Synthesis of imine-amine type of chiral ligands and their application in the asymmetric cyclopropanation of olefins with diazoacetates

Article abstract of DOI:10.1016/S0957-4166(01)00513-4

Novel chiral ligands 1, which possess both imine and amine moieties, were prepared from readily available homochiral materials. Copper complexes of 1 were prepared in situ and used in the asymmetric cyclopropanation of olefins with alkyl diazoacetates to

Full text of DOI:10.1016/S0957-4166(01)00513-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2801–2804
Synthesis of imine–amine type of chiral ligands and their
application in the asymmetric cyclopropanation of olefins with
diazoacetates
Jun-An Ma, Li-Xin Wang, Wei Zhang and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China
Received 26 September 2001; accepted 12 November 2001
Abstract—Novel chiral ligands 1, which possess both imine and amine moieties, were prepared from readily available homochiral
materials. Copper complexes of 1 were prepared in situ and used in the asymmetric cyclopropanation of olefins with alkyl
diazoacetates to give cyclopropanecarboxylates, inducing e.e. values of up to 87%. The size of the chelate ring in the copper
complexes influenced the enantioselectivity of the reaction. © 2001 Published by Elsevier Science Ltd.
1
. Introduction
to report the synthesis of new ligands 1 bearing N-het-
erocycles and a chiral azepine moiety as the first exam-
ple of imine–amine type of chiral ligands and their
application in the copper-catalyzed asymmetric cyclo-
propanation reaction.
Since the first example of copper-catalyzed enantiose-
lective cyclopropanation reported by Nozaki et al. in
966, various optically active copper complexes have
1
1
been synthesized and used as catalysts for the asymmet-
ric cyclopropanation of olefins with diazo esters. The
highly enantioselective copper catalysts included Cu–
2
. Results and discussion
2
3
4
Schiff base, Cu–semicorrin, Cu–bisoxazoline, Cu–7
5
6
bipyridine, Co–bis(dioxime), Cu–binaphthyldiimine
2
.1. Ligand syntheses
8
and Cu–pinene-[5,6]-bipyridine complexes. However,
the chiral ligands in these copper catalysts are limited
to either imine alcohols or bisimine type functionalities.
These ligands are soft bases and their complexes with
highly reduced transition metals are stabilized mainly
by back-bonding of metal electrons to the ligand.
To synthesize the desired chiral imine–amine type lig-
ands 1, we have developed two practical synthetic
routes outlined in Scheme 1. In one approach (route
A), ligands 1a and 1b were directly obtained by treat-
1
0
ment of (S)-2,2%-dibromomethyl-1,1%-binaphthyl
2
Kanemasa et al. have demonstrated that C -symmetric
with 2-aminomethylpyridine and 8-aminomethylquino-
line in one step with high yield (95% for 1a and 90% for
1b). In an alternative route (route B), ligands 1a and 1b
were prepared by alkylation of (S)-3,5-dihydro-4H-
2
secondary 1,2-diamines, which are strongly basic lig-
ands, also show excellent asymmetric induction in the
9
cyclopropanation reactions. In the course of our stud-
11
ies on the design of new N-containing chiral ligands, we
became interested in chiral bis-nitrogen ligands which
possess both imine and amine moieties. Herein, we wish
dinaphth[2,1-c:1%,2%-e]azepine 3 with 2-bromomethyl-
pyridine and 8-bromomethylquinoline. The yields are
also very high (97% for 1a and 91% for 1b).
N
CH2
N
CH2
N
N
1
a
1b
*
0
Corresponding author. Fax: +86 22 2350 0011; e-mail: qlzhou@public.tpt.tj.cn
957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00513-4

2
802
J.-A. Ma et al. / Tetrahedron: Asymmetry 12 (2001) 2801–2804
CH Br
2
ArCH NH /K CO
ArCH Br/K CO
2 2 3
2
2
2
3
N
CH Ar
NH
2
CH CN
CH CN
3
3
CH Br
2
route A
route B
2
1a Ar = 2-pyridinyl
b Ar = 8-quinolinyl
3
1
Scheme 1.
.2. Enantioselective cyclopropanation
2
cis=82:18) were obtained. This is consistent with the
trend previously reported in the asymmetric cyclo-
12
The asymmetric cyclopropanation reaction was carried
out by slow addition of diazoacetate to a refluxing
solution of olefins in chloroform containing copper
catalyst prepared in situ from [Cu(OTf)·(C H ) ] and
the ligand 1. No reaction occurred in refluxing
dichloromethane. The examination of catalyst loading
showed that 1.0 mol% of catalyst was necessary to
complete the reaction, and no differences in the
diastereoselectivity and the enantioselectivity have been
found when up to 4.0 mol% of catalyst was used. The
results are summarized in Table 1.
propanation with other copper-catalysts. The decrease
in e.e. for the product obtained on reaction with
D
-
menthyl diazoacetate in entries 7 and 8 may be
explained by a mismatching of the stereotopic interac-
tion between ligand and the ester group in the car-
benoid intermediate. The cyclopropanation of different
olefins was also examined. Substituted styrenes, espe-
cially those bearing an electron-withdrawing sub-
stituent, showed lower enantioselectivity than styrene
itself (entries 9–14 versus 5 and 6).
6
6 0.5
To explain the sense of asymmetric induction of our
new ligands, a working model has been proposed as
shown in Scheme 2. It is known that the copper–ligand
complex first reacts with alkyl diazoacetate to form a
metal–carbene complex, which then is attacked by the
olefin to give the cyclopropane product. The steric
interactions between the substituents of the ligand and
the ester group in the carbenoid intermediate determine
the direction of the approach of the olefin and thus
Variation in the structure of the diazoacetate has a
great influence on the diastereoselectivity and enan-
tioselectivity. For example, when the R group in the
diazoacetate is changed from ethyl to the bulkier dicy-
clohexylmethyl or L-menthyl in the cyclopropanation of
styrene (entries 1–6) both trans/cis ratios and enantiose-
lectivities increased significantly. The best result was
observed with
L-menthyl diazoacetate, where 87% e.e.
13
for the trans- and 83% e.e. for the cis-isomer (trans/
control the stereochemistry of the product. The com-
Table 1. Enantioselective cyclopropanation of olefins with diazoacetates
Cu(I) / L*
Ar
+
N2CHCO2R
CO R
2
CHCl / reflux
3
Ar
Entry
Ligand
Ar
R
Yield (%)a
cis/transb
% e.e. (cis)c
% e.e. (trans)c
1
2
3
4
5
6
7
8
9
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MePh
4-MePh
4-MeOPh
4-MeOPh
4-ClPh
4-ClPh
Et
Et
DCM
DCM
61
60
61
54
56
60
61
64
60
62
54
55
36
39
37:63
28:72
18:82
16:84
23:77
18:82
23:77
19:81
22:78
29:71
29:71
28:72
31:69
28:72
36
43
71
80
77
83
39
47
65
77
73
75
42
64
40
45
63
83
74
87
46
51
66
72
64
65
46
49
d
L
-Menthyl
-Menthyl
L
D
-Menthyl
-Menthyl
D
L
L
L
L
L
L
-Menthyl
-Menthyl
-Menthyl
-Menthyl
-Menthyl
-Menthyl
10
11
12
13
14
a
b
c
Isolated yield.
Measured by GC with a capillary column (HP-1, 30 m×0.32 mm ID).
Determined by GC analysis using capillary columns HP-1 (30 m×0.32 mm ID) and CP-SIL 24CB (30 m×0.25 mm ID) (for entries 1–4, after
re-esterification with (−)-menthol). The absolute configurations, (1S,2R) for the cis-isomers and (1R,2R) for the trans-isomers were determined
1
2c
by chiroptical comparison with the published values.
Dicyclohexylmethyl diazoacetate.
d

J.-A. Ma et al. / Tetrahedron: Asymmetry 12 (2001) 2801–2804
2803
Scheme 2.
parison of steric repulsion between the ligand and the
ester group connected to the carbenoid center showed
that the intermediate A is more stable than intermediate
B. For simplicity, we will only consider the intermediate
A in the following discussion. There are four possible
approaches for the styrene to the reaction center of A,
two (C and D) lead to cis-products, and another two (E
and F) provide trans-products. Although the trans/cis
ratio of the product appears to be determined exclu-
sively by the nature of the olefin and the diazoacetate,
the enantioselectivity is dependent on the interactions
of the ester group of the carbenoid, the ligand and the
olefin. In the case of the formation of cis-cyclopropane,
approach D is considered to suffer from less steric
repulsion as compared with approach C, leading to a
cis product with (1S,2R)-configuration. Similarly, the
approach F suffers from less steric hindrance than
approach E, providing the trans product with (1R,2R)-
configuration. The absolute configuration of both cis-
and trans-isomers of cyclopropanation products
obtained from the experiments agrees with the above
discussion.
3. Conclusion
In summary, two new chiral imine–amine type ligands
have been successfully synthesized and were used as
chiral ligands in the copper-catalyzed asymmetric cyclo-
propanation. Moderate to good enantioselectivities and
diastereoselectivities have been provided. The scope and
limitations of this type of ligand system in asymmetric
cyclopropanation and their applications in other metal-
catalyzed asymmetric reactions are now under investi-
gation in our laboratory.
4
. Experimental
4
.1. General
Melting points were measured with a Yanaco MP-500
1
apparatus and uncorrected. H NMR spectra were
recorded on a Bruker AC-P200 instrument using tetra-
methylsilane as an internal standard in deuterochloro-
form. IR spectra were obtained as KBr plates on a
Shimadzu 435 spectrophotometer. Mass spectra were
measured on a VG-7070E spectrometer using a solid
probe at 70 eV. Elemental analyses (C, H, N analyses)
were carried out on a Yanaco MT-3 analyzer. Chloro-
form was distilled over calcium sulfate. Acetonitrile was
distilled over calcium hydride.
It is noteworthy that the reactions with 1a were invari-
ably less enantioselective than the corresponding reac-
tions with 1b. Ligands 1a and 1b have similar electronic
properties, but the copper complexes formed in the
reaction have different chelate ring size. The ligand 1a,
upon coordination, forms a five-membered chelate ring,
while ligand 1b forms a six-membered ring. Because of
the consequent increase in the bite angle, the sub-
stituents of ligand 1b will be closer to the metal center
and the ester group in the intermediate, resulting in a
more efficient interaction. Thus, the reaction with 1b
showed relatively high enantioselectivity. A similar
trend in the effect of chelate ring size on the enantiose-
lectivity has also been observed in the asymmetric
cyclopropanations with pyridinyl–oxazoline and quino-
4
4
.2. Syntheses of the ligands
.2.1. (S)-3,5-Dihydro-4-(2-pyridinylmethyl)dinaphth[2,1-
c:1%,2%-e]azepine 1a. General procedure (route A): A mix-
ture of (S)-2,2%-dibromomethyl-1,1%-binaphthyl 2 (3.10
g, 7.04 mmol), 2-aminomethylpyridine (0.91 g, 8.44
mmol) and K CO (2.14 g, 15.49 mmol) was dissolved
2
3
in dry acetonitrile (30 mL) and stirred at room temper-
ature for 24 h. The mixture was then diluted with
dichloromethane (30 mL), filtered and evaporated to
dryness under reduced pressure. The crude product
1
4
linyl–oxazoline ligands.

2
804
J.-A. Ma et al. / Tetrahedron: Asymmetry 12 (2001) 2801–2804
obtained was purified by silica gel column chromatog-
raphy to give 1a as a white solid (2.58 g, 95% yield).
after re-esterification with (−)-menthol, by GC analysis
with a capillary column (HP-1, 30 m×0.32 mm ID). For
entries 9–12 in Table 1, enantiomeric excesses were
determined by GC analysis using a capillary column
CP-SIL 24CB (30 m×0.25 mm ID).
2
0
Mp 197–198°C. [h] +235.4 (c 1.0, CH Cl ); IR (KBr):
D
2
2
2
8
977.0, 2926.0, 2820.3, 1588.8, 1432.5, 1148.0, 1053.0,
19.1, 750.5 cm . H NMR: l (ppm) 3.28 (d, J=12.2
−1 1
Hz, 2H), 3.68 (d, J=12.2 Hz, 2H), 3.74 (d, J=14.0 Hz,
H), 3.87 (d, J=14.0 Hz, 1H), 7.20–7.96 (m, 15H), 8.75
dd, J=5.2 and 1.8 Hz, 1H). MS (EI): 294(100),
95(38), 265(27), 252(11), 93(74), 92(16). Anal. calcd for
C H N : C, 87.01; H, 5.73; N, 7.26. Found: C, 87.15;
1
(
2
Acknowledgements
2
8
22
2
H, 5.74; N, 7.10%.
Financial support from the National Natural Science
Foundation of China, the Major Basic Research Devel-
opment Program (grant No. G2000077506) and The
Ministry of Education of China are gratefully
acknowledged.
4
.2.2. (S)-3,5-Dihydro-4-(8-quinolinylmethyl)dinaphth-
[
2,1-c:1%,2%-e]azepine 1b. White solid, 90% yield. Mp
2
0
9
3
8
8–99°C. [h]D +215.2 (c 1.0, CH Cl ). IR (KBr):
2 2
049.0, 2926.0, 2802.0, 1590.0, 1496.0, 1128.6, 1039.1,
−
1 1
19.5, 752.1 cm . H NMR: l (ppm) 3.34 (d, J=12.0
Hz, 2H), 3.76 (d, J=12.2 Hz, 2H), 4.20 (d, J=14.6 Hz,
1
2
1
5
H), 4.62 (d, J=14.6 Hz, 1H). MS (EI): 436(4),
95(40), 294(100), 277(19), 265(29), 252(10), 157(10),
43(75), 115(10). Anal. calcd for C H N : C, 88.04; H,
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2
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6
6 0.5
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1
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measured by GC with a capillary column (HP-1, 30
m×0.32 mm ID). The enantiomeric excesses of cyclo-
propanes in entries 1–4 in Table 1 were determined,