The enantioselective diethylzinc addition to imines catalyzed by chiral Cu(II)-oxazoline complexes

Article abstract of DOI:10.1016/j.tetasy.2003.09.036

A series of copper complexes of chiral bisoxazolines has been applied in the catalytic diethylzinc addition to N-sulfonyl imines. It has been found that the tridentate ligands 3-5 provided higher enantioselectivity than bidentate ones. Addition of 4 A molecular sieves to the reaction system benefits the enantioselectivity. The optimal procedure for diethylzinc addition to different imines resulted in moderate yields and enantioselectivities of up to 82% ee.

Full text of DOI:10.1016/j.tetasy.2003.09.036

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3819–3821
The enantioselective diethylzinc addition to imines catalyzed by
chiral Cu(II)–oxazoline complexes
Xin Li, Lin-Feng Cun, Liu-Zhu Gong,* Ai-Qiao Mi* and Yao-Zhong Jiang
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China
Received 1 August 2003; accepted 16 September 2003
Abstract—A series of copper complexes of chiral bisoxazolines has been applied in the catalytic diethylzinc addition to N-sulfonyl
,
imines. It has been found that the tridentate ligands 3–5 provided higher enantioselectivity than bidentate ones. Addition of 4 A
molecular sieves to the reaction system benefits the enantioselectivity. The optimal procedure for diethylzinc addition to different
imines resulted in moderate yields and enantioselectivities of up to 82% ee.
© 2003 Elsevier Ltd. All rights reserved.
The important synthetic utility of chiral amines has
stimulated great interest in developing methods for the
asymmetric preparation of such molecules.1 Enantiose-
lective dialkylzinc addition to imines is one of the most
efficient approaches to chiral amines. Many chiral b-
amino alcohols have been designed to promote the
dialkylzinc addition with high enantioselectivity, but
stoichiometric amounts of ligands are required.2 Recent
studies in this area have revealed that several chiral
complexes, including copper-amidophosphine,3 chiral
Zr(IV) complexes,4 zinc complexes of [2,2]-paracy-
clophane-N,O-ligands,5 copper-Me-DuPhos6 etc. cata-
lyze the dialkylzinc addition to imines bearing different
protected groups with high enantioselectivity. Li et al.
have used the copper(I) pybox complex to catalyze the
direct-addition of terminal alkynes to imines with excel-
lent results.7 On the basis of this observation and
successful applications of copper–phosphine complexes
in diethylzinc additions to imines,3,6 we envisioned that
the chiral copper–oxazoline complexes should work as
catalysts to promote the dialkylzinc addition to imines
enantioselectively. To the best of our knowledge, the
evaluation of chiral copper–oxazoline complexes in
diethylzinc additions to imines has not been reported.
Herein, we present our preliminary results on this area
(Fig. 1).
Initially, to find out an optimal procedure, the diethylz-
inc addition to 6a was carried out under different
conditions with 3a as the chiral ligand. The results were
summarized in Table 1.
Figure 1. The chiral oxazolines used for this study.
* Corresponding authors. Fax: +86-28-85223978; e-mail: gonglz@cioc.ac.cn
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.036

3820
X. Li et al. / Tetrahedron: Asymmetry 14 (2003) 3819–3821
Table 1. The enantioselective diethylzinc addition to 6a catalyzed by complexes of 3aa
Entry
M
Mol% M
Mol% 3a
Temp. (°C)
Time (h)
Yield (%)c
Ee (%)d
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuOTf
10
10
10
10
10
10
10
12
10
10
10
10
10
10
10
10
10
12
10
10
10
10
25
25
0
9
9
26
21
62
55
71
60
58
62
60
41
25
24b
42
29b
65
32b
76
77
75
78
10
0
20
20
31
30
31
31
31
31
31
0
−20
−20
−20
−20
−20
−20
−20
9
10
11
Cu(acac)2
Zn(OTf)2
a The concentration of imine is 0.05 mol/L, and the ratio of Et2Zn to imine is 4.
b
,
Without MS 4 A.
c Isolated yield.
d The ee was determined with HPLC, and the absolute configuration of 7a was assigned as S by comparing retention time of HPLC with the
literature value.3a
Table 2. Enantioselective diethylzinc addition to imine 6a
in the presence of 10 mol% Cu(OTf)2 complexes of oxazo-
lines 1–5a
In the presence of 10 mol% catalyst formed in situ from
3a and a transition metal complex, the reaction worked
enantioselectively to provide the product 7a. The enan-
tioselectivity was sharply dependent on the reaction
conditions. Enantioselectivities ranging from 10 to 78%
ee values were observed with different copper com-
plexes (entries 1–10). The promoter generated from
Zn(OTf)2 and 3a gave both poor yield and enantioselec-
tivity for the test reaction (entry 11). The enantioselec-
tivity was highly sensitive to reaction temperature.
Lowering the reaction temperature led to a dramatic
increase in the enantioselectivity (entries 2, 4, and 6).
Entry
Oxazoline
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
1a
1b
2a
2b
3a
3b
3c
3d
4
41
33
21
41
58
35
32
47
32
71
0
0
9
1
,
Addition of 4 A molecular sieves (MS) benefited the
enantioselectivity (entries 1–6), a similar phenomenon
had also been observed in copper-pybox catalyzed het-
ero-Diels–Alder reaction and 1,3-dipolar cycloaddition
reactions.8,9 The ratio of Cu(OTf)2 to 3a had no obvi-
ous influence on either yield or enantioselectivity
(entries 6–8). Comparison of results presented in entries
6 and 9 indicated that Cu(OTf)2 had similar reactivity
and enantioselectivity to CuOTf. However, the catalyst
prepared from Cu(acac)2 and 3a exhibited much poorer
reactivity and stereocontrol to afford 7a with 41% yield
and less than 10% ee (entry 10).
77 (S)
23 (R)
15 (R)
43 (R)
23 (S)
50 (R)
9
10
5
a The ratio of oxazoline to Cu(OTf)2 is 1.2.
b Isolated yield.
c The ee was determined by HPLC.
The optimal procedure was then examined for the other
N-sulfonyl imines derived from different aldehydes, and
the results are given in Table 3. The reactions of
N-sulfonyl imines with diethylzinc worked readily to
provide chiral sulfonyl amides 7 with moderate yields of
28–62% and enantioselectivities of up to 82% ee. Gener-
ally, the absence of substituents containing heteroatoms
on the aromatic ring generated the product with higher
enantioselectivity (entries 1, 2, 8, and 9) than N-sulfo-
nyl imines with heteroatom substituent on the phenyl
ring (entries 3–7 and 10). This catalyst system provided
poor results for N-sulfonyl furyl imine, due to the low
reactivity of the substrate.
Under the optimal conditions, the Cu(II) complexes of
chiral oxazolines 1–5 were surveyed to catalyze the
diethylzinc addition to 6a. The results clearly indicated
that the enantioselectivity was determined by the struc-
ture of the oxazoline. In general, tridentate ligands 3–5
(entry 5–10) provided higher enantioselectivity than
bidentate oxazolines 1 and 2 (Table 2, entry 1–4).
Varying the substituent of the ligand led to an obvious
change in the enantioselectivity. The oxazoline 3a kept
the highest level of enantioselectivity among the exam-
ined ligands (entry 5).

X. Li et al. / Tetrahedron: Asymmetry 14 (2003) 3819–3821
Table 3. Enantioselective diethylzinc addition to N-sulfonylimines
3821
Entry
R
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
Ph 6a
58
52
60
62
37
52
60
51
40
58
77
70
63
64
57
64
61
82
74
53
4-MeC6H4 6b
4-BrC6H4 6c
4-ClC6H4 6d
2-ClC6H4 6e
4-FC6H4 6f
4-MeOC6H4 6g
1-Naphthyl 6h
2-Naphthyl 6I
9
10
11
2-Furyl 6k
28
19
a Isolated yield.
b The ee values were determined on HPLC.
In summary, we have demonstrated that the copper
complexes of chiral oxazolines can catalyze the
diethylzinc addition to N-sulfonyl imines. In the pres-
ence of 10 mol% the optimal catalyst in situ generated
from Cu(OTf)2 and 3a, the diethylzinc addition to
N-sulfonyl imines 6a–k produced 7a–k with moderate
yields and enantioselectivities of up to 82% ee.
Although this catalyst system is not competitive with
the known ones at the present stage,3–6 our results
suggest a way to design quite different chiral catalysts
from the copper–phosphine system for the organozinc
addition to imines.
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We are grateful for financial support from the National
Science Foundation of China (20102005).
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