Development of chiral catalysts by asymmetric activation for highly enantioselective diethylzinc addition to imines

Article abstract of DOI:10.1055/s-2005-863709

Based on the asymmetric activation concept, a library of chiral zinc complexes in situ formed by the combination of diimines derived from chiral 1,2-diphenyl-ethanene-1,2-diamine, BINOL derivatives, and diethylzinc are evaluated in the asymmetric addition of diethylzinc to N-acylimines. In the presence of 10 mol% L3ZnA1, high enantioselectivities and yields were provided for a wide range of aromatic imines in 1,2-dichloroethane at -25 °C.

Full text of DOI:10.1055/s-2005-863709

LETTER
615
Development of Chiral Catalysts by Asymmetric Activation for
Highly Enantioselective Diethylzinc Addition to Imines
Development of
C
a
hira
l
Cataly
i
sts by
-
A
symme
L
tric
A
ctivatione Zhang, Hua Liu, Xin Cui, Ai-Qiao Mi, Yao-Zhong Jiang, Liu-Zhu Gong*
Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, P. R. China
Graduate School of Chinese Academy of Sciences, Beijing, P. R. China
E-mail: gonglz@cioc.ac.cn
Received 26 December 2004
catalysts include copper-amidophosphine complexes,5
Abstract: Based on the asymmetric activation concept, a library of
chiral Zr(IV) complexes,6 zinc complexes of [2,2]-paracy-
chiral zinc complexes in situ formed by the combination of diimines
clophane-N,O-ligands7 as well as copper complexes of
derived from chiral 1,2-diphenyl-ethanene-1,2-diamine, BINOL
Me-DuPHOS and BozPHOS (Me-DuPHOS monoxide).8
derivatives, and diethylzinc are evaluated in the asymmetric addi-
tion of diethylzinc to N-acylimines. In the presence of 10 mol%
L3ZnA1, high enantioselectivities and yields were provided for a
come an important platform for engineering chiral cata-
wide range of aromatic imines in 1,2-dichloroethane at –25 °C.
Pioneered by Mikami,9 the asymmetric activation has be-
lysts.10 This concept has been successfully used for
Key words: asymmetric dialkylzinc addition, asymmetric activa-
developing efficient chiral catalysts to activate carbonyl
tion, imine
substrates, but seldom applied for the development of
chiral catalysts for the activation of imines.10 Inspired by
the successful use of [2,2]paracyclophane-based N,O-
Optically active amines are very important intermediates
ligands in the catalytic asymmetric diorganozinc addition
in the synthesis of natural products and physiologically
to imines 7 and by the asymmetric activation concept,9–11
active substances as well as pharmaceuticals.1 They are
we proposed that the combination of chiral imines A and
binaphthols L with diethylzinc generating active chiral
zinc complexes LZnA (Figure 1), that catalyze the dieth-
also extensively applied to the resolution of racemic com-
pounds and asymmetric synthesis as chiral auxilliaries.2
The nucleophilic addition of organometallic reagents to
ylzinc addition to aldehydes in high level of stereo-
imines provides one of the most convenient accesses to
control,11a–11c in principal, should efficiently catalyze the
chiral amines, and thus has received much attention.3 Im-
diethylzinc addition to N-acylimines 2 under suitable
conditions. Herein, we present our preliminary results of
portant advances have been made in the asymmetric addi-
tion of diorganozinc reagents to imines promoted by
using the asymmetric activation concept to engineer the
stoichiometric amounts of chiral ligands.3,4 Recently, cat-
chiral catalyst for asymmetric catalytic diethylzinc addi-
alytic asymmetric processes affording products in high
tion to imines with high yields and enantioselectivities.
enantiomeric purity have been reported.5–8 Representative
R1
R2
R2
Ph
N
Ph
N
*
*
N
N
Ph
Ph
Et2Zn
O
O
*
*
OH
OH
Zn
+
R1
R1
A
R2
R2
L
L1, R2 = Ph
L2, R2 = 4-ClC6H4
R1
LZnA
(1S,2S)-A
A1, R1 = H
A2, R1 = 4-Me
A3, R1 = 2,4,6-trimethyl
A4, R1 = 4-Cl
L3, R2 = 3,5-(CF3)2C6H3
L4, R2 = 2,4,6-Me3C6H2
L5, R2 = 3,5-Me2C6H3
L6, R2 = 4-t-BuC6H4
L7, R2 = α-naphth
A5, R1 = 3,4-(OH2)-
(1R,2R)-A6
A6, R1 = H
L8, R2 = β-naphth
L9, R2 = SiPh3
Figure 1 The combined catalysts evaluated for catalytic asymmetric diethylzinc addition to imines
SYNLETT 2005, No. 4, pp 0615–0618
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4.
0
3.
2
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5
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-863709; Art ID: U35704ST
© Georg Thieme Verlag Stuttgart · New York

616
H.-L. Zhang et al.
LETTER
Table 1 Catalyst Screeninga
A small library of catalysts generated from the combina-
tion of Ligands L and activators A with a constant ratio of
1:1 were screened to catalyze the asymmetric addition of
diethylzinc to 1a in toluene at room temperature, and the
results are shown in Table 1. Using A1 as an activator, we
initially examined the ligands L1–9 and found that the
3,3¢-substituents on the ligand had a considerable in-
fluence on both reactivity and enantioselectivity. If the
substituent is either too bulky or too small, the enantio-
selectivity is negatively affected. For example, using
complex L4ZnA1 or L9ZnA1 both containing compara-
bly bulky groups leads to almost racemic product (entries
4 and 9). The use of L1ZnA1 bearing a comparably small
phenyl group also provided a low enantioselectivity (11%
ee, entry 1). The best combined zinc complex for the
catalysis is L3ZnA1, which promoted the reaction in 86%
yield and 66% ee (entry 3).
O
H
O
O
10 mol% LZnA
H
Et2Zn
N
HN
H
HN
H
Et2Zn, r.t.,
toluene
SO2Tol
1a
2a
3a
Entry
1
A (activator)
L (ligand)
L1
Yield (%)b
61
ee (%)c
11
15
66
4
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A3
A4
A5
A6
–
2
L2
62
3
L3
86
4
L4
78
5
L5
68
17
20
12
8
6
L6
65
By using L3 as the optimal ligand, we investigated the ef-
fect of the activator on the reaction (entries 10–14). It was
found that the structural feature of the activator did not af-
fect the reaction as considerably as the ligand, but a simi-
lar conclusion can be drawn from the observation that the
activator with a too bulky substituent gives low enantio-
selectivity. Although the activator did not influence the
enantioselectivity as significantly as the ligand did, it was
important for improving the catalytic efficiency of the
combined catalyst. In the absence of an activator, the zinc
complexes of ligand L3 catalyzed the reaction to give the
product with 50% yield and 15% ee (entry 15). The use of
diethylzinc and activator A1 only leads to a racemic mix-
ture of product (entry 16). However, the combined use of
A1 and L3 displayed the significantly improved enantio-
selectivity of 66% ee (entry 3). The absolute configuration
of the activator seems not to have any influence on the ste-
reochemistry, thus the use of A6 as activator afforded
comparable ee to the use of A1 (entries 3 and 14).
7
L7
71
8
L8
73
9
L9
68
4
10
11
12
13
14
15
16
L3
80
52
40
55
54
67
15
<1
L3
55
L3
74
L3
73
L3
85
L3
50
A1
–
41
a Unless otherwise specified, the reaction was performed in 0.1 mmol
scale for 36 h, 3 equiv diethylzinc (1.0 M in hexane).
b Isolated yield based on analytically pure product 3a and imine
precursor 1a.
With the best combined catalyst L3ZnA1 in hand, we
then finely modified the reaction conditions to further im-
prove its catalytic efficiency (Table 2). Solvent screening
demonstrates that toluene, dichloromethane and 1,2-
dichloroethane are suitable solvents whereas low reaction
efficiency is observed in hexane and chloroform. At room
temperature and 0 °C higher enantioselectivities were ob-
tained by using toluene (entries 2 and 3) instead of hexane
(entry 1) or dichloromethane (entry 4). However, the
best enantioselectivities were observed at –25 °C in
dichloromethane or 1,2-dichloroethane affording product
3a in 91% yield and 83% ee. In contrast, the use of chlo-
roform led to diminished yield and low enantioselectvity
(entry 8).
c Determined by GC.
ities than electron-rich ones. Thus, enantioselectivities
>90% ee were observed using imines containing electron-
withdrawing groups (entries 1, 4, 5, 8, 9). A low enantio-
selectivity was found for an imine 2g possessing a strong
electron-donating group (entry 7). Interestingly, for the
first time, a high enantioselectivitiy was obtained for an
imine with sensitive functionality such as a cyano group.
The asymmetric addition of diethylzinc to imine 2h af-
forded the corresponding amides 3h in 94% enantiomeric
excess (entry 8).
In summary, for the first time, we demonstrated that
the catalysts developed on the basis of the asymmetric
activation concept are highly effective in asymmetric
catalytic diethylzinc addition to N-acylimines. The com-
plex L3ZnA1 is the best catalyst for the reaction and ex-
hibits excellent catalytic activity and provides the desired
amides in good to high enantiomeric purities. Thus, in the
presence of 10 mol% L3ZnA1, high enantioselectivities
of up to 94% ee and high yields of up to 91% were
The optimized protocol was subsequently extended to a
range of imine precursors bearing either electron-donat-
ing or electron-withdrawing groups by using 10 mol%
catalyst L3ZnA1. As shown in Table 3, the catalyst dis-
plays high enantioselectivities ranging from 71% to 94%
ee. The electronic properties of the imine precursors have
an obvious impact on the stereoselectivity. Generally,
electron-deficient imines provided higher enantioselectiv-
Synlett 2005, No. 4, 615–618 © Thieme Stuttgart · New York

LETTER
Development of Chiral Catalysts by Asymmetric Activation
617
Table 2 Optimization of Reaction Conditionsa
provided for a wide range of aromatic imines. The use of
this catalyst system in promoting other reactions with
imines is underway in our laboratory.
O
O
O
HN
H
Et2Zn
10 mol% L3ZnA1
H
N
HN
H
Et2Zn
SO2Tol
H
Acknowledgment
1a
2a
3a
We are grateful for financial support from the National Natural
Science Foundation of China (Projects 203900505 and 20325211).
Entry Solvent
Temp (°C) Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
Hexane
Toluene
Toluene
CH2Cl2
Toluene
CH2Cl2
r.t.
r.t.
0
40
30
36
48
36
36
36
36
98
86
47
66
78
69
78
82
83
53
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–25
–25
85
75
ClCH2CH2Cl –25
CHCl3 –25
91
<10
a Unless otherwise specified, the reaction was performed in 0.1 mmol
scale for 36 h, 3 equiv diethylzinc (1.0 M in hexane).
b Isolated yield based on analytically pure product 3a and imine
precursor 1a.
c Determined by GC.
Table 3 Asymmetric Addition of Diethylzinc to Iminesa
O
O
O
Et2Zn
H
HN
10 mol% L3ZnA1
N
H
HN
H
Et2Zn, ClCH2CH2Cl
–25 °C, 36 h
Ar
SO2Tol
Ar
H
Ar
1
2
3
Entry
Imines 2 (Ar)
3-BrC6H4 (2b)
3-ClC6H4 (2c)
C6H5 (2a)
Yield (%)b
ee (%)c
93
1
2
3
4
5
6
7
8
9
90
80
91
80
80
78
91
75
86
88
83
4-ClC6H4 (2d)
4-BrC6H4 (2e)
90
93
4-MeC6H4 (2f)
4-MeOC6H4 (2g)
4-CNC6H4 (2h)
4-CF3C6H4 (2i)
86
71
94
92
a Unless otherwise specified, the reaction was performed in 0.2 mmol
scale, 3 equiv diethylzinc (1.0 M in hexane).
b Isolated yield based on analytically pure products 3 and imine pre-
cursors 1.
c Determined by GC and the absolute configuration is assigned as R
by comparison of optical rotations with those in literature.7a
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Synlett 2005, No. 4, 615–618 © Thieme Stuttgart · New York

618
H.-L. Zhang et al.
LETTER
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Synlett 2005, No. 4, 615–618 © Thieme Stuttgart · New York