Synthesis of novel chiral bisoxazoline ligands containing 2,5-diaryl-1,3,4-oxadiazole and enantioselective cyclopropanation of styrene

Article abstract of DOI:10.1055/s-2002-35232

Practical synthesis of chiral C₂-symmetric substituted bisoxazoline ligands containing 2,5-diaryl-1,3,4-oxadiazole units was investigated. Five chiral bisoxazoline ligands containing 2,5-diphenyl-1,3,4-oxadiazole have been synthesized from 2,5-di-(o-carboxylphenyl)-1,3,4-oxadiazole and amino alcohols by methanesulfonyl chloride or p-toluenesulfonyl chloride assisted cyclization via hydroxy amide intermediate. Preliminary examination of copper complexes of new ligands as chiral catalysts in the enantioselective cyclopropanation of styrene with ethyl diazoacetate was performed. Enantioselectivities up to 35% ee and 87% ee for trans- and cis-2-phenylcyclopropanecarboxylate, respectively were observed.

Full text of DOI:10.1055/s-2002-35232

PAPER
2347
Synthesis of Novel Chiral Bisoxazoline Ligands Containing 2,5-Diaryl-1,3,4-
oxadiazole and Enantioselective Cyclopropanation of Styrene
Synthesis of
N
ove
a
l
Chira
l
Bis
-
oxazolin
M
e
Ligands:
E
nantiosele
i
ctive
C
n
yclopropana
g
tion of Styrene Du,* Zhan-Yue Wang,1 Dong-Cheng Xu, Wen-Ting Hua
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular
Engineering, Peking University, Beijing 100871, P. R. China
Fax +86(10)62751708; E-mail: dudm@pku.edu.cn
Received 11 June 2002; revised 12 August 2002
The usual method for preparation of chiral bisoxazoline is
Abstract: Practical synthesis of chiral C2-symmetric substituted
the reaction of diacid derivatives with chiral -amino al-
cohols. The enantiomerically pure -amino alcohols are
bisoxazoline ligands containing 2,5-diaryl-1,3,4-oxadiazole units
was investigated. Five chiral bisoxazoline ligands containing 2,5-
diphenyl-1,3,4-oxadiazole have been synthesized from 2,5-di-(o-
either commercially available or easily obtained by reduc-
carboxylphenyl)-1,3,4-oxadiazole and amino alcohols by methane- tion of the corresponding -amino acids.9 Many methods
sulfonyl chloride or p-toluenesulfonyl chloride assisted cyclization
have been reported for the synthesis of oxazoline
ligands.10 We have attempted to use a one-pot condensa-
via hydroxy amide intermediate. Preliminary examination of copper
complexes of new ligands as chiral catalysts in the enantioselective
tion procedure of the diacid with the amino alcohol in the
cyclopropanation of styrene with ethyl diazoacetate was performed.
presence of triphenylphosphine, carbon tetrachloride and
Enantioselectivities up to 35% ee and 87% ee for trans- and cis-2-
phenylcyclopropanecarboxylate, respectively were observed.
triethylamine,11 but poor yields were obtained by this
method for this series.
Key words: bisoxazoline, oxadiazole, enantioselective cyclopro-
panation
In the present work, the synthesis of ligands 3a–d and 5
using a two-step procedure gave good yields in each step.
Treatment of 2,5-di(o-carboxyphenyl)-1,3,4-oxadiazole
with refluxing thionyl chloride afforded the diacyl
dichloride, which was treated with -amino alcohol and
triethylamine to afford the corresponding chiral interme-
diate dihydroxy diamides 2a–d as solids in 60–83%
yields. Cyclization by activating the dihydroxy diamides
with thionyl chloride can give the bisoxazoline, but this
procedure cannot be repeated well on larger scale or even
small scale. However, we found that when dihydroxy dia-
mides 2a–d were treated with methanesulfonyl chloride
and triethylamine in dichloromethane at 0 °C afforded the
corresponding bismesylates, which were then cyclized by
heating in an aqueous methanolic solution of sodium hy-
droxide to give the desired bisoxazolines 3a–d in 54–83%
yields (Scheme 1). The latter procedure developed by
Denmark12 can work well on large scale and can be re-
peated well.
In recent years, the C2-symmetric chiral bisoxazolines
have become very useful ligands in the catalysis of many
reactions.2 High catalytic activities and enantiomeric ex-
cesses have been obtained for example in hydrosilylation
of ketone,3 allylic alkylation,4 Michael addition,5 Diels–
Alder cycloaddition,6 and cyclopropanation7 mainly using
C2-symmetric chiral ligands in conjunction with a suitable
transition metal ions. The conformational rigid frame-
work of the metal chelate with the presence of stereo-
centers close to the donor nitrogen atoms provides a well-
ordered chiral environment at the catalytic site. The size
of the chelate in the metal complex of bisoxazoline is an-
other important factor for the catalyst since it will control
the orientation of the substituents on the two oxazolines
around the metal ion. The design and synthesis of new
chiral oxazoline ligands have inspired many scientists to
work in this area. Our interest focuses on the studies of
enantioselective transition-metal catalysis of heterocyclic
ligands.8 In the design of the new ligands it was crucial to
have a rigid cyclic backbone, therefore a rigid system con-
taining a 2,5-diaryl-1,3,4-oxadiazole unit was chosen.
Hence, the incorporation of the 2,5-diaryl-1,3,4-oxadiaz-
ole unit and a chiral oxazoline unit in new ligands may re-
sult in unique properties for catalytic reaction. In this
paper, the synthesis, structure, and catalytic enantioselec-
tive cyclopropanation of styrene with the aforementioned
novel chiral bisoxazoline ligands containing 2,5-diaryl-
1,3,4-oxadiazole units are reported.
Diamide 4 was also synthesized according to the same
procedure as dihydroxy diamides 2a–d from 2,5-di-(o-
carboxylphenyl)-1,3,4-oxadiazole 1 and (1R,2S)-(–)-2-
amino-1-phenyl-1,3-propanediol, but with longer reaction
time, refluxing for 36 hours. Diamide 4 when treated with
methanesulfonyl chloride and triethylamine in dichlo-
romethane did not afford the corresponding bisoxazoline
5. However, treatment of diamide 4 with p-toluenesulfo-
nyl chloride and triethylamine in refluxing
dichloromethane13 can give the desired bisoxazoline 5 in
46% yield.
In order to evaluate the efficiency of these bisoxazoline
ligands in the copper(I)-catalyzed asymmetric cyclopro-
panation of olefins, we carried out the reaction of styrene
with ethyl diazoacetate to give the trans- and cis-cyclo-
propanes 6 and 7, as the model reaction. The reaction was
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2347,2352,ftx,en;F04702SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2348
D.-M. Du et al.
PAPER
N
N
N
N
1. SOCl2
O
O
R
O
O
HO
NH
HN
2.
CO2H
CO2H
H2N
OH
OH
R
R
Et3N, CH2Cl2
1
2
R: a, Ph; b, i-Bu; c, i-Pr; d, PhCH2
N
N
Scheme 2 Cyclopropanation reaction of styrene and ethyl diazo-
1. MsCl, Et3N
2. NaOH, EtOH-H2O
acetate
O
N
N
O
O
(i) The diastereoselectivity of the reaction favors trans se-
lectivity.
R
R
3
R: a, Ph; b, i-Bu; c, i-Pr; d, PhCH2
(ii) The enantioselectivity of the cis- isomer is higher than
that of the trans-isomer, and the highest ee values for cy-
clopropane (1R,2S)-7 were obtained with the benzyl sub-
stituted bisoxazoline 3d however with moderate chemical
yield. The best ee was up to 87% (entry 7).
N
N
N
N
O
p-TsCl, Et3N
O
O
O
OH
NH
O
O
HN
N
CH2Cl2, reflux
N
HO
(iii) The enantioselectivity was decreased when the tem-
perature was raised (entries 6, 8, and 10 vs entries 5, 7, and
9).
OH
HO
Ph
HO
Ph
OH
Ph
4
5
(iv) The introduction of a phenyl substituent at the 4-posi-
tion of the oxazoline ring has a pronounced effect on the
enantioselectivity of the reaction.
Scheme 1 Synthesis of new bisoxazolines 3a–d and 5
carried out at room temperature or 40 °C by slow addition
of ethyl diazoacetate to a solution of styrene in 1,2-dichlo-
roethane containing the copper(I)-bisoxazoline catalyst.
This was prepared in situ by adding the appropriate
amount of copper(I) trifluoromethanesulfonate benzene
complex [Cu(OTf) (C6H6)0.5] to the ligand.
(v) When a chiral substituent (phenylcarbinol) was intro-
duced at the 4-position (ligand 5), it also leads to a sharp
decrease in the ee, this may be the effect of hydroxy group
compared with benzyl group (entries 7, 8, 9, and 10).
(vi) The predominant formation of (1R,2R)-trans-cyclo-
propane 6 was observed irrespective of the reaction tem-
perature (r.t. or 40 °C; entries 3 and 4). In contrast to this
result, the preferred absolute configurations of cis-cyclo-
From the results given in Table 1, the following conclu-
sions can be made:
Table 1 Cyclopropanation of Styrene in the Presence of Diaryloxadiazole Bisoxazoline Ligands
Entry
Ligand
3a
3a
3b
3b
3c
Temp
r.t.
Time (h)
24
Yielda (%) trans/cisb
% eec (trans) Configd
% eec (cis) Configd
1
2
8
48
13
41
44
37
25
37
16
53
73:27
76:24
87:13
67:33
88:22
67:33
74:26
68:32
73:27
69:31
0.2
0.3
–
0.5
0.5
–
40 °C
r.t.
24
–
–
3
24
15
1R,2R
1R,2R
1S,2S
1S,2S
1R,2R
1R,2R
1S,2S
1S,2S
70
1S,2R
1R,2S
1R,2S
1S,2R
1R,2S
1R,2S
1S,2R
1S,2R
4
40 °C
r.t.
24
21
15
8
71
57
9
5
24
6
3c
40 °C
r.t.
24
7
3d
3d
5
24
20
35
9
87
66
12
7
8
40 °C
r.t.
24
9
24
10
5
40 °C
24
2
a Isolated yield, based on ethyl diazoacetate for the mixture of trans- and cis-products.
b Determined by 1H NMR of the crude product.
c By chiral HPLC using Chiralcel OD column.
d Based on the sign of optical rotation.14
Synthesis 2002, No. 16, 2347–2352 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Chiral Bisoxazoline Ligands: Enantioselective Cyclopropanation of Styrene
2349
propane 7 were changed from (1S,2R) to (1R,2S). This un-
usual stereochemical outcome may be ascribed to the
temperature change, which affects the conformation of
ligand and thus the complex. The same anomaly was also
observed in entries 5 and 6. Furthermore, the preferred ab-
solute configuration at C1 of trans-cyclopropane 6 was
antipodal to that of cis-cyclopropane 7 when the reaction
was conducted at room temperature (entries 3 and 5). Al-
though the real reason is still unclear at present, this un-
usual result may be attributed to the fact that the solubility
of the metal complex is low in the solvent, and different
ligands have different solubility. Thus these homo and/or
heterogeneous catalysts may have different ligand confor-
mation which is correlated with the result of asymmetric
induction.15 Furthermore, we obtained moderate to good
enantioselectivity for the cis-isomer 7 and need not to use
the bulky adamantyl substituted bisoxazoline or bulky es-
ter butyl diazocacetate. It is well known that the enanti-
oselectivity of the metal catalyzed cyclopropanation is
higher when the steric bulky ester is used,16–18 so there ex-
ists potential to optimize the enantioselectivity.
Figure 1 Perspective view of compound 3a, showing 30% probabi-
lity ellipsoids for the non-hydrogen atoms and the numbering scheme
of the atoms in the molecule.
In order to obtain a direct understanding of substituent ef-
fect of the new diaryl oxadiazole bisoxazoline ligands on
the enantioselectivity, the stereostructure of ligands 3a
and 3b were determined by X-ray crystal diffraction anal-
ysis.19 Compounds 3a and 3b were obtained as air-stable,
colorless plates, upon slow evaporation of a solution of 3a
or 3b in ethyl acetate-petroleum ether (2:1). A perspective
view of compound 3a is shown in Figure 1. The diaryl
1,3,4-oxadiazole is in a twist conformation in compound
3a. The C10-C12-C14 benzene ring has a dihedral angle
with O3-N3-N4 oxadiazole ring of 57.7°, while the other
benzene ring’s dihedral angle with this oxadiazole ring is
135.4°. The two benzene rings are almost perpendicular to
each other with a dihedral angle of 93.2° rather than co-
planar. A perspective view of compound 3b is shown in
Figure 2. Compound 3b has a similar stereostructure to
that of compound 3a, however, there are two independent
molecules in each unit cell of this molecule. From the
crystal structures of 3a and 3b, it turns out that larger sub-
stituent will result in a larger torsional strain between the
two oxazoline units in corresponding copper(I) complex,
and this can explain the dramatic decrease in ee. The con-
formation of the linking spacer may be affected by tem-
perature, and thus the diaryl oxadiazole bisoxazoline
copper(I) complex will result in different enantioselectiv-
ity at different temperatures.
Figure 2 Perspective view of compound 3b, showing 30% proba-
bility ellipsoids for the non-hydrogen atoms and the numbering
scheme of the atoms in the molecule.
azolines have potential to be used as catalyst for asymmet-
ric reaction. Further modification of the chemical
structure and studies in other asymmetric reactions are in
progress in our laboratory.
In conclusion, an efficient synthetic procedure was found
for synthesis of new chiral diaryl oxdiazole bisoxazoline
ligands. Preliminary results in asymmetric cyclopropana-
tion of styrene with ethyl diazoacetate have been ob-
tained. The C2-symmetric bisoxazoline 3a–d and 5
derived from diaryl oxdiazole present markedly different
reactivities in the asymmetric copper-catalyzed cyclopro-
panation. The highest enantioselectivity was obtained
with benzyl substituted bisoxazoline 3d. Although the
yield is moderate and trans enantioselectivity is low, these
results suggest that these novel diaryloxadiazole bisox-
Melting points were measured on an XT-4 melting point apparatus
and were uncorrected. 1H NMR spectra were recorded on a Bruker
ARX 400 spectrometer with tetramethylsilane (TMS) as the internal
standard. Infrared spectra were obtained on a Bruker Vector 22
spectrometer. Mass spectra were obtained on a VG-ZAB-HS mass
spectrometer. Optical rotations were measured on a Perkin-Elmer
241 MC spectrometer. Elemental analyses were carried out on an
Elementar Vario EL instrument. The optical purities of trans- and
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2350
D.-M. Du et al.
PAPER
cis-cyclopropanes were determined by HPLC analysis using a
chiral column (Daicel Chiralcel OD; eluent, hexane–i-PrOH 95:5;
flow rate, 0.5 mL/min; UV detector, 220nm). The retention times
for trans-isomers are 10.50 (1R,2R) and 13.34 (1S,2S) min, the cis-
isomers are 9.83 (1S,2R) and 11.13 (1R,2S) min. The absolute con-
figuration of the major enantiomer was assigned according to the
sign of the specific rotation. Solvents used were purified and dried
by standard procedures. Petroleum ether used had a bp 60–90 °C.
2,5-Di(o-carboxyphenyl)-1,3,4-oxadizole was synthesized accord-
ing to the literature produre.20
FAB-MS: m/z (%) = 481 (M + 1).
Anal. Calcd for C26H32N4O5: C, 64.98; H, 6.71; N, 11.67. Found: C,
64.83; H, 6.85; N, 11.92.
2,5-Bis{o-[N-(1 S)-(1 -benzyl-2 -hydroxyethyl)amido]phenyl}-
1,3,4-oxadiazole (2d)
Following general procedure I, 2,5-di-(o-carboxyphenyl)-1,3,4-ox-
adiazole (2.17 g, 7.0 mmol), SOCl2(40 mL), S-phenylalaninol(2.12
g, 14.0 mmol) and Et3N (8.0 mL) gave 2d as a colorless solid; 3.08
g (76.2%); mp 202–204 °C; [ ]D20 –135.8 (c 1, CHCl3).
IR (KBr): 3300, 3060, 3028, 2955, 2919, 2867, 1645, 1599, 1554,
1532, 1494 cm–1.
2,5-Bis{o-[N-(1 R)-(1 -phenyl-2 -hydroxyethyl)amido]phenyl}-
1,3,4-oxadiazole (2a); General Procedure I
1H NMR (DMSO-d6): = 2.74 (2 H, dd, J = 8.7, 13.6 Hz, CH2),
2.91 (2 H, dd, J = 5.6, 13.7 Hz, CH2), 3.38 (2 H, m, CH2), 3.50 (2
H, m, CH2), 4.08 (2 H, m, CH), 4.82 (2 H, t, J = 5.6 Hz, OH), 7.14–
7.19 (2 H, m, ArH), 7.23–7.29 (8 H, m, ArH), 7.39 (2 H, dd, J = 1.2,
7.4 Hz, ArH), 7.59–7.68 (4 H, m, ArH), 7.87 (2 H, dd, J = 1.3, 7.5
Hz, ArH), 8.48 (2 H, d, J = 8.3 Hz, NH).
A solution of 2,5-di-(o-carboxyphenyl)-1,3,4-oxadiazole (1.9 g, 6.1
mmol) and SOCl2 (34 mL) was refluxed for 8h. The excess SOCl2
was removed under reduced pressure, benzene (20 mL) was added
and the solvent was removed to afford the diacyl dichloride. The
above diacyl dichloride dissolved in CH2Cl2 (100 mL) was added
dropwise to a solution of R-phenylglycinol (1.65 g, 12.0 mmol) and
Et3N (6.9 mL) in CH2Cl2 (35 mL) at 0 °C and stirred at r.t. for 24 h.
The precipitate was filtered and washed with Et2O to afford 2a as a
FAB-MS: m/z = 577 (M + 1).
20
Anal. Calcd for C34H32N4O5: C, 70.82; H, 5.59; N, 9.72. Found: C,
70.56; H, 5.71; N, 9.68.
colorless powder; 2.7 g (82.1%); mp 226–228 °C; [ ]D –105.0
(c 0.1, MeOH).
IR (KBr): 3327, 3058, 3034, 2945, 2857, 1648, 1601, 1553, 1531,
1493, 1079, 1042, 1038, 703 cm–1.
1H NMR (DMSO-d6): = 3.65 (4 H, m, CH2), 4.89 (2 H, t, J = 5.6
Hz, OH), 5.04 (2 H, dd, J = 7.2, 14.2 Hz, CH), 7.20–7.71 (10 H, m,
ArH), 7.51–7.72 (8 H, m, ArH), 8.93 (2 H, d, J = 8.2 Hz, NH).
2,5-Bis{o-[(4’R)-4 -phenyloxazolin-2 -yl]phenyl} -1,3,4-oxadiaz-
ole (3a); General Procedure II
To an ice-cold solution of dihydroxy diamide 2a (1.1 g, 2.0 mmol)
and Et3N (1.4 mL, 10.1 mmol) in CH2Cl2 (30 mL) and DMF (10
mL) was added MsCl (0.36 mL, 4.6 mmol) via syringe. The reaction
mixture was allowed to warm to r.t. and was stirred for 24 h, then
poured into H2O (100 mL). The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 50 mL). The com-
bined extracts were washed with brine, dried over anhyd Na2SO4,
and filtered. The filtrate was concentrated in vacuo to afford the
crude bismesylate. The crude bismesylate was dissolved in EtOH
(20 mL) and a solution of NaOH (0.5 g) in H2O (20 mL) was added
to it. The reaction mixture was refluxed for 3 h. The EtOH was re-
moved under reduced pressure and the residue was extracted with
CH2Cl2 (3 50mL). The combined organic layers was washed with
3% HCl, then with 5% NaHCO3, and brine, dried over anhyd
Na2SO4, and filtered. The filtrate was concentrated in vacuo to give
a pale yellow oil. The oil was purified by column chromatography
on silica gel (EtOAc–petroleum ether, 2:3) followed by recrystalli-
zation from EtOAc–petroleum ether to give pure 3a; 0.67g (65.4%);
mp 156–158 °C; [ ]D20 +25.8 (c 1, CHCl3).
FAB-MS: m/z (%) = 549 (M + 1, 20), 292 (10), 257 (10), 217 (60),
181 (40), 126 (70), 91 (100).
Anal. Calcd for C32H28N4O5: C, 70.06; H, 5.14; N, 10.20. Found: C,
69.88; H, 4.90; N, 10.05.
2,5-Bis{o-[N-(1 S)-(1 -isobutyl-2 -hydroxyethyl)amido]phenyl} -
1,3,4-oxadiazole (2b)
Following general procedure I, 2,5-di-(o-carboxyphenyl)-1,3,4-ox-
adiazole (2.17 g, 7.0 mmol), SOCl2 (40 mL), S-leucinol (1.64 g,
14.0 mmol) and Et3N (8.0 mL) gave 2b as a colorless solid; 2.8 g
(78.6%); mp 173–175 °C; [ ]D20 –130.8 (c 1, CHCl3).
IR (KBr): 3309, 3068, 2955, 2871, 1646, 1599, 1530, 1492, 1438
cm–1.
1H NMR (CDCl3): = 0.93 (12 H, d, J = 6.6 Hz, CH3), 1.34 (2 H,
m, CH2), 1.52 (2 H, m, CH2), 1.70 (2 H, m, CH), 3.50 (2 H, dd,
J = 5.2, 11.3 Hz, CH2), 3.79 (2 H, dd, J = 3.2, 11.3 Hz, CH2), 4.03
(2 H, s, OH), 4.16 (2 H, m, CH), 6.54 (2 H, d, J = 8.1 Hz, CH2),
7.48–7.60 (6 H, m, ArH), 7.80 (2 H, d, J = 5.0 Hz, ArH).
IR (KBr): 2960, 2897, 1655, 1599, 1558, 1455, 1354, 1088 cm–1.
1H NMR (CDCl3): = 4.13 (2 H, t, J = 8.6 Hz, OCH), 4.68 (2 H,
dd, J = 8.6, 10.2 Hz, OCH), 5.31 (2 H, dd, J = 8.6, 10.2 Hz, CHN),
7.19–7.24 (10 H, m, ArH), 7.50–7.66 (4 H, m, ArH), 7.77–7.86 (2
H, m, ArH), 7.97–8.01 (2 H, m, ArH).
FAB-MS: m/z (%) = 509 (M + 1, 100), 491(10), 392(30), 292(90),
249(60), 160(70).
Anal. Calcd for C28H36N4O5: C, 66.12; H, 7.13; N, 11.02. Found: C,
66.23; H, 6.86; N, 10.92.
FAB-MS: m/z (%) = 513 (M + 1, 100), 393 (20), 273 (70).
Anal. Calcd for C32H24N4O3: C, 74.99; H, 4.72; N, 10.93. Found: C,
74.87; H, 4.64; N, 10.93.
2,5-Bis{o-[N-(1 S)-(1 -isopropyl-2 -hydroxyethyl)amido]phe-
nyl}-1,3,4-oxadiazole (2c)
Following general procedure I, 2,5-di-(o-carboxyphenyl)-1,3,4-ox-
adiazole (1.24 g, 4 mmol), SOCl2(70 mL), S-valinol (0.83 g, 8
mmol) and Et3N (4.6 mL) gave 2c as a solid; 1.15 g (60%); mp 208–
210 °C; [ ]D20 –107.6 (c 1, CHCl3).
2,5-Bis{o-[(4 S)-4 -isobutyloxazolin-2 -yl]phenyl]-1,3,4-oxadiaz-
ole (3b)
Following general procedure II, dihydroxy diamide 2b (1.1 g, 2.0
mmol), MsCl (0.36 mL, 4.6 mmol) and Et3N (1.4 mL, 10.1 mmol)
gave the crude bismesylate. The crude bismesylate was treated with
a NaOH–EtOH–H2O solution as above, column chromatography
(silica gel; EtOAc–petroleum ether, 3:7) followed by recrystalliza-
tion from EtOAc–petroleum ether gave 3b as a colorless solid; 0.78
g (82.5%); mp 75–76 °C; [ ]D20 –145 (c 0.5, MeOH).
IR (KBr): 3420, 3240, 2920, 2860, 1620, 1500 cm–1.
1H NMR (DMSO-d6): = 0.86 (6 H, d, J = 6.8 Hz, CH3), 0.88 (6 H,
d, J = 6.8 Hz, CH3), 1.88 (2 H, m, CH), 3.48 (4 H, t, J = 5.6 Hz,
CH2), 3.74 (2 H, m, CH), 4.56 (2 H, t, J = 5.4 Hz, OH), 7.61–7.72
(6 H, m, ArH), 7.89 (2 H, dd, J = 1.4, 7.4 Hz, ArH), 8.24 (2 H, d,
J = 8.8 Hz, NH).
IR (KBr): 2957, 2868, 1653, 1602, 1472, 1358 cm–1.
EI-MS: m/z = 473 (M + 1).
Synthesis 2002, No. 16, 2347–2352 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel Chiral Bisoxazoline Ligands: Enantioselective Cyclopropanation of Styrene
2351
1H NMR (CDCl3): = 0.82 (12 H, d, J = 6.6 Hz, CH3), 1.24 (2 H,
m, CH2), 1.54 (2 H, m, CH2), 1.67 (2 H, m, CH), 3.89 (2 H, t, J = 7.7
Hz, CH2), 4.27 (2 H, m, CH), 4.37 (2 H, dd, J = 7.8, 9.4 Hz, CH2),
7.58–7.63 (4 H, m, ArH), 7.84–7.86 (2 H, m, ArH), 7.96–7.98 (2 H,
m, ArH).
Anal. Calcd for C34H32N4O7: C, 67.09; H, 5.30; N, 9.21. Found: C,
66.90; H, 5.31; N, 9.23.
2,5-Bis(o-{(4 S)-4 -[(1R)-1-phenyl-1-hydroxymethyl]oxazolin-
2 -yl}phenyl)-1,3,4-oxadiazole (5)
To a solution of diamide 4 (2.44 g, 4.0 mmol) and anhyd Et3N (7
mL, 50.5 mmol) in CH2Cl2 (50 mL) was added MsCl and TsCl (2.3
g, 12.1 mmol) at r.t.. The reaction mixture was kept at reflux for 12
h. H2O (4 mL) was added and the solution was heated to reflux for
1 h. After cooling the reaction mixture was extracted with H2O (3
30 mL). The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3 50 mL). The organic layer was dried
over anhyd Na2SO4, and filtered. The filtrate was concentrated in
vacuo to afford the crude product. The crude product was purified
by column chromatography on silica gel (CHCl3–EtOAc, 1:2) to
give 5 as a colorless solid; 1.06 g (46.3%); mp 88–90 °C; [ ]D
–39.0 (c 0.1, CHCl3).
IR (KBr): 3448, 1653, 1453, 1363, 1052, 958 cm–1.
1H NMR (CDCl3): = 3.94 (2 H, t, J = 8.2 Hz, CH2), 4.11 (2 H, t,
J = 9.2 Hz, CH2), 4.34 (2 H, d, J = 7.6 Hz, CHPh), 4.55 (2 H, m,
CHN), 5.34 (2 H, s, OH), 7.02–7.26 (10 H, m, ArH), 7.58–7.73 (4
H, m, ArH), 7.80 (2 H, dd, J = 1.4, 7.2 Hz, ArH), 8.14 (2 H, dd,
J = 1.4, 7.6 Hz, ArH).
Anal. Calcd for C28H32N4O3: C, 71.16; H, 6.82; N, 11.86. Found: C,
71.30; H, 6.99; N, 11.64.
2,5-Bis{o-[(4 S)-4 -isopropyloxazolin-2 -yl]phenyl}-1,3,4-oxadi-
azole (3c)
Following general procedure II, dihydroxy diamide 2c (0.96 g, 2.0
mmol), MsCl (0.36 mL, 4.6 mmol) and Et3N (1.4 mL, 10.1 mmol)
gave the crude bismesylate. The crude bismesylate was treated with
a NaOH–EtOH–H2O solution as above, column chromatography
(silica gel; EtOAc–petroleum ether, 3:7) followed by recrystalliza-
tion from EtOAc–petroleum ether gave 3c as a colorless solid; 0.48
g (54%); mp 71–72 °C; [ ]D20 –82.7 (c 1, MeOH).
20
IR (KBr): 1680 cm–1.
1H NMR (CDCl3): = 0.83 (6 H, d, J = 6.8 Hz, CH3), 0.91 (6 H, d,
J = 6.8 Hz, CH3), 1.74 (2 H, m, CH), 4.00 (4 H, m, CH2), 4.27 (2H,
m, NCH), 7.54–7.65 (4 H, m, ArH), 7.84–7.96 (4 H, m, ArH).
EI-MS: m/z = 444 (M+).
Anal. Calcd for C26H28N4O3: C, 70.25; H, 6.35; N, 12.60. Found: C,
70.10; H, 6.30; N, 12.40.
HR-FAB: m/z calcd for C34H28N4O5: 573.2132. Found: 573.2131.
Asymmetric Cyclopropanation of Styrene; Typical Procedure
To a solution of the ligand (2.4 mol%) in ClCH2CH2Cl (1 mL) was
added [Cu(OTf)(C6H6)0.5] (2 mol%). After stirring at r.t. for 2 h, a
solution of styrene (8 mmol) in ClCH2CH2Cl (1 mL) was added, fol-
lowed by ethyl diazoacetate solution (10 L) and the mixture was
heated to 50–60 °C to initiate the reaction. Then the solution was
cooled to the desired temperature, the solution of ethyl diazoacetate
(2 mmol) in ClCH2CH2Cl (1 mL) was added dropwise over a period
of 7 h. The mixture was stirred for another 15 h and then quenched
with 10% NH4Cl (5 mL). The mixture was diluted with EtOAc (25
mL), and then the organic phase was separated. The organic phase
was washed with H2O and brine, dried over anhyd Na2SO4. The sol-
vent was removed under reduced pressure, the residue was purified
by column chromatography on silica gel (petroleum ether–EtOAc,
60:1) to afford the mixture of trans- and cis-2-phenyl-cyclopro-
pane-1-carboxylates as a colorless oil. The trans/cis ratio of this
mixture was analyzed by 1H NMR (200 MHz) in CDCl3 using TMS
as internal standard. The diastereomeric and enantiomeric excess
were determined by HPLC with a chiral column (Daicel Chiralcel
OD; eluent, hexane–i-PrOH, 95:5; flow rate, 0.5 mL/min; UV de-
tector, 220nm).
2,5-Bis{o-[(4 S)-4 -benzyloxazolin-2 -yl]phenyl}-1,3,4-oxadiaz-
ole (3d)
Following general procedure II, dihydroxy diamide 2d (2.3 g, 4.0
mmol), MsCl (0.75 mL, 9.5 mmol) and Et3N (3.0 mL, 22.8 mmol)
to afford the crude bismesylate. The crude bismesylate was treated
with a NaOH–EtOH–H2O solution as above, column chromatogra-
phy on silica gel (EtOAc–petroleum ether, 5:4) gave 3d as a color-
less oil; 1.75 g (80.9%); [ ]D20 –87.2 (c 2.3, CHCl3).
IR (KBr): 1670, 1520 cm–1.
1H NMR (CDCl3): = 2.64 (2 H, dd, J = 8.6, 13.6 Hz, CH2), 3.08 (2
H, dd, J = 5.4, 13.6 Hz, CH2), 4.01 (2 H, t, J = 8.6 Hz, CH2), 4.20 (2
H, t, J = 8.6 Hz CH2), 4.50 (2 H, m, CH), 7.09–7.30 (10 H, m, ArH),
7.56–7.65 (4 H, m, ArH), 7.84–7.99 (4 H, m, ArH).
EI-MS: m/z 541 (M + 1).
Anal. Calcd for C34H28N4O3: C, 75.54; H, 5.22; N, 10.36. Found: C,
75.34; H, 5.23; N, 10.21.
2,5-Bis{o-[N-(2 S, 3 S)-(1 ,3 -dihydroxy-3 -phenylpropyl)ami-
do]phenyl}-1,3,4-oxadiazole (4)
A solution of 2,5-di-(o-carboxyphenyl)-1,3,4-oxadiazole (2.17 g,
7.0 mmol) and SOCl2 (40 mL) was refluxed for 12 h. The excess
SOCl2 was removed under reduced pressure, benzene (20 mL) was
added and the solvent was removed to afford the diacyl dichloride.
A solution of the above diacyl dichloride in CH2Cl2 (50 mL) was
added dropwise to the suspension of (1R,2S)-(–)-2-amino-1-phe-
nyl-1,3-propanediol (2.2 g, 13.0 mmol) and Et3N (5.0 mL) in
CH2Cl2 (80 mL) at 0 °C and stirred at r.t. for 36 h. The precipitate
was filtered and washed with Et2O to give 4 as a colorless solid; 3.3
g (83.3%); mp 200–202 °C; [ ]D20 +28.0 (c 0.1, MeOH).
X-ray Crystallographic Analysis
A colorless crystal was selected and mounted on a fine-focus sealed
tube and used for data collection. Cell constants and an orientation
matrix for data collection were obtained by least-squares refinement
of the diffraction data from 25 reflections in the 2 range from 2.52
to 27.48 degree for compound 3a and 2.30 to 27.48 degree for com-
pound 3b in a Rigaku AFC6S diffractometer equipped with a graph-
ite crystal incident beam monochromator. Data were collected at
293K using MoK radiation ( = 0.71073 Å) and the -2 variable-
scan mode. The intensity data obtained were corrected for Lorentz
and polarization effects. An empirical absorption correction based
on -scan data was applied. The crystal structure was resolved by
the direct method using SHELXS-97,21 and full-matrix least-
squares refinement on F2 was performed with SHELXL-97 pro-
gram.22 All the non-hydrogen atoms were deduced from an E-map
and refined anisotropically. The positions of hydrogen atoms were
generated geometrically and included in structure factor calcula-
tions with assigned isotropic thermal parameters. All computations
were performed on a FOUNDER FP+ 5-166 586 personal computer.
IR (KBr): 3334, 3279, 3058, 3063, 2934, 2876, 1647, 1597, 1531,
1492, 1336, 1056 cm–1.
1H NMR (DMSO-d6): = 3.33 (2 H, m, OH), 3.54 (2 H, m, OH),
4.11(2 H, m, CHN), 4.70 (2 H, t, J = 10.8 Hz, CH2), 4.90 (2 H, t,
J = 4.4 Hz, CH2), 5.41 (2 H, d, J = 4.8 Hz, CHPh), 7.17–7.40 (12
H, m, ArH), 7.57–7.69 (4 H, m, ArH), 7.88 (2 H, d, J = 8.4 Hz,
ArH), 8.20 (2 H, d, J = 8.8 Hz, 2 H, NH).
FAB-MS: m/z (%) = 609 (M + 1, 6), 181 (100).
Synthesis 2002, No. 16, 2347–2352 ISSN 0039-7881 © Thieme Stuttgart · New York

2352
3a
D.-M. Du et al.
PAPER
(7) (a) Evans, D. A.; Woerpel, K. A.; Scott, M. J. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 430. (b) Gant, T. G.; Noe, M. C.;
Corey, E. J. Tetrahedron Lett. 1995, 36, 8745. (c) Kim, S.
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2001, 59, 1340. (b) Wang, Z. Y.; Du, D. M.; Wu, D.; Hua,
W. T. Synth. Commun. 2002, 32, in press.
C32H24N4O3, FW = 512.55, Monoclinic, space group P(2)1,
a = 8.971(2), b = 15.404(3), c = 9.541 (2) Å; = 90°, = 95.86
(3)°, = 90°, V = 1311.6 (5) Å3, Z = 2, F(000) = 536, Dc = 1.298 g/
cm3, = 0.085 mm–1. Crystal size 0.50 0.40 0.35 mm; Index
ranges 0 h 11, 0 k 20, –12 l 12; Reflections collected/unique,
3109/3109 (Rint = 0.0000); Data /restraints/parameters, 3109/1/353;
Goodness-of-fit on F2 0.845; Final
R indices [I>2 (I)]:
R1 = 0.0299, wR2 = 0.0536; Extinction coefficient 0.034 (2); Larg-
(9) (a) Seki, H.; Koga, K.; Matsuo, H.; Ohki, S.; Matsuo, I. I.;
Yamada, S. Chem. Pharm. Bull. 1965, 13, 995.
(b) Stanfield, C. F.; Parker, J. E.; Kanellis, P. J. Org. Chem.
1981, 46, 4799. (c) Giannis, A.; Sandhoff, K. Angew.
Chem., Int. Ed. Engl. 1989, 28, 218. (d) Mckennon, M. J.;
Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org. Chem. 1993,
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(10) (a) Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837.
(b) Breton, P.; Andre-Barres, C.; Langlois, Y. Synth.
Commun. 1992, 22, 2543. (c) Jones, R. C. F.; Ward, G. J.
Tetrahedron Lett. 1988, 29, 3853. (d) Gant, T. G.; Meyers,
A. I. Tetrahedron 1994, 50, 2297.
est diff. peak and hole, 0.101 and –0.091 eÅ–3.
3b
C28H32N4O3, FW = 472.58, Triclinic, space group P1,
a = 12.7271(6), b = 12.8305(2), c = 9.6886(1) Å; = 105.656 (3)°,
= 112.276 (2)°, = 101.700 (2)°, V = 1324.4 (5) Å3, Z = 2,
F(000) = 504, Dc = 1.185 g/cm3, = 0.078 mm-1. Crystal size 0.60
0.50 0.45 mm; Index ranges –16 h 16, –16 k 16, –12 l 11;
Reflections collected/unique, 5986/5986 (Rint = 0.0229); Data/re-
straints/parameters, 5986/3/656; Max. and min. transmission
1.0613 and 0.9047; Goodness-of-fit on F2 0.785; Final R indices
[I>2 (I)]: R1 = 0.0423, wR2 = 0.1046; Extinction coefficient 0.027
(3); Largest diff. peak and hole, 0.139 and –0.127 eÅ–3.
(11) (a) Vorbrüggen, H.; Krolikiewicz, K. Tetrahedron Lett.
1981, 22, 4471. (b) Vorbrüggen, H.; Krolikiewicz, K.
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(12) Denmark, S. E.; Nakajima, N.; Nicaise, O. J. C.; Faucher, A.
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(13) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer, T.; Rieck, H.;
Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.; Wiese,
B.; Helmchen, G. Tetrahedron 1996, 52, 7547.
(14) Aratani, T.; Nakanisi, Y.; Nozaki, H. Tetrahedron 1970, 26,
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(15) Uchida, T.; Irie, R.; Katsuki, T. Synlett 1999, 1793.
(16) Boulch, R.; Scheurer, A.; Mosset, P.; Saalfrank, R. W.
Tetrahedron Lett. 2000, 41, 1023.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (Grant No. 20172001 and 29872023).
References
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Synthesis 2002, No. 16, 2347–2352 ISSN 0039-7881 © Thieme Stuttgart · New York