Electronically controlled asymmetric cyclopropanation catalyzed by a new type of chiral 2,2'-bipyridine

Article abstract of DOI:10.1016/S0040-4039(00)01306-X

An optically active atropisomeric 2,2'-bipyridine was synthesized and its copper complex was used in the asymmetric cyclopropanation of para-substituted styrenes with e.e. values up to 86%; the enantioselectivity exhibited a substrate electronic effect in a linear free energy relationship. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01306-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7723–7726
Electronically controlled asymmetric cyclopropanation
catalyzed by a new type of chiral 2,2%-bipyridine
Hei Lam Wong, Yuan Tian and Kin Shing Chan*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
Received 5 June 2000; accepted 28 July 2000
Abstract
An optically active atropisomeric 2,2%-bipyridine was synthesized and its copper complex was used in
the asymmetric cyclopropanation of para-substituted styrenes with e.e. values up to 86%; the enantioselec-
tivity exhibited a substrate electronic effect in a linear free energy relationship. © 2000 Elsevier Science
Ltd. All rights reserved.
The use of transition metal complexes of chiral atropisomeric biaryls for asymmetric synthesis
has generated immense interest. The ligands based on the 1,1%-binaphthalene skeleton have
achieved significant successes in asymmetric catalysis1 especially the use of BINOL2 and
BINAP.3 Synthesis and application of chiral 2,2%-bipyridine ligands are also well explored.4 We
note that the chirality of these 2,2%-bipyridines comes from the chiral substituents which are far
away from the metal centers that play crucial roles in catalysis. Synthesis of atropisomeric
pyridines such as 8,8%-disubstituted-bis-1,1%-isoquinolines has appeared but facile racemization
still occurs.5 It is interesting to design a new type of chiral atropisomeric 2,2%-bipyridine.6 Here
we report the synthesis of a chiral atropisomeric bipyridine and its application in asymmetric
cyclopropanation.
Our recent success in the synthesis of extremely sterically hindered atropisomeric pyridyl
phenol7 has led us to explore the synthesis and catalytic activities of its dimer. As shown in
Scheme 1, a bromo-group was introduced to the ortho position of the pyridyl ring of 1 by
lithiation with tert-butyllithium and quenching with 1,2-dibromoethane. 2-Bromopyridylanisole
2 was then demethylated with 48% HBr/HOAc to give 3 which was subsequently separated into
enantiomers by chiral HPLC.8 Nickel(0) catalyzed homo-coupling of (S)-3 gave (S,S)-4 without
any racemization. Methylation of the chiral tetradentate ligand (S,S)-4 gave the chiral
bipyridine (S,S)-5.
* Corresponding author. E-mail: ksc@cuhk.edu.hk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01306-X

7724
t
Scheme 1. Reagents and conditions: (i) BuLi (1.5 equiv.), THF, −78°C, 1 h, BrCH2CH2Br (2 equiv.), THF, −78°C–rt,
4 h, 71%; (ii) 48% HBr (10 equiv.), HOAc, 120°C, 8 h, 95%; (iii) Daicel chiral OD column, hexane/2-propanol=8:1;
(iv) Ni(PPh3)2Cl2 (1 equiv.), Zn (2 equiv.), Et4NI (1.5 equiv.), THF, 60°C, 8 h, 89%; (v) NaOH (2 equiv.), MeOH,
rt, 1 h, Me2SO4 (2 equiv.), 40°C, 2 h, 90%
The copper complex of the chiral atropisomeric bipyridine 5 was applied to the asymmetric
cyclopropanation of styrene derivatives with ethyl diazoacetate. In general, good cyclopropane
conversion and diastereoselectivities were achieved, the major products, trans-cyclopropanes,
were obtained with good enantioselectivity (Table 1). The use of copper(I) triflate and copper(II)
triflate gave cyclopropanes with similar e.e. values and trans/cis ratios. When the reaction
temperature was lowered from 20 to 0°C, the e.e. of the trans-cyclopropane increased from 80
to 86%. When the catalyst loading was increased from 1 to 3% (Entry 4), the enantioselectivity
remained unchanged while the diastereoselectivity increased; the reason for this remains unclear.
Table 1
Asymmetric cyclopropanation of styrene with EDA catalyzed by the copper complex of (S,S)-5
Entry
X
Mol (%)
Time (h)
Temp (°C)
Yield (%)
Trans/cisa
e.e. (trans)b,c
1
2
3
4
1
1
2
2
3
1
1
1
4
5
8
20
20
20
0
72
89
88
95
92/8
79.4
80.1
80.2
86.0
86/14
85/15
86/14
24
a Determined by GC–MS.
b Determined by HPLC using chiral OD-H column.
c Absolute configuration was (1R,2R) by comparison of optical rotations with literature values (Ref. 13).

7725
Table 2
Asymmetric cyclopropanation of p-substituted styrene with EDA catalyzed by the copper-(S,S)-5
Entry
X
Time (h)
Trans/cisa
Yield (%)
e.e. (trans)b,c
1
2
3
4
OMe
Me
H
6
6
8
86/14
85/15
85/15
86/14
81
86
80
78
73.5
75.6
80.2
84.0
Cl
18
a Determined by GC–MS.
b Determined by HPLC using chiral OD-H column.
c Absolute configuration was (1R,2R) by comparison of optical rotations with literature values (Ref. 13).
Recently, much work has been done in order to study the electronic influence of the
catalyst9–11and the substrate12 in transition metal catalyzed reactions. When para-substituted
styrenes were subjected to cyclopropanation (Table 2), the most electron-poor olefin gave the
highest enantioselectivity. Furthermore, the enantioselectivity depended on the electronic nature
of the para-substituents and followed a linear free energy relationship (Fig. 1).
Figure 1. Plot of enantioselectivity versus Hammett constant |p
In summary, we have successfully demonstrated a linear Hammett plot for the substrate
electronic effect on catalytic asymmetric cyclopropanation using a new type of chiral atropiso-
meric 2,2%-bipyridine.

7726
Acknowledgements
We thank the Research Grants Council of Hong Kong (CUHK 2160102) for financial
support.
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