Chiral C2-symmetric ligands containing two binaphthyl units linked by 2,2′-bipyridyl bridge in asymmetric catalysis

Article abstract of DOI:10.1016/j.tetasy.2004.12.015

The catalytic activities of new chiral C₂-symmetric ligands 1-4 in the asymmetric alkylation of aromatic aldehydes with diethylzinc to give 1-arylpropanols are studied. In most cases, the yields were good and enantioselectivities up to 87% were

Full text of DOI:10.1016/j.tetasy.2004.12.015

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 727–731
Chiral C2-symmetric ligands containing two binaphthyl units
linked by 2,20-bipyridyl bridge in asymmetric catalysis
Xiao-Li Bai, Chuan-Qing Kang, Xu-Dong Liu and Lian-Xun Gao*
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese
Academy of Sciences, Graduate School of Chinese Academy of Sciences, Changchun 130022, PR China
Received 1 December 2004; accepted 17 December 2004
Available online 26 January 2005
Abstract—The catalytic activities of new chiral C2-symmetric ligands 1–4 in the asymmetric alkylation of aromatic aldehydes with
diethylzinc to give 1-arylpropanols are studied. In most cases, the yields were good and enantioselectivities up to 87% were observed.
Copper-catalyzed cyclopropanation proceeded with 651% enantioselectivity and ꢀ3:1 trans/cis-diastereoselectivity.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
efficient catalysts in a number of asymmetric reactions.
Bolm et al. reported C2-symmetric bipyridylalcohol
ligands and high asymmetric induction has been achieved
in additions of diethylzinc to aldehydes in the presence
of those ligands.36 We have synthesized a series of new
C2-symmetric chiral bipyridyl ligands 1–4 in which two
binaphthyl units are linked by 2,20-bipyridyl (Fig. 1).
The procedures of synthesis of these ligands have been
described previously.37 Herein, we report our results of
an efficiently enantioselective diethylzinc addition to
aromatic aldehydes catalyzed by bis-BINOLs 1c and
2b and 4c in the absence of Ti(OiPr)4. The evaluation
of these chiral ligands as chiral directors in asymmetric
copper(I)-catalyzed cyclopropanation38 of styrene with
a diazoester is also described.
Recently, Shibasaki et al. reported a novel class of
linked BINOL ligands, in which two BINOL units are
linked by carbon, oxygen or sulfur bridges. These
ligands introduced new possibilities for multifunctional
asymmetric catalysis.1–3 Phenylenebis(ethynyl)-tethered
bis-BINOL ligands have also been reported as enantio-
selective catalyst.4 Introduction of an appropriate tether
between two binaphthyl units would stabilize a dimeric
structure, allowing us to study the enantioselectivity of
the dimeric form.5–13 Enantioselective addition of dieth-
ylzinc to aldehydes is one of the most reliable methods
to prepare chiral alcohols14–16 and also a standard reac-
tion to test the reactivity and enantioselectivity of newly
designed chiral ligands. BINOL and its derivatives have
been widely employed as enantioselective catalysts in
this reaction.17 They can conduct the highly enantiose-
lective synthesis of a variety of chiral alcohols. But lim-
itation has also been identified, in most cases, the
reaction requires the use of both Et2Zn and Ti(OiPr)4.
Therefore, the search of efficient catalysts continues
for the enantioselective addition of diethylzinc to alde-
hydes. In asymmetric, transition metal catalyzed reac-
tion, ligands with sp2 nitrogen(s) as the coordinating
atom(s) constitute an important class.18–20 Over the past
15 years, chiral C2-symmetric bidentate N,N-coordinat-
ing ligands such as bis-oxazolines,21–25 sermicorrins,26–29
and 2,20-bipyridines30–35 have been reported to be highly
2. Results and discussion
2.1. Enantioselective addition of diethylzinc to aromatic
aldehydes
The containing hydroxyl groups C2-symmetric bipyr-
idine ligands 1c, 2b, and 4c were synthesized via depro-
tected of MOM protected ligands with conc HCl in
MeOH–THF.37 We tested their properties as catalysts
for the addition of diethylzinc to benzaldehyde (Scheme
1). The reaction was conducted at room temperature in
toluene by the sequential treatment of Et2Zn with a chi-
ral ligand and benzaldehyde (Table 1). As the results
summarized in Table 1 show, compound 2b gave the
highest enantioselectivity among the three ligands (entry
*
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author.
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X.-L. Bai et al. / Tetrahedron: Asymmetry 16 (2005) 727–731
N
N
N
N
OR
OR
RO
RO
RO
RO
OR
OR
2a R=C H
1a R=C H
2
5
6
13
5
2b R=H
1b R=C H
2
1c R=H
N
N
N
N
OR
OR
RO
RO
RO
RO
OR
OR
4a R=C H
6
13
5
4b R=C H
2
3 R=C H
2
5
4c R=H
Figure 1. Chiral C2-symmetric ligands (R,R)-1–4.
O
OH
amount of catalyst from 2% to 8% has a slight effect
on the enantioselectivity (entries 5, 6). With (R,R)-2b
being the best ligand, other aldehydes were also tested
(Table 2). Several observations were noticed: in most
cases, chemical yields of alcohols and enantioselectivities
were lower than benzaldehyde; enantioselectivity up to
87% ee was observed as for 1-naphthaldehyde; all reac-
tions required longer time for completion; not all sub-
strates favor the (R)-configuration isomer for (R,R)-2b.
Et2Zn, Cat
H
Scheme 1.
3). The low enantioselectivity of compounds 1c and 4c
indicated that the BINOLs tethered by bipyridyl at the
3-position are more suitable for this reaction than at
6-position. In ligands 1c and 4c, the hydroxy groups
are far away from the pyridine nitrogens, to prevent
the formation of a chelate zinc complex. This led to
low enantioselectivity. We then explored the conditions
for the use of ligand 2b in the reaction of diethylzinc
with benzaldehyde. From Table 1, it is clear that the
yields of the isolated 1-phenyl-1-propanol are good
and the enantioselectivities obtained are also satisfac-
tory in all cases. Solvents have a significant effect on
both the rate and enantioselectivity of the reaction.
THF (entry 7), CH2Cl2 (entry 8) and CH3CN (entry 9)
decreased the enantioselectivity and also the rate. Low
temperature leads to a slight increase in asymmetric
induction from 82% to 86% ee but had only a small
effect on the rate for (R,R)-2b (entry 4). Changing the
2.2. Asymmetric cyclopropanation catalyzed by Cu(I)
complexes
To explore further the scope of these chiral ligands, we
have briefly studied the cyclopropanation of styrene
with ethyl diazoacetate as the metallocarbene source
(Scheme 2). Following previous reports,43–49 we first
generated Cu(II) complexes from (TfO)2Cu (1 mol%)
and the respective ligands 1a,b,4a,b,2a, and 3, which
were reduced in situ with phenylhydrazine to the corre-
sponding Cu(I) species. The reaction was carried out in
CH2Cl2 in the presence of the catalyst via a slow addi-
tion of the diazoacetic ester over a period 3 h (Table
3). From Table 3 we obviously found that (R,R)-2a
has the best catalytic activity among the six ligands.
Table 1. Enantioselective addition of diethylzinc to benzaldehyde catalyzed by ligands 1c,4c,2ba
Entry
Catalyst
Solvent
Time (h)b
Temp (°C)
Yield (%)c
Ee (%)d
1
(R,R)-1c
(R,R)-4c
(R,R)-2b
(R,R)-2b
(R,R)-2b
(R,R)-2b
(R,R)-2b
(R,R)-2b
(R,R)-2b
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
24
24
12
12
24
24
24
24
24
22
22
22
0
82
77
88
90
98
95
66
63
46
66(R)
59(R)
82(R)
86(R)
80(R)
86(R)
54(R)
44(R)
48(R)
2
3
4
5e
6f
7
22
22
22
22
22
8
CH2Cl2
CH3CN
9
a Reactions were run with 5 mol% ligands unless otherwise stated.
b Reactions were monitored by GC.
c Isolated yield after chromatography.
d Determined by GC analysis using a chiral column (Chrompack Chirasil-DEX-CB column) or by HPLC analysis using a chiral column (OD-H
column). Absolute configuration was determined by comparing the sign of specific rotation.39–42
e Reactions were run with 2 mol% catalyst.
f Reactions were run with 8 mol% catalyst.

X.-L. Bai et al. / Tetrahedron: Asymmetry 16 (2005) 727–731
729
Table 2. Enantioselective addition of diethylzinc to aromatic aldehydes catalyzed by ligand 2ba
Substrate
Product
Time (h)b
Yield (%)c
56
Ee (%)d
O
OH
48
16(R)
H
Cl
Cl
O
H
HO
48
48
48
48
71
85
62
65
87(S)
45(R)
54(S)
74(R)
OH
OH
O
H
O
H
Me
Me
OH
O
H
OMe
OMe
a Reactions were run with 5 mol% ligands unless otherwise stated.
b Reactions were monitored by GC.
c Isolated yield after chromatography.
d Determined by GC analysis using a chiral column (Chrompack Chirasil-DEX-CB column) or by HPLC analysis using a chiral column (OD-H
column). Absolute configuration was determined by comparing the sign of specific rotation.
the OR groups closer to the metal. By contrast, the en-
trance of 2a is narrower than that in the previous ligands
(ligands 3 and 2a binaphthyl units linked by bipyridyl at
the 3-position). So in these ligands, the narrow entrance
contributes to the asymmetric induction. Low tempera-
ture leads to an increase in asymmetric induction from
39% to 51% ee (trans) but has little effect on either the
trans/cis selectivity on the rate for (R,R)-2a (entries 3
and 7). The amount of catalyst has almost no effect
on either the trans/cis selectivity or enantioselectivity
(entries 8 and 9). On prolonging the reaction time from
3 h to 12 h, the yield of product was increased, giving the
product in 99% yield (entry 10). Practically identical re-
sults were obtained with the Cu(I) complex generated
directly from (R,R)-2a and (CuOTf)2ÆC6H6 (entries 11
and 12).
CO2Et
CO2Et
+
Cu(OTf)x, Ligand
EDA, CH2Cl2
Scheme 2.
The results demonstrated that reactivities of the Cu
complexes of 1–4 as catalysts in asymmetric cycloprop-
anation correlate with the shape of the chiral cavity of
these ligands. Molecular models of ligand complexes
2a-M and 4b-M (Fig. 2) reveal important features con-
cerning the shape of the chiral cavity. The cavities of
1a,b,4a, and b have a relatively wide ꢀentranceꢁ (in these
ligands binaphthyl unit is linked by bipyridyl at the 6-
position), whereas ligand 3 is narrower, which brings
Table 3. Asymmetric cyclopropanation of styrene with ethyl diazoacetate catalyzed by Cu complexes of chiral ligands
Entry
Ligand
X
Mol (%)
Time (h)
Temp (°C)
Yield (%)
trans/cisa
Ee (trans)b,c
1
(R,R)-1a
(R,R)-1b
(R,R)-2a
(R,R)-3
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
1
1
1
2
5
1
1
1
3
3
20
20
20
20
20
20
0
72
95
94
90
92
92
75
87
88
99
78
82
67/33
66/34
62/38
67/33
62/38
65/35
64/36
60/40
68/32
64/36
72/28
60/40
4(1S,2S)
2
15(1S,2S)
39(1S,2S)
31(1S,2S)
6(1S,2S)
3
3
4
3
5
(R,R)-4a
(R,R)-4b
(R,R)-2a
(R,R)-2a
(R,R)-2a
(R,R)-2a
(R,R)-2a
(R,R)-2a
3
6
3
16(1S,2S)
51(1S,2S)
39(1S,2S)
40(1S,2S)
42(1S,2S)
35(1S,2S)
48(1S,2S)
7
3
8
3
20
20
20
20
0
9
3
10
11
12
12
3
3
a Determined by GC.
b Determined by chiral GC (Chirasil-DEX CB).
c Absolute configuration was (1S,2S) by comparison of specific rotations with the values in the literature.50

730
X.-L. Bai et al. / Tetrahedron: Asymmetry 16 (2005) 727–731
Figure 2. 3D representation of 4b-M and 2a-M.
3. Conclusions
CB or by HPLC analysis using a chiral column (OD-
H column).
In conclusion, a series of new chiral bis-binaphthyls
linked by 2,20-bipyridine ligands 1–4 has been applied
in the catalytic asymmetric alkylation of aromatic alde-
hydes with diethylzinc and copper-catalyzed cycloprop-
anation. In the enantioselective addition of diethylzinc
to aldehydes, enantiomeric excesses of up to 87% were
observed. In copper-catalyzed cyclopropanation, the
cyclopropanes could be obtained in moderate trans/cis
selectivity and enantioselectivity. New catalysts have
been shown to be promising in the above two types of
asymmetric catalytic reactions. We are continuing our
efforts on the use of these ligands in other catalytic
asymmetric reactions.
4.2. General procedure for asymmetric cyclopropanation
catalyzed by Cu(I) complexes
A solution of the ligand (0.06 mmol) and (TfO)2Cu
(18 mg, 0.05 mmol) in dichloromethane (5 mL) was stir-
red under nitrogen atmosphere at 20 °C for 1 h. The
solution was filtered through glass wool under nitrogen,
and to the filtrate were successively added phenyl-
hydrazine (5.9 lL, 0.06 mmol) and styrene (1 mL,
8.74 mmol). A solution of ethyl diazoacetate (3–5 mmol)
in dichloromethane (3 mL) was added dropwise over a
period of 3 h using a syringe pump. The mixture was
stirred for 12 h and concentrated in vacuum. The ratio
of trans and cis isomers was determined by capillary
GC. Separation of the isomers was performed by chro-
matography on a silica gel column with hexane/ethyl
acetate (20:1). Enantiomeric excesses for the products
were determined by chiral GC with Chirasil-DEX CB.
4. Experimental
GC measurements were carried out on a Shimadzu GC-
2010A instrument. HPLC utilized a Shimadzu LC-6AD
pump, a Shimadzu SPD-10A UV dectector, and Shima-
dzu Class-VP system controller software. Chem 3D
model derived from the software Hyperchem 7.5 of
Hyper cube, Inc. Products were purified by column
chromatography on silica gel (100–200 mesh). Reactions
were carried out in dry solvents under an argon atmo-
sphere, unless otherwise stated. THF was distilled from
sodium benzophenone ketyl. Toluene was distilled from
sodium. CH3CN and CH2Cl2 were dried over calcium
hydride.
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