Cis and enantioselective synthesis of 2-oxazoline-4-carboxylates through Lewis acid-catalyzed formal [3 + 2] cycloaddition of 5-alkoxyoxazoles with aldehydes

Article abstract of DOI:10.1021/jo990525d

In the presence of 2 equiv of (R)-methylaluminum β-binaphthoxide, which was prepared from (R)-2,2'-dihydroxy-1,1'-binaphthyl and trimethylaluminum, the reaction of 5-methoxy-2-(p-methoxyphenyl)oxazole with benzaldehyde in MeCN gave the corresponding 2-oxa

Full text of DOI:10.1021/jo990525d

7040
J . Org. Chem. 1999, 64, 7040-7047
Cis a n d En a n tioselective Syn th esis of 2-Oxa zolin e-4-ca r boxyla tes
th r ou gh Lew is Acid -Ca ta lyzed F or m a l [3 + 2] Cycloa d d ition of
5-Alk oxyoxa zoles w ith Ald eh yd es
Hiroyuki Suga,*,† Kosei Ikai,‡ and Toshikazu Ibata‡
Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University,
Wakasato, Nagano 380-8553, J apan, and Department of Chemistry, Graduate School of Science,
Osaka University, Toyonaka, Osaka 560-0043, J apan
Received March 24, 1999
In the presence of 2 equiv of (R)-methylaluminum â-binaphthoxide, which was prepared from (R)-
2,2′-dihydroxy-1,1′-binaphthyl and trimethylaluminum, the reaction of 5-methoxy-2-(p-methoxy-
phenyl)oxazole with benzaldehyde in MeCN gave the corresponding 2-oxazoline-4-carboxylate in
high yield (89%) with high stereoselectivity (cis/trans ) 92:8) and high enantioselectivity (88% ee
(cis)). Under the same conditions, enantioselectivity of the cis products obtained from the reaction
with para-substituted benzaldehydes was moderate. On the other hand, formal [3 + 2] cycloaddition
of 5-methoxy-2-(o-methoxyphenyl)oxazole with benzaldehyde or para- and meta-substituted benz-
aldehydes successfully proceeded only in the presence of 30 mol % of (R)-methylaluminum
â-binaphthoxide, which was prepared from (R)-2,2′-dihydroxy-1,1′-binaphthyl and 1.1-1.05 equiv
of trimethylaluminum, to give cis-2-oxazoline-4-carboxylates in high enantioselectivity (up to 90%
ee).
In tr od u ction
racemic methylaluminum â-binaphthoxide gave 2-oxazo-
line-4-carboxylates with high cis selectivity.6 We also
showed that tin(IV) chloride-catalyzed highly diastereo-
selective formal cycloaddition of 5-methoxyoxazoles with
chiral â-alkoxyaldehydes is extremely useful for the
synthesis of optically pure 2-amino-1,3,4-triols.7 In this
paper, we provide a full account of our investigation of
the highly enantioselective synthesis of cis-2-oxazoline-
4-carboxylates in the formal [3 + 2] cycloaddition of
2-aryl-5-methoxyoxazoles with aldehydes catalyzed by
chiral methylaluminum â-binaphthoxide.8
2-Oxazoline-4-carboxylates are versatile building blocks
in organic synthesis as masked â-hydroxy amino acids
and 2-amino-1,3-diols. 5-Substituted 2-oxazoline-4-car-
boxylates have cis and trans isomers at the relative
configuration of the 4- and 5-positions, and the transfor-
mation of cis and trans isomers gives erythro- and threo-
â-hydroxy amino acids or 2-amino-1,3-diols, respectively.
Furthermore, the importance of enantioselective synthe-
sis of 2-oxazoline-4-carboxylates in modern synthetic
methodology is apparent from the numerous synthetic
applications using 2-oxazoline-4-carboxylates as the build-
ing blocks.1-5 Trans isomers of 5-substituted 2-oxazoline-
4-carboxylate have been selectively synthesized by the
aldol reaction of isocyanoacetates with aldehydes under
thermodynamic control.1-3 For the enantioselective syn-
thesis of trans-2-oxazoline-4-carboxylates, ferrocenylphos-
phine-gold(I) complexes were found to be the most
effective catalyst in the reaction of isocyanoacetate with
aldehydes.3 However, the enantioselective synthesis of
cis-2-oxazoline-4-carboxylates has not been reported yet.5
Recently, we reported that regio- and stereoselective
formal [3 + 2] cycloaddition of 2-aryl-5-methoxyoxazoles
with aldehydes catalyzed by a stoichiometric amount of
Resu lts a n d Discu ssion
Rea ction of Oxa zole 1a w ith Ben za ld eh yd e in th e
P r esen ce of a Ch ir a l Lew is Acid . The reaction of
oxazole 1a with benzaldehyde was carried out under
several conditions in the presence of chiral catalyst A,
which was prepared by mixing (R)- or (S)-2,2′-dihydroxy-
1,1′-binaphthyl ((R)- or (S)-BINOL) and trimethylalumi-
num (hexane solution) in situ (Scheme 1 and Table 1).
We first examined the reaction under the previously
reported optimum conditions for the stereoselective
synthesis of racemic cis-2-oxazoline-4-carboxylates (Table
1, entries 1, 2, and 4).6 After isolation of cis-2-oxazoline-
† Shinshu University.
‡ Osaka University.
(4) (a) Kaneko, T.; Katsura, H. Bull. Chem. Soc. J pn. 1963, 36, 899.
(b) Seebach, D.; Aebi, J . D. Tetrahedron Lett. 1983, 24, 3311. (c) Gou,
D.-M.; Lui, Y.-C.; Chen, C.-S. J . Org. Chem. 1993, 58, 1287. (d)
Kingston, D. G.; Chaudhary, A. G.; Gunatilaka, A. A. L.; Middleton,
M. L. Tetrahedron Lett. 1994, 35, 4483.
(1) For a review of the syntheses of 2-oxazoline-4-carboxylates using
isocyanoacetates and conversion to â-hydroxyamino acid, see: Mat-
sumoto, K.; Moriya, T.; Suzuki, M. J . Synth. Org. Chem. J pn. 1985,
43, 7664.
(2) (a) Hoppe, D.; Scho¨llkopphf, U. J ustus Liebigs Ann. Chem. 1972,
763, 1. (b) Matsumoto, K.; Urabe, Y.; Ozaki, Y.; Iwasaki, T.; Miyoshi,
M. Agric. Biol. Chem. 1975, 39, 1869. (c) Matsumoto, K.; Ozaki, Y.;
Suzuki, M.; Miyoshi, M. Agric. Biol. Chem. 1976, 40, 2045. (d) Ozaki,
Y.; Matsumoto, K.; Miyoshi, M. Agric. Biol. Chem. 1978, 42, 1565.
(3) (a) Ito, Y.; Sawamura, M.; Hayashi, T. J . Am. Chem. Soc. 1986,
108, 6405. (b) Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett.
1987, 28, 6215; 1988, 29, 239. (c) Ito, Y.; Sawamura, M.; Shirakawa,
E.; Hayashizaki, K.; Hayashi, T. Tetrahedron Lett. 1988, 29, 235. (d)
Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T.
Tetrahedron 1988, 44, 5253.
(5) Gold(I)-catalyzed asymmetric aldol reaction of methy isocyano-
acetate with penta- and tetrafluorobenzaldehydes showed cis selectivity
(cis/trans ) 63:37-62:38) with high enentioselectivity (86-90% ee):
Soloshonok, V. A.; Hayashi, T. Tetrahedron Lett. 1994, 35, 2713.
(6) (a) Suga, H.; Shi, X.; Fujieda, H.; Ibata, T. Tetrahedron Lett.
1991, 32, 6911. (b) Suga, H.; Shi, X.; Ibata, T. J . Org. Chem. 1993, 58,
7397.
(7) Suga, H.; Fujieda, H.; Hirotsu, Y.; Ibata, T. J . Org. Chem. 1994,
59, 3359.
(8) Part of the present work has been presented as a communication
letter: Suga, H.; Ikai, K.; Ibata, T. Tetrahedron Lett. 1998, 39, 869.
10.1021/jo990525d CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

Enantioselective Synthesis of 2-Oxazoline-4-carboxylates
J . Org. Chem., Vol. 64, No. 19, 1999 7041
Ta ble 1. Rea ction of Oxa zole 1a w ith Ben za ld eh yd ea
entry
catalyst (mol %)
PhCHO, equiv
solvent
T, °C time, h yield, % cis/trans cis, % eeb(confign)c trans, % eeb
1
2
3
4
5
6
7
8
9
(R)-BINOL + AlMe3 (100)
(S)-BINOL + AlMe3 (100)
(S)-BINOL + AlMe3 (200)
(R)-BINOL + AlMe3 (200)
(R)-BINOL + AlMe3 (200)
(R)-BINOL + AlMe3 (200)
(R)-BINOL + AlMe3 (50)
(R)-BINOL + AlMe3 (30)
(R)-BINOL + AlMe3 (30)
(R)-BINOL + AlMe3 (30)
(R)-BINOL + AlMe3 (30)
1
1
1
1
1
CH2Cl2-MeCN
CH2Cl2-MeCN
CH2Cl2-MeCN
MeCN
0
0
0
rt
0
122
122
123
75
76
89
57
52
64
40
45
81
89
70
31
84
82
87:13
88:12
81:19
60:40
87:13
92:8
96:4
95:5
95:5
95:5
55 (4S,5S)d
55 (4R,5R)
70 (4R,5R)e
90 (4S,5S)
86 (4S,5S)
88 (4S,5S)f
75 (4S,5S)
65 (4S,5S)
82 (4S,5S)
67 (4S,5S)
74 (4S,5S)
13
12
5
2
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3
-10
8
10
10
10
10
10
-10 116
55
36
NDh
NDh
32
-10 163
-10
5
rt
25g
39.5
46
10
11
93:7
a
b
The reaction was carried out in the presence of catalyst A, which was prepared from Me3Al and Chiral BINOL. Determined by
HPLC analysis using Daicel Chiralpak AS (hexane/i-PrOH ) 9:1, flow 0.5 mL/min). c See the text for determination of the configuration.
[R]21 ) +144.5° (c 1.20, THF). e [R]19 ) -186.4° (c 1.20, THF). f [R]D ) +215.2° (c 1.23, THF). A solution of oxazole 1a was added
d
26
g
D
D
h
over a period of 115 h and then stirred for 25 h. The % ee was not determined.
Sch em e 1
Sch em e 2
Rea ction of Oxa zole 1a w ith P a r a -Su bstitu ted
Ben za ld eh yd e in th e P r esen ce of Ca ta lyst A. The
reactions of oxazole 1a with some para-substituted benz-
aldehydes were carried out under the conditions using 2
equiv of catalyst A in MeCN (Scheme 2, Table 2, entries
1, 4, and 8). Although these reactions proceeded in good
stereoselectivity (cis/trans ) 96:4-82:18), the enantio-
meric excess of the cis products was moderate. To
improve the enantioselectivity in the reaction with
substituted benzaldehydes and to determine the amount
of the catalyst, the effects of the position and number of
the methoxy substituents on the 2-aryl group were
investigated.
Rea ction of Oxa zoles 1a -d w ith Ben za ld eh yd e in
th e P r esen ce of Ca ta lyst A. In the preliminary experi-
ment, 5-methoxy-2-(o-methoxyphenl)oxazole 1b reacted
smoothly with benzaldehyde by using 30 mol % of
catalyst A to give 2-oxazoline-4-carboxylate 2b (cis/trans
) 85:15) in 79% chemical yield and 85% ee of cis-2b.
However, when the reaction was repeated several times,
it was seen that it did not have reproducibility in terms
of chemical yield and enantioselectivity. This might be
attributed to the slight difference in the ratio of AlMe3
and chiral BINOL in preparing the catalyst. The catalyst
was then prepared by mixing AlMe3 and (R)-BINOL in
four different ratios from 1.2:1.0 to 1.0:1.2, and the
reaction of oxazole 1b with benzaldehyde was carried out
(Table 3, entries 5-8). The use of a slight excess of AlMe3
(AlMe3/BINOL ) 1.05:1.0-1.1:1.0) showed high yield and
high enantioselectivity of cis-2-oxazoline-4-carboxylate 2b
(Table 3, entries 6 and 7).9 The reaction under these
4-carboxylate 2a by column chromatography, the enan-
tiomeric excess was determined by HPLC analysis using
a Daicel Chiralpak AS column. Moderate enantioselec-
tivity (55% ee) for cis-2a was observed under the condi-
tions by using 1 equiv of chiral catalyst A in CH2Cl2-
MeCN (1:1) at 0 °C (Table 1, entries 1 and 2). When 2
equiv of catalyst A was used in CH2Cl2-MeCN (1:1), the
enantioselectivity increased to 70% ee (Table 1, entry 3).
Using only MeCN as the solvent showed higher enanti-
oselectivity than that in CH2Cl2-MeCN (1:1) (Table 1,
entries 4-6). Under the optimum conditions at -10 °C
in the presence of 2 equiv of catalyst A, high yield (89%),
high stereoselectivity (cis/trans ) 92:8), and high enan-
tioselectivity (88% ee (cis)) were obtained (Table 1, entry
6). It is also interesting to note that the degree of the
steroselectivity (cis/ trans ) 98:2) and chemical yield
(79%) in the presence of racemic catalyst A6 were not
inconsistent with those (cis/trans ) 87:13-88:12, 52-
57% yield) obtained in the presence of chiral catalyst A
under the same conditions (0 °C, CH2Cl2-MeCN) (Table
1, entries 1 and 2). In the presence of 10 equiv of
benzaldehyde in MeCN, the reaction proceeded smoothly
using 30-50 mol % of chiral catalyst A. However, using
catalytic amount of catalyst A resulted in lower enanti-
oselectivity compared with that obtained using 2 equiv
of catalyst A (Table 1, entries 7, 8, 10, and 11). Slow
addition of a solution of oxazole 1a in MeCN also did not
give a satisfactory result in terms of chemical yield (Table
1, entry 9).

7042 J . Org. Chem., Vol. 64, No. 19, 1999
Ta ble 2. Rea ction of Oxa zoles 1a -c w ith Su bstitu ted Ben za ld eh yd esa
Suga et al.
trans, % eeb
entry
oxazole
aldehyde
T, °C
time, h
product
yield, %
cis/trans
cis, % eeb
1f,g
2
1a
1b
1c
1a
1b
1b
1c
1a
1b
1b
1a
1b
1a
1b
1a
1b
1a
1b
p-NO2C6H4CHO
p-NO2C6H4CHO
p-NO2C6H4CHO
p-ClC6H4CHO
-10
20
21
70
53
24
24
75
168
43
70
15
15
42
42
117
117
45
3a
3b
3c
4a
4b
5b
5c
6a
6b
7b
8a
8b
9a
81
83
74
93
89
52
60
78
72
57
89
85
75
82
61
51
66
70
82:18
73d
76d
75d
51
20d
31d
25d
2
-10
43:57 (54:46)c
88:12
3f
5
-10
4f,g
5
87:13
87:13
p-ClC6H4CHO
5
5
5
87
13
6
p-CNC6H4CHO
p-CNC6H4CHO
p-CH3C6H4CHOh
p-CH3C6H4CHO
p-CH3OC6H4CHO
m-NO2C6H4CHO
m-NO2C6H4CHO
m-ClC6H4CHO
m-ClC6H4CHO
m-CH3C6H4CHO
m-CH3C6H4CHO
m-CH3OC6H4CHO
m-CH3OC6H4CHO
71:29 (82:18)c
90:10
76d
75d
63
5d
7f
10d
31
8f,g
9
-10
96:4
88:12
54:46
90:10
73:27
91:9
83:17
93:7
5
rt
5
5
5
5
5
5
5
84
89
82
84
78
84
81
88
9
46
10
11
10
11f
12
13f
14
15f
16
17f
18
23
9b
NDe
25
10a
10b
11a
11b
88:12
97:3
87:13
NDe
33
78
90
5
45
29
a
The reaction was carried out in MeCN in the presence of catalyst A, which was prepared from (R)-BINOL and Me3Al in a ratio of
1:1.05. Determined by HPLC analysis using Daicel Chiralpak AS (hexane/i-PrOH ) 9:1, flow 0.5 mL/min). c Determined by 1H NMR
b
analysis before chromatographic separation. Determined by 1H NMR analysis using (R)-BINOL as shift reagent. e The % ee was not
d
determined. f Catalyst A was prepared from (R)-BINOL and Me3Al in a ratio of 1:1. Reactions were carried out with 3 equiv of aldehydes
g
h
in the presence of 2 molar amounts of catalyst A in MeCN. Five equiv of p-MeC6H4CHO was used.
Ta ble 3. Rea ction of Oxa zoles 1a -d w ith Ben za ld eh yd ea
entry
oxazole
catalyst, (R)-BINOL/AlMe3
T, °C
time, h
product
yield, %
cis/trans
cis, % eeb
trans, % eeb
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1.2:1
1:1
5
5
5
5
72
39.5
23
23
68
27
49
23
40
42
46
40
50
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
2d
90
84
85
85
16
92
82
90
35
64
63
63
83
96:4
95:5
92:8
92:8
84:16
85:15
83:17
81:19
96:4
94:6
90:10
92:8
79
67
65
69
66
84
87
77
83
84
70
70
80
41
NDc
27
1:1.1
1:1.2
1.2:1
1:1.05
1:1.1
1:1.2
1.2:1
1:1
25
5 to rt
5
5
5
rt
rt
rt
rt
5
NDc
15
13
18
54
NDc
27
1:1.1
1:1.2
1:1
33
21
59:41
a
The reaction was carried out in MeCN in the presence of catalyst A, which was prepared from Me3Al and (R)-BINOL in the ratio
listed in the table. Determined by HPLC analysis using Daicel Chiralpak AS (hexane/i-PrOH ) 9:1, flow 0.5 mL/min). c The % ee was
not determined.
b
conditions also had reproducibility in terms of yields and
enantioselectivity. On the other hand, utilization of 1.2
equiv of (R)-BINOL in preparation of the catalyst showed
lower yield and enantioselectivity of cis adduct 2b. In the
case of reactions of oxazole 1a and 1c, however, the use
of a slight excess (1.2 equiv) of (R)-BINOL in preparation
of the catalyst showed slightly better enantioselectivity
rather than by using a slight excess (1.2 equiv) of Me3Al
(Table 3, entries 1-4 and 9-12).
2-(2,6-Dimethoxyphenyl)oxazole 1d also underwent the
formal [3 + 2] cycloaddition with benzaldehyde to give
the corresponding products in high yield and with good
enantioselectivity of cis-oxazoline. However, the reaction
showed lower stereoselectivity (cis/trans ) 59:41).
6-position (catalyst D) of chiral BINOL moiety, the
reactions of oxazoles 1a ,b,d with benzaldehyde were also
carried out (Figure 1, Table 4, entries 2, 4-6, and 8).
These catalysts, including catalyst C,10 which is one of
the best aluminum Lewis acids for asymmetric synthesis,
did not exhibit better enantioselectivity than that in the
presence of catalyst A. In the case of reactions using
catalyst B, trans-2-oxazoline-4-carboxylates were pre-
dominantly produced, probably due to inhibition of the
transition state that produces cis products by steric inter-
action of the 3-phenyl group (Table 4, entries 2, 4, and
8). Generally, the enantiomeric excess of minor trans-2-
oxazoline-4-carboxylates by the catalyst A-catalyzed re-
action was low.11 However, in the reaction of oxazole 1a
in the presence of catalyst B, the highest enantioselec-
tivity of trans-oxazoline was obtained (Table 4, entry 2).
Rea ction of Oxa zoles 1a ,b,d in th e P r esen ce of
Ca ta lyst B, C, or D. In the presence of the catalysts
having a phenyl (catalyst B) or a triphenysilyl group
(catalyst C)10 on the 3-position and a bromo group on the
(10) (a) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J . Am.
Chem. Soc. 1988, 110, 310. (b) Maruoka, K.; Itoh, T.; Araki, Y.;
Shirasaka, T.; Yamamoto, H. Bull. Chem. Soc. J pn. 1988, 61, 2975.
(c) Maruoka, K.; Yamamoto, H. J . Am. Chem. Soc. 1989, 111, 789. (d)
Marioka K.; Banno, H.; Yamamoto, H. J . Am. Chem. Soc. 1990, 112,
7791.
(11) This may be attributable to the concomitant formation of minor
trans-oxazolines by Lewis acid-promoted isomerization of cis-oxazolines
through a ring-opening-recyclization pathway involving racemization
of the 4- and 5-positions.
(9) In the case of 1b, the reaction using 2 equiv of the catalyst (-10
°C, 168 h, 35% yield) gave unsatisfactory results in terms of stereo-
selcetivity (cis/trans ) 49:51) and enantioselectivity (cis: 62% ee),
probably due to decomposition and epimerization of the product under
the reaction conditions. In the presence of 20 mol % of the catalyst
(Me3Al/(R)-BINOL ) 1:1.05), the reaction (5 °C, 45 h) did not complete
(61% yield, recovered 1b: 31%) and showed low selectivity (cis/trans
) 79:21, cis: 63% ee).

Enantioselective Synthesis of 2-Oxazoline-4-carboxylates
J . Org. Chem., Vol. 64, No. 19, 1999 7043
Ta ble 4. Rea ction of Oxa zoles 1a ,b,d w ith Ben za ld eh yd e by Usin g (R)-bin ol Der iva tivesa
entry
oxazole
catalyst (Ln/AlMe3)
T, °C
time, h
product
yield, %
cis:trans
cis, % eeb
trans, % eeb
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1d
1d
A (1:1)
B (1:1)
5
5
5
5
5
5
5
5
39.5
25
27
21.5
22
113.5
50
2a
2a
2b
2b
2b
2b
2d
2d
84
89
92
83
87
68
83
80
95:5
67
33
84
52
64
50
80
64
NDc
71
15
43
54
10
21
45
39:61
85:15
29:71
66:34
87:13
59:41
16:84
A (1:1.05)
B (1:1.05)
C (1:1.05)
D (1:1.05)
A (1:1)
B (1:1)
23
a
b
The reaction was carried out in MeCN in the presence of the catalyst listed in the table. Determined by HPLC analysis using Daicel
Chiralpak AS (hexane/i-PrOH ) 9:1, flow 0.5 mL/min). c The % ee was not determined.
independent of the electronic character of the para
substituents of the benzaldehyde derivatives. Oxazole 1c
also underwent formal [3 + 2] cycloaddition with electron-
deficient para-substituted benzaldehydes to give cis-
oxazoline-4-carboxylates in high cis and good enantiose-
lectivity. In the reactions of oxazoles 1a and 1b with
several kinds of meta-substituted benzaldehydes, the
enantiomeric excess and cis selectivity of cis-oxazolines
were also very high independent of the electronic char-
acter of the substituents (Table 2, entries 11-18).
Absolu te Con figu r a tion of cis-2-Oxa zolin e-4-ca r -
boxyla te. The absolute configuration of cis-2-oxazoline-
4-carboxylate cis-2a was determined by the optical
rotation after conversion to threo-â-phenylserine. Thus,
2-oxazoline cis-2a (88% ee) was first converted to 2-ox-
azoline trans-2a (70% ee) by treatment of triethylamine
in MeCN under reflux in 73% yield. The resulting trans-
2a was hydrolyzed by concentrated hydrochloric acid at
50 °C in MeOH and then 6 N hydrochloric acid at 80-
100 °C. After treatment with Amberlite IRA-120B(H+),
threo-â-phenylserine was obtained in 50% overall yield.
By comparing the optical rotation ([R]18D ) +29.9° (c 2.0,
6 N HCl)) of the synthesized threo-â-phenylserine with
that of the natural threo-â-phenylserine ([R]18 ) -50.2
D
( 2° (c 2.0, 6N HCl)),12 the configuration of cis-2a was
determined as (4S,5S) (Scheme 3).
Th e Mech a n ism for Cis a n d En a n tioselectivity.
It has been proposed that the formal [3 + 2] cycloaddition
of oxazoles with tetracyanoethylene,13 4-phenyl-3H-1,2,4-
triazole-3,5-(4H)-dione,14a diethyl azodicarboxylate,14b ni-
trosobenzene,15 and diethyl oxomalonate16 proceeds
through a stepwise pathway involving zwitterionic in-
termediates. According to an interpretation of the step-
F igu r e 1. Catalysts A-D.
wise pathway, the Lewis acid activates the aldehydes by
accelerating the initial attack of the oxazoles on the
aldehydes in the reaction of 5-alkoxyoxazoles with alde-
hydes. In the catalyst A-catalyzed reaction of oxazole
1a -c with benzaldehyde derivatives, a stable 1:1 complex
of catalyst A with aldehydes may be the initial interme-
diate of the reaction. On the basis of the structure of this
stable complex π, we anticipate an antiperiplanar or
synclinal approach of the C4-C5 double bond of the
oxazoles to the carbonyl group of complex π (Figure 2).
In the re-face attack on complex π, the sterically less-
hindered approach X, which showed the approach of
Reaction of Oxazoles 1a-c with Su bstitu ted Ben z-
a ld eh yd e in th e P r esen ce of Ca ta lyst A. As described
above, the highest enantioselectivity of cis-2-oxazoline-
4-carboxylate cis-2b was obtained by the reaction of
oxazole 1b with benzaldehyde under the conditions in
MeCN in the presence of about 30% of catalyst A, which
was prepared by mixing AlMe3 and (R)-BINOL in a 1.1-
1.05:1.0 ratio (Table 3, entries 6 and 7). The reactions of
oxazole 1b with several kinds of para-substituted ben-
zaldehydes were preformed under similar conditions
(Table 2, entries 2, 5, 6, 9, and 10). In all cases, good
enantiomeric excess of cis-2-oxazolines was obtained
Sch em e 3

7044 J . Org. Chem., Vol. 64, No. 19, 1999
Suga et al.
F igu r e 2. Approaches X, X′, Y, and Y′.
hindrance between the naphthyl moiety and aryl groups
of the oxazoles. In the case of si-face attack, antiperipla-
nar approaches Y and Y′ seem to be much less favorable
than approach X because of the steric repulsion between
the methyl group of the aluminum center and the
oxazoles (Figure 2).
Con clu sion
We have developed new methodology for the cis and
enantioselective synthesis of synthetically useful 2-ox-
azoline-4-carboxylates by the methylaluminum â-binaph-
thoxide-catalyzed reaction of 2-aryl-5-alkoxyoxazoles with
substituted benzaldehydes. The above-described meth-
odology has the advantage of high enantioselectivity and
cis selectivity over previously reported methods for the
synthesis of 2-oxazoline-4-carboxylates. Normally, the use
of Lewis acids as catalysts in reactions of heterocyclic
compounds is expected to have limitations in the activa-
tion and control of the reactions because the Lewis acids
may form complexes with heterocyclic compounds. We
believe that our success in the stereo- and enantiocontrol
of formal [3 + 2] cycloaddition of 5-alkoxyoxazoles in the
present work presents a new guiding principle for the
use of Lewis acids for the reaction of heterocyclic com-
pounds.
F igu r e 3. Postulated transition state.
oxazole 1b as exemplified below, seems to be the most
favorable. Approach X corresponds to an antiperiplanar
attack of the C4-C5 double bond of the oxazoles on the
carbonyl group of the aldehyde as shown in transition
state model T-A, and this approach gives (4S,5S)-cis-
2-oxazoline-4-carboxylates through a stepwise pathway
involving zwitterionic intermediate I (Figure 3). Ap-
proaches such as X′ are unfavorable because of steric
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded at 270 and 67.8 MHz, respectively. Chemical shifts
are expressed in parts per million downfield from tetrameth-
ylsilane as an internal standard. Mass spectra were recorded
at 70 eV with a direct inlet. For preparative column chro-
matogtaphy, Wakogel C-300 and silica gel 60 (Merck) were
employed. Medium-pressure liquid chromatography was car-
ried out using a column packed with silica gel 60 (Merck, size
0.040-0.063 mm). All reactions were carried out under an
argon atmosphere in dried glassware.
(12) L-(-)-threo-â-Phenylserine: [R]18D ) -50.2 ( 2° (c 2.0, 6 N HCl).
Vogler, K. Helv. Chim. Acta 1950, 33, 2111.
(13) (a) Ibata, T.; Isogami, Y.; Nakano, S.; Tamura, H. J . Chem. Soc.,
Chem. Commun. 1986, 1692. (b) Ibata, T.; Isogami, Y.; Nakawa, H.;
Tamura, H.; Suga, H.; Shi, X.; Fujieda, H. Bull. Chem. Soc. J pn. 1992,
65, 1771.
(14) (a) Ibata, T.; Isogami, Y.; Tamura, H. Chem. Lett. 1988, 1551.
(b) Ibata, T.; Suga, H.; Isogami, Y.; Tamura, H.; Shi, X. Bull. Chem.
Soc. J pn. 1992, 65, 2998.
(15) (a) Suga, H.; Ibata, T. Chem. Lett. 1991, 1221. (b) Suga, H.;
Shi, X.; Ibata, T. Bull. Chem. Soc. J pn. 1998, 71, 1231.
(16) Suga, H.; Shi, X.; Ibata, T. Chem. Lett. 1994, 1673.
Ma ter ia ls. MeCN and CH2Cl2 were purified by the method
repored previously.6,7 5-Alkoxy-2-aryloxazoles (1a -d ) were

Enantioselective Synthesis of 2-Oxazoline-4-carboxylates
J . Org. Chem., Vol. 64, No. 19, 1999 7045
synthesized from glycin methyl ester hydrochloride by the
method described in the literature.17
Met h yl (4S,5S)-2-(3,4,5-t r im et h oxyp h en yl)-5-p h en yl-
cis-2-oxa zolin e-4-ca r boxyla te (cis-2c): colorless prisms (eth-
yl acetate-hexane); mp 126.1-129.1 °C; IR (KBr) 1748, 1640
2-(p-Meth oxyp h en yl)-5-m eth oxyoxa zole (1a ): pale yel-
low crystals (benzene-hxane); mp 80.5-82.2 °C; IR (KBr) 1622
1
cm-1; H NMR (CDCl3) δ 3.23 (3H, s), 3.92 (9H, s), 5.30 (1H,
1
cm-1; H NMR (CDCl3) δ 3.84 (3H, s), 3.93 (3H, s), 6.15 (1H,
d, J ) 10.9 Hz), 5.93 (1H, d, J ) 10.9 Hz), 7.30-7.36 (7H, m);
13C NMR (67.8 MHz, CDCl3) δ 51.68 (q), 56.33 (q), 60.96 (q),
74.16 (d), 83.04 (d), 105.97 (d), 126.37 (d), 128.30 (d), 122.01
(s), 135.90 (s), 141.49 (s), 153.15 (s), 166.42 (s), 169.52 (s); MS
m/z (rel intensity) 371 (M+, 72), 312 (77), 265 (50), 195 (base
peak), 119 (28), 91 (20). Anal. Calcd for C20H21NO6: C, 64.68;
H, 5.70; N, 3.77. Found: C, 64.62; H, 5.76; N, 3.76.
s), 6.93 (2H, dt, J ) 8.6 Hz, 1.7 Hz), 7.80 (2H, dt, J ) 8.6 Hz,
1.7 Hz). Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.24; H, 5.49; N, 6.78.
2-(o-Meth oxyp h en yl)-5-m eth oxyoxa zole (1b): colorless
crystals (CH2Cl2-hexane); mp 66.4-69.6 °C; IR (KBr) 1614
1
cm-1; H NMR (CDCl3) δ 3.94 (3H, s), 3.95 (3H, s), 6.25 (1H,
Meth yl (4S,5S)-2-(2,6-d im eth oxyp h en yl)-5-p h en yl-cis-
2-oxa zolin e-4-ca r boxyla te (cis-2d ): colorless needles (ben-
s), 6.99-7.04 (2H, m), 7.37 (1H, ddd, J ) 8.9 Hz, 7.6 Hz, 1.7
Hz), 7.84 (1H, dd, J ) 7.6 Hz, 1.7 Hz). Anal. Calcd for C11H11
-
zene-hexane); mp 117.7-119.4 °C; [R]23 ) +129.9° (c 0.51,
D
NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.44; H, 5.52; N,
6.76.
CHCl3), >98% ee after recrystallization; IR (KBr) 1753, 1670
1
cm-1; H NMR (CDCl3) δ 3.23 (3H, s), 3.89 (6H, s), 5.38 (1H,
2-(3,4,5-Tr im eth oxyph en yl)-5-m eth oxyoxazole (1c): pale
yellow crystals (benzene-hexane); mp 107.2-109.8 °C; IR (KBr)
d, J ) 11.2 Hz), 5.92 (1H, d, J ) 11.2 Hz), 7.31-7.49 (8H, m);
13C NMR (CDCl3) δ 51.6 (q), 56.1 (q), 74.2 (d), 82.6 (d), 103.9
(d), 106.9 (s), 126.9 (d), 128.0 (d), 128.5 (d), 132.0 (d), 136.4
(s), 159.1 (s), 163.6 (s), 169.5 (s). Anal. Calcd for C19H19NO5:
C, 66.85; H, 5.61; N, 4.10. Found: C, 66.50; H, 5.72; N, 4.11.
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-(p-n itr op h en yl)-
cis-2-oxa zolin e-4-ca r boxyla te (cis-3b): colorless solid (ben-
1
1618 cm-1; H NMR (CDCl3) δ 3.88 (3H, s), 3.92 (6H, s), 3.95
(3H, s), 6.18 (1H, s), 7.15 (2H, s). Anal. Calcd for C13H15NO5:
C, 58.86; H, 5.70; N, 5.28. Found: C, 58.93; H, 5.75; N, 5.29.
2-(2,6-Dim eth oxyp h en yl)-5-m eth oxyoxa zole (1d ): col-
orless crystals (benzene-hexane); mp 84.9-86.6 °C (from
benzene-hexane); IR (KBr) 1615 cm-1; 1H NMR (CDCl3) δ 3.80
(6H, s), 3.92 (3H, s), 6.25 (1H, s), 6.59 (2H, d, J ) 8.6 Hz),
7.35 (1H, t, J ) 8.6 Hz); 13C NMR (CDCl3) δ ) 56.1, 58.3, 98.9,
zene-hexane); mp 136.6-139.5 °C; [R]23 ) +124.3° (c 0.48,
D
CHCl3), 80% ee after recrystallization; IR (KBr) 1736, 1639,
1
1513, 1351, 1314 cm-1; H NMR (CDCl3) δ 3.27 (3H, s), 3.96
103.8, 106.9, 131.9, 147.4, 160.0, 161.1. Anal. Calcd for C12H13
-
(3H, s), 5.41 (1H, d, J ) 10.9 Hz), 5.98 (1H, d, J ) 10.9 Hz),
7.02-7.08 (2H, m), 7.49-7.59 (3H, m), 7.90 (1H, dd, J ) 7.9,
2.0 Hz), 8.22 (2H, d, J ) 8.9 Hz); 13C NMR (CDCl3) δ 51.9,
56.1, 74.5, 81.0, 111.9, 115.7, 120.5, 123.4, 127.3, 131.7, 133.4,
143.6, 147.9, 158.9, 165.7, 169.0. Anal. Calcd for C18H16N2O6:
C, 60.67; H, 4.53; N, 7.86. Found: C, 60.74; H, 4.58; N, 7.81.
Meth yl (4S,5S)-2-(3,4,5-tr im eth oxyp h en yl)-5-(p-n itr o-
p h en yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-3c): pale yellow
solid (benzene-hexane); mp 191.0-193.9 °C; IR (KBr) 1728,
1637, 1520, 1340, 1308 cm-1; 1H NMR (CDCl3) δ 3.28 (3H, s),
3.92 (9H, s), 5.37 (1H, d, J ) 10.9 Hz), 6.01 (1H, d, J ) 10.9
Hz), 7.33 (2H, s), 7.50 (2H, d, J ) 8.9 Hz), 8.23 (2H, d, J ) 8.9
Hz); 13C NMR (CDCl3) δ 51.9, 56.3, 60.9, 74.1, 81.7, 105.9,
123.4, 123.5, 127.2, 129.8, 143.1, 147.9, 153.1, 166.2, 168.9. A
satisfactory analytical result was not obtained due to the
instability of cis-3c.
NO4: C, 61.27; H, 5.57; N, 5.95. Found: C, 61.52; H, 5.62; N,
5.92.
Typ ica l Exp er im en ta l P r oced u r e for th e Rea ction of
Oxa zoles 1b w ith Ben za ld eh yd e or Su bstitu ted Ben za l-
d eh yd e in th e P r esen ce of a Ca ta lytic Am ou n t of Ca ta -
lyst A. To a solution of (R)-2,2′-dihydroxy-1,1′-binaphthyl (85.9
mg, 0.30 mmol) in MeCN (6 mL) was added a 1.05 M hexane
solution of Me3Al (0.30 mL, 0.315 mmol), and the resulting
solution was stirred at room temperature for 1 h. After the
mixture was cooled to -20 °C, a solution of oxazole 1b (0.205
g, 1.0 mmol) and benzaldehyde or substituted benzaldehyde
(10.0 mmol) in MeCN (6 mL) was added. The mixture, after
being stirred at the temperature for the time cited in Tables
2 and 3, was quenched with a saturated solution of NaHCO3.
The aqueous layer was extracted with CH2Cl2 (30 mL × 3),
the separated organic layer was dried over anhydrous MgSO4,
and the solvent was removed under reduced pressure. The
residue was chromatographed over silica gel using hexanes-
ehtyl acetate as an eluent to give 2-oxazoline-4-carboxylate
2b-11b. The cis/ trans ratio was evaluated on the basis of the
1H NMR spectrum or from the amount of the products after
separation. The enantiomeric exess was determined by HPLC
analysis (Dicel Chiralpak AS, hexane-iPrOH, 9/1 v/v, flow rate
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-(p-ch lor op h en -
yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-4b): pale yellow vis-
cous oil; [R]22 ) +258.7° (c 0.34, CHCl3), 87% ee; IR (neat)
D
1749, 1647 cm-1; 1H NMR (CDCl3) δ 3.27 (3H, s), 3.94 (3H, s),
5.33 (1H, d, J ) 11.2 Hz), 5.87 (1H, d, J ) 11.2 Hz), 7.01-
7.05 (2H, m), 7.310 (2H, s), 7.314 (2H, s), 7.47-7.50 (1H, m),
7.89 (1H, dd, J ) 7.9, 2.9 Hz); 13C NMR (CDCl3) δ 51.8, 56.1,
74.3, 81.5, 111.9, 116.1, 120.4, 127.8, 128.4, 131.7, 133.2, 134.4,
134.8, 158.9, 165.7, 169.3; HRMS (EI) calcd for C18H16NO4Cl
(M+) 345.0769, found 345.0785.
1
0.5 mL/min) or by H NMR analysis using (R)-2,2′-dihydroxy-
1,1′-binaphthyl as shift reagent after separation of cis product.
Spectroscopic data of cis- and trans-2-oxazoline-4-carboxy-
lates 2a , 3a , 4a , and 6a were previously reported.6
Meth yl (4S,5S)-2-(o-m eth oxyph en yl)-5-(p-cyan oph en yl)-
cis-2-oxa zolin e-4-ca r boxyla te (cis-5b): white amorphous
solid; [R]22D ) +234.3° (c 0.30, CHCl3), 76% ee; IR (KBr) 2228,
1748, 1644 cm-1; 1H NMR (CDCl3) δ 3.26 (3H, s), 3.95 (3H, s),
5.38 (1H, d, J ) 10.9 Hz), 5.92 (1H, d, J ) 10.9 Hz), 7.02-
7.07 (2H, m), 7.48-7.55 (3H, m), 7.66 (2H, d, J ) 8.3 Hz), 8.22
(1H, dd, J ) 7.9, 2.0 Hz); 13C NMR (CDCl3) δ 51.9, 56.1, 74.4,
81.2, 111.9, 112.4, 115.7, 118.4, 120.4, 127.1, 131.7, 132.0,
133.4, 141.6, 158.9, 165.6, 169.0; HRMS (EI) calcd for
Meth yl (4S,5S)-2-(p-m eth oxyp h en yl)-5-p h en yl-cis-2-ox-
a zolin e-4-ca r boxyla te (cis-2a ): [R]26 ) +215.2° (c 1.23,
D
THF), 88% ee.
Meth yl (4S,5S)-2-(p-m eth oxyph en yl)-5-(p-n itr oph en yl)-
cis-2-oxa zolin e-4-ca r boxyla te (cis-3a ): [R]28 ) +168.2° (c
D
1.01, CHCl3), 73% ee.
Meth yl (4S,5S)-2-(p-m eth oxyp h en yl)-5-(p-ch lor op h en -
19H16N2O4 (M+) 336.1112, found 336.1120.
yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-4a ): [R]28 ) +64.4°
C
D
Meth yl (4S,5S)-2-(3,4,5-tr im eth oxyp h en yl)-5-(p-cya n o-
(c 0.86, CHCl3), 51% ee.
ph en yl)-cis-2-oxazolin e-4-car boxylate (cis-5c): yellow amor-
Met h yl (4S,5S)-2-(p -m et h oxyp h en yl)-5-(p -t olyl)-cis-2-
phous; IR (KBr) 2229, 1745, 1649 cm-1 1H NMR (CDCl3) δ
;
oxa zolin e-4-ca r boxyla te (cis-6a ): [R]28 ) +75.5° (c 0.98,
D
3.27 (3H, s), 3.92 (9H, s), 5.34 (1H, d, J ) 10.9 Hz), 5.95 (1H,
d, J ) 10.9 Hz), 7.32 (2, s), 7.43 (2H, d, J ) 8.3 Hz), 7.66 (2H,
d, J ) 8.3 Hz). A satisfactory analytical result was not obtained
due to instability of cis-5c.
CHCl3), 63% ee.
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-p h en yl-cis-2-ox-
a zolin e-4-ca r boxyla te (cis-2b): pale yellow viscous oil; [R]25
D
) +241.4° (c 1.06, ΤΗF), 85% ee; ΙR (ΚΒr) 1739, 1628 cm-1
;
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-(p-tolyl)-cis-2-
1H NMR (CDCl3) δ 3.23 (3H, s), 3.92 (3H, s), 5.30 (1H, d, J )
10.9 Hz), 5.93 (1H, d, J ) 10.9 Hz), 7.30-7.36 (9H, m); HRMS
(EI) calcd for C18H17NO4 (M+) 311.1158, found 311.1183.
oxa zolin e-4-ca r boxyla te (cis-6b): yellow viscous oil; [R]22
D
) +138.4° (c 0.52, CHCl3), 84% ee; IR (neat) 1750, 1646 cm-1
;
1H NMR (CDCl3) δ 2.33 (3H, s), 3.24 (3H, s), 3.93 (3H, s), 5.31
(1H, d, J ) 10.9 Hz), 5.86 (1H, d, J ) 10.9 Hz), 6.99-7.04
(2H, m), 7.14 (2H, d, J ) 7.9 Hz), 7.23 (2H, d, J ) 7.9 Hz),
(17) Grifanti, M.; Sein, M. L. Ann. Chim. (Rome) 1965, 55, 578.

7046 J . Org. Chem., Vol. 64, No. 19, 1999
Suga et al.
) +155.3 °C (c 2.35, CHCl3); IR (neat) 1750, 1645 cm-1 1H
NMR (CDCl3) δ 2.34 (3H, s), 3.24 (3H, s), 3.95 (3H, s), 5.32
(1H, d, J ) 10.9 Hz), 5.86 (1H, d, J ) 10.9 Hz), 7.00-7.10
(2H, m), 7.12-7.23 (4H, m), 7.49 (1H, ddd, J ) 7.9, 5.6, 1.7
Hz), 7.91 (1H, dd, J ) 7.9, 1.7 Hz); 13C NMR (CDCl3) δ 21.4,
51.6, 56.1, 74.5, 82.3, 111.8, 116.4, 120.3, 123.2, 123.5, 128.1,
7.45-7.51 (1H, m), 7.90 (1H, td, J ) 7.6, 2.0 Hz); 13C NMR
(CDCl3) δ 21.1, 51.6, 74.4, 82.2, 111.8, 116.4, 120.3, 126.3,
128.8, 131.7, 133.0, 133.1, 138.3, 158.9, 165.7, 169.7; HRMS
(EI) calcd for C19H19NO4 325.1315, found 325.1337.
;
Met h yl (4S,5S)-2-(o-m et h oxyp h en yl)-5-(p -m et h oxy-
p h en yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-7b): yellow vis-
cous oil; [R]22 ) +138.4° (c 0.52, CHCl3), 89% ee; IR (neat)
131.7, 133.0, 137.8, 158.9, 165.8, 169.0. Anal. Calcd for C19H19-
NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.14; H, 5.90; N,
4.26.
D
1741, 1637 cm-1; 1H NMR (CDCl3) δ 3.28 (3H, s), 3.80 (3H, s),
3.94 (3H, s), 5.31 (1H, d, J ) 10.9 Hz), 5.86 (1H, d, J ) 10.9
Hz), 6.86 (2H, d, J ) 8.9 Hz), 6.99-7.04 (2H, m), 7.26 (2H, d,
J ) 8.9 Hz), 7.48 (1H, d, J ) 7.9 Hz), 7.89 (1H, dd, J ) 7.9,
1.7 Hz); 13C NMR (CDCl3) δ 51.7, 55.2, 56.1, 74.3, 82.1, 111.8,
113.6, 116.4, 120.3, 127.8, 131.7, 132.3, 133.0, 158.9, 159.7,
165.7, 169.7; HRMS (EI) calcd for C19H19NO5 (M+) 341.1264,
found 341.1236.
Met h yl (4S,5S)-2-(p -m et h oxyp h en yl)-5-(m -m et h oxy-
p h en yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-11a ): colorless
needles (benzene-hexane); mp 118.0-120.5 °C; [R]22
)
D
+205.9° (c 0.51, CHCl3), 80% ee after recrystallization; IR
1
(KBr) 1751, 1645 cm-1; H NMR (CDCl3) δ 3.28 (3H, s), 3.78
(3H, s), 3.88 (3H, s), 5.27 (1H, d, J ) 10.6 Hz), 5.87 (1H, d, J
) 10.6 Hz), 6.83-6.93 (3H, m), 6.96 (2H, d, J ) 8.9 Hz), 7.25
(1H, t, J ) 7.9 Hz), 8.04 (2H, d, J ) 8.9 Hz); 13C NMR (CDCl3)
δ 51.8, 55.3, 55.4, 74.1, 82.7, 111.8, 113.8, 114.2, 118.7, 119.3,
129.3, 130.6, 137.6, 159.5, 162.7, 166.4, 169.7. Anal. Calcd for
Meth yl (4S,5S)-2-(p-m eth oxyph en yl)-5-(m-n itr oph en yl)-
cis-2-oxa zolin e-4-ca r boxyla te (cis-8a ): colorless needles
(benzene-hexane); mp 107.5-109.8 °C; [R]25 ) +199.5° (c
D
0.51, CHCl3), 78% ee after recrystallization; IR (KBr) 1733,
1
1660, 1548, 1312 cm-1; H NMR (CDCl3) δ 3.28 (3H, s), 3.89
C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found: C, 66.89; H,
5.63; N, 4.08.
(3H, s), 5.35 (1H, d, J ) 10.9 Hz), 5.99 (1H, d, J ) 10.9 Hz),
6.98 (2H, dt, J ) 8.9, 2.0 Hz), 7.51-7.57 (1H, m), 7.65 (1H, d,
J ) 7.9 Hz), 8.04 (2H, dt, J ) 8.9, 2.0 Hz), 8.19 (2H, m); 13C
NMR (CDCl3) δ 51.9, 55.5, 74.2, 81.4, 114.0, 118.7, 121.4, 123.5,
129.4, 130.7, 132.2, 138.5, 148.1, 163.0, 166.3, 169.2. Anal.
Calcd for C18H16N2O6: C, 60.67; H, 4.53; N, 7.86. Found: C,
60.69; H, 4.58; N, 7.81.
Met h yl (4S,5S)-2-(o-m et h oxyp h en yl)-5-(m -m et h oxy-
p h en yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-11b): pale yel-
low viscous oil; [R]23 ) +199.2° (c 0.88, CHCl3), 90% ee; IR
D
1
(neat) 1747, 1643 cm-1; H NMR (CDCl3) δ 3.27 (3H, s), 3.79
(3H, s), 3.94 (3H, s), 5.33 (1H, d, J ) 10.9 Hz), 5.86 (1H, d, J
) 10.9 Hz), 6.82-7.05 (5H, m), 7.25 (1H, t, J ) 7.9 Hz), 7.45-
7.52 (1H, m), 7.91 (1H, dd, J ) 7.9, 2.0 Hz); 13C NMR (CDCl3)
δ 51.7, 55.3, 56.1, 74.4, 82.1, 111.8, 111.9, 114.1, 116.3, 118.8,
120.3, 129.2, 131.7, 133.0, 137.7, 158.9, 159.5, 165.8, 169.6.
Anal. Calcd for C19H19NO5: C, 66.85; H, 5.61; N, 4.10. Found:
C, 66.70; H, 5.61; 3.94.
Meth yl (4S,5S)-2-(o-m eth oxyph en yl)-5-(m-n itr oph en yl)-
cis-2-oxa zolin e-4-ca r boxyla te (cis-8b): colorless needles
(benzene-hexane); mp 115.2-117.3 °C; [R]25 ) +254.1° (c
D
0.51, CHCl3), >98% ee after recrystallization; IR (KBr) 1741,
1648, 1494, 1342, 1318 cm-1; 1H NMR (CDCl3) δ 3.27 (3H, s),
3.99 (3H, s), 5.40 (1H, d, J ) 10.9 Hz), 6.01 (1H, d, J ) 10.9
Hz), 7.01-7.07 (2H, m), 7.49-7.57 (2H, m), 7.69 (1H, d, J )
7.6 Hz), 7.87 (1H, d, J ) 7.9 Hz, 8.19 (1H, dt, J ) 7.9, 1.0 Hz),
8.37 (1H, s); 13C NMR (CDCl3) δ 51.9, 56.1, 74.3, 81.1, 111.8,
115.9, 120.5, 121.6, 123.5, 129.2, 131.7, 132.4, 133.3, 138.7,
148.2, 158.9, 166.0, 169.0. Anal. Calcd for C18H16N2O6: C,
60.67; H, 4.53; 7.86. Found: C, 60.89; H, 4.62; N, 7.86.
Meth yl (4S,5S)-2-(p-m eth oxyp h en yl)-5-(m -ch lor op h en -
yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-9a ): colorless needles
(benzene-hexane); mp 87.5-89.8 °C; [R]20D ) +202.2° (c 0.51,
CHCl3), 78% ee after recrystallization; IR (KBr) 1739, 1656
Although a small amount of trans products could not be
isolated purely or did not give satisfactry analytical data after
separation by chromatograpy, these products could be char-
1
acterized by H NMR.
Meth yl 2-(o-m eth oxyp h en yl)-5-p h en yl-tr a n s-2-oxa zo-
lin e-4-ca r boxyla te (tr a n s-2b): pale yellow viscous oil; IR
(KBr) 1739, 1628, 1599, 1465, 1437, 1348, 1259, 1124, 1095,
1042, and 751 cm-1; 1H NMR (CDCl3) δ 3.85 (3H, s), 3.88 (3H,
s), 4.84 (1H, d, J ) 7.6 Hz), 5.85 (1H, d, J ) 7.6 Hz), 6.98-
7.03 (2H, m), 7.34-7.51 (6H, m), 7.86-7.89 (1H, m).
Meth yl 2-(3,4,5-tr im eth oxyp h en yl)-5-p h en yl-tr a n s-2-
oxa zolin e-4-ca r boxyla te (tr a n s-2c): pale yellow viscous oil;
1H NMR (CDCl3) δ 3.86 (3H, s), 3.91 (9H, s), 4.81 (1H, d, J )
7.6 Hz), 5.88 (1H, d, J ) 7.6 Hz), 7.32 (2H, s), 7.36-7.42 (5H,
m).
Meth yl 2-(2,6-d im eth oxyp h en yl)-5-p h en yl-tr a n s-2-ox-
a zolin e-4-ca r boxyla te (tr a n s-2d ): colorless viscous oil; IR
(KBr) 1741, 1664, 1595, 1477, 1435, 1306, 1257, 1223, 1174,
1113, 1055, 1030, 982, 729, and 700 cm-1; 1H NMR (CDCl3) δ
3.86 (9H, s), 4.83 (1H, d, J ) 7.3 Hz), 5.89 (1H, d, J ) 7.3 Hz),
7.31-7.53 (8H, m).
1
cm-1; H NMR (CDCl3) δ 3.30 (3H, s), 3.88 (3H, s), 5.27 (1H,
d, J ) 10.9 Hz), 5.86 (1H, d, J ) 10.9 Hz), 6.97 (2H, dt, J )
8.9, 2.0 Hz), 7.15-7.30 (4H, m), 8.03 (2H, dt, J ) 8.9, 2.0 Hz);
13C NMR (CDCl3) δ 51.8, 55.5, 74.1, 81.9, 113.9, 119.0, 124.5,
126.4, 128.7, 129.6, 130.6, 134.3, 138.2, 162.8, 166.3, 169.4.
Anal. Calcd for C18H16NO4Cl: C, 62.52; H, 4.66; N, 4.05.
Found: C, 62.65; H, 4.68; 4.04.
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-(m -ch lor op h en -
yl)-cis-2-oxa zolin e-4-ca r boxyla te (cis-9b): colorless needles
(benzene-hexane); mp 86.8-89.8 °C; [R]25D ) +214.9° (c 0.51,
CHCl3), >98% ee after recrystallization; IR (KBr) 1741, 1648
Meth yl 2-(o-m eth oxyp h en yl)-5-(p-n itr op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-3b): yellow viscous oil; IR
(neat) 2949, 2841, 1736, 1639, 1602, 1519, 1492, 1464, 1435,
1
cm-1; H NMR (CDCl3) δ 3.29 (3H, s), 3.96 (3H, s), 5.43 (1H,
d, J ) 10.9 Hz), 5.87 (1H, d, J ) 10.9 Hz), 7.01-7.05 (2H, m),
7.22-7.31 (3H, m), 7.45 (1H, s), 7.50 (1H, ddd, J ) 8.3, 7.6,
1.7 Hz), 7.87 (1H, dd, J ) 7.9, 2.0 Hz); 13C NMR (CDCl3) δ
51.8, 56.0, 74.4, 81.5, 111.8, 116.2, 120.4, 124.6, 126.6, 128.6,
129.4, 124.6, 126.6, 128.6, 129.4, 131.7, 133.1, 134.3, 138.3,
158.9, 165.8, 169.2. Anal. Calcd for C18H16NO4Cl: C, 62.52;
H, 4.66; N, 4.05. Found: C, 62.51; H, 4.66; N, 4.05.
1
1347, 1259, 1181, 1123, 1043, 1020, 885, 755 cm-1; H NMR
(CDCl3) δ 3.89 (3H, s), 3.95 (3H, s), 4.79 (1H, d, J ) 7.6 Hz),
5.96 (1H, d, J ) 7.6 Hz), 7.00-7.06 (2H, m), 7.51 (1H, t, J )
8.6 Hz), 7.64 (2H, d, J ) 8.9 Hz), 7.88 (1H, dd, J ) 7.9, 1.7
Hz), 8.26 (2H, d, J ) 8.9 Hz).
Meth yl 2-(3,4,5-tr im eth oxyp h en yl)-5-(p-n itr op h en yl)-
tr a n s-2-oxa zolin e-4-ca r boxyla te (tr a n s-3c): yellow solid;
IR (KBr) 2941, 1717, 1652, 1588, 1557, 1523, 1504, 1464, 1417,
1366, 1348, 1286, 1249, 1234, 1173, 1129, 1099, 1005, 847, 741
Meth yl (4S,5S)-2-(p-m eth oxyp h en yl)-5-(m -tolyl)-cis-ox-
a zolin e-4-ca r boxyla te (cis-10a ): colorless prisms (benzene-
hexane); mp 86.4-88.9 °C; [R]24 ) +149.9° (c 0.49, CHCl3),
D
cm-1; H NMR (CDCl3) δ 3.90 (3H, s), 3.92 (9H, s), 4.76 (1H,
1
1
64% ee after recrystallization; IR (KBr) 1754, 1642 cm-1; H
NMR (CDCl3) δ 2.33 (3H, s), 3.24 (3H, s), 3.87 (3H, s), 5.26
(1H, d, J ) 10.9 Hz), 5.86 (1H, d, J ) 10.9 Hz), 6.96 (2H, dt,
J ) 8.9, 2.0 Hz), 7.06-7.12 (3H, m), 7.19-7.25 (1H, m), 8.04
(2H, dt, J ) 8.9, 2.0 Hz); 13C NMR (CDCl3) δ 21.4, 51.6, 55.4,
74.1, 82.9, 113.9, 119.4, 123.4, 126.9, 128.1, 129.4, 130.6, 136.0,
138.0, 162.7, 166.5, 169.8. Anal. Calcd for C19H19NO4: C, 70.14;
H, 5.89; N, 4.30. Found: C, 70.35; H, 5.95; N, 4.32.
d, J ) 7.6 Hz), 5.99 (1H, d, J ) 7.6 Hz), 7.31 (2H, s), 7.58 (2H,
d, J ) 8.6 Hz), 8.28 (2H, d, J ) 8.6 Hz).
Meth yl 2-(o-m eth oxyp h en yl)-5-(p-ch lor op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-4b): pale yellow viscous
1
oil; H NMR (CDCl3) δ 3.85 (3H, s), 3.93 (3H, s), 4.78 (1H, d,
J ) 7.6 Hz), 5.82 (1H, d, J ) 7.6 Hz), 6.99-7.04 (2H, m), 7.37
(4H, s), 7.45-7.51 (1H, m), 7.86 (1H, dd, J ) 8.0, 1.7 Hz).
Meth yl 2-(o-m eth oxyp h en yl)-5-(p-cya n op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-5b): pale yellow viscous
Meth yl (4S,5S)-2-(o-m eth oxyp h en yl)-5-(m -tolyl)-cis-2-
oxa zolin e-4-ca r boxyla te (cis-10b): yellow viscous oil; [R]20
D

Enantioselective Synthesis of 2-Oxazoline-4-carboxylates
J . Org. Chem., Vol. 64, No. 19, 1999 7047
1
oil; H NMR (CDCl3) δ 3.88 (3H, s), 3.95 (3H, s), 4.72 (1H, d,
Meth yl 2-(p-m eth oxyp h en yl)-5-(m -tolyl)-tr a n s-2-oxa zo-
lin e-4-ca r boxyla te (tr a n s-10a ): pale yellow viscous oil; H
NMR (CDCl3) δ 2.36 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 4.78
(1H, d, J ) 7.6 Hz), 5.83 (1H, d, J ) 7.6 Hz), 6.94 (2H, dt, J )
8.9, 2.0 Hz), 7.14-7.30 (4H, m), 8.01 (2H, dt, J ) 8.9, 2.0 Hz).
1
J ) 7.6 Hz), 5.89 (1H, d, J ) 7.6 Hz), 6.92-7.09 (2H, m), 7.42-
7.73 (5H, m), 7.84 (1H, d, J ) 8.3 Hz).
Meth yl 2-(3,4,5-tr im eth oxyp h en yl)-5-(p-cya n op h en yl)-
tr a n s-2-oxa zolin e-4-ca r boxyla te (tr a n s-5c): pale yellow
solid; IR (KBr) 2947, 2228, 1731, 1645, 1588, 1506, 1468, 1442,
Meth yl 2-(o-m eth oxyp h en y)-5-(m -tolyl)-tr a n s-2-oxa zo-
lin e-4-ca r boxyla te (tr a n s-10b): yellow viscous oil; IR (neat)
2949, 1740, 1637, 1601, 1579, 1491, 1462, 1435, 1366, 1320,
1416, 1376, 1346, 1232, 1183, 1133, 1098, 1006, 992, 851 cm-1
;
1H NMR (CDCl3) δ 3.89 (3H, s), 3.92 (9H, s), 4.75 (1H, d, J )
7.6 Hz), 5.89 (1H, d, J ) 7.6 Hz), 7.30 (2H, s), 7.51 (2H, d, J
) 8.3 Hz), 7.71 (2H, d, J ) 8.3 Hz).
1261, 1180, 1123, 1081, 1044, 1022, 984, 792, 757, 701 cm-1
;
1H NMR (CDCl3) δ 2.37 (3H, s), 3.85 (3H, s), 3.93 (3H, s), 4.83
(1H, d, J ) 7.6 Hz), 5.81 (1H, d, J ) 7.6 Hz), 6.98-7.03 (2H,
m), 7.14-7.30 (4H, m), 7.47 (1H, ddd, J ) 7.9, 5.6, 2.0 Hz),
7.87 (1H, dd, J ) 7.9, 2.0 Hz).
Meth yl 2-(o-m eth oxyp h en yl)-5-(p-tolyl)-tr a n s-2-oxa zo-
lin e-4-ca r boxyla te (tr a n s-6b): pale yellow viscous oil; IR
(neat) 2949, 1738, 1636, 1601, 1580, 1515, 1495, 1463, 1435,
1324, 1261, 1181, 1123, 1081, 1044, 1022, 983, 917, 757, 732
Met h yl 2-(p -m et h oxyp h en yl)-5-(m -m et h oxyp h en yl)-
tr a n s-2-oxa zolin e-4-ca r boxyla te (tr a n s-11a ): pale yellow
cm-1; H NMR (CDCl3) δ 2.36 (3H,s), 3.84 (3H, s), 3.93 (3H,
1
s), 4.82 (1H, d, J ) 7.6 Hz), 5.80 (1H, d, J ) 7.6 Hz), 6.97-
7.02 (2H, m), 7.20 (2H, d, J ) 7.9 Hz), 7.31 (2H, d, J ) 7.9
Hz), 7.43-7.50 (1H, m), 7.86 (1H, dd, J ) 7.9, 2.0 Hz).
1
viscous oil; H NMR (CDCl3) δ 3.81 (3H, s), 3.85 (3H, s), 3.87
(3H, s), 4.79 (1H, d, J ) 7.6 Hz), 5.84 (1H, d, J ) 7.6 Hz),
6.86-6.98 (5H, m), 7.26-7.31 (1H, m),8.01 (2H, d, J ) 8.9 Hz).
Meth yl
2-(o-m eth oxyp h en yl)-5-(p-m eth oxyp h en yl)-
Met h yl 2-(o-m et h oxyp h en yl)-5-(m -m et h oxyp h en yl)-
tr a n s-2-oxa zolin e-4-ca r boxyla te (tr a n s-11b): pale yellow
tr a n s-2-oxa zolin e-4-ca r boxyla te (tr a n s-7b): yellow viscous
oil; IR (neat) 2951, 1741, 1637, 1582, 1514, 1493, 1462, 1435,
1
viscous oil; H NMR (CDCl3) δ 3.81 (3H, s), 3.85 (3H, s), 3.93
1327, 1251, 1178, 1123, 1081, 1042, 982, 832, 757 cm-1 1H
;
(3H, s), 4.83 (1H, d, J ) 7.6 Hz), 5.82 (1H, d, J ) 7.6 hz), 6.86-
NMR (CDCl3) δ 3.81 (3H, s), 3.84 (3H, s), 3.92 (3H, s), 4.83
(1H, d, J ) 7.3 Hz), 5.79 (1H, d, J ) 7.3 Hz), 6.92 (2H, d, J )
7.9 Hz), 6.97-7.00 (2H, m), 7.35 (2H, d, J ) 7.9 Hz), 7.46 (1H,
t, J ) 7.9 Hz), 7.85 (1H, d, J ) 7.9 Hz).
7.50 (7H, m), 7.81-7.89 (1H, m).
Con ver sion of 2-Oxa zolin e cis-2a to th r eo-P h en ylser in .
A solution of 2-oxazoline cis-2a (0.162 g, 0.520 mmol) and
triethylamine (1.05 g, 1.45 mL, 10.4 mmol) in MeCN was
heated under reflux for 45 h. After the solvent was removed
under reduced pressure, the residue was chromatographed
over silica gel using hexanes-ethyl acetate (9:1 vol /vol) as
eluent to give 2-oxazoline tr a n s-2a (0.118 g, 73%, 70% ee by
HPLC analysis). A solution of the resulting trans-2a (0.116 g,
0.373 mmol) in concentrated HCl (2 mL) and MeOH (2 mL)
was heated at 50 °C for 6 h and in 6 M HCl at 80 °C for 14 h
and then 100 °C for 5 h. After extraction of the mixture with
ethyl acetate (30 mL), the water layer was evaporated in vacuo.
The residue was treated through Amberlite IRA-120B (H+) to
Meth yl 2-(p-m eth oxyp h en yl)-5-(m -n itr op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-8a ): yellow viscous oil; IR
(neat) 2952, 1735, 1637, 1608, 1576, 1526, 1509, 1480, 1457,
1436, 1421, 1350, 1256, 1207, 1171, 1080, 1027, 842, 738, 686
cm-1; H NMR (CDCl3) δ 3.88 (3H, s), 3.89 (3H, s), 4.77 (1H,
1
d, J ) 7.6 Hz), 5.97 (1H, d, J ) 7.6 Hz), 6.96 (2H, dt, J ) 8.0,
2.0 Hz), 7.59 (1H, t, J ) 7.9 Hz), 7.74 (1H, d, J ) 7.9 Hz), 8.02
(2H, dt, J ) 8.9, 2.0 Hz), 8.22 (1H, ddd, J ) 7.9, 2.3, 1.0 Hz),
8.27 (1H, t, J ) 2.3 Hz).
Meth yl 2-(o-m eth oxyp h en yl)-5-(m -n itr op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-8b): pale yellow viscous
oil; IR (neat) 2951, 1735, 1639, 1601, 1581, 1528, 1490, 1464,
1435, 1351, 1317, 1251, 1180, 1123, 1078, 1043, 1021, 994, 757,
give threo-phenylserin (0.034 mg, 50%, [R]18 ) +29.9° (c 2.0,
D
6 N HCl)).
733, 695 cm-1; H NMR (CDCl3) δ 3.90 (3H, s), 3.99 (3H, s),
1
Ack n ow led gm en t. We gratefully acknowledge the
assistance of Mr. T. Tomita of Mitsubishi Gas Chemical
Corp. and the generous supply of chiral BINOL. The
authors are gratful to Mr. Hiroshi Moriguchi, Faculty
of Engineering, Osaka University, for obtaining mass
spectra. Those works were supported by a Grant-in-Aid
for Science Research (No. 07740499) from the Ministry
of Education, Science and Culture, J apan. We also wish
to express special thanks to Professor Akikazu Kakehi
and Professor Suketaka Ito (Shinshu University) for
useful comments and suggestions.
4.79 (1H, d, J ) 7.3 Hz), 5.98 (1H, d, J ) 7.3 Hz), 7.00-7.06
(2H, m), 7.51 (1H, d, J ) 7.9 Hz), 7.60 (1H, t, J ) 7.9 Hz),7.77
(1H, d, J ) 7.6 Hz), 7.85 (1H, d, J ) 7.9 Hz), 8.22 (1H, d, J )
8.3 Hz), 8.43 (1H, s).
Meth yl 2-(p-m eth oxyp h en y)-5-(m -ch lor op h en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-9a ): pale yellow viscous
oil; IR (neat) 2950, 1734, 1636, 1608, 1575, 1510, 1476, 1457,
1435, 1421, 1309, 1256, 1204, 1170, 1080, 1027, 1009, 990, 841,
789, 741, 691 cm-1; 1H NMR (CDCl3) δ 3.87 (6H, s), 4.75 (1H,
d, J ) 7.6 Hz), 5.84 (1H, d, J ) 7.6 Hz), 6.95 (2H, dt, J ) 8.6
Hz), 7.26-7.37 (4H, m), 8.01 (2H, dt, J ) 8.6 Hz).
Meth yl 2-(o-m eth oxyph en yl)-5-(m-ch lor oph en yl)-tr a n s-
2-oxa zolin e-4-ca r boxyla te (tr a n s-9b): pale yellow viscous
oil; IR (neat) 2950, 1739, 1637, 1600, 1575, 1492, 1464, 1434,
1259, 1224, 1205, 1181, 1123, 1080, 1043, 1023, 990, 789, 755,
Su p p or t in g In for m a t ion Ava ila b le: Copies of 1H and
13C NMR spectra of new cis-2-oxazoline-4-carboxylates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
694 cm-1; H NMR (CDCl3) δ 3.87 (3H, s), 3.95 (3H, s), 4.78
(1H, d, J ) 7.3 Hz), 5.83 (1H, d, J ) 7.3 Hz), 6.99-7.04 (2H,
m), 7.27-7.34 (3H, m), 7.46-7.52 (2H, m), 7.85 (1H, dd, J )
7.9, 2.0 Hz).
J O990525D