Studies of copper-bisoxazoline-catalyzed asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene

Article abstract of DOI:10.1021/op050203d

In the [bis{(4R)-(1-naphthyl)-5,5-dimethyloxazoline}/copper]-catalyzed asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexadiene with tert-butyl diazoacetate, the effects of a counterion of the copper complex were studied. The[CuCl/bisoxazoline/ Ph₃CPF₆] catalyst was found to enhance both the catalytic efficiency and the stereoselectivity (the catalyst 0.2 mol %, yield 92%, trans/cis = 88/12, 96% ee for the trans product), compared to our previously reported CuOTf/bisoxazoline catalyst. The density functional calculations were performed to elucidate the effects of the counterion as well as the effects of the gem-dimethyl groups at the 5-position on the bisoxazoline ligand.

Full text of DOI:10.1021/op050203d

Organic Process Research & Development 2006, 10, 245−250
Studies of Copper-Bisoxazoline-Catalyzed Asymmetric Cyclopropanation of
2,5-Dimethyl-2,4-hexadiene
Makoto Itagaki,*,† Katsuhisa Masumoto,† Katsuhiro Suenobu,‡ and Yohsuke Yamamoto§
Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka
554-8558, Japan, Tsukuba Research Laboratory, Sumitomo Chemical Co., Ltd., 6, Kitahara, Tsukuba, Ibaraki 300-3294,
Japan, and Department of Chemistry, Graduate School of Science, Hiroshima UniVersity 1-3-1, Kagamiyama,
Higashi-Hiroshima, Hiroshima 739-8526, Japan
Abstract:
Although previously reported copper catalysts 1-3 achieved
high stereoselectivities (Scheme 1 and Table 1), high catalyst
loading (1 mol %) or an industrially expensive diazoacetate
(l-menthyl diazoacetate or dicyclohexylmethyl diazoacetate)
was needed.3,9-12 Scott et al. reported the asymmetric
cyclopropanation of DMHD with tert-butyl diazoacetate
catalyzed by the copper complex with biaryl Schiff-base
ligand 4, but the trans selectivity and the enantioselectivity
were moderate (Table 1).13
In the [bis{(4R)-(1-naphthyl)-5,5-dimethyloxazoline}/copper]-
catalyzed asymmetric cyclopropanation of 2,5-dimethyl-2,4-
hexadiene with tert-butyl diazoacetate, the effects of a counterion
of the copper complex were studied. The[CuCl/bisoxazoline/
Ph3CPF6] catalyst was found to enhance both the catalytic
efficiency and the stereoselectivity (the catalyst 0.2 mol %, yield
92%, trans/cis ) 88/12, 96% ee for the trans product),
compared to our previously reported CuOTf/bisoxazoline
catalyst. The density functional calculations were performed
to elucidate the effects of the counterion as well as the effects
of the gem-dimethyl groups at the 5-position on the bisoxazoline
ligand.
We recently disclosed two new catalysts; a combination
catalyst composed of a 5-nitro-substituted salicylaldimine-
14
copper complex 5 with an equivalent of Al(OEt)3 and
CuOTf/2,2-bis{2-[(4R)-(1-naphthyl)-5,5-dimethyloxazolinyl]}-
propane 6 catalyst.15 However, although the 5/Al(OEt)3
catalyst shows high catalytic efficiency (0.1 mol % catalyst,
90% yield) and achieves >90% ee of the trans product,14
the trans selectivity still remains moderate (trans/cis ) 78/
22). In addition, the CuOTf/6 catalyst achieved higher trans
selectivity and enantioselectivity (trans/cis ) 87/13, 96%ee
for the trans product) than those with the 5/Al(OEt)3 catalyst,
but the catalyst loading is high (0.5 mol %).15 When the
catalyst loading of CuOTf/6 is low (0.2 mol %), the chemical
yield, the trans selectivity, and the enantioselectivity were
decreased (see Table 3).
Therefore, we needed to look for a more efficient catalyst
than the CuOTf/6 catalyst for the asymmetric cyclopropana-
tion of DMHD with a simple alkyl diazoacetate. In this
article, we especially describe the full details of the asym-
metric cyclopropanation with the Cu(I)/bisoxazoline catalyst
system. After the effect of the bridge moiety in the
bisoxazoline ligands and the effects of a counteranion were
examined, we found that the CuCl/6/Ph3CPF6 catalyst shows
higher catalytic efficiency (0.2 mol %, Y 92%, trans/cis )
88/12, 96%ee for the trans product) than the CuOTf/6
catalyst. Furthermore, density functional (DFT) calculations
for the Cu(I)/6 system were carried out to elucidate the effects
of the substituents and the counteranions.
Introduction
3-(1-Isobutenyl)-2,2-dimethyl cyclopropanecarboxylic acid
(chrysanthemic acid) is a key intermediate of pyrethroid
insecticides, and the (1R,3R) isomer ((+)-trans isomer))
shows the highest insecticidal activity among the four isomers
of the chrysanthemate.1-3 Therefore, we have been engaged
in industrially applicable asymmetric catalysis for the cy-
clopropanation of 2,5-dimethyl-2,4-hexadiene (DMHD) with
diazoacetate, which is one of the most efficient methods in
the synthesis of the optically active chrysanthemic acid
esters.4-8 The industrially applicable process for us needs
the following: (1) good enantioselectivity and trans selectiv-
ity, (2) use of a simple alkyl diazoacetate such as ethyl or
tert-butyl diazoacetate, by which chrysanthemic acid is
cheaply and readily obtained with a strong acid or a strong
base from the corresponding chrysanthemic acid ester, (3)
low catalyst loading (high catalyst efficiency).
* Corresponding author. E-mail: itagakim@sc.sumitomo-chem.co.jp.
† Organic Synthesis Research Laboratory, Sumitomo Chemical Co., Ltd.
‡ Tsukuba Research Laboratory, Sumitomo Chemical Co., Ltd.
§ Hiroshima University.
(1) Matsui, M.; Yamamoto, I. Naturally Occurring Insectisides; Jacobsen, M.;
Crosby, D. G., Eds.; Marcel Dekkar: New York, 1971.
(2) Arlt, D.; Jautelat, M.; Lantzsch, R. Angew. Chem., Int. Ed. Engl. 1981, 20,
703-722
(3) Aratani, T. Pure Appl. Chem. 1985, 57, 1839-1844.
(4) (a) Doyle, M. P. In Catalytic Asymmetric synthesis; Ojima, I., Ed.; VCH
Publishers: New York, 1993. (b) Doyle, M. P. In Catalytic Asymmetric
synthesis, 2nd ed.; Ojima, I., Ed.; VCH Publishers: New York, 2000.
(5) Singh, V. K.; Gupta, A. D.; Sekar, G. Synthesis 1997, 137-149.
(6) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919-7946.
(7) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; John Wiley & Sons: New York,
1998.
(9) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1975, 1707-1710.
(10) Aratani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett. 1977, 2599-2602.
(11) Lowenthal, R. E.; Masamune, S. Tetrahedron Lett. 1991, 32, 7373-7376.
(12) Kanemasa, S.; Hamura, S.; Harada, E.; Yamamoto, H. Tetrahedron Lett.
1994, 35, 7985-7988.
(13) Sanders, C. J.; Gillespie, K. M.; Scott, P. Tetrahedron: Asymmetry 2001,
12, 1055-1061.
(8) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, B. A. Chem. ReV. 2003,
(14) Itagaki, M.; Hagiya, K.; Kamitamari, M.; Masumoto, K.; Suenobu, K.;
Yamamoto, Y. Tetrahedron 2004, 60, 7835-7843.
103, 977-1050.
10.1021/op050203d CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/11/2006
Vol. 10, No. 2, 2006 / Organic Process Research & Development
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245

Scheme 1. Structures of Aratani’s catalyst 1, Masamune’s CuClO4/2 catalyst, Kanemasa’s CuOTf/3 catalyst, Scott’s CuOTf/4
catalyst, and Itagaki’s 5/Al(OEt)3 and CuOTf/6 catalysts
Table 1. Previously reported asymmetric cyclopropanation
of DMHD with diazoacetate (RDA) catalyzed by the copper
complexes in Scheme 1
methylene-bridged-bisoxazoline 7 catalyst slightly decreased
in both the trans/cis ratio and the enantioselectivity (entry
2), while the CuOTf/cyclopropylidene-bridged-bisoxazoline
8 catalyst provided almost the same stereoselectivities as the
CuOTf/isopropylidene-bridged bisoxazoline 6 catalyst (en-
tries 1 and 3).
catalyst
ee (%)
loadinga/
catalyst T/°C mol %
R )
in RDA
yield
(%) trans/cis transb cisc
Effect of a Counterion in the Copper(I)-Bisoxazoline
Complex on the Catalytic Activity and Stereoselectivity.
Since successful results were not obtained by change of the
bridge moiety in the bisoxazoline ligands, we focused on
the effects of counterions in the Cu(I)/6 catalyst system. In
general, CuOTf is often used as a catalyst precursor for the
copper-bisoxazoline-catalyzed asymmetric cyclopropana-
tion.7 However, Evans’ research group demonstrated that the
counterions of the Cu(II)-bisoxazoline complex catalyst
remarkably affected the reaction rate in a Lewis acid
catalyzed Diels-Alder reaction and that [Cu(II)-bisoxazo-
line](SbF6)2 shows higher reactivity than Cu(II)-bisoxazo-
line](OTf)2.16 In addition, Fraile et al. studied counterion
effects in the asymmetric cyclopropanation of styrene
catalyzed by Cu(I)- or Cu(II)-bisoxazoline catalyst sys-
tems.17 We therefore prepared Cu(I)/6 complex catalysts with
various kinds of counterions (X) as shown in Scheme 3 and
examined the chemical yield and the stereoselectivities for
the cyclopropanation of DMHD.
1
2
3
4
5
6
40
0
0
20
20
0
1
1
1
1
0.1
0.5
l-menthyl
(C6H11)2CH 78
75
93/7
95/5
88/12
75/25
78/22
87/13
94 46
94 NDd
88 NDd
72 NDd
91 62
l-menthyl
47
98
90
83
tBu
tBu
tBu
96 71
a Based on RDA. b 1R,3R as a major enantiomer. c 1R,3S as a major
enantiomer. d Not determined.
Results and Discussion
Effect of the Bridge Moiety in the Bisoxazoline
Compounds. We recently reported that 0.5 mol % of
CuOTf/6 catalyst provided 83% yield, an 87/13 trans/cis
ratio, and 96%ee at 0 °C with tert-butyl diazoacetate as the
major (1R,3R)-isomer of the tert-butyl chrysanthemate in a
communication.15 However, 0.5 mol % catalyst loading still
remains high for industrial application. We therefore syn-
thesized new bis{(4R)-(1-naphthyl)-5,5-dimethyloxazoline}
ligands (7 and 8 in Scheme 2) and investigated the effects
of the bridge moiety in the bisoxazoline for high catalytic
efficiency and high stereoselectivities. Bisoxazoline ligands
(7 and 8) were synthesized in the same manner as our
recently reported procedure.15 The results of asymmetric
cyclopropanation of DMHD with tert-butyl diazoacetate are
shown in Table 2, using 0.5 mol % catalyst at 0 °C. In
comparison with the CuOTf/6 catalyst (entry 1), the copper-
Shown in Table 3 are the results of cyclopropanation of
DMHD with tert-butyl diazoacetate at 0 °C using the Cu-
(I)/6 catalysts. Under 0.5 mol % catalyst loading, CuCl/6/
AgPF6 and CuCl/6/AgSbF6 provided higher chemical yield
(87%) and slightly higher trans selectivity (t/c ) 88/12) than
CuOTf/6 (83%, t/c ) 87/13 (entries 1, 4, and 5). Meanwhile,
(16) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc.
1999, 121, 7559-7573.
(17) Fraile, J. M.; Garc´ıa, J. I.; Mayoral, J. A.; Tarnai, T. J. Mol. Catal. A 1999,
144, 85-89.
(15) Itagaki, M.; Masumoto, K.; Yamamoto, Y. J. Org. Chem. 2005, 70, 3292-
3295.
246
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Vol. 10, No. 2, 2006 / Organic Process Research & Development

Scheme 2. Structures of bisoxazoline ligands 7 and 8
Table 2. Asymmetric cyclopropanation of
2,5-dimethyl-2,4-hexadiene (DMHD) with tert-butyl
diazoacetate (TBDA) catalyzed by copper-bisoxazoline
complexes
Table 3. Asymmetric cyclopropanation of DMHD with
tert-butyl diazoacetatef (TBDA) catalyzed by Cu(I)/6
complexes with various kinds of counterions with in EtOAc
at 0 °C
eec (%)
eec (%)
entry in Cu-cat. solvent T/°C (%) trans/cisb transd cise
catalyst yielda
ligand
yield
entry
catalyst system
CuOTf/6
CuOTf/6
Cu(CH3CN)4PF6/6
CuCl/AgPF6/6
CuCl/AgSbF6/6
CuCl/Ph3CPF6/6
CuCl/Ph3CPF6/6
CuCl/Ph3CPF6/6
CuCl/Ph3CB(C6F5)4/6
mol % (%) trans/cisb transd cise
1
2
3
4
5
6
7
8
9
0.5
0.2
0.5
0.5
0.5
0.5
0.2
0.1
0.5
83
72
82
87
88
91
92
87
94
87/13
85/15
87/13
88/12
88/12
88/12
88/12
87/13
82/18
96
89
95
96
94
96
96
93
85
71
61
70
74
73
74
71
67
61
1
2
3
6
7
8
EtOAc
EtOAc
EtOAc
0
0
0
83
84
80
87/13
85/15
87/13
96
90
95
71
60
70
a Based on TBDA and determined by GC analysis with n-decane as an internal
standard (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100 °C).
b Determined by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 100 °C). c Determined by GC analysis (DB-210, 30 m × 0.25 mm ID,
0.25 mm film, column temp 115 °C) after transformation into l-menthyl
e
chrysanthemate. d 1R,3R as a major enantiomer. 1R,3S as a major enantiomer.
a Based on TBDA and determined by GC analysis with n-decane as an internal
standard (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column temp 100 °C).
b Determined by GC analysis (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 100 °C). c Determined by GC analysis (DB-210, 30 m × 0.25 mm ID,
0.25 mm film, column temp 115 °C) after transformation into l-menthyl
chrysanthemate. d 1R,3R as a major enantiomer. e 1R,3S as a major enantiomer.
f TBDA was added to the solution containing DMHD and the catalyst over 3 h
at 0 °C.
Scheme 3. Tentative structures of [Cu(I)/6]X complexes
dimethyl groups at the 5-position on the bisoxazoline moiety
enhances trans selectivity and enantioselectivity (for example,
t
in the case of N2CHCO2 Bu: 2,2-bis{2-[(4R)-phenyl-
Ph3CPF6 was used in place of AgPF6, because Ph3CPF6 is
much easier to handle in air for the catalyst preparation than
AgPF6. As a result of the use of Ph3CPF6, a higher chemical
yield (91%) with t/c ) 88/12 and 96%ee for the trans product
was obtained than that with the use of AgPF6 (entries 4 and
6). Subsequently, [Cu/6]B(C6F5)4 from Ph3CB(C6F5)4 pro-
vided the highest chemical yield, but both the trans selectivity
and the enantioselectivity were decreased (entry 9).
When the catalyst loading was reduced from 0.5 mol %
to 0.2 mol % in the case of CuOTf/6, both the chemical
yield and the stereoselectivities were decreased (entries 1
and 2). Meanwhile, it should be noted that 0.2 mol % of
CuCl/6/Ph3CPF6 catalyst loading gave the same level of the
yield and stereoselectivity as those with 0.5 mol % (entries
6 and 7) and that the yield and stereoselectivity were just
slightly decreased under 0.1 mol % CuCl/6/Ph3CPF6 catalyst,
compared to 0.5 mol % (entry 8). These results show that
Cu(I)/bisoxazoline with the PF6 complex has a higher
catalytic efficiency for asymmetric cyclopropanation of
DMHD.
oxazolinyl]}propane (trans/cis ) 80/20, ee of trans ) 80%)
vs 2,2-bis{2-[(4R)-phenyl-5,5-dimethyloxazolinyl]}propane
(trans/cis ) 84/16, ee of trans ) 88%)).15 To clarify the
effects of the gem-dimethyl groups at the 5-position of the
oxazoline ring in the copper-bisoxazoline catalyst, DFT
calculations employing simplified models of the Cu/bis{(4R)-
phenyloxazolinyl}methane complex and the Cu/bis{(4R)-
phenyl-5,5-dimethyloxazolinyl}methane complex were car-
ried out. Based on theoretical studies about the copper-
catalyzed cyclopropanation with diazo compounds reported
by several groups18-20 including us,21 the catalytic key
intermediates for determining the stereoselectivities can be
considered to be a copper-bisoxazoline-carbene complex.
Scheme 4 shows the most energetically favored conformation
of carbene A for the unsubstituted bisoxazoline and carbene
B for the 5,5-gem-dimethyl substituted bisoxazoline based
(18) Fraile, J. M.; Garc´ıa, J. I.; Mart´ınez-Merino, V.; Mayoral, J. A.; Salvatella,
L. J. Am. Chem. Soc. 2001, 123, 7616-7625.
(19) Rasmusen, T.; Jensen, J. F.; Østergaard, N.; Tanner, D.; Ziegler, T.; Norrby
P.-O. Chem.sEur. J. 2002, 8, 177-184.
(20) Fraile, J. M.; Garc´ıa, J. I.; Gil, M. J.; Mart´ınez-Merino, V.; Mayoral, J. A.;
Salvatella, L. Chem.sEur. J. 2004, 10, 758-765.
(21) Suenobu, K.; Itagaki, M.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 7271-
7280.
Theoretical Study on the Effect of the Introduction of
gem-Dimethyl Groups at the 5-Position on the Oxazoline
Moiety. We already disclosed that the introduction of gem-
Vol. 10, No. 2, 2006 / Organic Process Research & Development
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247

Scheme 4. Minimized structures of the unsubstituted bisoxazoline-copper-carbene complex (carbene A) on the left side and
the gem-dimethyl substituted bisoxazoline-copper-carbene complex (carbene B) on the right based on the DFT calculations
(B3LYP/6-31G(d))
Table 4. Calculated dihedral angles (deg) for carbene A and
carbene B
N1-C2-C3-C4 in carbene B (140.0°) is remarkably larger
than that of carbene A (121.3°). These results suggest that
the Si-face side of the carbene carbon in carbene B might
be more spacious than that in carbene A and that the energy
of the transition state in the reaction of carbene B with the
diene on the Si-face side could be more stabilized than that
of carbene A. Consequently, the higher selectivity for the
(1R,3R) isomer could be attributed to the introduction of the
geminal-dimethyl groups in the case of carbene B when
compared with carbene A.
parameter
carbene A
carbene B
N1-C2-C3-C4
N2-C5-C6-C7
121.3
116.1
140.0
34.8
on the DFT calculations. It is noted that an attack of DMHD
at the carbene carbon on the Si-face side produces the (1R)-
chrysanthemate.
Calculations of the Structural Parameters of the
[Copper-Carbene]OTf and of [Copper-Carbene]PF6.
Comparisons of LUMO energy on the carbene carbon
between the copper carbene complex with OTf and that with
PF6 were performed based on the DFT calculations (B3LYP/
6-31G(d)) employing the simplified models (ligand: an
unsubstituted bisoxazoline at the 5-position), in which the
counterion is assumed to coordinate to the copper atom.
Shown in Scheme 5 is a minimized structure of the [copper-
carbene]OTf complex (carbene C) on the left side and the
[copper-carbene]PF6 complex (carbene D) on the right.
The electronic energy barriers of rotation for the C2-C3
bond on each carbene complex A and B were calculated
(B3LYP/6-31G(d)). The calculated energy barriers are found
to be 9 kcal/mol for the carbene A and 50 kcal/mol for the
carbene B.
These results indicated that the conformation is relatively
rigid especially in carbene B and that the most stable
conformation in the carbene complex determines the stereo-
selectivities. Thus, the dihedral angles of the copper carbene
complexes A and B with the most favored conformation are
summarized in Table 4. It is clear that the dihedral angle
Scheme 5. Minimized structures of the [copper-carbene-bisoxazoline]OTf complex (carbene C) and the
[copper-carbene-bisoxazoline]PF6 complex (carbene D) based on the DFT calculations (B3LYP/6-31G(d))
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Table 5. Calculated energies of LUMO (eV) on the C1 and
bond distances (Å) for the [copper-carbene]OTf complex
and the [copper-carbene]PF6 complex
mediate for bisoxazoline compounds 6, 7, and 8 was also
prepared based on our previously reported procedure.15
Optical rotations were measured on a JASCO DIP-370.
Melting points were measured with a METTLER TOLEDO
TYPE FP62. The absolute configurations of enantiomerically
pure bisoxazolines 7 and 8 were determined by the absolute
configurations of the major enantiomers of the trans products
in the copper-bisoxazoline catalyzed cyclopropanation,
based on the results in which the (R)-configured ligand 6
predominantly provided the (1R,3R)-isomer of trans chry-
santhemate.
parameter
carbene C
carbene D
LUMO
Cu-C1
Cu-N1
Cu-N2
-2.6789
1.795
1.974
-3.0050
1.786
1.950
1.946
1.929
Subsequently, structural parameters of those complexes are
summarized in Table 5.
General Procedure for Preparation of Bisoxazolines
(7) and (8). Preparation of N,N′-Bis[2-hydroxy-2-methyl-
(1R)-(1-naphthyl)propyl]cyclopropane-1,1-dicarbox-
amide (9). A solution of (R)-1-amino-1-(1-naphthyl)-2-
methyl-2-propanol (1.50 g, 6.97 mmol) and Et3N (0.84 g,
8.29 mmol) in CH2Cl2 (13 mL) was cooled to -10 °C. 1,1-
Cyclopropane dicarboxylic acid dichloride (0.58 g, 3.48
mmol) prepared by the reaction of 1,1-cyclopropane dicar-
boxylic acid with 2.5 equiv of SOCl2 was then added
dropwise over 3 min. The reaction mixture was allowed to
warm to 20 °C and stirred for 7 h. Subsequently, aqueous
HCl (1 N, 15 mL) was added in one portion. The organic
phase was separated, washed with aqueous NaHCO3 (5%,
20 mL), washed with H2O (5 mL), dried over Na2SO4, and
concentrated under reduced pressure to give compound 9 as
a white solid which was used in the next step without further
As a result, the LUMO energy of carbene D is found to
be lower than that of carbene C (-2.6789 eV for OTf and
-3.0050 eV for PF6). These results are consistent with the
fact that the copper carbene complex with PF6 has higher
electrophilic reactivity toward DMHD than that with OTf.
Furthermore, carbene D is found to be a more compact
complex than carbene C, because the bond distances (Cu-
C1, Cu-N1, and Cu-N2) around the copper atom in
carbene D were shorter than those in carbene C. The
enhancement of the stereoselectivities of the cyclopropana-
tion might be due to the fact that the chiral carbon in the
bioxazoline ligand of carbene D could be closer to the
carbene carbon than that of carbene C.
Conclusions
In conclusion, the effects of the structure of the bridge
moiety in the bisoxazoline ligands and a counterion X in
the [Cu(I)/bisoxazoline]X complex catalysts were examined
for asymmetric cyclopropanation of 2,5-dimethyl-2,4-hexa-
diene with tert-butyl diazoacetate. The structure of the bridge
moiety did not affect the catalyst efficiency nor the stereo-
selectivities. Meanwhile, the Cu/2,2-bis{(4R)-(1-naphthyl)-
5,5-dimethyloxazoline}propane 6 /Ph3CPF6 catalyst prepared
in situ was found to show higher catalytic efficiency and
slightly higher stereoselectivities than the CuOTf/6 catalyst.
The CuCl/6/Ph3CPF6 catalyst gave 92% yield, an 88/12 trans/
cis ratio, and 96%ee for the trans product using 0.2 mol %
at 0 °C. A theoretical study with DFT calculations (B3LYP/
6-31G(d)) clarified the effects of the gem-dimethyl groups
at the 5-position on the oxazoline ring and the counterion in
the copper(I)-carbene complex.
1
purification (1.91 g, quant). H NMR (300 MHz, CD3OD)
δ 8.31 (d, J ) 9.0 Hz, 2H), 7.85 (d, J ) 9.0 Hz, 2H), 7.76
(d, J ) 9.0 Hz, 2H), 7.54-7.32 (m, 8H), 5.86 (s, 2H), 4.87
(s, 4H), 1.35 (s, 6H), 1.32 (s, 4H), 0.97 (s, 6H); 13C NMR
(75 MHz, CD3OD) δ 172.4, 137.6, 135.5, 134.0, 130.2,
129.2, 127.9, 127.5, 127.1, 126.8, 126.7, 125.3, 74.0, 57.2,
30.8, 29.1, 27.7, 16.4. HRMS-EI (m/z): [MH+] calcd for
C33H37N2O4, 525.2747; found, 525.2773.
Preparation of Bis{2-[(4R)-(1-naphthyl)-5,5-dimethyl-
oxazolinyl]}methane (7). (R)-1-Amino-1-(1-naphthyl)-2-
methyl-2-propanol (1.20 g, 5.57 mmol), dimethyl malonate
(0.368 g, 2.79 mmol), and xylene (anhydrous, 60 mL) were
charged into a Schlenk tube, and the reaction mixture was
heated to reflux for 13 h. Ti(OiPr)4 (79 mg, 0.28 mmol) was
then added to the solution in one portion, and the reaction
mixture was refluxed for 31 h with removal of the water
byproduct. After the reaction mixture was cooled to 20 °C,
the solution was concentrated under reduced pressure. The
resulting pale yellow oil was purified by column chroma-
tography (alumina neutral, hexane: AcOEt ) 10:1 to 2:1) to
give a white solid 7, which appeared pure by 1H NMR. The
solid was recrystallized from CH2Cl2/hexane to give a white
powder (0.7 g, 54%). Mp 201.6-202.2 °C; [R]D ) -240 (c
) 0.11, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.95-7.87
(m, 4H), 7.77 (d, J ) 9.0 Hz, 2H), 7.59-7.43 (m, 8H), 5.81
(s, 2H), 3.61 (s, 2H), 1.82 (s, 6H), 0.84 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 162.3, 134.9, 133.6, 131.6, 129.1, 127.8,
126.2, 125.4, 125.3, 122.7, 88.1, 73.6, 29.6, 29.1, 23.5. Anal.
Calcd for C31H30N2O2: C, 80.49%; H, 6.54%; N, 6.06%.
Found: C, 79.9%; H, 6.3%; N, 5.5%. HRMS-EI (m/z):
[MH+] calcd for C31H31N2O2, 463.2380; found, 463.2396.
Experimental Section
General. Unless otherwise noted, all reactions were
carried out under a nitrogen atmosphere. AcOEt, CH2Cl2,
and xylene as the solvents were dehydrated by molecular
sieves 4A before use. Et3N was dried over sodium hydroxide.
Ti(OiPr)4, dimethylmalonate, and 1,1-cyclopropane dicar-
boxylic acid dichloride were purchased from Tokyo Kasei
Kogyo Co., Ltd. (TCI), and CuOTf was purchased from
Aldrich. tert-Butyl diazoacetate was prepared according to
literature prpcedure.22 The bisoxazoline compound 6 was
prepared based on our previously reported procedure.15 (R)-
1-Amino-1-(1-naphthyl)-2-methyl-2-propanol as the inter-
(22) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker, D. A.;
Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc. 1990, 112, 1906-1912.
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249

1,1-Bis{2-[(4R)-(1-naphthyl)-5,5-dimethyloxazolinyl]}-
cyclopropane (8). Bisamide alcohol 9 (1.83 g, 3.49 mmol)
and xylene (anhydrous, 100 mL) were charged into a Schlenk
tube, and the reaction mixture was heated to reflux to dissolve
the alcohol completely. Ti(OiPr)4 (99 mg, 0.35 mmol) was
then added to the solution in one portion, and the reaction
mixture was refluxed for 48 h with removal of the water
byproduct. After the reaction mixture was cooled to 20 °C,
the solution was concentrated under reduced pressure. The
resulting pale yellow oil was purified by column chroma-
tography (alumina basic, hexane/AcOEt ) 4:1) to give a
a period of 3 h at 0 °C, and then the mixture was further
stirred at the same temperature for 0.5 h. The reaction
mixture was filtered through silica gel and then analyzed by
GC (DB-1, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 100 °C - 10 min to 250 °C) using the internal method
with n-decane as a standard for determining the yield and
trans/cis ratio. After concentration of the reaction mixture
under reduced pressure, part of the residue containing 1.13
g of tert-butyl chrysanthemate (5 mmol) was dissolved in
10 mL of toluene. Trifluoroacetic acid (57 mg, 0.5 mmol)
was then added to the solution, and the solution was refluxed
for 3 h to afford chrysanthemic acid, which was analyzed
by GC (DB-210, 30 m × 0.25 mm ID, 0.25 mm film, column
temp 115 °C) after transformation into the l-menthyl chry-
santhemate with SOCl2, pyridine, and l-menthol. The abso-
lute configurations of the products were determined by
comparison of the GC elution order of the enantiomers with
authentic samples.
1
white solid, which appeared pure by H NMR. The solid
was recrystallized from CH2Cl2/hexane to give a white
powder (1.23 g, 72%). Mp 54.0-56.0 °C; [R]D ) -194 (c
) 0.11, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.94-7.86
(m, 4H), 7.78 (d, J ) 9.0 Hz, 2H), 7.54-7.46 (m, 8H), 5.76
(s, 2H), 1.77 (s, 6H), 1.75-1.69 (m, 2H), 1.61-1.53 (m,
6H), 0.83 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.0,
135.2, 133.6, 131.6, 129.0, 127.7, 126.1, 125.5, 125.3, 122.8,
87.8, 73.2, 28.9, 23.4, 19.2, 14.6. Anal. Calcd for C33H32-
N2O2: C, 81.12%; H, 6.60%; N, 5.73%. Found: C, 80.4%;
H, 6.3%; N, 5.3%. HRMS-EI (m/z): [MH+] calcd for
C33H33N2O2, 489.2536; found, 489.2532.
General Procedure for Cyclopropanation. CuCl (1.98
mg, 0.02 mmol), the bisoxazoline ligand 6 (0.022 mmol),
and Ph3CPF6 (0.022 mmol) were dissolved in 5 mL of
EtOAc, and the solution was stirred for 30 min. 2,5-
Dimethyl-2,4-hexadiene (3.86 g, 70 mmol) was added to the
solution, and the reaction mixture was cooled to 0 °C. A
solution of tert-butyl diazoacetate (1.41 g, 10 mmol) in 5
mL of ethyl acetate was added dropwise to the solution over
Computational Methods
Geometry optimizations of all stable structures reported
here were performed with the B3LYP hybrid density
functional method implemented in the Gaussian 03 pro-
gram.23,24 The 6-31G(d) basis set was used for all atoms.
Normal coordinate analysis confirmed that all stationary
points discussed in this article are stable structures. Each
optimized structure shown in Schemes 4 and 5 is the most
stable conformer with respect to the Gibbs free energy (25
°C) among several conformers obtained for each calculation
model.
Acknowledgment
We thank Prof. Dr. E. Nakamura and Dr. T. Aratani for
their helpful advice and discussions related to our work.
Furthermore, M.I. thanks Dr. G. Suzukamo for giving the
opportunity to begin this study and for his helpful advice on
our work.
(23) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision B.04; Gaussian, Inc.: Wallingford, CT, 2004.
Supporting Information Available
Cartesian coordinates of stationary points of the carbenes
A, B, C, and D based on the DFT calculations. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Received for review October 17, 2005.
OP050203D
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