Novel chiral copper complexes of N,P-ferrocenyl ligands with central and planar chirality as efficient catalyst for asymmetric addition of diethylzinc to imines

Article abstract of DOI:10.1016/j.tetasy.2005.06.005

A new type of chiral copper complexes of N,P-ferrocenyl ligands with central and planar chirality as efficient catalyst was applied to the enantioselective addition of diethylzinc to N-diphenylphosphinoylimines. The (R)- and (S)-enantiomers of the additio

Full text of DOI:10.1016/j.tetasy.2005.06.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2531–2534
Novel chiral copper complexes of N,P-ferrocenyl ligands
with central and planar chirality as efficient catalyst for
asymmetric addition of diethylzinc to imines
Min-Can Wang,* Lan-Tao Liu, Yuan-Zhao Hua, Jun-Song Zhang, Yan-Yan Shi and
De-Kun Wang
Department of Chemistry, Zhengzhou University, Zhengzhou, Henan 450052, China
Received 20 May 2005; accepted 1 June 2005
Abstract—A new type of chiral copper complexes of N,P-ferrocenyl ligands with central and planar chirality as efficient catalyst was
applied to the enantioselective addition of diethylzinc to N-diphenylphosphinoylimines. The (R)- and (S)-enantiomers of the addi-
tion reaction were obtained for this transformation. In the presence of 6 mol % of bidentate ligand 1 and 12 mol % of Cu(OTf)2, the
asymmetric addition process affords N-diphenylphosphinoylamides in up to 97% ee and 95% yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ral copper complex of N,P-ferrocenyl ligands with cen-
tral and planar chirality represents an efficient catalyst
promoting the enantioselective addition of diethylzinc
to the C@N bond of N-diphenylphosphinoylimines with
up to 97% ee and 95% isolated yield.
The discovery and development of new efficient catalytic
asymmetric methods for the preparation of chiral
amines by the addition of organometallic reagents to
C@N of imines is an important objective in organic
synthesis.1 While there have been numerous efforts to
control the stereoselectivity of this reaction either
by chiral auxiliaries1b,c,2 or (stoichiometric) chiral
ligands,1e,3 the catalytic asymmetric addition of simple
alkyl metals has only been achieved very recently.4–10
Indeed, recent studies in this area have revealed that
the catalytic generation of reactive organometal–chiral
ligand complexes from the corresponding less reactive
organometallic reagents in situ under mild conditions
catalyzed the addition of organometallic reagents to
imines bearing different protecting groups with high
enantioselectivity. Among these, copper complexes of
O,P-ligands,6 rhodium complexes,7 zirconium complexes
of peptidic Schiff-base ligands,8 copper complexes of
P,P-ligands,9 and copper complexes of N,S-ligands,10
showed impressive success. To the best of our knowl-
edge, the evaluation of chiral copper complexes of
N,P-ligands in diethylzinc addition to imines has not
been reported. Herein, we report that a new type of chi-
Over the past few years, ferrocenyl derivatives, because
of their planar chirality, rigid bulkiness, ease of deriva-
tization, and stability,1 have attracted growing atten-
tion as chiral ligands in asymmetric catalysis, with
excellent asymmetric induction being realized in many
types of asymmetric reactions.11 Our interest in the
application of chiral ferrocenyl ligands in the catalytic
asymmetric reaction12 promoted us to explore chiral
ferrocenyl ligands in the use of a new catalytic asym-
metric system.
2. Results and discussion
Chiral ferrocenyl ligands 1–4 were easily synthesized
according to the literature.13 (Fig. 1). They have the
advantage of being quite stable in air and more
attractively are commercially available. Our initial
efforts focused on the identification of the optimal
copper(II) complexes in terms of both yields and ee in
the presence of 12 mol % of Cu(OTf)2 and 6 mol % of
chiral N,P-ferrocenyl ligands. Two pairs of enantiomers
1 and 2, and 3 and 4, with N,P chelating atoms were
*
Corresponding author. Fax: +86 371 67769024; e-mail:
wangmincan@zzu.edu.cn
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.005

2532
M.-C. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 2531–2534
˚
Me
H
4 A MS could affect their reactions very obviously both
Me
Me
H
Me
H
H
in yields and enantiomeric excesses.14 We then examined
the effects of the ratio of Cu(OTf)2 to ligand 2 on either
yield or enantioselectivity (Table 2, entries 2, 4–8). When
6 mol % of ligand 2 was used, lowering the amount of
Cu(OTf)2 from 12 to 6 or 3 mol %, even if the overall
yield was increased slightly (Table 2, entries 2, 4 and
5), a decrease in product ee was observed. Doubling
the amounts of Cu(OTf)2 relative to chiral ligand 2
was selected for further optimization. An increase in
ligand loading from 6 to 8 mol % led to a decrease in
product ee and yield. Decreasing the amount of ligand
from 6 to 4 or 2 mol % was detrimental to the enantio-
selectivity. So, the combination of 6 mol % of chiral
ligand 2 and 12 mol % of Cu(II) salt seemed the most
suitable catalyst for the alkylation of imines. One equiv-
alent more of Cu salts than the amount of ligands ap-
peared to be reasonable; this was also found in other
systems.9
NMe2 Me2N
Ph2P
NMe2
Me2N
Ph2P
PPh2
PPh2
PPh2
Fe
Fe
Fe
Fe
Ph2P
4
1
3
2
(S,R)-BPPFA
(S,R)-PPFA
(R,S)-BPPFA
(R,S)-PPFA
Figure 1. The chiral ferrocenyl ligands used for this study.
screened, with the results summarized in Table 1 (entries
1–4).
As can be seen from Table 1, the addition of diethylzinc
to the C@N bond of N-diphenylphosphinoylimine led to
the protected amine in 50–91% yields with 34–92% ee
(entries 1–4). It was shown that both enantioselectivity
and reactivity were very sensitive to the structure of
the chiral ligands. When bidentate ligand 1 and its enan-
tiomer 2 were employed, the addition of diethylzinc to
the N-diphenylphosphinoylimine afforded outstanding
ee values (92% ee) and high chemical yields (85%,
91%, Table 1, entries 1 and 2). Tridentate ligand 3 and
its enantiomers 4 not only showed moderate catalytic
activity (50%), but also gave the product with low ee val-
ues (42–45% ee, Table 1, entries 3 and 4). These observa-
tions suggest that N,P-bidentate coordination of the
ligands to the catalytically active copper species might
be crucial for obtaining high asymmetric induction
and yields.
Table 2. Optimization of the reaction conditions of the stereoselective
alkylation of imines
O
P
O
P
Ph
Ph
Ph
Ph
Cu(OTf)2 (x mol%)
HN
∗
N
(S,R)-PPFA (y mol%)
Et2Zn, toluene,
0 ˚C - r t
Ph
Et
Ph
H
Entry
x
y
Temp (°C) Yield (%)a ee (%)b Config.c
1
12
12
12
6
6
6
6
6
6
8
4
2
rt
0
92
91
90
92
94
88
90
90
91
92
91
90
87
89
87
86
S
S
S
S
S
S
S
S
2
3d
4
rt
0
5
3
0
6
16
8
0
Table 1. The Cu(OTf)2-ferrocenyl ligands catalyzed Et2Zn addition to
N-diphenylphosphinoylimines
7
0
8
4
0
O
P
O
P
Ph
Ph
Ph
Ph
a Isolated yield.
Cu(OTf)2 (12 mol%)
Ligand (6 mol%)
HN
N
b Enantiomeric excesses were determined by HPLC on chiral station-
ary phase.
*
Et2Zn, toluene, 0oC , 24 h
Ph
Ph
H
c Absolute configuration was assigned by comparing retention time on
HPLC with the literature values.9,15
Et
Entry
Ligand
Yield (%)a
ee (%)b
Config.c
d
˚
4 A MS were added.
1
2
3
4
(R,S)-PPFA 1
(S,R)-PPFA 2
(R,S)-BPPFA 3
(S,R)-BPPFA 4
85
91
50
50
92
92
42
45
R
S
R
S
These reaction conditions were then tested on other N-
phosphinoylimines derived from different arylaldehydes
in the presence of bidentate ligands 1 and 2 with the re-
sults shown in Table 3. As can be seen from Table 3,
good yields and high to excellent enantioselectivities
could be achieved for various aromatic N-phosphinoyl-
imines containing ortho-, para- and meta-substituents on
the benzene ring (Table 3, entries 3–12). The presence of
electron-donating or electron-withdrawing substituents
on the aromatic ring is also compatible with these reac-
tion conditions. The best asymmetric induction (as high
as 97% ee) was found by using an imine bearing a 2-
MeOC6H4 group as the substrate in the presence of
bidentate ligand 1 (Table 3, entry 5). It is advantageous
that imines derived from furfural can be converted to
adducts in 85% yields and 90% ees (entries 13 and 14),
because the products are useful intermediates for the
synthesis of biologically active compounds.16 These re-
sults are comparable with the best literature values hith-
a Isolated yield.
b Enantiomeric excesses were determined by HPLC.
c Absolute configuration was assigned by comparing the retention time
on HPLC with the literature value.9,15
Bidentate ligand 2 was chosen as the best chiral ligand
for further optimization, with the results shown in Table
2. We first investigated the effect of reaction temperature
on enantioselectivity. Lowering the reaction tempera-
ture from room temperature (20–25 °C) to 0 °C led to
a slight enhancement in the additional selectivity from
91% to 92% (Table 2, entries 1 and 2). Addition of
˚
4 A molecular sieves (MS) to the reaction system did
not benefit the enantioselectivity or the yield of the
products (Table 2, entries 3 vs 1). In contrast,
Gong and other groups have reported that the use of

M.-C. Wang et al. / Tetrahedron: Asymmetry 16 (2005) 2531–2534
Table 3. Addition of Et2Zn to N-diphenylphosphinoylimines
2533
O
P
O
P
Ph
Ph
Ph
Ph
Cu(OTf)2 (12 mol%)
L (6 mol%)
HN
*
N
Et2Zn, toluene, r. t
Ar
Et
Ar
H
12-18
5-11
Ligand
Entry
Ar
Time (h)
Yield (%)a
ee (%)b
Config.c
1
2
Ph 5
Ph 5
(R,S)-PPFA 1
(S,R)-PPFA 2
24
24
85
91
92 12
92 12
R
S
O
6
6
3
(R,S)-PPFA 1
48
75
84 13
R
O
O
4
(S,R)-PPFA 2
48
76
84 13
S
O
5
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
4-MeOC6H4
7
7
8
8
(R,S)-PPFA 1
(S,R)-PPFA 2
(R,S)-PPFA 1
(S,R)-PPFA 2
(R,S)-PPFA 1
(S,R)-PPFA 2
(R,S)-PPFA 1
(S,R)-PPFA 2
(R,S)-PPFA 1
(S,R)-PPFA 2
24
24
48
48
48
48
48
48
48
48
95
95
73
76
94
94
92
92
85
85
97 14
95 14
88 15
86 15
92 16
91 16
88 17
88 17
90 18
90 18
R
S
R
S
R
S
R
S
R
S
6
7
8
9
4-MeC6H4
4-MeC6H4
9
9
10
11
12
13
14
4-ClC6H4 10
4-ClC6H4 10
2-Furyl 11
2-Furyl 11
a Isolated yield.
b Enantiomeric excesses were determined by HPLC on chiral stationary phase.
c Absolute configuration was assigned by comparing the retention time on HPLC with the literature value.9,15
erto reported for the asymmetric addition of diethylzinc
to N-phosphinoylimines.9,10
diphenylphosphinoylimines. In the presence of bidentate
ligands 1 and 2, the asymmetric addition process affords
N-diphenylphosphinoylamides in high to excellent ee
and good yields in toluene under mild conditions. The
availability of a pair of antipodal chiral amines sug-
gested that his new synthetic method for enantiomeri-
cally pure amines might be a potential procedure used
in the synthesis of some natural products, physiologi-
cally active substances and pharmaceutical compounds.
Efforts are underway to elucidate the mechanistic details
of this catalytic system and to study the role of planar
chirality in the asymmetric addition of diethylzinc to
N-diphenylphosphinoylimines.
Although the mechanistic details of the asymmetric pro-
cess are currently unclear, they should be analogous to
the well-studied chemistry of organocuprates.17 The cat-
alytically active species is the copper(I) complex, which
can be formed at the initial reaction stage through the
in situ reduction of the copper(II) complex by Et2Zn,
followed by a 1,4-conjugate addition-type alkylation.
Additional studies demonstrated that the total process
can be extended to asymmetric amine synthesis. The
acidic hydrolysis of the phosphinamides liberated the
corresponding aromatic primary amines with no loss
of enantiomeric purity.3a,18 The first availability of a
pair of antipodal chiral amines, compared with other
catalytic asymmetric systems, is of critical importance
to organic synthesis because the two enantiomers of
biologically active compounds often exhibit quite differ-
ent types of biological activity in pharmaceutical and
agricultural application. Hence, this new synthetic meth-
od for enantiomerically pure amines might be a poten-
tial procedure used in drug synthesis and biological
and related fields.
Acknowledgements
We are grateful to the National Natural Sciences Foun-
dation of China (NNSFC: 20172047), Henan Outstand-
ing Youth Program 2001, and the Education
Department of Henan Province for the financial
support.
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