantial increase in
Table 2. Scope study using various aldehydesa
Entry Aldehyde
Yieldb (%) Eec (%) Config.d
1
Benzaldehyde
99
95
96
97
95
97
89
93
92
69
80
84
87
81
75
77
46
R
R
R
R
R
R
R
R
R
R
R
2
2-Naphthaldehyde
1-Naphthaldehyde
o-Anisaldehyde
m-Anisaldehyde
p-Anisaldehyde
3
4
5
6
7
p-Chlorobenzaldehyde 99
8
Isovaleraldehyde
Hexanal
Heptanal
99
96
93
9
10
11
trans-Cinnamaldehyde 74
a For reaction conditions, see footnotes.
b Isolated yield after column chromatography.
c Ee was determined by GC analysis using a chiral column (Supelco b-
dex 120).
L* (10 mol%)
O
OH
toluene
o
d Determined by comparison of retention times with literature values.10
Et Zn
2
H
0
C, 18-24 h
N
9
8
We carried out control experiments to assess the role of
the fluxional group and the permanent chirality in deter-
mining the level of enantioselectivity. In the first set of
experiments, we set out to examine the effect of the per-
manent chirality on selectivity in diethylzinc addition to
benzaldehyde (Scheme 3). Three ligands derived from
(1R,2S)-(À)-ephedrine 10a–c were prepared using the
procedure outlined in Scheme 1. The results from addi-
tion experiments using ligands 10a–c are tabulated in
Table 3. In these experiments, the enantioselectivity
L* =
N N
HO
R
7a-g
Scheme 2.
Table 1. Evaluation of chiral relay ligands in diethylzinc addition to
benzaldehyde
Entry
Ligand
Yielda (%)
Eeb (%)
Config.c
1
7a
7b
7c
7d
7e
7f
96
97
88
98
99
99
99
50
77
81
76
81
89
93
R
R
R
R
R
R
R
2
O
OH
L* (10 mol%)
toluene
0 ˚C, 18-24 h
3
Et Zn
2
H
4
5
6
7d
8
9
7g
a Isolated yield after column chromatography.
N
10a R = Me
10b R = Phenyl
10c R = 1-Naphthyl
b Ee was determined by GC analysis using a chiral column (Supelco
b-dex 120).
N
N
HO
Ph
R
c Determined by comparison of retention times with literature values.10
d Reaction was carried out at room temperature.
Scheme 3.

M. P. Sibi, L. M. Stanley / Tetrahedron: Asymmetry 15 (2004) 3353–3356
3355
for the product correlated with the size of the fluxional
group: the larger the fluxional group, the higher the
selectivity (Table 3, entries 1–3). This is the same trend
as observed with the pseudoephedrine ligand series 7
(see Table 1). However, the level of selectivity with lig-
and 7 was much higher than that obtained from ligand
10. For example, pseudoephedrine ligand 7f with a
naphthylmethyl fluxional group gave 89% ee (Table 1,
entry 6) whereas the corresponding ephedrine ligand
10c gave only 50% ee (Table 3, entry 3). This was
surprising since literature reports demonstrate that
tridentate ligands (1R,2S)-N-[2-(dimethylamino)ethyl]-
ephedrine and (1S,2S)-N-[2-(dimethylamino)ethyl]pseudo-
ephedrine both catalyzed the addition of diethylzinc to
benzaldehyde in high enantioselectivities.11 This was
also the case when the tridentate lithium salts of (S)-
N-[1-methylpyrrolidin-2-yl)methyl] derivatives of ephe-
drine and pseudoephedrine were employed as chiral cat-
alysts.12,13 The absolute stereochemistry for the product
using 7f or 10c was R. This suggests that the secondary
hydroxyl group is the primary controller of product
stereochemistry.
that the pseudoephedrine derived ligands are more selec-
tive. Furthermore, the absolute stereochemistry was the
same regardless of the ligand used (7f, 10c, 11, or 12).
The results we have obtained so far suggest that the role
of the fluxional group in 7 and 10 in determining face
selectivity is still not very clear.14 It is evident that the
size of the fluxional group impacts selectivity. However,
the data also suggests that the pyrazole containing the
fluxional may only function as a bulky group and thus
the correlation between size and enantioselectivity.
3. Conclusion
In conclusion, a new modular ligand system has been
shown to catalyze the addition of diethylzinc to various
aldehydes in excellent yields with moderate to high selec-
tivity. The efficiency of the ligand system was found to
be highly dependent on both the size of the substituent
on the fluxional nitrogen and the permanent chirality
employed. At this point it is not clear if the fluxional
group is the major contributor to face selectivity by
adapting a preferred conformation or the ligand as a
whole is responsible. A new series of ligands with chiral-
ity adjacent to the fluxional nitrogen in question will be
developed in the future to more clearly answer this
question.
Table 3. Diethylzinc addition to benzaldehyde using ephedrine derived
ligandsa
Entry
Ligand
Yieldb (%)
Eec (%)
Config.d
1
2
3
10a
10b
10c
60
90
94
15
40
50
R
R
R
a For reaction conditions see Ref. 9.
b Isolated yield after column chromatography.
Acknowledgements
c Ee was determined by GC analysis using a chiral column (Supelco
b-dex 120).
This work was supported by the National Science Foun-
dation (NSF-CHE-0316203 and NSF-EPS-0132289).
d Determined by comparison of retention times with literature values.10
To understand further the role of the pyrazole substitu-
ent incorporating the fluxional group, we prepared two
pyridine derived ligands that mimic the basic structure
present in 7 or 10 and evaluated them in diethylzinc
additions (Scheme 4). Reaction with the pseudoephe-
drine derived ligand 11 was more selective than that with
12 derived from ephedrine (68% ee for 11 compared to
41% ee with 12). The trend in level of enantioselectivity
for ligands 11 and 12 is the same as that for 7f and 10c in
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3356
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solution of the appropriate aldehyde (1.0mmol) and ligand