Atropisomeric bisoxazoline ligands with a bridge across the 5,5′-position of biphenyl for asymmetric catalysis

Article abstract of DOI:10.1016/j.tetlet.2007.04.007

A new family of atropisomeric bisoxazoline ligands 2 with a bridge across the 5,5′-position of biphenyl has been developed. The axial chirality of this type of ligands can be retained by macro-ring strain produced by 5,5′-linkage of biphenyls even without

Full text of DOI:10.1016/j.tetlet.2007.04.007

Tetrahedron Letters 48 (2007) 4083–4086
Atropisomeric bisoxazoline ligands with a bridge across
the 5,50-position of biphenyl for asymmetric catalysis
Feijun Wang, Yong Jian Zhang, Hao Wei, Jiaming Zhang and Wanbin Zhang*
Department of Chemistry, School of Chemistry and Chemical Technology, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai 200240, PR China
Received 28 February 2007; revised 3 April 2007; accepted 4 April 2007
Available online 11 April 2007
Abstract—A new family of atropisomeric bisoxazoline ligands 2 with a bridge across the 5,50-position of biphenyl has been devel-
oped. The axial chirality of this type of ligands can be retained by macro-ring strain produced by 5,50-linkage of biphenyls even
without 6,60-substituents on biphenyls. The Pd(II)-2d complex as catalyst showed high catalytic activity and enantioselectivity
for asymmetric Wacker-type cyclization of allylphenols.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The design and synthesis of effective chiral ligands have
played a significant role in advancement of asymmetric
catalysis, and have attracted a great deal of attention
from both academia and industry. Thousands of chiral
ligands have been developed and applied in various cat-
alytic asymmetric reactions to produce enantiomerically
pure compounds.1 Among them, atropisomeric biaryl
ligands, such as BINAP,2 BINOL,3 and boxax,4 have
been explored as effective templates for many transition
metal-catalyzed asymmetric reactions.5 Atropisomerism
results from restricted rotation around biaryl axis pro-
duced by ortho-substituents. Generally, enantiomerically
stable biaryls require at least three ortho-substituents to
prevent racemization.6 Therefore, for all of the reported
bidendate atropisomeric biphenyl ligands, there is at
least one steric hindered group at 6- or 60-position on
biphenyls for the sake of stable axial chirality. In con-
trast to traditional atropisomeric biaryl ligands, we
introduce a novel atropisomeric framework 1 (Fig. 1),
in which the biphenyls have only two coordinating
groups next to the axis. The axial chirality of biphenyls
is expected to be retained by macro-ring strain produced
by 5,50-linkage of biphenyls. We hypothesize that com-
pounds 1 with more bulky coordinating groups may
lead to more stable axial chirality, and the length of
backbone carbon chain can control the conformational
flexibility of atropisomeric ligands to provide more suit-
able chiral environment for asymmetric catalysis.
O
O
H
H
L
L
L
L
H
H
(CH2)n
(CH2)n
O
O
1 (aR)
1 (aS)
L = Coordination Group
Figure 1. Atropisomeric bisoxazoline ligands with a bridge across the
5,50-position of biphenyl.
On the other hand, C2-symmetric bisoxazoline ligands
with an axially chiral biaryl backbone as an effective
ligand family have been successfully used in some
important asymmetric reactions due to their synergistic
asymmetric induction by combination of the central chi-
rality of oxazoline rings and the axial chirality of back-
bone.7 Moreover, the two atropdiastereomers of the
ligands can be easily separated by introducing optically
active oxazoline moieties. Thus, we report herein the
synthesis of a new family of atropisomeric bisoxazoline
ligands with a bridge across the 5,50-position of biphenyl,
2,20-bisoxazolinyl-5,50-(polymethylenedioxy)biphenyls
2, the evaluation of their stability of axial configura-
tions, and their application in Pd(II)-catalyzed Wac-
ker-type cyclization.
*
Our synthetic approach to diastereomeric pure (S,aR)-
and (S,aS)-2 is depicted in Scheme 1. Ullman coupling
Corresponding author. Tel./fax: +86 21 5474 3265; e-mail: wanbin@
sjtu.edu.cn
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.007

4084
F. Wang et al. / Tetrahedron Letters 48 (2007) 4083–4086
RO
O
COOMe
Br
c
a
COOMe
COOMe
H
H
COOMe
COOMe
(CH2)n
OMe
RO
b
O
3
6a, n = 8;
6b, n = 10
4 (R = Me)
5 ( R = H)
O
O
2a, n = 8, R = iPr;
H
H
d
R
R
N
N
2b, n = 8, R = Bn;
(CH2)n
2c, n = 8, R =
2d, n = 8, R = Ph;
2e, n = 10, R = Pr
tBu;
i
O
O
2
Scheme 1. Reagents and conditions: (a) Cu; (b) (i) AlCl3, 1-dodecanethiol, CH2Cl2; (ii) SOCl2, MeOH; (c) Br(CH2)nBr, K2CO3, DMF; (d) (i) amino
alcohol, K2CO3, MeOH; (ii) MsCl, Et3N, CH2Cl2.
of methyl 2-bromo-4-methoxybenzoate (3)8 with acti-
vated copper powder furnished biphenyl skeleton 4 in
61% yield. Demethylation of 4 with aluminum chloride
and 1-dodecanethiol afforded a mixture of the corre-
sponding diphenol diester 5, diphenol monoacid and
diphenol diacid. This mixture was further converted to
diphenol diester 5 by esterification with SOCl2 and
methanol in 81% yield from 4. Cyclization of 5 with
1,8-dibromooctane and 1,10-dibromodecane led to the
key intermediates 6a and 6b in 41% and 39% yields,
respectively. Direct treatment of 6a with (S)-valinol gave
the amides as a mixture of diastereomeric isomers,9
which were subjected to the oxazoline ring formation
by treatment with methanesulfonyl chloride in the pres-
ence of triethylamine to give 2a in 45% yield from 6a.10
These diastereomeric isomers were conveniently sepa-
rated by column chromatography. In the same way, bis-
oxazolines 2b–e were prepared in 35–44% yields from 6a
or 6b. For 2c, derived from (S)-t-leucinol, only one dia-
stereomer was obtained in 35% yield after oxazoline ring
formation. The sense of axial chirality of 2a was deter-
mined by the major Cotton effects (CE) in the CD spec-
tra. The CD curve of one of the two diastereomers of 2a
displayed two negative CE at 328.6 nm and 271.4 nm.
This signed feature is the characteristic of (S)-configura-
tion at chiral axis, which was in contrast with the spectra
in the literature of axially chiral biphenyl compounds.11
The axial configurations of 2b–e were assigned by com-
parison of their chemical shifts of aryl proton in 1H
NMR spectrum with that of 2a.
without any racemization of axial chirality. However,
when the temperature was increased to 100 ꢁC, the
ligands underwent racemization in DMSO-d6 (Table 1).
It was found that the bulkiness of substituents on the
oxazoline ring and the length of backbone carbon chains
had a remarkable influence on the stability of axial con-
figuration for bisoxazoline 2. For ligand 2a with octa-
methylenedioxy bridge, the free energy barrier to axial
torsion is 129.9 kJ molꢀ1 and the half-life periods is
1
18.3 h at 100 ꢁC, which were determined by H NMR
spectrum12 (entry 1). When the substituents on the oxaz-
oline rings changed into more bulky tert-butyl groups,
the half-life periods markedly increased to 49.1 h (entry
2). For bisoxazoline 2e, in which the ligand backbone
bears longer decamethylenedioxy ring, the half-life
periods obviously decreased to 4.9 h, which gave D
Gà = 126.8 kJ molꢀ1(entry 3). Thus, it can be concluded
that the ligands with more bulky coordination groups
and more suitable backbone polymethylenedioxy ring
provide more stable axial chirality, as we have hypothe-
sized above.
Table 1. Free energy barriers and rates of racemization for atropiso-
meric bisoxazolines 2 in DMSO-d6 at 373 Ka
O
O
O
O
K1
H
H
H
H
R
R
R
R
N
N
N
N
(CH2)n
(CH2)n
K-1
To evaluate the stability of axial configuration of bis-
oxazoline ligands 2, two pairs of atropdiastereomers
(S,aS)-2a and (S,aR)-2a, (S,aS)-2e and (S,aR)-2e were
dissolved in various deuterated organic solvents (chloro-
form-d, acetone-d6, methanol-d4 and DMSO-d6) respec-
tively, and stirred at room temperature for 48 h. As a
result, no interconversions of the two atropdiastereo-
mers were found in any solvent system by determination
O
O
O
O
2 (S,aR)
2 (S,aS)
Entry Ligand K1
K
DGà
t1/2
(h)
ꢀ1
(hꢀ1
)
(hꢀ1
)
(kJ molꢀ1
)
1
2
3
2a
2c
2e
1.81 · 10ꢀ2 1.98 · 10ꢀ2 129.9
6.03 · 10ꢀ3 8.09 · 10ꢀ3 133.3
4.86 · 10ꢀ2 9.44 · 10ꢀ2 126.8
18.3
49.1
4.9
1
of H NMR spectrum. Even the temperature at 60 ꢁC,
the ligands still maintained stable axial configuration
a Determined by 1H NMR spectrum analysis.

F. Wang et al. / Tetrahedron Letters 48 (2007) 4083–4086
4085
Pd(II)-catalyzed intramolecular Wacker-type cycliza-
tions have emerged as a versatile strategy in the
construction of a range of heterocycles.13 However,
asymmetric oxidative cyclizations with chiral Pd(II)-
complexes have received relatively little attention.
Although Hayashi and Uozumi have made an impor-
tant breakthrough on the Pd(II)-catalyzed enantioselec-
tive Wacker-type cyclization of 2-allylphenols with
chiral bisoxazoline ligands based on binaphthyl back-
bone (boxax),14 only a few ligands have been success-
fully applied in this type of cyclization.15 To evaluate
effectiveness of our atropisomeric bisoxazoline ligands
tivity decreased to 79% ee (entry 7). A series of o-allyl-
phenols can be cyclized to the corresponding 2,3-
dihydrobenzofurans 8 using Pd(II)-2d as a catalyst. As
exemplified by the substrates with methyl group in 4-,
5- and 6-positions of o-allylphenol (entries 8–10), the
enantioselectivity was affected slightly by the steric prop-
erties of these substrates, but the yield for 6-methyl-2-
allylphenol 7d was correspondingly low in the same
reaction conditions. For other substituted o-allylphenols
7e–h, the enantioselectivities were delicately affected by
the steric and electronic properties of the substrates (en-
tries 11–14). For 2-(2,3-dimethyl-2-butenyl)-1-naphthol
(7i), the cyclization gave the corresponding dihydro-
naphtho[1,2-b]furan 8i with good isolated yield and high
enantioselectivity (93% ee, entry 15).
2
in Wacker-type cyclization, typically, 2-(2,3-di-
methyl-2-butenyl)phenol (7a) was used as a model sub-
strate for the oxidative cyclization. The reactions were
catalyzed by 10 mol % of the Pd(II)-2 complexes gener-
ated in situ by mixing Pd(OCOCF3)2 with bisoxazolines
2 in the presence of p-benzoquinone as reoxidant in
methanol at 60 ꢁC (Table 2). It was found that the
catalytic efficiency largely depended on the axial confi-
guration. Thus, the palladium complex with (S,aR)-2a
showed remarkably higher catalytic activity and enantio-
selectivity than that with corresponding diastereomer
(S,aS)-2a in the cyclization (entries 1 and 2). Changing
the substituents on the oxazoline rings of ligands had
a little influence on the enantioselectivity, and the high-
est selectivity (85% ee) was obtained with phenyl-substi-
tuted 2d as the ligand (entries 4 and 5). When the
reactions were carried out at 35 ꢁC for 3 d, the enantio-
selectivities had a little increase, but the isolated yields
were remarkably low (entries 3 and 6). With (S,aR)-2e,
which had decamethylenedioxy bridge, the enantioselec-
In summary, we have developed a new family of atrop-
isomeric bisoxazoline ligands 2 with a bridge across the
5,50-position of biphenyl. It was demonstrated that the
axial chirality of this type of ligands can be retained
by macro-ring strain produced from 5,50-linkage of
biphenyls even without 6,60-substituents. The Pd(II)-2d
complex as catalyst showed high catalytic activity and
enantioselectivity in Wacker-type cyclization of allyl-
phenols 7. Further studies will focus on the development
and application of this class of atropisomeric ligands.
Acknowledgements
This work was supported by the National Natural Sci-
ence Foundation of China (grant nos. 20572070 and
20502015), the Ministry of Education of China (EYTP
and SRFDP).
Table 2. Pd(II)-catalyzed asymmetric Wacker-type cyclizationa
Supplementary data
Pd(CF3COO)2, ligand
R
R
benzoquinone
methanol
O
OH
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.04.007.
7
8
Entry Ligand
Substrate
R
Yieldb (%) eec (%)
1
2
3d
4
(S,aS)-2a 7a
H
H
H
H
H
H
H
4-Me
5-Me
6-Me
4-OMe
6-OMe
4-F
4-Ph
8
87
39
85
82
45
86
74
81
41
73
55
80
62
6
83
84
75
85
87
79
88
89
91
86
85
86
87
93
(S,aR)-2a 7a
(S,aR)-2a 7a
(S,aR)-2b 7a
(S,aR)-2d 7a
(S,aR)-2d 7a
(S,aR)-2e 7a
(S,aR)-2d 7b
(S,aR)-2d 7c
(S,aR)-2d 7d
(S,aR)-2d 7e
(S,aR)-2d 7f
(S,aR)-2d 7g
(S,aR)-2d 7h
(S,aR)-2d 7i
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