Highly efficient chiral copper Schiff-base catalyst for asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene

Article abstract of DOI:10.1016/j.tet.2004.06.073

A remarkable increase in catalytic activity is found for the asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene with diazoacetate by use of the chiral copper Schiff-base complexes, which are derived from substituted salicylaldehydes, chiral aminoalcohols, and copper acetate monohydrate. Furthermore, a combination of a chiral copper Schiff-base with a Lewis acid showed an increase in yield (up to 90%) and in enantioselectivity (up to 90% ee) for the asymmetric cyclopropanation of the diene with t-butyl diazoacetate at 20°C.

Full text of DOI:10.1016/j.tet.2004.06.073

Tetrahedron 60 (2004) 7835–7843
Highly efficient chiral copper Schiff-base catalyst for asymmetric
cyclopropanation of 2,5-dimethyl-2,4-hexadiene
a
a
a
Makoto Itagaki,a Koji Hagiya, Masashi Kamitamari, Katsuhisa Masumoto,
,
*
Katsuhiro Suenobua and Yohsuke Yamamotob
aOrganic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugade-naka, 3-chome, Konohana-ku,
Osaka 554-8558, Japan
bDepartment of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan
Received 18 April 2004; revised 14 June 2004; accepted 15 June 2004
Available online 20 July 2004
Abstract—A remarkable increase in catalytic activity is found for the asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene with
diazoacetate by use of the chiral copper Schiff-base complexes, which are derived from substituted salicylaldehydes, chiral aminoalcohols,
and copper acetate monohydrate. Furthermore, a combination of a chiral copper Schiff-base with a Lewis acid showed an increase in yield
(up to 90%) and in enantioselectivity (up to 90% ee) for the asymmetric cyclopropanation of the diene with t-butyl diazoacetate at 20 8C.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
many asymmetric cyclopropanations of styrene with
diazoacetate have been reported over the last 20 years
(Scheme 1).1–4,8–10
Catalytic asymmetric cyclopropanation of alkenes with
diazoacetate has been a powerful tool in the synthesis of
chiral cyclopropyl esters, which are very important
intermediates for biologically active compounds.1–4 3-(1-
In Aratani’s catalyst, the structure of the chiral amino-
alcohol part played an important role on the enantio-
selectivity,6,7 so that the modification of the aminoalcohol
has been tried to achieve higher enantioselectivity up to
1999. In 2000, Li et al. reported an investigation on the
framework of the benzene ring of salicylaldehyde in the
copper Schiff-base complex for the asymmetric cyclo-
propanation of styrene, and more than 98% ee of the cis
product was obtained with i-butyl diazoacetate using the
copper Schiff-base catalyst 3b derived from 5-nitrosalicyl-
aldehyde.11 They also applied the copper Schiff-base
catalyst 3b to the cyclopropanation of 2,5-dimethyl-2,4-
hexadiene with l-menthyl diazoacetate with 1 mol% catalyst
loading. However the enantioselectivity of the trans product
and the trans/cis ratio were moderate (74% ee, t/c¼72/28),
and the catalytic amount used in their report (1 mol%)
should increase the cost of the cyclopropane products
(Scheme 2).12
Isobutenyl)-2,2-dimethyl
cyclopropanecarboxylate
(chrysanthemate) is of particular importance as an inter-
mediate of pyrethroid insecticides, and the (1R,3R) isomer
((þ)-trans isomer) shows the most insecticidal activity
among the four isomers of the chrysanthemate.5 Among the
efficient catalysts which have been developed, copper
Schiff-base complexes derived from chiral aminoalcohols
are very attractive catalysts. Using this kind of catalysts,
Aratani first achieved a high ee (94%) and trans/cis ratio
(93/7) for the cyclopropanation of 2,5-dimethyl-2,4-hexa-
diene with l-menthyl diazoacetate to give the chrysanthe-
mate, and Aratani’s asymmetric process leads to successful
industrial application in the synthesis of chiral 2,2-
dimethylcyclopropane carboxylic acid, by asymmetric
cyclopropanation of isobutene with ethyl diazoacetate.5–7
To the best of our knowledge, only a few successful reports,
in which high trans selectivity and high enatioselectivity
were achieved, have been presented in the asymmetric
cyclopropanation of the diene as a substrate, although
Therefore, we have developed new highly efficient catalysts
for the cyclopropanation of the dienes with a simple alkyl
diazoacetate such as ethyl or t-butyl diazoacetate, which
means that the formed chrysanthemate would be easy to
convert to the chiral chrysanthemic acid as the intermediate
for pyrethroid insecticides. Here, we report that the copper
Schiff-base catalysts derived from 5-substituted salicyl-
aldehyde with an electron-withdrawing group remarkably
Keywords: Asymmetric cyclopropanation; Copper Schiff-base; Lewis acid;
Diazoacetate; 2,5-Dimethyl-2,4-hexadiene.
*
Corresponding author. Tel.: þ81-824247430; fax: þ81-824240723;
e-mail address: itagakim@sc.sumitomo-chem.co.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.073

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M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
Scheme 1. The structures of Aratani’s catalysts R-1648, and the results of the cyclopropanation of 2,5-dimethyl-2,4-hexadiene with l-menthyl diazoacetate
with 1 mol% catalyst loading.
on the salicylaldehyde framework did not show a remark-
able difference with 0.5 mol% catalyst (entries 3, 7, 11). All
cases with 0.1 mol% catalysts 1a, 2a, and 3a decreased not
only in the yield but also in enantioselectivity, compared to
those with 0.5 mol% (entries 1 vs. 2, 5 vs. 6, 9 vs. 10).
However, almost the same yield and ee were retained in
each case with 0.1 mol% catalysts 1b, 2b, and 3b as those
with 0.5 mol% catalyst (entries 3 vs. 4, 7 vs. 8, 11 vs. 12).
These results clearly indicated that the copper Schiff-base
catalysts derived from salicylaldehyde lose catalytic activity
faster than those derived with 5-nitrosalicylaldehyde.
Actually, we analyzed the reaction mixture based on the
structure of the used catalyst 2a after the cyclopropanation
by HPLC. We found that not only the original copper
Scheme 2. Structures of Li’s catalyst 3b, and the results of the
cyclopropanation of 2,5-dimethyl-2,4-hexadine with l-menthyl diazoace-
tate with 1 mol% catalyst loading.
complex 2a but also the corresponding Schiff-base ligand
Table 1. Asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene
(DMHD) with EDAa
enhanced the catalytic efficiency for the asymmetric
mol%b
Yield (%)c
trans/cisd
ee (%)e
cyclopropanation of 2,5-dimethyl-2,4-hexadiene. Further-
more, we found that a combination of a copper Schiff-base
complex with a Lewis acid achieved 90% yield and more
than 90% ee with t-butyl diazoacetate at 20 8C with
0.1 mol% catalyst loading.
Entry
Catalyst
transf
cisg
1
2
3
4
5
6
7
8
1a
1a
1b
1b
2a
2a
2b
2b
3a
3a
3b
3b
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
95
80
97
96
96
83
97
96
96
82
96
95
61/39
63/37
61/39
61/39
58/42
60/40
58/42
58/42
55/45
58/42
54/46
54/46
60
32
59
58
65
40
67
65
80
44
80
78
59
30
50
48
69
39
65
60
61
39
60
56
2. Results and discussion
2.1. Effect of substituents of aminoalcohol framework
and salicylaldehyde framework on the stereoselectivity
and the catalytic efficiency
9
10
11
12
a
The results of the asymmetric cyclopropanation of 2,5-
dimethyl-2,4-hexadiene (DMHD) with ethyl diazoacetate
(EDA) are shown in Table 1, using the copper Schiff-base
complexes as catalysts as shown in Scheme 3. They were
synthesized from chiral aminoalcohols, salicylaldehyde
derivatives, and copper(II) acetate hydrate (Scheme 4). In
the order of 1a, 2a, and 3a, the enantioselectivety of the
trans product was enhanced, while the trans/cis ratio of the
product was lowered in the presence of 0.5 mol% catalyst
loading (entries 1, 5, 9).7 The results are consistent with
those of Aratani,7 although the presence of a nitrogen group
Reaction conditions: 10 mmol of EDA, 70 mmol of DMHD, 5 mL of
ethyl acetate, 80 8C, 0.01 mmol of the monomerized copper complex with
0.5 mol of phenylhydrazine to the binuclear complex as shown in
Scheme 4.
Mol% of the mononuclear complex based on EDA.
Based on EDA and determined by GC analysis with n-decane as internal
standard.
b
c
d
e
Determined by GC analysis (DB-1, 30 m£0.25 mm ID, 0.25 mm film,
column temp. 100 8C).
Determined by LC analysis (Sumichiral OA-2500 (25 cm£4 mm ID, 5
mm film)£2, UV 220 nm, n-hexane 0.7 mL/min).
1R,3R as a major enantiomer.
f
g
1R,3S as a major enantiomer.

M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
7837
Scheme 3. Structures of the copper Schiff-base catalysts 1a-1b, 2a-2b, 3a-3b.
Scheme 4. Synthesis of copper Schiff-base complexes 1-3. (a) D-alanine methyl ester hydrochloride; (b) substituted salicylaldehyde; (c) copper acetate
monohydrate, NaOH.
Scheme 5. The structure of the used catalyst 2a after the cyclopropanation.
did not exist in the reaction mixture any more, and an adduct
of ethyl diazoacetate with the phenol oxygen of the Schiff-
base ligand was detected as shown in Scheme 5.
Li et al. described that reducing the electron density on the
salicylaldehyde framework by the introduction of a nitro
group favors the enantioselectivity for the cyclopropanation
of styrene. Although our results above suggest that the
introduction of a nitro group does not affect the enantio-
selectivity, the catalytic robustness can be enhanced more
strongly with the Cu–O bond from the phenol.
Therefore, several Schiff-bases with various electron-with-
drawing substituents on the salicylaldehyde framework
in copper complex 2 were examined (Scheme 6). We
found that 5-substituted copper complexes with an
Scheme 6. Structures of the copper catalysts 2a-2k.

7838
M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
Figure 1. Comparison of catalytic efficiency between 2a and 2b at 80 8C.
electron-withdrawing group were more effective for the
enantioselectivity than 3-substituted ones, except for the
fluorine substituted complex.
2.2. Effect of temperatures on the selectivity
Under lower temperatures for the reaction, higher enantio-
meric excesses of the product were obtained, but the yield of
the product was lowered with the catalyst 2b or 3b, as
shown in Table 3.
Comparison of turnover numbers between 2a and 2b is
shown in Figure 1. A remarkable decrease in both the yield
and ee was observed with higher turnover numbers in the
case of 2a, while in the case of catalyst 2b, the ratio of the
decrease in the yield and the ee is much smaller than that by
2a.
Table 3. The influence of reaction temperature and alkyls in diazoacetate
(RDA) in the presence of 0.1mol%a of the catalystsb
Entry Catalyst R in RDA Temp Yield trans/cis
(8C)
ee
(%)c
transd cise
(%)
These results suggested that the copper Schiff-base catalyst
derived from the 5-substituted salicylaldehyde with an
electron-withdrawing group becomes more efficient for the
asymmetric cyclopropanation of the diene, although the
same performance is essentially exhibited in enantio-
selectivity as the unsubstituted copper complex on the
salicylaldehyde moiety. This point is also different from
the introduction of a nitro group in salicylaldehyde at the
5-position in the copper complex which enhanced the
enantioselectivity for the cyclopropanation of styrene by Li
et al. (Table 2).
1
2
3
4
5
6
7
8
9
10
2b
2b
2b
2b
2b
2b
3b
3b
3b
3b
Et
Et
Et
t-Bu
t-Bu
t-Bu
Et
Et
t-Bu
t-Bu
80
20
0
80
20
0
80
0
80
20
96
58
35
88
27
6
95
56
87
11
58/42
58/42
57/43
72/28
78/22
79/21
54/46
50/50
72/28
77/23
65
75
83
83
91
93
78
82
84
93
60
70
78
55
63
64
56
67
20
23
a
Mol% of mononuclear complex based on RDA.
b
c
Reaction conditions: 0.01 mmol of catalyst as the monomeric copper
complex, 10 mmol of RDA, 70 mmol of DMHD, 5 mL of ethyl acetate.
Determined by LC analysis (Chiral AGP (25 cm£4 mm ID, 5 mm film)
£2, UV 210 nm, 20 mM KH2PO4/CH3CN¼87/13 (v/v), 0.5 mL/min) in
the case where N2CHCOt2Bu was used.
Table 2. Asymmetric cyclopropanation of DMHD with EDA using 2 as the
catalysta
d
e
1R,3R as a major enantiomer.
1R,3S as a major enantiomer.
Entry
Catalyst
mol%b
Yield (%)
trans/cis
ee (%)
transc
cisd
A bulky group in the diazoacetate was reported to increase
the enantioselectivity and trans/cis ratio.5 When t-butyl
diazoacetate was used, the enantiomeric excesses for the
trans product reached 93% in the case of both catalysts 2b
and 3b at 0 8C, although the yield was low. The trans/cis
ratio was slightly better with 2b than 3b. The slow rate of
the process and the low yield of the product could be
dramatically improved by addition of a Lewis acid.
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
83
96
97
98
97
94
97
97
96
97
60/40
58/42
59/41
60/40
58/42
60/40
58/42
58/42
60/40
59/41
40
65
55
42
65
46
63
62
43
62
39
60
48
33
58
40
57
58
41
57
2j
2.3. Effect of a Lewis acid on the selectivity
a
Reaction conditions: 10 mmol of EDA, 70 mmol of DMHD, 5 mL of
ethyl acetate, 80 8C, 0.01 mmol of the monomerized copper complex with
0.5 mol phenylhydrazine to the binuclear complex as shown in Scheme 6.
Mol% of the mononuclear complex based on EDA.
1R,3R as a major enantiomer.
In order to achieve high yields and high enantioselectivities,
addition of an equimolar amount of a Lewis acid was
examined with 0.1 mol% catalyst 2b at 0 or 20 8C. The
results are shown in Table 4. It is noteworthy that addition of
b
c
d
1R,3S as a major enantiomer.

M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
7839
Table 4. Asymmetric cyclopropanation of DMHD with EDA using the new catalyst system, consistent for the copper Schiff-base complex and various Lewis
acids (LA)a
Entry
Cu-complex
LA
Temp
(8C)
Yield
(%)
trans/cis
ee
(%)
transb
cisc
1
2
3
4
5
6
7
8
9
10
2b
2b
2b
2b
2b
2b
2b
2b
3b
3b
None
None
HfCl4
B(C6F5)4
Al(OC6F5)3
Ti(O–iPr)4
Al(OEt)3
Al(OEt)3
None
20
0
58
35
84
91
91
85
95
86
56
83
58/42
57/43
58/42
58/42
58/42
58/42
58/42
57/43
50/50
49/51
75
83
76
76
72
76
77
84
82
83
70
78
71
71
68
70
71
79
67
68
20
20
20
20
20
0
0
0
Al(OEt)3
a
Reaction conditions: 0.01 mmol of the copper Schiff-base complex as the monomeric copper complex, 0.01 mmol of Lewis acid, 10 mmol of EDA, 70 mmol
of DMHD, 5 mL of ethyl acetate.
1R,3R as a major enantiomer.
1R,3S as a major enantiomer.
b
c
Table 5. The effect of adding Al(OEt)3 to the copper Schiff-base catalyst on the asymmetric cyclopropanation of DMHD with RDAa
Entry
Cu-complex
LA
R in RDA
Temp (8C)
Yield (%)
trans/cis
ee (%)
transb
cisc
1
2
3
4
2b
2b
3b
3b
None
t-Bu
t-Bu
t-Bu
t-Bu
20
20
20
20
27
90
11
86
78/22
78/22
77/23
77/23
91
91
93
93
63
62
23
24
Al(OEt)3
None
Al(OEt)3
a
Reaction conditions: 0.01 mmol of copper Schiff-base as the monomeric copper complex, 0.01 mmol of Lewis acid, 10 mmol of RDA, 70 mmol of DMHD,
5 mL of ethyl acetate.
1R,3R as a major enantiomer.
1R,3S as a major enantiomer.
b
c
a Lewis acid increased the reaction rate, and even at 20 8C a
90% ee is the first case of the asymmetric cyclopropanation
of DMHD with t-butyl diazoacetate. It should be noted the
t-butyl chrysanthemate formed is easy to hydrolyze to
convert to chrysanthemic acid by an acid catalyst, which is a
key intermediate for synthetic pyrethroids.
95% yield was obtained in the presence of Al(OEt)3 (77%
ee, entries 7 vs. 1); the reaction proceeded smoothly at 0 8C
to give 86% yield and 84% ee (entries 8 vs. 2). The
combination of the copper complex 3b with Al(OEt)3 was
also examined with EDA, and enhancement of the yield was
observed (entries 9 vs. 10).
2.4. Study of the possible mechanism based on the
calculations
Furthermore, when t-butyl diazoacetate was used instead of
ethyl diazoacetate, 91% yield and 91%ee for the trans
product were obtained at 20 8C in the presence of 0.1 mol%
of 2b combined with Al(OEt)3 (entries 1 vs. 2, in Table 5).
The use of the catalyst composed of 3b and Al(OEt)3 also
achieved 86% yield and 93% ee.
In order to probe the possible mechanism of the asymmetric
induction, hybrid density functional calculations were
carried out. As the details of the calculation were reported
elsewhere,13 these calculations suggested that the catalytic
key intermediate can be the copper(I) carbene complex
bearing the intramolecular hydrogen bond between the
hydrogen of the hydroxyl group and the carbonyl oxygen of
the ester group in the case of catalyst 2b as shown in
Scheme 7.
Aratani achieved more than 90% ee for the trans product
with 1 mol% of a chiral [(R)-N-salicylidene-2-amino-1,1-
di(2-n-octyloxy-5-t-butylphenyl)-1-propanol]
copper
complex as a catalyst in the asymmetric cyclopropanation
of DMHD with l-menthyl diazoacetate, while more than
90% ee for the trans product was achieved using 2,6-t-butyl-
4-methylphenyl diazocetate catalyzed by a copper-chiral-
bisoxazoline complex.
The reaction proceeds by the [2þ1] addition from DMHD to
the carbene carbon of the Cu(I)–carbene complex. The
enantioselectivity of the chrysanthemate calculated from the
Boltzmann distribution of the nine transition states was
qualitatively consistent with the experimental result
that the (þ)-trans(1R,3R) isomer is predominantly
To the best of our knowledge, the achievement of more than

7840
M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
Scheme 7. Structures of the copper(I) carbene complex from catalyst 2b.
Scheme 8. Schematic representation of the possible orientation of DMHD, which approaches the carbene carbon of the Cu(I)–carbenoid complex for methyl
chrysanthemate.
produced. Scheme 8 shows the most favorable transition
state for the (þ)-trans(1R,3R) isomer and the (2)-
trans(1S,3S) isomer, respectively. The conformations of
the 9-ring-members bearing the intramolecular hydrogen
bond in the copper(I) carbene complex are different from
each other, leading the formation of the enantio-isomer of
the trans chrysanthemate. The trans/cis ratio should depend
on the steric repulsion among the isobutenyl group of
DMHD, the ester group on the Cu(I)–carbene complex, and
a substituent X on the phenyl group.
These results suggested that Al(OEt)3 coordinates with the
oxygen atom of the nitro group on the salicylaldehyde
moiety in the copper carbene complex in the use of the
complex 2b and Al(OEt)3, and that lowered the electron
density on the carbene carbon of the carbene complex
to enhance the reactivity toward DMHD as shown in
Scheme 9.
Table 6. The effect of substituents at the 5-position on the salicylaldehyde
group in copper Schiff-base 2 with Al(OEt)3 as the catalyst on the
asymmetric cyclopropanation of DMHD with EDAa
The introduction of the electron-withdrawing substituents
on the benzene ring of the salicylaldehyde moiety in the
copper complex enhances the electrophilicity of the carbene
carbon through the copper atom. This enhancement should
bring about the high reactivity of the Cu(I)–carbene
complex toward the diene.
Entry Cu-complex Lewis acid Yield (%) trans/cis
ee (%)
transb cisc
1
2
3
4
5
6
7
8
9
10
2a
2a
2b
2b
2e
2e
2g
2g
2h
2h
None
Al(OEt)3
None
Al(OEt)3
None
Al(OEt)3
None
Al(OEt)3
None
Al(OEt)3
5
6
60/40
60/40
57/43
57/43
57/43
57/43
58/42
57/43
58/42
58/42
38
36
83
84
84
83
84
85
84
85
36
35
78
79
81
76
79
80
78
80
35
86
35
72
29
37
32
33
2.5. Possible mechanism for effect of addition of Lewis
acids
The effect of Lewis acids can also be explained based on the
following experimental results in Table 6. Although the
effect of Al(OEt)3 is not observed in 2a and 2h (entries 1 vs
2, 9 vs. 10), remarkable enhancement of the yield of the
product was observed at 0 8C in 2e as well as 2b (entries 3
vs. 4, 5 vs. 6). In the case of 2g, a slight enhancement of the
yield was observed (entries 7 vs. 8).
a
Reaction conditions: 0.01 mmol of copper Schiff-base as the monomeric
copper complex, 0.01 mmol of Al(OEt)3, 10 mmol of EDA, 70 mmol of
DMHD, 5 mL of ethyl acetate, 0 8C, 3h.
1R,3R as a major enantiomer.
1R,3S as a major enantiomer.
b
c

M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
7841
hexane and gave the product as a white solid (8.1 g, 71%).
[a]D¼87.2 (c¼1, CHCl3); mp 102–103 8C; 1H NMR
(CDCl3) d 7.63 (d, J¼1.7 Hz, 2H), 7.60 (d, J¼1.3 Hz,
2H), 7.50–7.12 (m, 6H), 4.14 (q, J¼6.4 Hz, 1H), 0.94 (d,
J¼6.6 Hz, 3H).
4.1.2. (R)-2-Amino-1,1-di(2-methoxyphenyl)-1-propanol.
Yield 75%, white solid; [a]D¼35.5 (c¼1, CHCl3); mp 89–
1
90 8C; H NMR (CDCl3) d 7,66 (d, J¼1.3 Hz, 2H), 7.19–
6.73 (m, 6H), 5.31 (s, 1H), 4.33 (q, J¼6.5 Hz, 1H), 3.58 (s,
3H), 3.52 (s, 3H), 1.01 (d, J¼6.6 Hz, 3H).
4.1.3. (R)-Amino-1,1-di(2-n-butoxy-5-t-butylphenyl)-1-
propanol. Purified by column chromatography (SiO2,
n-hexane/AcOEt¼10/1!MeOH). Yield 55%, pale yellow
1
viscous oil; [a]D¼35.3 (c¼1, CHCl3); H NMR (CDCl3) d
7.70 (s, 2H), 7.24–7.12 (m, 2H), 6.73–6.64 (m, 2H), 5.24
(s, 1H), 4.27 (q, J¼6.5 Hz, 1H), 3.81–3.67 (m, 4H), 1.59–
1.43 (m, 6H), 1.38–1.23 (m, 2H), 1.34 (s, 9H), 1.33 (s, 9H),
1.03 (d, J¼6.3 Hz, 3H), 0.89 (t, J¼7.3 Hz, 6H).
Scheme 9. Tentative scheme for the addition to the copper complex 2b.
3. Conclusions
4.2. The Schiff bases. General procedure for 4a, 5a, and
6a
New copper Schiff-base complexes derived from substituted
salicylaldehydes bearing an electron-withdrawing group at
the 5-position were found to be highly efficient for
asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexa-
diene with diazoacetate. These compounds demonstrated
much more remarkable enhancement of the turnover
number than the copper catalyst derived from the salicyl-
aldehyde. In addition, we found that high yield and high
enantioselectivity with highly catalytic efficiency using
t-butyl diazoacetate was achieved by addition of a Lewis
acid such as Al(OEt)3. The products were easily converted
to chrysanthemic acid.
4.2.1. (R)-(N-Salicylidene)-2-amino-1,1-diphenyl-1-pro-
panol 4a. (R)-2-Amino-1,1-diphenyl-1-propanol (5.00 g,
22.0 mmol) and salicylaldehyde (2.69 g, 22.0 mmol) were
dissolved in toluene (30 mL), and the mixture was refluxed
for 1 h. Methanol was removed under vacuum and the
residue was purified by column chromatography (SiO2,
n-hexane:ethyl acetate¼1:1) to afford the pure Schiff base
4a (7.09 g, 97%) as yellow solid. [a]D¼236.8 (c¼1,
1
CHCl3); mp 112–113 8C; H NMR (CDCl3) d 12.63 (s,
1H), 8.37 (s, 1H), 7.56–7.48 (m, 4H), 7.35–7.15 (m, 8H),
6.89–6.81 (m, 2H), 4.57 (q, J¼6.5 Hz, 1H), 2.67 (s, 1H),
1.25 (d, J¼6.6 Hz, 3H).
4. Experimental
Compound 5a. Yield 96%, yellow solid; [a]D¼2166 (c¼1,
CHCl3); mp 141–142 8C; 1H NMR (CDCl3) d 13.91 (s, 1H),
8.29 (s, 1H), 7.72–7.61 (m, 2H), 7.26–6.72 (m, 10H), 5.37
(s, 1H), 5.06 (q, J¼6.4 Hz, 1H), 3.56 (s, 3H), 3.53 (s, 3H),
1.33 (d, J¼6.6 Hz, 3H).
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere. Optical rotations were measured on
a JASCO DIP-370. Melting points were measured with a
METTLER TOLEDO TYPE FP62. NMR spectra were
recorded by a Bruker DPX-300NMR spectrometer with
trimethyl silane as an internal standard (d value in CDCl3).
The yields and ee values were determined by GC analyses
with a capillary column and LC analyses with a chiral
column in the cyclopropanation, respectively.
Compound 6a. Yield 95%, yellow viscous oil; [a]D¼2135
(c¼1, CHCl3); 1H NMR (CDCl3) d 8.17 (s, 1H), 7.69–7.66
(m, 2H), 7.21–6.61 (m, 7H), 5.21 (s, 1H), 4.84(q, J¼6.4 Hz,
1H), 3.78–3.61 (m, 4H), 1.51–1.18 (m, 8H), 1.41 (d,
J¼6.5 Hz, 3H), 1.34 (s, 9H), 1.20 (s, 9H), 0.86 (t, J¼7.3 Hz,
6H).
4.1. Aminoalcohol
4.3. General procedure for 4b, 5b, 5c, 5d, 5e, 5f, 5g, 5h,
5i, 5j, and 6b
4.1.1. (R)-2-Amino-1,1-diphenyl-1-propanol. The methyl
ester hydrochloride of D-alanine (7.0 g, 50.1 mmol) was
added to a cooled Grignard solution derived from
bromobenzene (41.6 g, 265 mmol) and magnesium (6.7 g,
276 mmol) in THF at 0 8C. The mixture was stirred for 3 h
at room temperature and then added to cooled 2%
hydrochloric acid (200 mL) at 0 8C. 150 mL of toluene
was added to the mixture, and the aqueous phase was
separated. The aqueous solution was neutralized with
ammonium hydroxide, and 150 mL of toluene was added
to the mixture. The organic phase was separated, washed
with saturated brine, dried, and concentrated. The pale
yellow solid was obtained, recrystallized from CH2Cl2-n-
4.3.1. (R)-(N-5-Nitrosalicylidene)-2-amino-1,1-diphenyl-
1-propanol 4b. (R)-2-Amino-1,1-diphenyl-1-propanol
(2.00 g, 8.80 mmol) and 5-nitrosalicylaldehyde (1.47 g,
8.80 mmol) were dissolved in toluene (20 mL) and the
mixture was refluxed for 1 h. The reaction mixture was then
cooled to room temperature, and the precipitated Schiff-
base was filtered and washed with heptane/toluene (¼2/1
(v/v)) to yield the pure Schiff base 4b (3.22 g, 97%) as a
yellow solid. [Anal. Found: C, 70.1%; H, 5.4%; N, 7.4%.
Calcd for C22H20N2O4: C, 70.21%; H, 5.32%; N, 7.45%];

7842
M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
[a]D¼285.0 (c¼1, CHCl3); mp 208–209 8C; 1H NMR
(CDCl3) d 8.26 (s, 1H), 8.15–8.12 (m, 2H), 7.54–7.20 (m,
10H), 6.89–6.82 (m, 1H), 4.65 (q, J¼6.6 Hz, 1H), 2.61 (s,
1H), 1.29 (d, J¼6.6 Hz, 3H).
Compound 5i. Yield 97%, yellow solid; [Anal. Found:
C, 72.0%; H, 6.2%; N, 2.9%. Calcd for C24FH24NO4·0.5-
C7H8: C, 72.51%; H, 6.20%; N, 3.08%]; [a]D¼2105
(c¼1, CHCl3); mp 102–104 8C; 1H NMR (CDCl3)
d 8.23 (s, 1H), 7.68 (d, J¼7.8 Hz, 1H), 7.61 (d,
J¼7.8 Hz, 1H), 7.25–6.70 (m, 8H), 5.42 (s, 1H), 5.09
(q, J¼6.5 Hz, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 1.29 (t,
J¼6.5 Hz, 3H).
Compound 5b. Yield 95%, yellow solid; [Anal. Found: C,
68.1%; H, 5.8%; N, 5.6%. Calcd for C22H20N2O4·0.5C7H8:
C, 68.45%; H, 5.85%; N, 5.85%]; [a]D¼2131 (c¼1,
1
CHCl3); mp 128–130 8C; H NMR (CDCl3) d 8.10–8.03
(m, 3H), 7.67–7.52 (m, 2H), 7.27–6.65 (m, 8H), 5.66 (s,
1H), 5.26 (q, J¼6.5 Hz, 1H), 3.62 (s, 6H), 1.41 (d,
J¼6.6 Hz, 3H).
Compound 5j. Yield 78%, yellow solid; [Anal. Found: C,
70.1%; H, 6.0%; N, 3.4%. Calcd for C24FH24NO4: C,
70.40%; H, 5.91%; N, 3.42%]; [a]D¼2168 (c¼1,
CHCl3); mp 116–118 8C; 1H NMR (CDCl3) d 8.16 (s,
1H), 7.69 (d, J¼7.8 Hz, 1H), 7.58 (d, J¼7.8 Hz, 1H),
7.25–6.71 (m, 7H), 6.51–6.45 (m, 1H), 5.49 (s, 1H), 5.13
(q, J¼6.5 Hz, 1H), 3.57 (s, 3H), 3.55 (s, 3H), 1.34 (t,
J¼6.6 Hz, 3H).
Compound 5c. Yield 91%, yellow solid; [Anal. Found: C,
68.2%; H, 5.8%; N, 5.6%. Calcd for C22H20N2O4·0.5C7H8:
C, 68.45%; H, 5.85%; N, 5.85%]; [a]D¼2389 (c¼1,
CHCl3); mp 132–135 8C; 1H NMR (CDCl3) d 8.25 (s,
1H), 7.72–7.61 (m, 2H), 7.23–6.69 (m, 9H), 5.33 (s, 1H),
5.03 (q, J¼6.5 Hz, 1H), 3.55 (s, 3H), 3.51 (s, 3H), 2.23 (s,
3H), 1.31 (d, J¼6.5 Hz, 3H).
Compound 6b. Yield 95%, yellow solid; [Anal. Found: C,
72.2%; H, 8.1%; N, 4.6%. Calcd for C38H52N2O6: C,
72.15%; H, 8.23%; N, 4.43%]; [a]D¼2153 (c¼1, CHCl3);
1
Compound 5d. Yield 96%, yellow solid; [Anal. Found: C,
62.3%; H, 5.1%; N, 7.8%. Calcd for C24H23N3O8·0.5C7H8:
C, 62.61%; H, 5.16%; N, 7.97%]; [a]D¼2242 (c¼1,
CHCl3); mp 144–147 8C; 1H NMR (CDCl3) d 8.92 (d,
J¼3.0 Hz, 1H), 8.30 (d, J¼3.1 Hz, 1H), 8.25–8.21 (m, 1H),
7.63 (d, J¼7.8 Hz, 1H), 7.50 (d, J¼7.9 Hz, 1H), 7.29–6.78
(m, 6H), 5.81 (s, 1H), 5.41(bs, 1H), 3.65 (s, 3H), 3.64 (s,
3H), 1.41 (t, J¼6.6 Hz, 3H).
m.p. 67–69 8C; H NMR (CDCl3) d 8.05–7.98 (m, 2H),
7.84 (s, 1H), 7.61 (s, 1H), 7.55 (m, 1H), 7.25–7.21 (m, 1H),
7.25–7.21 (m, 1H), 7.12–7.08 (m, 1H), 6.76–6.64 (m, 3H),
5.49 (s, 1H), 5.08 (m, 1H), 3.84–3.72 (m, 4H), 1.53–1.46
(m, 7H), 1.35 (s, 9H), 1.33–1.26 (m, 4H), 1.16 (s, 9H),
0.93–0.87 (m, 6H).
4.4. The copper complex
Compound 5e. Yield 94%, yellow solid; [Anal. Found: C,
71.2%; H, 6.2%; N, 2.6%. Calcd for C26H27NO6·0.5C7H8:
C, 71.50%; H, 6.31%; N, 2.83%]; [a]D¼2122 (c¼1,
CHCl3); mp 115–117 8C; 1H NMR (CDCl3) d 8.18 (d,
J¼4.5 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J¼7.8 Hz, 1H), 7.59
(d, J¼7.8 Hz, 1H), 7.28–6.72 (m, 7H), 5.53 (s, 1H), 5.35
(bs, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 3.56 (s, 3H), 1.36 (t,
J¼6.6 Hz, 3H).
General procedure. 4.90 g (11.2 mmol) of the Schiff-base
2b was dissolved in 250 g of ethyl acetate, and 2.24 g
(11.2 mmol) of copper acetate monohydrate was added to
the above solution. The mixture was refluxed for 1 h, and
aqueous sodium hydroxide was then added and further
stirred for 30 min at room temperature. The organic layer
was separated, washed with water, dried, concentrated in
vacuo, and 5.47 g of the copper Schiff-base complex was
obtained as a deep green solid. Yield 98%. The copper
complex was used without further purification. [LC-MS
(positive mode); m/z¼997]; [a]D¼546 (c¼0.1%, CHCl3);
mp 160–163 8C (dec.).
Compound 5f. Yield 93%, yellow solid; [Anal. Found: C,
69.1%; H, 6.0%; N, 2.9%. Calcd for C26H27NO6: C,
69.47%; H, 6.06%; N, 3.12%]; [a]D¼2235 (c¼1, CHCl3);
1
mp 135–138 8C; H NMR (CDCl3) d 8.18 (s, 1H), 7.89
(d, J¼7.8 Hz, 1H), 7.70 (d, J¼7.8 Hz, 1H), 7.52 (d,
J¼7.8 Hz, 1H), 7.26–6.62 (m, 7H), 5.44 (s, 1H), 5.10 (bs,
1H), 3.89 (s, 3H), 3.55 (s, 3H), 3.54 (s, 3H), 1.33 (t,
J¼6.6 Hz, 3H).
4.5. Cyclopropanation
Under a nitrogen atmosphere, 4.96 mg (0.010 mmol) of the
copper complex 2b was dissolved in 5 mL of ethyl acetate,
and 7.71 g (70.0 mmol) of 2,5-dimethyl-2,4-hexadiene was
added to the solution. 1 mL (0.01 mmol) of phenylhydrazine
was added by a microsyringe and the temperature of the
reaction mixture was then raised to 80 8C. 8 mL of a
solution of ethyl diazoacetate (1.14 g, 10 mmol) in ethyl
acetate was added dropwise over 2 h using a syringe pump
at 80 8C. After further stirring for 30 min at 80 8C, the
reaction mixture was analyzed by GC (DB-1,
30 m£0.25 mm ID, 0.25 mm film, column temp. 100 8C–
10 min to 250 8C) using the internal method with n-decane
as a standard for determining the yield and trans/cis ratio,
and LC Sumichiral OA-2500 (25 cm£4 mm ID, 5 mm
film)£2, UV 220 nm hexane 0.7 mL/min) for determining
the enantioselectivity. Products were determined by com-
parison of the LC elution order of the enantiomers with
authentic samples.
Compound 5g. Yield 62%, yellow solid; [Anal. Found: C,
73.4%; H, 6.1%; N, 5.9%. Calcd for C25H24N2O4·0.5C7H8:
C, 74.00%; H, 6.11%; N, 6.06%]; [a]D¼2142 (c¼1,
CHCl3); mp 120–122 8C; 1H NMR (CDCl3) d 8.07 (s,
1H), 7.67 (d, J¼7.8 Hz, 1H), 7.55 (d, J¼7.8 Hz, 1H), 7.38–
6.74 (m, 8H), 5.57 (s, 1H), 5.21 (q, J¼6.6 Hz, 1H), 3.60 (s,
3H), 3.58 (s, 3H), 1.37 (t, J¼6.6 Hz, 3H).
Compound 5h. Yield 94%, yellow solid; [Anal. Found: C,
67.3%; H, 5.6%; N, 2.6%. Calcd for C25F3H24NO4·0.5C7H8:
C, 67.71%; H, 5.59%; N, 2.77%]; [a]D¼2103 (c¼1,
CHCl3); mp 108–110 8C, 1H NMR (CDCl3) d 8.25 (s,
1H), 7.69 (d, J¼7.8 Hz, 1H), 7.60 (d, J¼7.8 Hz, 1H), 7.42–
6.72 (m, 8H), 5.47 (s, 1H), 5.16 (q, J¼6.3 Hz, 1H), 3.60 (s,
3H), 3.58 (s, 3H), 1.34 (t, J¼6.6 Hz, 3H).

M. Itagaki et al. / Tetrahedron 60 (2004) 7835–7843
7843
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1977, 2599.
Acknowledgements
6. Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett.
1975, 1707.
The authors would like to thank Professor Dr. E. Nakamura
and Dr. T. Aratani for their helpful advice and discussions
related to our work. Furthermore, M. I would like to thank
Dr. G. Suzukamo for giving the opportunity to begin this
study and for his helpful advice on our work.
7. Aratani, T. Pure Appl. Chem. 1985, 57, 1839.
8. Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32,
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9. Kanemasa, S.; Hamura, S.; Harada, E.; Yamamoto, H.
Tetrahedron Lett. 1994, 35, 7985.
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2. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds;
Wiley: New York, 1998.
12. In Ref. 11, the yield of the cyclopropanation of the diene was
not recorded.
13. Suenobu, K.; Itagaki, M.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 7271.
3. Singh, V. K.; Gupta, A. D.; Sekar, G. Synthesis 1997, 137.
4. Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54,
7919.