The effects of lewis acid on the 1,3-dipolar cycloaddition reaction of C-arylaldonitrones with alkenes

Article abstract of DOI:10.1248/cpb.50.908

The regio- and stereoselectivity of the 1,3-dipolar cycloaddition reactions of C-aryl-N-alkylaldonitrones (1a-e) with some alkenes were found to be affected significantly by the addition of Lewis acid. The rate of the reaction was also affected by adding the Lewis acid. In the reactions using allyl alcohol as a dipolarophile an addition of Lewis acid caused a remarkable acceleration of the reaction and a great change in the stereoselectivity. In the reactions using ethyl acrylate as a dipolarophile the regioselectivity was reversed whether the reaction was performed in the presence or the absence of Lewis acid; i.e. isoxazolidine-5-carboxylates were obtained mainly in the absence of Lewis acid although isoxazolidine-4-carboxylates were obtained mainly in the presence of Lewis acid. When the reaction of C,N-diarylaldonitrones (1k, 1m, 1n) with ethyl acrylate was carried out in the presence of Lewis acid, the cleavage of the N-O bond of the cycloadducts giving γ-aminoalcohols was also observed besides a reverse phenomenon of regioselectivity.

Full text of DOI:10.1248/cpb.50.908

908
Chem. Pharm. Bull. 50(7) 908—921 (2002)
Vol. 50, No. 7
The Effects of Lewis Acid on the 1,3-Dipolar Cycloaddition Reaction of
C-Arylaldonitrones with Alkenes
Tomio SHIMIZU,* Masaya ISHIZAKI, and Nobuo NITADA
Kyoto Institute of Technology, Faculty of Engineering, Materials Science; Matsugasaki, Sakyo-ku, Kyoto 606–8585, Japan.
Received January 31, 2002; accepted April 10, 2002
The regio- and stereoselectivity of the 1,3-dipolar cycloaddition reactions of C-aryl-N-alkylaldonitrones
(1a—e) with some alkenes were found to be affected significantly by the addition of Lewis acid. The rate of the
reaction was also affected by adding the Lewis acid. In the reactions using allyl alcohol as a dipolarophile an ad-
dition of Lewis acid caused a remarkable acceleration of the reaction and a great change in the stereoselectivity.
In the reactions using ethyl acrylate as a dipolarophile the regioselectivity was reversed whether the reaction was
performed in the presence or the absence of Lewis acid; i.e. isoxazolidine-5-carboxylates were obtained mainly in
the absence of Lewis acid although isoxazolidine-4-carboxylates were obtained mainly in the presence of Lewis
acid. When the reaction of C,N-diarylaldonitrones (1k, 1m, 1n) with ethyl acrylate was carried out in the pres-
ence of Lewis acid, the cleavage of the N–O bond of the cycloadducts giving g-aminoalcohols was also observed
besides a reverse phenomenon of regioselectivity.
Key words cycloaddition; nitrone; Lewis acid; regioselectivity; stereoselectivity
and regioselectively by introducing Lewis acid (see Chart 131)
1,3-Dipolar cycloaddition reaction has been known to be
and 236)). The Lewis acid can complexed with both the ni-
one of useful methods for the synthesis of five-membered
heterocycles.1—3) Some five-membered heterocyclic rings
trone and the dipolarophile in the reaction shown in Chart
1.31) Two transition states shown in the Chart may be re-
found in the structure of natural products has been built up
directly by the reaction.3,4) Though several dipoles other than
garded as significant. Diastereoselectivity of the reaction has
nitrones have been used for the synthesis of natural products,
nitrones have been found to have wide applications.4) Some
functional groups found in the structure of natural products
have been known to be prepared all at once by ring-opening
reaction of the cycloadducts.5—21)
been well explained on the basis of the difference of steric
hindrance in the two transition states. The benzoyl group of
C-benzoylnitrone has an influence on the regioselectivity of
the cycloaddition reaction shown in Chart 2.36)
In these examples shown above, Lewis acid can also inter-
act with several functional groups other than oxygen atom of
nitrone group. In this study, we investigated some effects of
Lewis acids on the reaction of nitrone that substituted with
two hydrocarbon groups (inert group to Lewis acid) with
dipolarophile that substituted with one functional group (ac-
tive group to Lewis acid). Concretely, C,N-diaryl- and N-
alkyl-C-arylaldonitrones were chosen for the substrate. C-
Alkylaldonitrones were not chosen because of the thermoin-
stability. Results from the C,N-diaryllnitrones were quite dif-
ferent from those from C-aryl-N-alkylnitrones by appear-
ance, though the exact nature of the two reactions is the
same.
The structure and stereochemistry of the cycloadducts de-
pend largely on electronic nature of dipole and dipolarophile
because 1,3-dipolar cycloaddition reaction is one of repre-
sentative concerted reactions.1—3) Total synthesis of natural
product has been effectively achieved by using 1,3-dipolar
cycloaddition that shows high selectivity in stereo-, regio-,
and diastereoselectivity. Some Diels–Alder reactions have
been known to be speeded up and to proceed stereo- and re-
gioselectively by adding Lewis acid.22—24) On the other hand,
another situation occurs in 1,3-dipolar cycloaddition reaction
because 1,3-dipoles show zwitter ionic character. Most 1,3-
dipoles have been known to react with Lewis acid to give sta-
ble ionic salts and, consequently, any cycloaddition reaction
was not observed. On the other hand, a few 1,3-dipoles have
been known to react with Lewis acid to give unstable ionic
salts that exhibit 1,3-dipolar nature and undergo high selec-
tive cycloaddition reaction with dipolarophiles.25—41) Some
1,3-dipolar cycloaddition reactions of nitrones and alkenes
have been known to be speeded up and to proceed stereo-
Results and Discussions
1,3-Dipolar Cycloaddition Reaction of N-Alkyl-C-aryl-
nitrones with Dipolarophiles in the Absence of Lewis
Acid The reaction of N-benzyl-C-phenylnitrone (1a) with a
variety of mono- and 1,1-disubstituted alkenes (2A—P) was
carried out under various conditions and the results ware
Chart 1. Titanium Catalyzed Nitrone–Alkene Cycloaddition31)
To whom correspondence should be addressed. e-mail: shimizu@chem.kit.ac.jp
© 2002 Pharmaceutical Society of Japan

July 2002
909
Chart 2. Lewis Acid Catalyzed Cycloaddition of C-Benzoylnitrone and Allyl Alcohol36)
Chart 3. 1,3-Dipolar Cycloaddition Reaction of Nitrone (1a) with Dipolarophiles (2A—P)
Table 1. 1,3-Dipolar Cycloaddition Reaction of 1a with Dipolarophiles (2)
Dipolarophilea)
R1
Reaction conditions
Time
Total
yields of
adducts
Ratio of
adducts
3 : 3؅ : 4 : 4؅
Run
No.
Recovery
of 1a
2
R2
Solventb)
Additivec)
None
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
ZnBr2
ZnCl2
TiCl4
BF3·Et2O
None
MgBr2·Et2O
None
None
None
None
None
MgBr2·Et2O
MgBr2·Et2O
MgBr2·Et2O
ZnBr2
None
None
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
2A
2A
2A
2A
2A
2A
2A
2A
2B
2B
2C
2D
2E
2F
2G
2G
2G
2G
2G
2H
2I
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
CN
Ph
OBu
OAc
CH2Br
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OAc
CH(OH)C3H7
C(OH)(CH3)2
CH2O Allyl
CH2SCH3
C6H13
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Neat
Toluene
Toluene
Toluene
Toluene
Benzene
CCl4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
Benzene
Benzene
7 h
24 h
16 h
16 h
22 h
22 h
48 h
48 h
8 h
24 h
30 h
36 h
34 h
45 h
32 h
2 h
12 h
18 h
24 h
40 h
32 h
60 h
27 h
24 h
96 h
20 h
24 h
22 h
0%
10%
20%
14%
46%
50%
25%
64%
0%
61%
0%
0%
18%
20%
0%
0%
0%
0%
30%
0%
10%
25%
0%
25%
53%
0%
97%
74%
78%
85%
47%
47%
21%
15%
94%
32%
96%
94%
60%
75%
95%
62%
79%
97%
68%
98%
50%
50%
98%
65%
30%
99%
31%
99%
10 : 72 : 4 : 14
6 : 14 : 43 : 37
10 : 14 : 49 : 27
9 : 33 : 39 : 19
8 : 21 : 54 : 17
6 : 27 : 50 : 17
0 : 41 : 35 : 24
0 : 15 : 65 : 20
30 : 34 : 6 : 30
28 : 25 : 15 : 32
76 : 24
63 : 37
62 : 38
70 : 30
62 : 38
22 : 78
24 : 76
23 : 77
36 : 64
66 : 34
60 : 40
60 : 40
66 : 34
75 : 25
73 : 27
65 : 35
52 : 48
2J
None
None
None
None
None
MgBr2·Et2O
None
2K
2L
2M
2N
2N
2P
CH3
CH3
CH3
CO2Et
CO2Et
CN
68%
0%
70 : 30
a) Ten-fold excess of dipolarophile was used. b) All reactions except for run No. 12 were carried out at the refluxing temperature of the solvent. Reaction shown in run No.
12 was carried out at the boiling temperature of the dipolarophile (94 °C). c) All reactions using Lewis acid were carried out under nitrogen atmosphere. An equimolar amount of
Lewis acid and nitrone was used in all cases except for runs No. 3 and 4. In runs No. 3 and 4, the Lewis acid was used twice and 0.3, respectively, as much as nitrone.
summarized in Chart 3 and Table 1. All four possible cy- one regioisomer, 5-substituted isoxazolidines, was observed
cloadducts (3, 3؅, 4, 4؅), two regioisomers and the two in reactions using the other types of alkenes (2C—P) as a
stereoisomers, were obtained from the reactions using elec- dipolarophile. Any reaction was not observed in the treat-
tron-deficient alkenes such as ethyl acrylates (2A) and acry- ment of 1a with isopropenyl acetate (2Q) and methyl iso-
lonitrile (2B). On the other hand, an exclusive formation of propenyl ether (2R) at the temperature below 110 °C.

910
Vol. 50, No. 7
The structure of the cycloadducts was established as Hd) at 4-position of exo and endo cycloadducts of 1a and
below. C-Aryl-N-methylnitrone has been known to react with alkenes (2A—G) were shown in Table 2 along with the value
styrene or the other monosubstituted alkenes to give 5-substi- of the differences (HbϪHa, HdϪHc) between the chemical
tuted isoxazolidines regioselectively43,51) (see Chart 451)). The shifts. Determination of the stereochemistry of the cy-
structures of major and minor products of the reaction have cloadducts (3, 3؅) could be easily made by the comparison of
been known to be cis- and trans-3,5-disubstituted isoxazo- the differences between the chemical shifts of the methylene
lidines (3 and 3؅), respectively, on the basis of the analyses of protons at the ring of the two isomers. The structures of cis-
1
the H-NMR spectra51): though, in cis-isomer, the magnetic and trans-3,4-disubstituted isoxazolidines (4, 4؅) were also
environment of one proton (Ha) at 4-position of the isoxazo- established on the basis of the analyses of the 1H-NMR spec-
lidines is quite different from that of the other proton (Hb) at tra. Regioisomers (4, 4؅) are easily distinguishable from the
the same position of the ring, those of the corresponding two other regioisomers (3, 3؅) by comparison the coupling pat-
protons (Hc, Hd) of trans-isomer resemble each other. In terns of the ring protons of them. Determination of the ster-
other words, the difference in the chemical shift of the two eochemistry of the cycloadducts (4aA, 4؅aA) could be easily
protons (Ha, Hb) in cis-isomer (3) is larger than those in made from the chemical shifts of the ethyl group in the ester
trans-isomer (3؅). The major formation of cis-isomer (3) can group at 4-position of isoxazolidine ring. The ester group of
be explained as a result of sterically unhindered exo attack of the cycloadduct (4aA) is in cis relationship with neighboring
the two substrates in the transition state of the reaction (see phenyl group and, consequently, the former group suffers a
Chart 5).
The chemical shifts of methylene protons (Ha, Hb, Hc,
Chart 4. Authorized Structures of Nitrone–Alkene Cycloadducts
Chart 5. Two Possible Alkene’s Approaches to Nitrone (1a); (bulkiness of
R1 and R2: R1ϾR2)
Chemical shifts of the ring protons (HaϪHd) were shown in the parentheses at d
unit.51)
Table 2. Chemical Shifts of Ring Protons (Ha–Hd) of 2,3,5-Trisubstituted Isoxazolidine 3 and 3Ј
Compound
Substituent
cis-3, ppm
trans-3؅, ppm
Ar
R
R1
No.
Ha
Hb
D(HbϪHa)
No.
Hc
Hd
D(HdϪHc)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
CH3
Bn
Bn
Bn
Bn
CO2Et
CN
Ph
OBu
OAc
CH2Br
3aA 2.65 (ddd)
3aB 2.62 (ddd)
3aC 2.43 (dt)
3aD 2.31 (ddd)
3aE 2.41 (ddd)
3aF 2.23 (dt)
3aG 2.25 (dt)
3bG 2.26 (ddd)
3cG 2.04 (ddd)
3dG 2.36 (ddd)
3eG 2.06 (ddd)
2.99 (ddd)
3.08 (ddd)
3.15 (dt)
2.89 (ddd)
3.04 (ddd)
2.92 (dt)
2.79 (dt)
2.75 (ddd)
2.80 (dt)
2.82 (dt)
2.80 (dt)
0.34
0.46
0.72
0.58
0.63
0.69
0.54
0.49
0.76
0.46
0.74
0.43
0.32
3؅aA 2.71 (dt)
3؅aB 2.79 (dt)
3ЈaC 2.60 (ddd)
3؅aD 2.46 (ddd)
3؅aE 2.63 (dd)
3ЈaF 2.51 (dt)
3؅aG 2.37 (dt)
3؅bG 2.37 (dt)
2.78 (ddd)
2.99 (ddd)
2.75 (dt)
2.64 (ddd)
2.63 (dd)
2.57 (ddd)
2.55 (ddd)
2.50 (ddd)
0.07
0.20
0.15
0.18
0.00
0.06
0.18
0.13
0.29
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OH
CH2OAc
CH(OH)Pr
C(OH)Me2
CH2O-Allyl
CH2SCH3
C6H13-n
CO2Et
o-Tol
2-Naphthyl
o-Anisyl
2-Pyridyl
6-Me-2-pyridyl CH3
2-Quinolyl
2-Furyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3؅bG 2.18—2.33 (m) 2.55 (ddd)
3؅cG 2.43—2.53 (m) 2.55—2.65 (m)
0.12
3؅dG
3؅fG
3؅gG
3؅hG
2.51—2.60 (m, 2H)
2.46—2.78 (m, 2H)
2.50—2.70 (m, 2H)
2.63—2.75 (m, 2H)
Ͻ0.1
ca. 0.15
ca. 0.1
Ͻ0.1
0.17
0.00
0.13
0.11
0.13
Ͻ0.1
0.18
0.26
0.20
0.25
3gG 2.36—2.48 (m) 2.85(dt)
3hG 2.50—2.53 (m) 2.83 (dt)
3iG 2.40—2.60 (m) 2.91 (dt)
CH3
CH3
Bn
Bn
Bn
Bn
Bn
Bn
Ph
0.41
a)
a)
a)
3jG
3aH 2.00—2.10 (m) 2.83 (dt)
3؅iG 2.34—2.50 (m) 2.53—2.64 (m)
0.78
0.56
0.38
0.74
0.72
0.79
0.35
0.37
0.36
3؅aH 2.41 (t)
3؅aI 2.36 (dt)
3ЈaJ 2.56 (ddd)
3؅aK 2.38 (dt)
2.41 (t)
2.45—2.53 (m)
2.67 (dt)
3aI
3aJ
2.23 (ddd)
2.23 (dt)
2.79 (dt)
2.56—2.65 (m)
2.78 (dt)
2.88 (dt)
2.78 (dt)
3.06 (dt)
3.04 (dt)
3.07 (dt)
3aK 2.16 (ddd)
3aL 2.16 (ddd)
3aM 2.04 (ddd)
3kA 2.71 (dt)
3mA 2.67 (dt)
3nA 2.71 (dt)
2.51 (ddd))
3؅aL
2.45—2.50 (m, 2H)
3؅aM 2.18 (ddd)
3؅kA 2.69 (ddd)
3؅mA 2.71 (ddd)
3؅nA 2.69 (dt)
2.36 (dt)
2.95 (ddd)
2.91 (ddd)
2.94 (ddd)
Tol-p CO2Et
Cl-Ph CO2Et
a) This compound was not obtained.

July 2002
911
Chart 6. Functional Group Transformations for Structure Elucidation of the Cycloadducts (3؅aA, 3؅aB, 3؅aG)
shielding effect of the latter group. The methylene protons of
the ester group of 4aA appears at d 3.70 ppm though those of
4؅aA at d 4.26 ppm. Major product from the reaction of N-
methylnitrone (1b) with ethyl acrylate (2A) has been re-
ported to be not 3؅A but 3A.49) The result differs from our
one. Therefore, a reduction was carried out to the major
product with a view to obtaining definite information on the
structure. Our elucidation was found to be correct from the
evidence that the spectra of the reduction product were fully
consistent with those of cis-2-benzyl-5-(hydroxymethyl)-3-
phenylisoxazolidine (3؅aG) that obtained form the reaction
of 1a with allyl alcohol (2G) (see Chart 6).
The structures of cycloadducts (3aB, 3؅aB, 4aB, 4ЈaB)
from acrylonitrile (2B) were deduced from the comparison of
1
their H-NMR spectra with those of 3aA, 3؅aA, 4aA, and
4؅aA, respectively. To make sure of the structures of cy-
cloadducts from acrylonitrile a functional group transforma-
Chart 7. Interaction Scheme of Nitrone (1a) with Alkenes (2A—M)
tion of cyano group into ester group was also done. The
structure of cycloadducts (3aN, 3؅aN) from ethyl methacry-
late (2N) was decided tentatively by considering the cycload-
dition reaction mechanistically as shown below.
The formation of four cycloadducts, i.e., two regioisomers
and two stereoisomers, may be supposed for the 1,3-dipolar
cycloaddition reaction of nitrone (1a) with monosubstituted
alkenes or 1,1-unsymmetrically disubstituted alkenes. Though
one regioisomer, 5-monosubstituted or 5,5-unsymmetrically
Chart 8. Reaction of N-Methylnitrone (1b—j) with Allyl Alcohol (2G)
disubstituted isoxazolidine (3aC—3aP, 3؅aC—3؅aP), was son with that of 2C—2M. The former reaction leads 4-sub-
formed exclusively in many reactions (runs No. 11—15, stituted isoxazolidines (4aA, 4؅aA) and the latter one leads
20—26, 28) summarized in Table 1, a formation of a small 5-substituted isoxazolidines (3aA, 3ЈaA) (see Chart 7). Tak-
amount of the other regioisomer, 4-substituted isoxazolidine ing into account of steric factor shown in Chart 5, 3aA may
(4aA, 4؅aA, 4aB, 4؅aB), was also observed in the reaction be supposed to be formed mainly. But the endo-adduct
with electron-deficient alkenes such as acrylate (2A) and (3؅aA) was generated in an amount larger than exo-adducts
acrylonitrile (2B) (runs No. 1, 9). These results are consistent (3aA). This result can be explained as a result of secondary
with previous studies on 1,3-dipolar cycloaddition reaction orbital interaction between the ester group with the nitrogen
of nitrone.1—3,42—50)
atom of nitrone group (see run No. 1 in Table 1).
The formation and the ratio of two stereoisomers can be
The results of the reaction of 1a with ethyl methacrylate
explained on the basis of both electronic and steric factors as (2N) can be explained as follows. LUMO of methacrylate
follows. Aldonitrones such as 1a have been known to be sta- (2N) is higher than that of acrylate (2A) and, consequently, a
ble in Z-configuration.1—3,42—50,52) Monosubstituted alkenes dipole-HOMO/dipolarophile-LUMO controlled reaction
such as 2C—M have been known to have relatively high hardly occurs. Thus, 4N and 4؅N were not obtained from the
HOMO and to undergo exclusively a dipole-LUMO/dipo- reaction. In the exo transition state of Chart 5, more bulky
larophile-HOMO controlled reaction with the Z-aldonitrone substituent (methyl group) occupies exo position and ester
(1a) (see Chart 7).1—3) Though the reaction proceeds with group occupies endo position in which the secondary orbital
high regioselectivity, the stereoselectivity of the reaction was interaction shown above acts effectively. In the endo transi-
poor one. Transition states leading to two stereoisomers are tion state, two unfavored situations cooperate. Thus, the
shown in Chart 5. Steric repulsion between substituents in amount of exo-adducts (3aN) exceeded that of endo adducts
the exo transition state that leading to cis-3,5-disubstituted (3؅aN).
isoxazolidine (3) is smaller than those in endo transition state
that leading to trans-one (3؅). Consequently, 3 was formed trone (1a) could be estimated from the Table 1 to be 2A, 2B
exclusively (see runs No. 11—15, 20—26, 28). (electron-deficient monosubstituted alkenes)Ͼ2N, 2P (elec-
The order of the reactivity of various alkenes towards ni-
A dipole-HOMO/dipolarophile-LUMO controlled reaction tron-deficient 1,1-disubstituted alkenes)Ͼ2C (alkene substi-
also occurs beside a dipole-LUMO/dipolarophile-HOMO tuted with conjugative group)Ͼ2D (electron-rich alkenes
controlled reaction in cases using 2A and 2B because the en- substituted with powerful electron-donating group)Ͼ2E
ergy level of LUMO of these alkenes is very low in compari- (electron-rich alkenes substituted with weak electron-donat-

912
Vol. 50, No. 7
Table 3. 1,3-Dipolar Cycloaddition Reaction of 1b—i with Allyl Alcohol (2G)a,b)
Nitrone
Reaction conditions
Ratio of
adducts
cis-3 : trans-3Ј
Run
No.
Recovery
of 1a
Total yields of
adducts
1
Ar
Time
Additivec)
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
1b
1b
1c
1c
1d
1d
1e
1e
1f
Ph
Ph
o-Tol
o-Tol
2-Naphthyl
2-Naphthyl
o-Anisyl
o-Anisyl
Mesityl
Mesityl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
2-Pyridyl
6-Methyl-2-pyridyl
6-Methyl-2-pyridyl
6-Methyl-2-pyridyl
2-Quinolyl
2-Quinolyl
2-Furyl
24 h
3 h
21 h
6 h
24 h
5 h
22 h
5 h
42 h
2 h
24 h
2 h
24 h
42 h
10 h
21 h
2 h
None
MgBr2·Et2O
None
MgBr2·Et2O
None
MgBr2·Et2O
None
MgBr2·Et2O
None
MgBr2·Et2O
None
MgBr2·Et2O
ZnCl2
ZnBr2
Ti[OC3H7-i]4
None
MgBr2·Et2O
MgBr2·Et2O
None
MgBr2·Et2O
None
MgBr2·Et2O
14%
0%
0%
0%
0%
0%
0%
0%
85%
95%
0%
0%
40%
0%
0%
0%
0%
0%
0%
10%
0%
0%
84%
62%
50%
65%
50%
50%
70%
70%
0%
60 : 40
22 : 78
63 : 37
20 : 80
55 : 45
25 : 75
67 : 33
28 : 72
— : —
— : —
60 : 40
100 : 0
100 : 0
85 : 15
60 : 40
50 : 50
60 : 40d)
100 : 0d)
50 : 50
— : —
0 : 100
0 : 100
1f
0%
1g
1g
1g
1g
1g
1h
1h
1h
1i
60%
80%
35%
65%
80%
70%
50%
60%
20%
0%
8 h
8 h
32 h
40 h
2 h
1i
1j
1j
55%
40%
2-Furyl
a) All reactions were carried out in toluene at the refluxing temperature. b) Ten-fold excess of allyl alcohol was used. c) All reactions using Lewis acid were carried out
under nitrogen atmosphere. An equimolar amounts of Lewis acid and nitrone was used in all catalyzed reactions. d) Trans-isomer (3؅hG) was found to be suffered succeeding
complex reactions and disappeared upon long heationg under the conditions.
ing group)Ͼ2F—M (unactivated alkenes)ϾϾ2Q, 2R (elec-
tron-rich 1,1-disubstituted alkenes). It was found from this
result that nitrone (1a) shows the representative reactivity
known as Sustmann type II.
Many reactions of allyl alcohol (2G) with a variety of N-
methylnitrones (1b—j), of which carbon atom was substi-
tuted with a variety of aryl groups, were also carried out. The
results were summarized in Chart 6 and Table 3. The results
similar to that from 1a were obtained in all cases except for
two nitrones (1f, 1j). In the case of C-mesitylnitrone (1f) the
nitrone was recovered unchanged and this result can be ex-
plained as a result of the steric effect of the bulky mesityl
group, i.e., the coplanarity of mesityl group and nitrone
group was broken by the steric hindrance and, consequently,
the reactivity of the nitrone (1f) was reduced remarkably. In
the case of C-(2-furyl)nitrone (1j) an exclusive formation
Chart 9. Interaction Scheme of Nitrone (1) with Acrylate (2A) in the Pres-
ence of MgBr2
of trans-3-(2-furyl)-5-(hydroxymethyl)-isoxazolidine (3؅jG)
was observed. At present we could not find a reasonable ex-
planation for this result.
Comparing the result from the Lewis acid catalyzed reac-
tion of 1a and ethyl acrylate (2A) with that of uncatalyzed re-
action, two obvious changes were observed (see runs No. 1,
2). One is a retardation of the reaction by adding Lewis acid
and the other is a remarkable change in both the stereoselec-
tivity and the regioselectivity. Isoxazoline-4-carboxylates (4,
4؅) were always the main product in the Lewis acid catalyzed
reactions. The serious retardation of the reaction was ob-
served in cases using Lewis acid other than magnesium bro-
mide. The retardation of the reaction can be explained as fol-
lows. Stable salt, which shows no reactivity toward 2A, was
formed from nitrone (1a) and magnesium bromide at once.
The stable salt is in equiliblium with 1a and free liberated
Lewis acid but the equiliblium constant is so small that the
1,3-Dipolar Cycloaddition Reaction of N-Alkyl-C-aryl-
nitrones with Dipolarophiles in the Presence of Lewis
Acid The reaction of C-aryl-N-alkylnitrone (1a—j) with
alkenes (2A—P) was also carried out in the presence of a va-
riety of Lewis acid under various conditions. In reactions
using allyl alcohol (2G) or ethyl acrylate (2A) as a dipo-
larophile some remarkable changes were observed and the
results were summarized in Table 1 and 3. As a result of em-
ploying some different types of Lewis acid as the catalyst it
was found that magnesium bromide etherate was the most ef-
fective catalyst to cause a dramatic change (see runs No. 2,
5—8, 16, 19). The minimum amount of the catalyst needed
to cause the dramatic change was found to be an equimolar
amount with nitrone (see runs No. 2—4).

July 2002
913
cycloadducts were formed gradually. The major formation of has brought about no improvement in the stereoselectivity
isoxazolidine-4-carboxylates in the Lewis acid catalyzed re- (compare run 30 with runs 32, 34, and 36 in Table 3). At pre-
actions can be explained as a result of nitrone-HOMO/dipo- sent we could not find a reasonable explanation for this re-
larophile-LUMO interaction (see Chart 9). Though the inter- sult.
action is small in the absence of Lewis acid, it is significant
When the phenyl group at the carbon atom of nitrone (1b)
in the presence of Lewis acid because a chelation of Lewis was substituted for heteroaromatic groups, those are capable
acid with carbonyl oxygen atom of acrylate occurs and, con- of chelating with Lewis acid effectively, such as 2-pyridyl, 6-
sequently, an energy level of the LUMO lowered consider- methyl-2-pyridyl, and 2-quinolyl groups, the Z-exo transition
ably.
state shown in Chart 11 may become more favorable one
Comparing the result from the Lewis acid catalyzed reac- than E-exo transition state.37) In fact, the former two nitrones
tion of 1a and allyl alcohol (2G) with that of uncatalyzed re- (1g, 1h) gave cis-cycloadducts (3gG, 3hG) exclusively. On
action, two obvious changes were observed (see runs No. 15, the other hand, owing to the strongness of the chelation be-
16). One is an acceleration of the reaction by adding the tween 2-quinolyl group and Lewis acid, Lewis acid may be
Lewis acid and the other is a remarkable change in the stereo- interacted only with nitrone (1i) to give stable salt and, con-
selectivity. This result may be explained on the basis of the sequently, any cycloaddition reaction with allyl alcohol may
difference of the nitrone’s configuration as follows. Though not be expected (see run 48). However, trans-cycloadduct
the stable configuration of nitrone (1a) has been known to be (3؅jG) was obtained from the catalyzed reaction, that took
Z-form in the absence of Lewis acid, it may be E-form in the place more rapidly than analogous non-catalyzed reaction. It
presence of Lewis acid. The formation of salts between ni- is obvious that Lewis acid acts in the rete-determining step of
trone (1a) and magnesium bromide is apparent by the separa- the reaction but we could not find a reasonable explanation
tion from the benzene solution of sparing soluble precipitate, for this result at present.
from which the nitrone (1a) was recovered quantitatively by
Reactions of nitrone 1a with nine dipolarophiles other
the treatment with aqueous alkaline solution. The salt reacts than acrylate, allyl alcohol and the some derivatives (2A, 2G,
gradually with allyl alcohol to give nitrone-magnesium-allyl 2H—K) were also carried out in the presence of magnesium
alcohol complex, in which magnesium can be ragard as an bromide. In cases of styrene (2C), allyl bromide (2F), allyl
atom that binds E-nitrone and allyl alcohol in the situation methyl sulfid (2L), 1-octene (2M), and methacrylonitrile
like E-exo transition state (see Chart 10).
(2P) both starting materials were recovered unchanged and
Some derivatives of allyl alcohol, such as O-acylated allyl this result may be ascribed mainly to the formation of stable
alcohol (2H), O-allylated allyl alcohol (2K), a-alkylated salt between 1a and magnesium bromide. In cases of electron
allyl alcohols (2I, 2J), and allyl methyl sulfid (2L), were also rich alkenes such as butyl vinyl ether (2D) and vinyl acetate
examined. Though these dipolarophiles behave in a similar (2E) any cycloadducts were not obtained because the Lewis
manner as allyl alcohol (2G) in the absence of Lewis acid, a acid caused the polymerization of the alkenes in preference
quite different behavior was observed in the presence of to cycloaddition with 1a. In cases of acrylonitrile (2B) and
Lewis acid. These dipolarophiles (2H—L) can not form the ethyl methacrylate (2N), minor changes in the regio- and/or
binded exo transition state because the steric hindrance stereoselectivity were observed though the drastic retardation
around the oxygen atom and, consequently, no cycloadduct of the reaction rate was also observed.
was formed. Both substrates were recovered in high yield
from the reaction mixtures.
The Effect of Lewis Acid on 1,3-Dipolar Cycloaddition
Reaction of C,N-Diarylnitrones with Dipolarophiles The
When the phenyl group at the carbon atom of nitrone (1b) reaction of C-phenyl-N-arylnitrones (1k—n) with ethyl acry-
was substituted for more bulky aromatic groups such as 2- late (2A) or ethyl methacrylate (2N) was carried out under
tolyl, 2-naphthyl, and o-anisyl, the E-exo transition state several conditions and the results were summarized in Chart
shown in Chart 10 may become more favorable one than Z- 12 and Table 4. In the absence of Lewis acid the formation of
exo transition state. But the introduction of these aryl groups all or some of four possible cycloadducts (3, 3؅, 4, 4؅) was
Chart 10. Binding Effect of Two Substrates (1a and 2G) by Magnesium Atom
Chart 11. Binding Effect of Two Substrates (1g and 2G) by Magnesium Atom

914
Vol. 50, No. 7
Chart 12. 1,3-Dipolar Cycloaddition Reaction of 1k, 1m, and 1n with 2A or 2N
Table 4. 1,3-Dipolar Cycloaddition Reaction of 1k, 1m, and 1n with 2A or 2Na)
Nitrone
Reaction conditionsb)
Time
Total
yields of
adducts
Ratio of adducts
Run
No.
Ratio of
5- : 4-c)
Alkene 2
1
R
Solvent
Additive
3 : 3؅ : 5 : 4 : 4؅: 6
51
52
51
51
52
51
51
51
52
54
55
56
1k
H
H
CH3
CH3
Cl
Cl
H
H
2A
2A
2A
2A
2A
2A
2N
2N
2N
2N
2N
2N
CHCl3
CHCl3
3 h
6 h
7 h
18 h
3 h
6 h
3 h
24 h
3 h
18 h
9 h
20 h
—
97%
60%
96%
58%
97%
63%
100%
57%
97%
60%
100%
31%d)
26 : 44 : 0 : 14 : 16 :
0 : 0 : 28 : 0 : 32 : 40
0
70 : 30
28 : 72
66 : 34
21 : 79
64 : 36
13 : 87
100 : 0
88 : 12
100 : 0
100 : 0
100 : 0
100 : 0
1k
1m
1m
1n
1n
1k
MgBr2·Et2O
—
MgBr2·Et2O
—
MgBr2·Et2O
—
MgBr2·Et2O
—
Benzene
Benzene
CHCl3
Benzene
CHCl3
Benzene
Benzene
Benzene
Benzene
Benzene
25 : 41 : 0 : 13 : 21 :
0 : 0 : 21 : 0 : 0 : 79
22 : 42 : 0 : 12 : 24 :
0 : 0 : 13 : 0 : 24 : 63
85 : 15 : 0 : 0 : 0 :
0 : 0 : 88 : 12 : 0 :
87 : 13 : 0 : 0 : 0 :
0 : 0 : 100 : 0 : 0 :
88 : 12 : 0 : 0 : 0 :
0 : 0 : 100 : 0 : 0 :
0
0
0
0
0
0
0
0
1k
1m
1m
1n
CH3
CH3
Cl
MgBr2·Et2O
—
MgBr2·Et2O
1n
Cl
a) Molar ratio of nitrone, alkene, and Lewis acid was 1 : 10 : 1. b) All reactions were carried out in the solvent at the refluxing temperature. c) Symbol (5-) shows 5-sub-
stituted isoxazolidine (3, 3؅) and it’s derivatives (5). Symbol (4-) shows 4-substituted isoxazolidine (4, 4؅) and it’s derivatives (6). d ) Compound (8nN) was also obtained in 10%
yield.
tion of N-arylnitrone (1k—n) was slower in the catalyzed re-
action than in the non-catalyzed one.
The generation of g-aminoalcohols (5, 6, 8) can be ex-
plained as a result of a ring-opening reaction of initial cy-
cloadducts, 2,3-diarylisoxazolidines (3, 3؅, 4, 4؅), because
the former compounds were obtained effectively by the treat-
ment of the latter compounds with magnesium bromide (see
Chart 13 and Table 5).
The regioselectivity of the cycloaddition reaction could be
deduced from the comparison of the total amount of isoxazo-
lidine-5-carboxylates and the ring opening products (3, 3؅, 5,
Chart 13. Reaction of 2-Arylisoxazolidines with MgBr2
8) with that of isoxazolidine-4-carboxylates and the ring
opening products (4, 4؅, 6) (see Table 4). In the reaction of
nitrones (1k—n) with ethyl acrylate (2A), two opposite re-
sults in regioselectivity were obtained whether the reaction
was carried out in the presence or the absence of Lewis acid.
This result may be explained in a similar manner as de-
scribed in the reaction of N-alkylnitrone (1a) with 2A.
Similar reactions using ethyl methacrylate (2N) or styrene
(2C) instead of 2A were also carried out. Comparing the re-
sult from the Lewis acid catalyzed reaction of 1k and ethyl
acrylate (2N) with that of uncatalyzed reaction, a retardation
of the reaction by adding Lewis acid was observed and g-(2-
observed and the total yield of the cycloadducts went up to
over 96%. This result resembles to that of the corresponding
N-alkylnitrone (1a). However, the isolated yields of cy-
cloadducts were poor in the similar reactions that carried out
in the presence of magnesium bromide because the cy-
cloadducts undergo further ring opening reaction under the
reaction conditions. Products from these catalyzed reactions
were not isoxazolidines (3, 3؅, 4), but g-aminoalcohols (5, 6,
8), a ring opening product of the isoxazolidines and its
brominated one, and benzalaniline (7). The rate of consump-

July 2002
915
a)
Table 5. Lewis Acid Catalyzed Ring Opening Reaction of Isoxazolidines 3, 3Ј, 4, and 4؅
Isoxazolidines
Total
yields of
5, 8, 4؅, 6
Run
No.
Reaction
time
Ratio of
5 : 8 : 4؅: 6
Ratio of
Substituents
R1
Ratio of
(3ϩ3Ј) : (4ϩ4Ј)
5- : 4-b)
R
R2
63
64
65
66
67
68
H
H
CH3
CH3
Cl
CO2Et
CH3
CO2Et
CH3
CO2Et
CH3
H
CO2Et
H
CO2Et
H
CO2Et
70 : 30
100 : 0
66 : 34
100 : 0
64 : 36
100 : 0
3 h
4 h
6 h
10 h
3 h
12 h
89%
83%
85%
66%
70%
51%
69 : 0 : 15 : 16
100 : 0 : 0 : 0
68 : 0 : 0 : 32
85 : 15 : 0 : 0
68 : 0 : 24 : 8
67 : 33 : 0 : 0
69 : 31
100 : 0
68 : 32
100 : 0
68 : 32
100 : 0
Cl
a) A benzene solution of an equimolar mixture of isoxazolidines and the Lewis acid was heated to reflux. b) Symbol (5-) shows 5-substituted isoxazolidines (3, 3؅) and it’s
ring-opening derivatives (5, 8). Symbol (4-) shows 4-substituted isoxazolidine (4, 4؅) and it’s ring-opening derivative (6).
Chart 14. The Mechanism of the Ring-Opening Reaction by MgBr2
(phenylamino)-1,3-di-phenyl-1-propanol (8kC) were ob-
tained in 13, 28, and 10% yields, respectively, from the treat-
ment of 2,3,5-triphenylisoxazolidines (3kC), prepared by the
reaction of 1k and styrene (2C) in the absence of Lewis acid,
with magnesium bromide. The formation of the latter com-
pound (7kC) can be explained only by stepwise bromination
shown in path A.
bromoaryl)aminoalcohols (5kN, 5؅kN) were the only
isolable compounds from the reaction mixtures. A remark-
able change in both the stereoselectivity and the regioselec-
tivity was not observed. Both cycloadduts and g-aminoalco-
hols were not obtained from reaction of 1k—n with styrene
(2C) in the presence of Lewis acid.
Reaction Mechanism of the Ring Opening Reaction of
Isoxazolidines Following reagents have been known so far
to be effective for the reductive cleavage of N–O bond of
isoxazolidine; LiAlH4,10,11,17) Zn/AcOH,14—16,21) Raney
nickel,9) H2-Pd/carbon,8,13,18,21) H2-PdCl2,12) and H2-
Pd(OH)2.12,20) Though our method described above contains a
problem that aryl group at the nitrogen atom of the isoxazo-
lidines suffers bromination, it may be simplest method for
the cleavage of N–O bond of isoxazolidines.
The mechanism of the formation of g-(2-bromoaryl)-
aminoalcohols (5) from 2-arylisoxazolidines (3) may be ex-
plained as a result of a series of reactions via path A shown
in Chart 14; i.e., (i) chelation of magnesium bromide to the
oxygen atom of 2,3-diphenylisoxazolidiens (3), (ii) heteroly-
sis of the N–O bond to give carbocation, (iii) a nucleophilic
addition of bromo anion to ortho-position of the 2-phenyl
group in the isoxazolidine ring, (iv) a prototropy giving mag-
nesium salt of g-(2-bromoaryl)aminoalcohol, and (v) hydrol-
ysis of the salt to free g-(2-bromoaryl)aminoalcohol (5) in
working up the reaction mixture with water. Though another
more directive pathway (path B in the Chart 14) that consists
of concerted bromination reaction may also be supposed, this
could be ruled out by the following evidence. 3-(2-Bro-
mophenyl)amino-1,3-diphenyl-1-propanol (5kC), N-(4-bro-
mophenyl)-3-amino-1,3-diphenyl-1-propanol (7kC), and 3-
Though similar reaction mechanism was reported on the
reaction of N-arylisoxazolidine with hydrochloric acid,53,54)
a
quite different mechanism may be proposed for the ring-
opening reaction from the evidence that the generation of a
small amount of non-brominated g-aminoalcohole (8kC,
8mN) was observed.
It has been known that several reductants are effective for
the reductive cleavage of the N–O bond of isoxazolidines.
We described in this paper that Lewis acid is effective to give
drastic changes in the stereoselectity and the regioselectivity
in nitrone cycloaddition and also effective to give reductive
cleavage of the N–O bond of the 2-phenylisoxazolidines
reagent though the benzene ring of the 2-phenylisoxazo-
lidines underwent halogenation reaction.
Experimental
1H-NMR spectra (300 MHz) and 13C-NMR spectra (75 MHz) were mea-
sured and expressed in ppm (d) using residual CHCl3 (d: 7.26) and CDCl3
(d: 77.0), respectively, as the internal standards. Infrared spectra (IR) were
recorded on a Nicolet Model 205 spectrophotometer. High resolution mass
spectra (HRMS) (EI, unless otherwise stated) were taken for most of the key
liquid products together with, or in place of, elemental analyses. Melting
points were obtained on a Yanagimoto micro melting point determination
apparatus and are uncorrected. Flush colum chromatography was performed
using silica gel (Merck silica gel).
Materials C-Phenyl-N-benzylnitrone (1a) was prepared according to

916
Vol. 50, No. 7
the method described in the literature.55,56)
added benzaldehyde (7.0 g, 66 mmol) and the mixture was heated to reflux
for 1 h. Yellowish crude crystals were obtained by evaporation of the solvent
from the reaction mixture by a rotary evaporator, from which nitrone (1k)
was obtained in 70% yield (9.1 g) as colorless crystals by filtration with cy-
clohexane; mp. 106—111 °C (lit.56) mp. 112—114 °C); 1H-NMR (CDCl3) d:
7.45—7.50 (m, 6H), 7.76—7.79 (m, 2H), 7.92 (s, 1H), 8.38—8.41 (m, 2H).
C-Phenyl-N-(p-tolyl)nitrone (1m) In the same manner as described in
the synthesis of 1k, nitrone (1m) was obtained from p-nitrotoluene as color-
less crystals in 45% total yield; mp. 122—125 °C (lit.60,61) mp. 127—
Preparation of C-Aryl-N-methylnitrones (1b—f).56—59) Typical Proce-
dure: Preparation of N-Methyl-C-phenylnitrone (1b) To a chloroform
solution (30 ml) of N-methylhydroxyl-amine hydrochloride (420 mg,
5.0 mmol) and benzaldehyde (530 mg, 5.0 mmol) was added triethylamine
(750 ml, 7.5 mmol) and the mixture was stirred for 22 h at the room tempera-
ture. After an evaporation of the solvent by rotary evaporator, water was
added to the white crystalline residue and extracted with benzene several
times. The benzene solution was dried with anhydrous magnesium sulfate.
Evaporation of the solvent by rotary evaporator gave colorless crystals,
which was mixed well with cyclohexane and filtered to give N-methyl-C-
phenylnitrone (1b) as colorless crystals in 78% yield (530 mg); mp. 73—
75 °C (lit.56) mp. 84 °C); 1H-NMR: 3.89 (s, 3H), 7.36 (s, 1H), 7.40—7.43 (m,
3H), 8.19—8.22 (m, 2H).
1
128 °C); H-NMR (CDCl3) d: 2.40 (s, 3H), 7.25 (d, 2H, Jϭ8.7 Hz), 7.43—
7.48 (m, 3H), 7.65 (d, 2H, Jϭ8.7 Hz), 7.89 (s, 1H), 8.36—8.40 (m, 2H).
C-Phenyl-N-(4-chlorophenyl)nitrone (1n) In the same manner as de-
scribed in the synthesis of 1k, nitrone (1n) was obtained from p-chloroni-
trobenzene as colorless crystals in 40% total yield; mp. 171—174 °C (lit.60)
mp. 176—177 °C); 1H-NMR (CDCl3) d: 7.44 (d, 2H, Jϭ9.0 Hz), 7.45—7.49
(m, 3H), 7.73 (d, 2H, Jϭ9.0 Hz), 7.89 (s, 1H), 8.36—8.39 (m, 2H).
N-Methyl-C-(2-tolyl)nitrone (1c) In the same manner as described in
the synthesis of 1b, nitrone (1c) was obtained as a colorless oil in 98% yield;
1H-NMR (CDCl3) d: 2.37 (s, 3H), 3.91 (s, 3H), 7.17—7.22 (m, 1H), 7.26—
7.31 (m, 2H), 7.52 (s, 1H), 9.09—9.12 (m, 1H). Anal. Calcd for C9H11NO:
C, 72.45; H, 7.43; N, 9.39. Found: C, 72.40; H, 7.28; N, 9.55.
N-Methyl-C-(2-naphthyl)nitrone (1d) In the same manner as de-
scribed in the synthesis of 1b, nitrone (1d) was obtained as colorless crystals
in 98% yield; mp. 107—109 °C (lit.57) mp. 106—108 °C); 1H-NMR (CDCl3)
d: 3.49 (s, 3H), 7.51 (dd, 2H, Jϭ2.4, 9.6 Hz), 7.51 (s, 1H), 7.80—7.83 (m,
1H), 7.84—7.90 (m, 2H), 7.91—7.95 (m, 1H), 9.20 (s, 1H).
Reaction of Nitrones with Dipolarophiles in the Absence of Lewis
Acid. Typical Procedure: Reaction of 1a with Ethyl Acrylate (2A)
A
benzene solution (25 ml) of 1a (1.06 g, 5.0 mmol) and ethyl acrylate (5.0 g,
50 mmol) was heated to reflux for 7 h. After an evapolation of the solvent
and an excess amount of ethyl acrylate by rotary evapolator, colorless oily
residue was passed through the column chromatography packed with silica
gel to give cis- and trans-2-benzyl-5-(ethoxycarbonyl)-3-phenylisoxazo-
lidines (3aA, 3؅aA) and cis- and trans-2-benzyl-4-(ethoxycarbonyl)-3-
phenylisoxazolidines (4aA, 4؅aA) in 97% total yields (1.51 g). The ratio of
the four isomers (3aA, 3؅aA, 4aA, 4؅aA) was found to be 10 : 72 : 4 : 14, re-
spectively, by the analysis of the 1H-NMR spectra. Some of the four isomers
were isolated by the chromatography though the yields were poor. Chloro-
form and the mixed solvent with ethanol were used for the eluent.
(3R*,5S*)-2-Benzyl-5-(ethoxycarbonyl)-3-phenylisoxazolidine (3aA):
1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 2.65 (ddd, 1H, Jϭ4.8, 8.7,
12.6 Hz), 2.99 (ddd, 1H, Jϭ7.8, 9.3, 12.6 Hz), 3.78 (d, 1H, Jϭ13.8 Hz), 4.01
(d, 1H, Jϭ13.8 Hz), 4.25 (q, 2H, Jϭ7.2 Hz), 4.25 (dd, 1H, Jϭ7.8, 8.7 Hz),
4.63 (dd, 1H, Jϭ4.8, 9.3 Hz), 7.22—7.50 (m, 10H). HR-MS m/z; 311.1520
(Calcd for C19H21NO3: 311.1521).
C-(o-Anisyl)-N-methylnitrone (1e) In the same manner as described in
the synthesis of 1b, nitrone (1e) was obtained as colorless crystals in 98%
1
yield; mp. 65—68 °C; H-NMR (CDCl3) d: 3.85 (s, 3H), 3.88 (s, 3H), 6.87
(d, 1H, Jϭ8.4 Hz), 7.02 (t, 1H, Jϭ7.5 Hz), 7.36 (t, 1H, Jϭ7.8 Hz), 7.82 (s,
1H), 9.24 (d, 1H, Jϭ7.8 Hz). Anal. Calcd for C9H11NO2: C, 65.44; H, 6.71;
N, 8.48. Found: C, 65.38; H, 6.66; N, 8.55.
C-Mesityl-N-methylnitrone (1f) In the same manner as described in
the synthesis of 1b, nitrone (1f) was obtained as colorless crystals in 98%
1
yield; mp. 65—68 °C; H-NMR (CDCl3) d: 2.26 (s, 9H), 3.90 (s, 3H), 6.88
(s, 2H), 7.54 (s, 1H). Anal. Calcd for C11H15NO: C, 74.54; H, 8.53; N, 7.90.
Found: C, 74.40; H, 8.77; N, 8.10.
(3R*,5R*)-2-Benzyl-5-(ethoxycarbonyl)-3-phenylisoxazolidine (3؅aA):
1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 2.71 (dt, 1H, Jϭ8.7, 12.3 Hz),
2.78 (ddd, 1H, Jϭ4.8, 7.2, 12.3 Hz), 3.96 (d, 1H, Jϭ14.4 Hz), 4.03 (d, 1H,
Jϭ14.4 Hz), 4.05 (dd, 1H, Jϭ7.2, 8.7 Hz), 4.24 (q, 2H, Jϭ7.2 Hz), 4.66 (dd,
1H, Jϭ4.8, 8.7 Hz), 7.22—7.50 (m, 10H). HR-MS m/z; 311.1524 (Calcd for
C19H21NO3: 311.1521).
N-Methyl-C-(2-pyridyl)nitrone (1g) In the same manner as described
in the synthesis of 1b, nitrone (1g) was obtained as colorless crystals in 98%
yield; mp. 45—48 °C; 1H-NMR (CDCl3) d: 3.92 (s, 3H), 7.26—7.30 (m,
1H), 7.69 (s, 1H), 7.76 (t, 1H, Jϭ7.8 Hz), 8.62 (d, 1H, Jϭ4.8 Hz), 9.10 (d,
1H, Jϭ8.1 Hz). Anal. Calcd for C7H8N2O: C, 61.75; H, 5.92; N, 20.58.
Found: C, 61.77; H, 5.90; N, 20.71.
(3R*,4R*)-2-Benzyl-4-(ethoxycarbonyl)-3-phenylisoxazolidine (4aA):
1H-NMR (CDCl3) d: 0.78 (t, 3H, Jϭ7.5 Hz), 3.57 (dd, 1H, Jϭ6.9, 10.5 Hz),
3.70 (q, 2H, Jϭ7.5 Hz), 3.74 (d, 1H, Jϭ14.1 Hz), 4.01 (d, 1H, Jϭ14.1 Hz),
4.12—4.26 (m, 3H), 7.22—7.50 (m, 10H). HR-MS m/z; 311.1515 (Calcd for
C19H21NO3: 311.1521).
(3R*,4S*)-2-Benzyl-4-(ethoxycarbonyl)-3-phenylisoxazolidine (4ЈaA):
1H-NMR (CDCl3) d: 1.24 (t, 3H, Jϭ7.2 Hz), 3.44 (dt, 1H, Jϭ6.3, 7.8 Hz),
3.80 (d, 1H, Jϭ13.8 Hz), 3.96 (d, 1H, Jϭ13.8 Hz), 4.10 (d, 1H, Jϭ7.8 Hz),
4.17 (dd, 1H, Jϭ7.5, 14.1 Hz), 4.18 (dd, 1H, Jϭ7.5, 14.1 Hz), 4.25 (q, 2H,
Jϭ7.2 Hz), 7.22—7.50 (m, 10H). HR-MS m/z; 311.1517 (Calcd for
C19H21NO3: 311.1521).
N-Methyl-C-(6-methyl-2-pyridyl)nitrone (1h) In the same manner as
described in the synthesis of 1b, nitrone (1h) was obtained as colorless crys-
tals in 98% yield; mp. 44—46 °C; 1H-NMR (CDCl3) d: 2.53 (s, 3H), 3.89 (s,
3H), 7.14 (d, 1H, Jϭ7.8 Hz), 7.65 (s, 1H), 7.66 (t, 1H, Jϭ7.8 Hz), 8.91 (d,
1H, Jϭ7.8 Hz). Anal. Calcd for C8H10N2O: C, 63.98; H, 6.71; N, 18.65.
Found: C, 63.88; H, 6.59; N, 18.51.
N-Methyl-C-(2-quinolyl)nitrone (1i) In the same manner as described
in the synthesis of 1b, nitrone (1i) was obtained as colorless crystals in 98%
yield; mp. 98—100 °C; 1H-NMR (CDCl3) d: 3.97 (s, 3H), 7.55 (t, 1H,
Jϭ7.5 Hz), 7.71 (t, 1H, Jϭ7.5 Hz), 7.81 (d, 1H, Jϭ8.4 Hz), 7.86 (s, 1H),
8.02 (d, 1H, Jϭ8.4 Hz), 8.23 (d, 1H, Jϭ8.7 Hz), 9.11 (d, 1H, Jϭ8.7 Hz).
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.05. Found: C, 71.10; H,
5.69; N, 14.90.
The following compounds were prepared in yields shown in Table 1 ac-
cording to Typical Procedure.
(3R*,5S*)-2-Benzyl-5-cyano-3-phenylisoxazolidine (3aB): 1H-NMR
(CDCl3) d: 2.62 (ddd, 1H, Jϭ3.6, 8.4, 12.9 Hz), 3.08 (dt, 1H, Jϭ9.0,
12.9 Hz), 3.77 (dd, 1H, Jϭ8.1, 9.0 Hz), 3.77 (d, 1H, Jϭ15.3 Hz), 4.10 (d,
1H, Jϭ15.3 Hz), 4.82 (dd, 1H, Jϭ3.6, 9.0 Hz), 7.26—7.53 (m, 10H). HR-
MS m/z; 264.1260 (Calcd for C17H16N2O: 264.1263).
C-(2-Furyl)-N-methylnitrone (1j) In the same manner as described in
the synthesis of 1b, nitrone (1j) was obtained as colorless crystals in 98%
yield; mp. 80—82 °C (lit.58,59) mp. 91—92 °C); 1H-NMR (CDCl3) d: 3.83 (s,
3H), 6.55 (d, 1H, Jϭ3.6 Hz), 7.47 (s, 1H), 7.53 (s, 1H), 7.75 (d, 1H,
Jϭ3.6 Hz).
(3R*,5R*)-2-Benzyl-5-cyano-3-phenylisoxazolidine (3؅aB): 1H-NMR
(CDCl3) d: 2.78 (dt, 1H, Jϭ8.7, 12.9 Hz), 2.99 (ddd, 1H, Jϭ4.2, 6.9,
12.9 Hz), 3.98 (d, 1H, Jϭ13.8 Hz), 4.04 (d, 1H, Jϭ13.8 Hz), 4.22 (dd, 1H,
Jϭ6.9, 8.7 Hz), 4.82 (dd, 1H, Jϭ4.2, 8.7 Hz), 7.30—7.53 (m, 10H). HR-MS
m/z; 264.1265 (Calcd for C17H16N2O: 264.1263).
Preparation of C,N-Diarylnitrones (1k—n).56,60,61) Typical Procedure:
Preparation of C,N-diphenylnitrone (1k) To a dispersion of zinc dust
(31 g, 0.48 mol) in 50% aqueous ethanol (400 ml) was added nitrobenzene
(25 g, 0.20 mol) with stirring. The reaction was initiated by the dropwise ad-
dition of a saturated aqueous solution of ammonium chloride (13 g,
0.24 mol). The temperature of the mixture rose to reflux by the addition of
ammonium chloride (about 70 °C). When the temperature of the reaction
mixture dropped to 50 °C, the basic zinc salts were filtered off by a glass
funnel using a celite bed. Sodium chloride was added to the warm filtrate
until the saturated solution was obtained. After cooling the mixture to room
temperature, the mixture was further cooled in a freezer over a knight (at
about Ϫ20 °C). Colorless crystals of phenylhydroxylamine was precipitated
from the solution and obtained in 66% yield (13.0 g) by filtration: mp. 78—
80 °C.
(3R*,4S*)-2-Benzyl-4-cyano-3-phenylisoxazolidine (4aB): 1H-NMR
(CDCl3) d: 3.68 (d, 1H, Jϭ14.4 Hz), 3.73 (dt, 1H, Jϭ7.2, 8.7 Hz), 3.95 (d,
1H, Jϭ8.7 Hz), 4.05 (d, 1H, Jϭ14.4 Hz), 4.17 (dd, 1H, Jϭ7.2, 8.7 Hz), 4.36
(t, 1H, Jϭ8.7 Hz), 7.30—7.53 (m, 10H). HR-MS m/z; 264.1270 (Calcd for
C17H16N2O: 264.1263).
(3R*,4R*)-2-Benzyl-4-cyano-3-phenylisoxazolidine (4؅aB): 1H-NMR
(CDCl3) d: 3.39 (dt, 1H, Jϭ4.8, 8.1 Hz), 3.79 (d, 1H, Jϭ14.1 Hz), 3.98 (d,
1H, Jϭ8.1 Hz), 4.01 (d, 1H, Jϭ14.1 Hz), 4.20—4.31 (m, 2H), 7.26—7.50
(m, 10H). HR-MS m/z; 264.1266 (Calcd for C17H16N2O: 264.1263).
(3R*,5S*)-2-Benzyl-3,5-diphenylisoxazolidine (3aC): 1H-NMR (CDCl3)
To an ethanol solution of phenylhydroxylamine (6.5 g, 66 mmol) was

July 2002
917
d: 2.43 (ddd, 1H, Jϭ7.5, 9.3, 12.3 Hz), 3.15 (dt, 1H, Jϭ7.2, 12.3 Hz), 3.92
(3R*,5R*)-2-Benzyl-5-(1-hydroxybutyl)-3-phenylisoxazolidine (3؅aI-2):
(d, 1H, Jϭ14.1 Hz), 4.09 (dd, 1H, Jϭ7.2, 9.3 Hz), 4.11 (d, 1H, Jϭ14.1 Hz), Diastereomer B: 1H-NMR (CDCl3) d: 0.92 (t, 3H, Jϭ7.2 Hz), 1.20—1.60
5.27 (t, 1H, Jϭ7.5 Hz), 7.22—7.54 (m, 15H). HR-MS m/z; 315.1629 (Calcd
(m, 4H), 2.50—2.68 (m, 2H), 3.56 (s, 1H), 3.63 (d, 1H, Jϭ14.4 Hz), 3.79
(dd, 1H, Jϭ8.1, 9.0 Hz), 3.95—4.04 (m, 2H), 3.99 (d, 1H, Jϭ14.4 Hz), 4.16
(ddd, 1H, Jϭ2.4, 6.0, 8.4 Hz), 7.21—7.50 (m, 10H). HR-MS m/z; 311.1889
for C22H21NO: 315.1623).
(3R*,5R*)-2-Benzyl-3,5-diphenylisoxazolidine (3؅aC): H-NMR (CDCl3)
1
d: 2.60 (ddd, 1H, Jϭ6.3, 8.4, 12.6 Hz), 2.75 (dt, 1H, Jϭ8.4, 12.6 Hz), (Calcd for C20H25NO2: 311.1885).
3.97—4.15 (m, 1H), 5.23—5.30 (m, 1H), 7.22—7.54 (m, 15H). HR-MS
(3R*,5S*)-2-Benzyl-5-(1-methyl-1-hydroxyethyl)-3-phenylisoxazolidine
m/z; 315.1626 (Calcd for C22H21NO: 315.1623).
(3aJ): 1H-NMR (CDCl3) d: 1.13 (s, 3H), 1.28 (s, 3H), 1.82—1.95 (br s, 1H),
(3R*,5S*)-2-Benzyl-5-butoxy-3-phenylisoxazolidine (3aD): 1H-NMR 2.23 (dt, 1H, Jϭ8.4, 11.4 Hz), 2.56—2.65 (m, 1H), 3.73 (d, 1H, Jϭ14.1 Hz),
(CDCl3) d: 0.91 (t, 3H, Jϭ7.2 Hz), 1.33—1.45 (m, 2H), 1.53—1.63 (m,
2H), 2.31 (ddd, 1H, Jϭ3.0, 9.3, 12.9 Hz), 2.89 (ddd, 1H, Jϭ6.3, 8.1,
3.70—3.80 (m, 1H), 4.03 (d, 1H, Jϭ14.1 Hz), 4.03 (dd, 1H, Jϭ8.4,
11.4 Hz), 7.21—7.50 (m, 10H). HR-MS m/z; 297.1731 (Calcd for
12.9 Hz), 3.40 (dt, 1H, Jϭ6.6, 9.6 Hz), 3.68 (d, 1H, Jϭ14.7 Hz), 3.70 (dd, C19H23NO2: 297.1729).
1H, Jϭ8.1, 9.3 Hz), 3.71 (dt, 1H, Jϭ6.6, 9.6 Hz), 4.03 (d, 1H, Jϭ14.7 Hz),
(3R*,5R*)-2-Benzyl-5-(1-methyl-1-hydroxyethyl)-3-phenylisoxazolidine
5.16 (dd, 1H, Jϭ3.0, 6.3 Hz), 7.21—7.56 (m, 10H). HR-MS m/z; 311.1880 (3؅aJ): 1H-NMR (CDCl3) d: 1.10 (s, 3H), 1.19 (s, 3H), 2.56 (ddd, 1H,
(Calcd for C20H25NO2: 311.1885).
Jϭ6.0, 9.9, 12.3 Hz), 2.67 (dt, 1H, Jϭ7.8, 12.3 Hz), 3.37 (s, 1H), 3.62 (d,
(3R*,5R*)-2-Benzyl-5-butoxy-3-phenylisoxazolidine (3؅aD): 1H-NMR 1H, Jϭ14.1 Hz), 3.79 (dd, 1H, Jϭ7.8, 9.9 Hz), 3.95 (d, 1H, Jϭ14.1 Hz),
(CDCl3) d: 0.97 (t, 3H, Jϭ7.2 Hz), 1.40—1.48 (m, 2H), 1.58—1.67 (m, 3.93—3.98 (m, 1H), 7.24—7.48 (m, 10H). HR-MS m/z; 297.1733 (Calcd for
2H), 2.46 (ddd, 1H, Jϭ4.8, 10.2, 12.6 Hz), 2.64 (ddd, 1H, Jϭ0.9, 6.6, C19H23NO2: 297.1729).
12.6 Hz), 3.43 (dt, 1H, Jϭ6.9, 9.3 Hz), 3.82 (dt, 1H, Jϭ6.9, 9.3 Hz), 4.09 (s,
(3R*,5S*)-5-(Allyloxymethyl)-2-benzyl-3-phenylisoxazolidine (3aK):
2H), 4.32 (dd, 1H, Jϭ 6.6, 10.2 Hz), 5.19 (d, 1H, Jϭ4.8 Hz), 7.21—7.45 (m, 1H-NMR (CDCl3) d: 2.04 (ddd, 1H, Jϭ6.3, 9.0, 12.6 Hz), 2.78 (dt, 1H,
10H). HR-MS m/z; 311.1884 (Calcd for C20H25NO2: 311.1885).
Jϭ7.8, 12.6 Hz), 3.47 (dd, 1H, Jϭ4.5, 10.2 Hz), 3.71 (t, 1H, Jϭ6.9 Hz), 3.77
(3R*,5S*)-5-Acetoxy-2-benzyl-3-phenylisoxazolidine (3aE): 1H-NMR (d, 1H, Jϭ14.7 Hz), 3.92—4.07 (m, 3H), 3.98 (d, 1H, Jϭ14.7 Hz), 4.35—
(CDCl3) d: 2.11 (s, 3H), 2.41 (ddd, 1H, Jϭ3.0, 9.3, 13.8 Hz), 3.04 (ddd, 1H, 4.44 (m, 1H), 5.11—5.33 (m, 2H), 5.79—5.98 (m, 1H), 7.20—7.50 (m,
Jϭ6.6, 8.1, 13.8 Hz), 3.80 (d, 1H, Jϭ14.7 Hz), 3.80 (dd, 1H, Jϭ8.1, 9.3 Hz),
4.08 (d, 1H, Jϭ14.7 Hz), 6.36 (dd, 1H, Jϭ3.0, 6.6 Hz), 7.22—7.57 (m,
10H). HR-MS m/z; 297.1364 (Calcd for C18H19NO3: 297.1365).
10H). HR-MS m/z; 309.1725 (Calcd for C20H23NO2: 309.1729).
(3R*,5R*)-5-(Allyloxymethyl)-2-benzyl-3-phenylisoxazolidine (3؅aK):
1H-NMR (CDCl3) d: 2.38 (dt, 1H, Jϭ7.8, 12.3 Hz), 2.51 (ddd, 1H, Jϭ5.4,
(3R*,5R*)-5-Acetoxy-2-benzyl-3-phenylisoxazolidine (3؅aE): 1H-NMR 7.8, 12.3 Hz), 3.54 (d, 1H, Jϭ4.5 Hz), 3.77 (d, 1H, Jϭ14.7 Hz), 3.83 (d, 1H,
(CDCl3) d: 2.08 (s, 3H), 2.63 (dd, 2H, Jϭ3.0, 8.4 Hz), 4.02 (d, 1H,
Jϭ13.8 Hz), 4.15 (d, 1H, Jϭ13.8 Hz), 4.25 (t, 1H, Jϭ8.4 Hz), 6.39 (t, 1H,
Jϭ8.1 Hz), 3.92—4.07 (m, 3H), 3.98 (d, 1H, Jϭ14.7 Hz), 4.35—4.44 (m,
1H), 5.11—5.33 (m, 2H), 5.79—5.98 (m, 1H), 7.20—7.50 (m, 10H). HR-
Jϭ3.0 Hz), 7.24—7.51 (m, 10H). HR-MS m/z; 297.1372 (Calcd for MS m/z; 309.1729 (Calcd for C20H23NO2: 309.1729).
C18H19NO3: 297.1365).
(3R*,5S*)-2-Benzyl-5-(methylthio)-3-phenylisoxazolidine (3aL): 1H-
(3R*,5S*)-2-Benzyl-5-(bromomethyl)-3-phenylisoxazolidine (3aF): mp. NMR (CDCl3) d: 2.03 (s, 3H), 2.16 (ddd, 1H, Jϭ6.0, 9.0, 12.6 Hz), 2.66 (dd,
1
74—76 °C; H-NMR (CDCl3) d: 2.23 (ddd, 1H, Jϭ5.4, 9.0, 12.6 Hz), 2.92
(dt, 1H, Jϭ7.5, 12.6 Hz), 3.46 (dd, 1H, Jϭ8.1, 9.6 Hz), 3.66 (dd, 1H, Jϭ5.7,
9.6 Hz), 3.75 (d, 1H, Jϭ14.7 Hz), 3.86 (dd, 1H, Jϭ7.5, 9.0 Hz), 4.00 (d, 1H,
Jϭ14.7 Hz), 4.39—4.48 (m, 1H), 7.23—7.44 (m, 10H).
1H, Jϭ6.6, 13.5 Hz), 2.88 (dt, 1H, Jϭ7.5, 12.6 Hz), 2.90 (dd, 1H, Jϭ6.6,
13.5 Hz), 3.74 (d, 1H, Jϭ14.4 Hz), 3.86 (dt, 1H, Jϭ6.6, 13.5 Hz), 3.98 (d,
1H, Jϭ14.1 Hz), 4.13 (dt, 1H, Jϭ5.4, 8.1 Hz), 7.21—7.45 (m, 10H). HR-
MS m/z; 299.1338 (Calcd for C18H21NOS: 299.1344).
(3R*,5R*)-2-Benzyl-5-(bromomethyl)-3-phenylisoxazolidine (3؅aF): Col-
(3R*,5R*)-2-Benzyl-5-(methylthio)-3-phenylisoxazolidine (3؅aL): 1H-
orless oil; 1H-NMR (CDCl3) d: 2.51 (dt, 1H, Jϭ8.7, 12.6 Hz), 2.57 (ddd, NMR (CDCl3) d: 2.18 (s, 3H), 2.45—2.50 (m, 2H), 2.67 (dd, 1H, Jϭ6.9,
1H, Jϭ5.1, 7.5, 12.6 Hz), 3.42 (dd, 1H, Jϭ6.6, 10.2 Hz), 3.50 (dd, 1H, 13.8 Hz), 2.75 (dd, 1H, Jϭ4.8, 14.4 Hz), 3.75 (d, 1H, Jϭ14.1 Hz), 3.98 (dd,
Jϭ7.2, 10.2 Hz), 3.76 (d, 1H, Jϭ14.4 Hz), 3.88 (dd, 1H, Jϭ7.5, 8.7 Hz), 1H, Jϭ14.1 Hz), 4.35—4.49 (m, 2H), 7.20—7.50 (m, 10H). HR-MS m/z;
3.98 (d, 1H, Jϭ14.4 Hz), 4.42—4.50 (m, 1H), 7.24—7.47 (m, 10H).
(3R*,5S*)-2-Benzyl-5-(hydroxymethyl)-3-phenylisoxazolidine (3aG): 1H-
NMR (CDCl3) d: 1.63 (br s, 1H), 2.25 (ddd, 1H, Jϭ5.4, 9.3, 12.3 Hz), 2.79
(dt, 1H, Jϭ8.1, 12.3 Hz), 3.66 (d, 1H, Jϭ14.4 Hz), 3.74—3.83 (m, 3H), 3.99
299.1343 (Calcd for C18H21NOS: 299.1344).
(3R*,5R*)-2-Benzyl-5-(methylthio)-3-phenylisoxazolidine (3aM): 1H-
NMR (CDCl3) d: 0.88 (t, 3H, Jϭ6.9 Hz), 1.23—1.40 (m, 8H), 1.45—1.60
(m, 1H), 1.73—1.86 (m, 1H), 1.99 (ddd, 1H, Jϭ7.2, 8.7, 12.0 Hz), 2.78 (dt,
(d, 1H, Jϭ14.4 Hz), 4.30—4.39 (m, 1H), 7.24—7.48 (m, 10H). HR-MS m/z; 1H, Jϭ7.2, 12.0 Hz), 3.84 (d, 1H, Jϭ14.1 Hz), 3.94 (d, 1H, Jϭ11.7 Hz),
269.1621 (Calcd for C17H19NO2: 269.1416).
3.99 (d, 1H, Jϭ14.1 Hz), 4.16—4.26 (m, 1H), 7.20—7.50 (m, 10H). HR-MS
m/z; 323.2244 (Calcd for C22H29NO: 323.2249).
(3R*,5R*)-2-Benzyl-5-(hydroxymethyl)-3-phenylisoxazolidine (3؅aG):
1H-NMR (CDCl3) d: 1.83 (brs, 1H), 2.37 (dt, 1H, Jϭ8.7, 12.3 Hz), 2.55
(ddd, 1H, Jϭ5.4, 7.8, 12.3 Hz), 3.56—3.82 (m, 3H), 3.70 (d, 1H,
Jϭ14.4 Hz), 3.98 (d, 1H, Jϭ14.4 Hz), 4.03—4.39 (m, 1H), 7.24—7.48 (m,
10H). HR-MS m/z; 269.1622 (Calcd for C17H19NO2: 269.1416).
(3R*,5S*)-5-(Acetoxymethyl)-2-benzyl-3-phenylisoxazolidine (3aH): H- 3.99 (d, 1H, Jϭ14.1 Hz), 4.16—4.26 (m, 1H), 7.20—7.50 (m, 10H). HR-MS
(3R*,5S*)-2-Benzyl-5-(methylthio)-3-phenylisoxazolidine (3؅aM): 1H-
NMR (CDCl3) d: 0.88 (t, 3H, Jϭ6.9 Hz), 1.23—1.40 (m, 8H), 1.45—1.60
(m, 1H), 1.73—1.86 (m, 1H), 2.18 (ddd, 1H, Jϭ6.3, 8.4, 12.0 Hz), 2.36 (dt,
1 H, Jϭ8.1, 12.3 Hz), 3.74 (d, 1H, Jϭ14.1 Hz), 3.88 (d, 1H, Jϭ11.1 Hz),
1
NMR (CDCl3) d: 2.00—2.10 (m, 1H), 2.02 (s, 3H), 2.83 (dt, 1H, Jϭ8.1,
12.9 Hz), 3.77 (d, 1H, Jϭ14.7 Hz), 3.83 (t, 1H, Jϭ8.1 Hz), 4.00 (d, 1H,
Jϭ14.7 Hz), 4.11 (d, 1H, Jϭ11.4 Hz), 4.53 (d, 1H, Jϭ11.1 Hz), 4.38—4.47 (3aN): H-NMR (CDCl3) d: 1.33 (t, 3H, Jϭ7.2 Hz), 1.59 (s, 3H), 2.32 (dd,
(m, 1H), 7.17—7.45 (m, 10H). HR-MS m/z; 311.1518 (Calcd for 1H, Jϭ9,6, 12.6 Hz), 3.10 (dd, 1H, Jϭ6.9, 12.6 Hz), 3.97 (s, 2H), 4.06 (dd,
m/z; 323.2239 (Calcd for C22H29NO: 323.2249).
Ethyl (3R*,5R*)-2-Benzyl-5-methy-3-phenylisoxazolidin-5-carboxylate
1
C19H21NO3: 311.1521).
1H, Jϭ6.9, 9.6 Hz), 4.25 (q, 2H, Jϭ7.2 Hz), 7.20—7.45 (m, 10H). HR-MS
(3R*,5R*)-5-(Acetoxymethyl)-2-benzyl-3-phenylisoxazolidine (3؅aH): m/z; 325.1678 (Calcd for C20H23NO3: 325.1678).
1H-NMR (CDCl3) d: 2.08 (s, 3H), 2.41 (t, 2H, Jϭ8.1 Hz), 3.74 (d, 1H,
Ethyl (3R*,5S*)-2-Benzyl-5-methy-3-phenylisoxazolidin-5-carboxylate
Jϭ14.4 Hz), 3.83 (t, 1H, Jϭ8.1 Hz), 4.00 (d, 1H, Jϭ14.7 Hz), 4.12 (d, 1H, (3؅aN): 1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 1.54 (s, 3H), 2.49 (dd,
Jϭ11.1 Hz), 4.35 (d, 1H, Jϭ11.1 Hz), 4.38—4.47 (m, 1H), 7.17—7.45 (m,
1H, Jϭ8.4, 12.6 Hz), 3.03 (dd, 1H, Jϭ8.4, 12.6 Hz), 3.76 (d, 1H,
Jϭ15.3 Hz), 3.81 (t, 1H, Jϭ8.4 Hz), 3.99 (d, 1H, Jϭ15.3 Hz), 4.24 (q, 2H,
10H). HR-MS m/z; 311.1514 (Calcd for C19H21NO3: 311.1521).
(3R*,5S*)-2-Benzyl-5-(1-hydroxybutyl)-3-phenylisoxazolidine (3aI): H- Jϭ7.2 Hz), 7.20—7.45 (m, 10H). HR-MS m/z; 325.1684 (Calcd for
1
NMR (CDCl3) d: 0.92 (t, 3H, Jϭ7.2 Hz), 1.31—1.55 (m, 4H), 2.23 (ddd,
1H, Jϭ5.4, 9.3, 12.6 Hz), 2.79 (dt, 1H, Jϭ8.1, 12.6 Hz), 3.05 (d, 1H,
C20H23NO3: 325.1678).
(3R*,5R*)-2-Benzyl-5-cyano-5-methyl-3-phenylisoxazolidine (3aP): 1H-
Jϭ4.5 Hz), 3.65 (d, 1H, Jϭ14.4 Hz), 3.65—3.72 (m, 1H), 3.79 (dt, 1H, NMR (CDCl3) d: 1.70 (s, 3H), 2.50 (dd, 1H, Jϭ9.0, 12.6 Hz), 3.13 (dd, 1H,
Jϭ8.1, 9.3 Hz), 3.97 (d, 1H, Jϭ14.4 Hz), 3.97—4.03 (m, 1H), 7.21—7.50
(m, 10H). HR-MS m/z; 311.1880 (Calcd for C20H25NO2: 311.1885).
(3R*,5R*)-2-Benzyl-5-(1-hydroxybutyl)-3-phenylisoxazolidine (3؅aI-1):
Diastereomer A: 1H-NMR (CDCl3) d: 0.92 (t, 3H, Jϭ7.2 Hz), 1.34—1.56
Jϭ6.3, 12.6 Hz), 4.06 (d, 1H, Jϭ13.8 Hz), 4.14 (d, 1H, Jϭ13.9 Hz), 4.42
(dd, 1H, Jϭ6.3, 9.3 Hz), 7.26—7.44 (m, 10H). HR-MS m/z; 278.1417
(Calcd for C18H18N2O: 278.1419).
(3R*,5S*)-2-Benzyl-5-cyano-5-methyl-3-phenylisoxazolidine (3ЈaP): 1H-
(m, 4H), 1.90—2.05 (br s, 1H), 2.36 (dt, 1H, Jϭ8.1, 12.3 Hz), 2.45 (m, 1H), NMR (CDCl3) d: 1.69 (s, 3H), 2.67 (dd, 1H, Jϭ9.0, 12.9 Hz), 2.83 (dd, 1H,
3.48—3.54 (m, 1H), 3.73 (d, 1H, Jϭ14.1 Hz), 3.76—3.85 (m, 1H), 3.98 (d, Jϭ8.4, 12.9 Hz), 3.77 (d, 1H, Jϭ15.3 Hz), 3.83 (t, 1H, Jϭ8.7 Hz), 4.06 (d,
1H, Jϭ14.1 Hz), 4.13 (dt, 1H, Jϭ5.4, 8.1 Hz), 7.21—7.50 (m, 10H). HR- 1H, Jϭ15.3 Hz), 7.25—7.56 (m, 10H). HR-MS m/z; 278.1422 (Calcd for
MS m/z; 311.1888 (Calcd for C20H25NO2: 311.1885).
C18H18N2O: 278.1419).

918
Reaction of 1b with Ethyl Acrylate (2A) A benzene solution (25 ml)
Vol. 50, No. 7
(d, 1H, Jϭ7.5 Hz). HR-MS m/z; 223.1208 (Calcd for C12H17NO3: 223.1208).
(3R*,5R*)-5-(Hydroxymethyl)-3-(2-methoxyphenyl)-2-methylisoxazoli-
dine (3؅eG): 1H-NMR (CDCl3) d: 2.20 (br s, 1H), 2.51—2.60 (m, 2H), 2.61
(s, 3H), 3.60—3.70 (m, 1H), 3.80—3.85 (m, 1H), 3.82 (s, 3H), 3.91—4.06
(m, 1H), 4.26—4.35 (m, 1H), 6.86 (d, 1H, Jϭ7.8 Hz), 6.95 (t, 1H,
Jϭ7.5 Hz), 7.23 (t, 1H, Jϭ7.5 Hz), 7.45 (d, 1H, Jϭ7.5 Hz). HR-MS m/z;
223.1202 (Calcd for C12H17NO3: 223.1208).
(3R*,5S*)-5-(Hydroxymethyl)-2-methy-3-(2-pyridyl)isoxazolidine (3gG):
1H-NMR (CDCl3) d: 2.36—2.48 (m, 1H), 2.59 (s, 3H), 2.85 (dt, 1H, Jϭ8.7,
12.6 Hz), 3.60—3.75 (m, 2H), 3.75—3.91 (m, 2H), 4.31—4.39 (m, 1H),
7.11 (t, 1H, Jϭ6.0 Hz), 7.38 (d, 1H, Jϭ7.8 Hz), 7.59 (t, 1H, Jϭ7.8 Hz), 8.44
(d, 1H, Jϭ5.1 Hz). HR-MS m/z; 194.1064 (Calcd for C10H14N2O2:
194.1055).
(3R*,5R*)-5-(Hydroxymethyl)-2-methy-3-(2-pyridyl)isoxazolidine
(3؅gG): H-NMR (CDCl3) d: 2.46—2.61 (m, 2H), 2.60 (br s, 1H), 2.65 (s,
3H), 3.62 (dd, 1H, Jϭ4.8, 12.0 Hz), 3.81 (dd, 2H, Jϭ2.7, 12.0 Hz), 4.30—
4.38 (m, 1H), 7.19 (t, 1H, Jϭ6.0 Hz), 7.45 (d, 1H, Jϭ7.8 Hz), 7.67 (t, 1H,
Jϭ7.8 Hz), 8.54 (d, 1H, Jϭ4.8 Hz). HR-MS m/z; 194.1064 (Calcd for
C10H14N2O2: 194.1055).
(3R*,5S*)-5-(Hydroxymethyl)-2-methy-3-(6-methyl-2-pyridyl)isoxazoli-
dine (3hG): 1H-NMR (CDCl3) d: 2.50—2.53 (m, 1H), 2.52 (s, 3H), 2.67 (s,
3H), 2.83 (dt, 1H, Jϭ8.7, 12.6 Hz), 3.72 (dd, 1H, Jϭ4.2, 12.0 Hz), 3.80—
3.96 (m, 3H), 4.40—4.50 (m, 1H), 7.04 (d, 1H, Jϭ7.8 Hz), 7.18 (d, 1H,
Jϭ7.8 Hz), 7.54 (t, 1H, Jϭ7.8 Hz). HR-MS m/z; 208.1217 (Calcd for
C11H16N2O2: 208.1212).
(3R*,5R*)-5-(Hydroxymethyl)-2-methy-3-(6-methyl-2-pyridyl)isoxazoli-
dine (3؅hG): 1H-NMR (CDCl3) d: 2.50—2.70 (m, 2H), 2.51 (s, 3H), 2.64 (s,
3H), 3.61 (dd, 1H, Jϭ5.1, 12.0 Hz), 3.77 (dd, 1H, Jϭ3.0, 12.0 Hz), 3.81—
3.94 (m, 2H), 4.30—4.38 (m, 1H), 7.02 (d, 1H, Jϭ7.8 Hz), 7.24 (d, 1H,
Jϭ7.8 Hz), 7.54 (t, 1H, Jϭ7.8 Hz). HR-MS m/z; 208.1216 (Calcd for
C11H16N2O2: 208.1212).
of 1b (270 mg, 2.0 mmol) and ethyl acrylate (2.0 g, 20 mmol) was heated to
reflux for 3 h. After an evapolation of the solvent and an excess amount of
ethyl acrylate by rotary evapolator, colorless oily residue was passed through
the column chromatography packed with silica gel to give cis- and trans-5-
(ethoxycarbonyl)-2-methyl-3-phenylisoxazolidines (3bA, 3؅bA) and cis- and
trans-4-(ethoxycarbonyl)-2-methyl-3-phenylisoxazolidines (4bA, 4؅bA) in
95% total yields (447 mg). The ratio of the four isomers (3aA, 3؅aA, 4aA,
4؅aA) was found to be 21 : 58 : 9 : 12, respectively, by the analysis of the 1H-
NMR spectra. Some of the four isomers were isolated by the chromatogra-
phy though the yields were poor. Chloroform and the mixed solvent with
ethanol were used for the eluent.
(3R*,5S*)-5-(Ethoxycarbonyl)-2-methyl-3-phenylisoxazolidine (3bA):
1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 2.58—2.68 (m, 1H), 2.96 (ddd,
1H, Jϭ7.2, 9.3, 12.9 Hz), 2.61 (s, 3H), 3.75—3.86 (m, 1H), 4.26 (q, 2H,
Jϭ7.2 Hz), 4.62 (dd, 1H, Jϭ5.7, 9.3 Hz), 7.27—7.42 (m, 5H). HR-MS m/z;
235.1204 (Calcd for C13H17NO3: 235.1208).
(3R*,5R*)-5-(Ethoxycarbonyl)-2-methyl-3-phenylisoxazolidine (3؅bA):
1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 2.62—2.79 (m, 2H), 2.69 (s,
3H), 3.65—3.74 (m, 1H), 4.25 (q, 2H, Jϭ7.2 Hz), 4.68 (dd, 1H, Jϭ5.4,
9.9 Hz), 7.26—7.41 (m, 5H). HR-MS m/z; 235.1215 (Calcd for C13H17NO3:
235.1208).
(3R*,4R*)-4-(Ethoxycarbonyl)-2-methyl-3-phenylisoxazolidine (4bA):
1H-NMR (CDCl3) d: 0.75 (t, 3H, Jϭ7.2 Hz), 2.65 (s, 3H), 3.56 (dd, 1H,
Jϭ6.9, 10.5 Hz), 3.70 (q, 2H, Jϭ7.2 Hz), 4.12—4.25 (m, 3H), 7.22—7.50
(m, 5H). HR-MS m/z; 235.1211 (Calcd for C13H17NO3: 235.1208).
(3R*,4S*)-4-(Ethoxycarbonyl)-2-methyl-3-phenylisoxazolidine (4؅bA):
1H-NMR (CDCl3) d: 1.22 (t, 3H, Jϭ7.2 Hz), 2.64 (s, 3H), 3.44 (dt, 1H,
Jϭ6.3, 7.8 Hz), 4.10 (d, 1H, Jϭ7.8 Hz), 4.12—4.24 (m, 2H). 4.25 (q, 2H,
Jϭ7.2 Hz), 7.22—7.50 (m, 5H). HR-MS m/z; 235.1217 (Calcd for
C13H17NO3: 235.1208).
1
Reaction of C-Aryl-N-methylnitrone (1b—j) with Allyl Alcohol (2G)
in the Absence of Lewis Acid These reactions were carried out according
to the method described in the reaction of 1a with 2A except for using
toluene as the solvent. Yields and the ratio of cis- and trans-3-aryl-5-(hy-
droxymethyl)-2-methylisoxazolidines (3, 3Ј) were summarized in Table 3.
1H-NMR spectral data of the isoxazolidines were as follows.
(3R*,5S*)-5-(Hydroxymethyl)-2-methyl-3-phenylisoxazolidine (3bG):
1H-NMR (CDCl3) d: 1.63 (br s, 1H), 2.25 (ddd, 1H, Jϭ5.4, 9.3, 12.3 Hz),
2.61 (s, 3H), 2.79 (dt, 1H, Jϭ8.1, 12.3 Hz), 3.74—3.83 (m, 3H), 4.30—4.39
(m, 1H), 7.24—7.48 (m, 5H). HR-MS m/z; 193.1105 (Calcd for C11H15NO2:
193.1103).
(3R*,5R*)-5-(Hydroxymethyl)-2-methyl-3-phenylisoxazolidine (3؅bG):
1H-NMR (CDCl3) d: 1.83 (br s, 1H), 2.37 (dt, 1H, Jϭ8.7, 12.3 Hz), 2.55
(ddd, 1H, Jϭ5.4, 7.8, 12.3 Hz), 2.61 (s, 3H), 3.56—3.82 (m, 3H), 4.03—
4.39 (m, 1H), 7.24—7.48 (m, 5H). HR-MS m/z; 193.1109 (Calcd for
C11H15NO2: 193.1103).
(3R*,5S*)-5-(Hydroxymethyl)-2-methy-3-(2-quinolyl)isoxazolidine
(3iG): 1H-NMR (CDCl3) d: 2.40—2.60 (m, 1H), 2.60 (br s, 1H), 2.69 (s,
3H), 2.91 (dt, 1H, Jϭ8.4, 12.6 Hz), 3.76 (dd, 1H, Jϭ5.1, 11.4 Hz), 3.83 (dd,
1H, Jϭ3.0, 12 Hz), 4.05—4.17 (m, 1H), 4.44—4.54 (m, 1H), 7.52 (t, 1H,
Jϭ8.1 Hz), 7.64 (d, 1H, Jϭ8.7 Hz), 7.70 (t, 1H, Jϭ8.4 Hz), 7.79 (d, 1H,
Jϭ8.1 Hz), 8.07 (d, 1H, Jϭ8.4 Hz), 8.16 (d, 1H, Jϭ8.7 Hz). HR-MS m/z;
244.1214 (Calcd for C14H16N2O2: 244.1212).
(3R*,5R*)-5-(Hydroxymethyl)-2-methy-3-(2-quinolyl)isoxazolidine
(3؅iG): 1H-NMR (CDCl3) d: 2.60 (br s, 1H), 2.63—2.75 (m, 2H), 2.69 (s,
3H), 3.67 (dd, 1H, Jϭ5.1, 12.0 Hz), 3.83 (dd, 1H, Jϭ3.0, 12.0 Hz), 3.95—
4.05 (m, 1H), 4.37—4.44 (m, 1H), 7.52 (t, 1H, Jϭ8.1 Hz), 7.64 (d, 1H,
Jϭ8.7 Hz), 7.70 (t, 1H, Jϭ8.4 Hz), 7.79 (d, 1H, Jϭ8.1 Hz), 8.07 (d, 1H,
Jϭ8.4 Hz), 8.16 (d, 1H, Jϭ8.7 Hz). HR-MS m/z; 244.1218 (Calcd for
C14H16N2O2: 244.1212).
(3R*,5R*)-3-(2-Furyl)-5-(hydroxymethyl)-2-methylisoxazolidine (3ЈjG):
1H-NMR (CDCl3) d: 2.34—2.50 (m, 1H), 2.53—2.64 (m, 1H), 2.65 (s, 3H),
2.82 (br s, 1H), 3.59 (dd, 2H, Jϭ4.5, 12.0 Hz), 3.78 (dd, 1H, Jϭ3.0,
12.0 Hz), 4.30—4.45 (m, 1H), 6.27 (d, 1H, Jϭ3.0 Hz), 6.31 (dd, 1H, Jϭ1.8,
3.0 Hz), 7.37 (d, 1H, Jϭ1.8 Hz). HR-MS m/z; 183.0899 (Calcd for
C9H13NO3: 183.0895).
Transformation of 3aA, 3؅aA, 4aA, and 4؅aA into 3؅aG, 3aG, 4؅aG,
and 4aG To a suspension of lithium alminium hydride (110 mg, 2.9 mmol)
in dry tetrahydrofuran (THF) (15 ml) was added a dry-THF solution (5 ml)
(3R*,5S*)-5-(Hydroxymethyl)-2-methyl-3-(2-methylphenyl)isoxazolidine
1
(3cG): H-NMR (CDCl3) d: 2.04 (ddd, 1H, Jϭ5.4, 9.6, 12.6 Hz), 2.20 (br s,
1H), 2.35 (s, 3H), 2.61 (s, 3H), 2.80 (dt, 1H, Jϭ8.1, 12.3 Hz), 3.62 (dd, 1H,
Jϭ4.8, 12.0 Hz), 3.68—3.78 (m, 1H), 3.84 (dd, 1H, Jϭ3.0, 12.0 Hz), 4.30—
4.40 (m, 1H), 7.12—7.24 (m, 3H), 7.47—7.51 (m, 1H). HR-MS m/z;
207.1258 (Calcd for C12H17NO2: 207.1259).
(3R*,5R*)-5-(Hydroxymethyl)-2-methyl-3-(2-methylphenyl)isoxazolidine
1
(3؅cG): H-NMR (CDCl3) d: 2.18—2.33 (m, 1H), 2.20 (br s, 1H), 2.35 (s,
of
a mixture of 3aA, 3؅aA, 4aA, and 4؅aA (290 mg, 0.93 mmol;
3H), 2.55 (ddd, 1H, Jϭ6.0, 8.1, 12.0 Hz), 2.61 (s, 3H), 3.62 (dd, 1H, Jϭ4.8,
12.0 Hz), 3.68—3.78 (m, 1H), 3.84 (dd, 1H, Jϭ3.0, 12.0 Hz), 4.30—4.40
(m, 1H), 7.12—7.24 (m, 3H), 7.47—7.51 (m, 1H). HR-MS m/z; 207.1266
(Calcd for C12H17NO2: 207.1259).
(3R*,5S*)-5-(Hydroxymethyl)-2-methyl-3-(2-naphthyl)isoxazolidine
(3dG): 1H-NMR (CDCl3) d: 1.95 (br s, 1H), 2.36 (ddd, 1H, Jϭ5.7, 9.6,
12.6 Hz), 2.61 (s, 3H), 2.82 (dt, 1H, Jϭ8.1, 12.6 Hz), 3.60—3.70 (m, 2H),
3.84—3.92 (m, 1H), 7.46—7.54 (m, 3H), 7.80—7.86 (m, 4H). HR-MS m/z;
243.1256 (Calcd for C15H17NO2: 243.1259).
(3R*,5R*)-5-(Hydroxymethyl)-2-methyl-3-(2-naphthyl)isoxazolidine
(3؅dG): 1H-NMR (CDCl3) d: 1.95 (br s, 1H), 2.43—2.53 (m, 1H), 2.55—
2.65 (m, 1H), 2.61 (s, 3H), 3.60—3.70 (m, 2H), 3.84—3.92 (m, 1H), 7.46—
7.54 (m, 3H), 7.80—7.86 (m, 4H). HR-MS m/z; 243.1258 (Calcd for
C15H17NO2: 243.1259).
10 : 72 : 4 : 14 mixture, respectively) at room temperature under an atmos-
phere of nitrogen and, then, the mixture was heated to reflux for 2 h with
stirring. The reaction mixture was cooled down well and poured carefully
into separatory funnel containing ice-water (50 ml). Saturated aqueous solu-
tion (20 ml) of potassium carbonate and chloroform (40 ml) were also added
to the cooled mixture, which was shaken well. Emulsion thus formed was
filtered through a glass funnel, fitted with Celite bed, and then the bed was
washed well with chloroform. The chloroform layer was dried with anhy-
drous magnesium sulfate, from which the solvent was evaporated to give a
mixture of 3aG, 3؅aG, 4aG, and 4؅aG (10 : 70 : 5 : 15 mixture, respectively)
in 99% total yield (248 mg).
Alcoholysis of Nitrile (3؅aN) An ethanol solution (10 ml) of 3؅aN
(300 mg, 1.14 mmol) and p-toluenesulfonic acid monohydrate (300 mg,
1.58 mmol) was heated to 120 °C in a sealed tube and maintained at the tem-
perature for 15 h with stirring. Evapolation of the solvent from the reaction
mixture gave crystalline mass, which was dissolved in water and, then, ex-
tracted with chloroform several times. The combined toluene solution was
dried with anhydrous magnesium sulfate, from which the solvent was evapo-
lated by rotary evapolator. Viscous yellowish oily residue was passed
(3R*,5S*)-5-(Hydroxymethyl)-3-(2-methoxyphenyl)-2-methylisoxazoli-
1
dine (3eG): H-NMR (CDCl3) d: 2.06 (ddd, 1H, Jϭ5.7, 9.0, 12.3 Hz), 2.20
(br s, 1H), 2.61 (s, 3H), 2.80 (dt, 1H, Jϭ8.1, 12.3 Hz), 3.60—3.70 (m, 1H),
3.80—3.85 (m, 1H), 3.82 (s, 3H), 3.91—4.06 (m, 1H), 4.26—4.35 (m, 1H),
6.86 (d, 1H, Jϭ7.8 Hz), 6.95 (t, 1H, Jϭ7.5 Hz), 7.23 (t, 1H, Jϭ7.5 Hz), 7.45

July 2002
919
through the column chromatography packed with silica gel to give ester
(3؅aA) in 165 mg (53%) yield. Chloroform and the mixed solvent with
ethanol were used for the eluent.
3.77 (q, 2H, Jϭ7.2 Hz), 4.30 (t, 1H, Jϭ8.4 Hz), 4.56 (t, 1H, Jϭ8.1 Hz), 4.91
(d, 1H, Jϭ8.7 Hz), 6.89—7.53 (m, 9H). HR-MS m/z; 331.0972 (Calcd for
C18H18NO3Cl: 331.0975).
Reactions of N-Alkylnitrones (1a—j) with Alkenes (2A—P) in the
Presence of Lewis Acids. Typical Procedure To a toluene solution
(25 ml) of 1a (211 mg, 1.0 mmol) and allyl alcohol (580 mg, 10 mmol) was
added magnesium bromide etherate (260 mg, 1.0 mmol), and the mixture
was heated to reflux for 2 h under nitrogen atmosphere with vigorous stir-
ring. After cooling, water was added and extracted with toluene several
times. The combined toluene solution was dried with anhydrous magnesium
sulfate, from which the solvent and an excess amount of acrylate were evap-
olated by rotary evapolator. Viscous colorless oily residue was passed
through the column chromatography packed with silica gel using a mixed
solvent of chloroform and methanol (25 : 1) to give cis- and trans-2-benzyl-
5-(hydroxymethyl)-3-phenylisoxazolidines (3aG, 3؅aG) in 14% (38 mg) and
48% (129 mg) yields, respectively.
Results of the other reactions were summarized in Tables 1 and 3.
Reactions of C-Phenyl-N-arylnitrones (1k—n) with 2A or 2N in the
Absence of Lewis Acids These reactions were carried out according to the
Typical Procedure described in the reaction of 1a with 2A. Reaction condi-
tions and yields of products were shown in Table 4. 1H-NMR spectral data of
the isoxazolidines were as follows;
Ethyl (3R*,4S*)-2-(4-Chlorophenyl)-3-phenylisoxazolidin-4-carboxylate
(4؅nA): 1H-NMR (CDCl3) d: 1.21 (t, 3H, Jϭ7.2 Hz), 3.55 (ddd, 1H, Jϭ5.7,
6.6, 7.8 Hz), 4.19 (q, 2H, Jϭ7.2 Hz), 4.31 (dd, 1H, Jϭ6.9, 8.4 Hz), 4.38 (t,
1H, Jϭ8.1 Hz), 4.93 (d, 1H, Jϭ6.0 Hz), 6.90 (d, 2H, Jϭ9.0 Hz), 7.17 (d, 2H,
Jϭ9.0 Hz), 7.25—7.43 (m, 3H), 7.48—7.54 (m, 2H). HR-MS m/z; 331.0976
(Calcd for C18H18NO3Cl: 331.0975).
Ethyl (3R*,5R*)-5-Methyl-2,3-diphenylisoxazolidin-5-carboxylate (3kN):
1H-NMR (CDCl3) d: 1.09 (t, 3H, Jϭ7.2 Hz), 1.65 (s, 3H), 2.35 (dd, 1H,
Jϭ9.0, 12.9 Hz), 3.35 (dd, 1H, Jϭ7.2, 12.6 Hz), 4.02 (q, 2H, Jϭ7.2 Hz),
4.77 (dd, 1H, Jϭ7.2, 9.0 Hz), 6.84—7.49 (m, 10H). HR-MS m/z; 311.1524
(Calcd for C19H21NO3: 311.1521).
Ethyl (3R*,5S*)5-Methyl-2,3-diphenylisoxazolidin-5-carboxylate (3؅kN):
1H-NMR (CDCl3) d: 1.27 (s, 3H), 1.61 (s, 3H), 2.68 (dd, 1H, Jϭ9.0,
12.9 Hz), 3.04 (dd, 1H, Jϭ6.6, 12.9 Hz), 4.22 (q, 2H, Jϭ7.2 Hz), 4.48 (dd,
1H, Jϭ6.6, 9.0 Hz), 6.84—7.49 (m, 10H). HR-MS m/z; 311.1528 (Calcd for
C19H21NO3: 311.1521).
Ethyl (3R*,5R*)-5-Methyl-2-(4-methylphenyl)-3-phenylisoxazolidin-5-
carboxylate (3mN): 1H-NMR (CDCl3) d: 1.31 (t, 3H, Jϭ7.2 Hz), 1.63 (s,
3H), 2.33 (dd, 1H, Jϭ9.0, 12.3 Hz), 2.41 (s, 3H), 3.31 (dd, 1H, Jϭ6.9,
12.3 Hz), 4.05 (q, 2H, Jϭ7.2 Hz), 4.70 (dd, 1H, Jϭ7.2, 9.0 Hz), 6.85—7.48
(m, 9H). HR-MS m/z; 325.1684 (Calcd for C20H23NO3: 325.1678).
Ethyl (3R*,5S*)-2,3-Diphenylisoxazolidin-5-carboxylate (3kA): 1H-NMR
(CDCl3) d: 1.25 (t, 3H, Jϭ7.2 Hz), 2.71 (dt, 1H, Jϭ6.3, 12.6 Hz), 3.06 (dt,
1H, Jϭ8.4, 12.6 Hz), 4.21 (q, 2H, Jϭ7.2 Hz), 4.68 (dd, 1H, Jϭ6.3, 8.4 Hz),
4.78 (dd, 1H, Jϭ6.3, 8.4 Hz), 6.95—7.51 (m, 10H). HR-MS m/z; 297.1366
(Calcd for C18H19NO3: 297.1365).
Ethyl
(3R*,5S*)-5-Methyl-2-(4-methylphenyl)-3-phenylisoxazolidin-5-
1
carboxylate (3؅mN): H-NMR (CDCl3) d: 1.30 (t, 3H, Jϭ7.2 Hz), 1.60 (s,
3H), 2.22 (s, 3H), 2.65 (dd, 1H, Jϭ9.0, 12.6 Hz), 3.03 (dd, 1H, Jϭ6.9,
12.6 Hz), 4.21 (q, 2H, Jϭ7.2 Hz), 4.40 (dd, 1H, Jϭ6.6, 9.0 Hz), 6.85—7.48
(m, 9H). HR-MS m/z; 325.1685 (Calcd for C20H23NO3: 325.1678).
Ethyl (3R*,5R*)-2-(4-Chlorophenyl)-5-methyl-3-phenylisoxazolidin-5-
carboxylate (3nN): 1H-NMR (CDCl3) d: 1.14 (t, 3H, Jϭ7.2 Hz), 1.64 (s,
3H), 2.34 (dd, 1H, Jϭ9.1, 12.3 Hz), 3.33 (dd, 1H, Jϭ7.2, 12.3 Hz), 4.04 (q,
2H, Jϭ7.2 Hz), 4.69 (dd, 1H, Jϭ7.2, 9.6 Hz), 6.84—7.46 (m, 9H). HR-MS
m/z; 345.1140 (Calcd for C19H20NO3Cl: 345.1132).
Ethyl (3R*,5R*)-2,3-Diphenylisoxazolidin-5-carboxylate (3؅kA): 1H-
NMR (CDCl3) d: 1.23 (t, 3H, Jϭ7.2 Hz), 2.69 (ddd, 1H, Jϭ6.6, 7.8,
12.6 Hz), 2.95 (ddd, 1H, Jϭ5.7, 7.2, 12.6 Hz), 4.19 (q, 2H, Jϭ7.2 Hz),
4.72—4.79 (m, 2H), 6.92—7.56 (m, 10H). HR-MS m/z; 297.1369 (Calcd for
C18H19NO3: 297.1365).
Ethyl (3R*,4R*)-2,3-Diphenylisoxazolidin-4-carboxylate (4kA): 1H-NMR
(CDCl3) d: 0.91 (t, 3H, Jϭ6.9 Hz), 3.65—3.82 (m, 1H), 3.76 (q, 2H,
Jϭ6.9 Hz), 4.33 (t, 1H, Jϭ8.1 Hz), 4.56 (t, 1H, Jϭ7.8 Hz), 5.01 (d, 1H,
Jϭ9.0 Hz), 6.92—7.56 (m, 10H). HR-MS m/z; 297.1360 (Calcd for
C18H19NO3: 297.1365).
Ethyl (3R*,5S*)-2-(4-Chlorophenyl)-5-methyl-3-phenylisoxazolidin-5-
carboxylate (3؅nN): 1H-NMR (CDCl3) d: 1.29 (t, 3H, Jϭ7.2 Hz), 1.60 (s,
3H), 2.67 (dd, 1H, Jϭ9.0, 12.6 Hz), 3.03 (dd, 1H, Jϭ6.9, 12.6 Hz), 4.21 (q,
2H, Jϭ7.2 Hz), 4.41 (dd, 1H, Jϭ6.6, 9.0 Hz), 6.84—7.46 (m, 9H). HR-MS
m/z; 345.1144 (Calcd for C19H20NO3Cl: 345.1132).
Ethyl (3R*,4S*)-2,3-Diphenylisoxazolidin-4-carboxylate (4؅kA): 1H-
NMR (CDCl3) d: 1.20 (t, 3H, Jϭ7.2 Hz), 3.55 (ddd, 1H, Jϭ5.7, 6.9, 7.8 Hz),
4.13 (q, 2H, Jϭ7.2 Hz), 4.32 (dd, 1H, Jϭ6.9, 8.4 Hz), 4.37 (dd, 1H, Jϭ7.8,
8.4 Hz), 5.01 (d, 1H, Jϭ5.7 Hz), 6.92—7.56 (m, 10H). HR-MS m/z;
297.1366 (Calcd for C18H19NO3: 297.1365).
Reactions of C-Phenyl-N-arylnitrones (1k—n) with 2A or 2N in the
Presence of Lewis Acids. Typical Procedure To a chloroform solution
(25 ml) of 1k (211 mg, 1.0 mmol) and ethyl acrylate (1.0 g, 10 mmol) was
added magnesium bromide etherate (260 mg, 1.0 mmol), and the mixture
was heated to reflux for 6 h under nitrogen atmosphere with vigorous stir-
ring. After cooling, water was added and extracted with chloroform several
times. The combined chloroform solution was dried with anhydrous magne-
sium sulfate, from which the solvent and an excess amount of acrylate were
evapolated by rotary evapolator. Viscous yellow oily residue was passed
through the column chromatography packed with silica gel using a mixed
solvent of chloroform and ethanol to give a pair of diastereomer of ethyl
4-(2-bromophenylamino)-2-hydroxybutanoate (5kA), a pair of diastereomer
of ethyl 3-(2-bromophenylamino)-2-(hydroxymethyl)-3-phenylpropanoate
(6kA), and 4؅kA in 17% (64 mg), 46% (174 mg), and 19% (56 mg) yields,
respectively.
Ethyl (3R*,5S*)-2-(4-Methylphenyl)-3-phenylisoxazolidin-5-carboxylate
1
(3mA): H-NMR (CDCl3) d: 1.24 (t, 3H, Jϭ7.2 Hz), 2.26 (s, 3H), 2.67 (dt,
1H, Jϭ6.3, 12.6 Hz), 3.04 (dt, 1H, Jϭ8.4, 12.6 Hz), 4.19 (q, 2H, Jϭ7.2 Hz),
4.60 (dd, 1H, Jϭ6.3, 8.4 Hz), 4.78 (dd, 1H, Jϭ6.3, 8.4 Hz), 6.88—7.54 (m,
9H). HR-MS m/z; 311.1522 (Calcd for C19H21NO3: 311.1521).
Ethyl (3R*,5R*)-2-(4-Methylphenyl)-3-phenylisoxazolidin-5-carboxylate
(3؅mA): 1H-NMR (CDCl3) d: 1.26 (t, 3H, Jϭ7.2 Hz), 2.25 (s, 3H), 2.71
(ddd, 1H, Jϭ6.9, 7.5, 12.6 Hz), 2.91 (ddd, 1H, Jϭ5.7, 7.2, 12.6 Hz), 4.20 (q,
2H, Jϭ7.2 Hz), 4.67 (t, 1H, Jϭ7.2 Hz), 4.75 (dd, 1H, Jϭ5.7, 7.5 Hz), 6.88—
7.54 (m, 9H). HR-MS m/z; 311.1510 (Calcd for C19H21NO3: 311.1521).
Ethyl (3R*,4R*)-2-(4-Methylphenyl)-3-phenylisoxazolidin-4-carboxylate
1
(4mA): H-NMR (CDCl3) d: 0.90 (t, 3H, Jϭ7.2 Hz), 2.73 (s, 3H), 3.62—
3.81 (m, 1H), 3.75 (q, 2H, Jϭ7.2 Hz), 4.34 (t, 1H, Jϭ8.1 Hz), 4.54 (t, 1H,
Jϭ7.8 Hz), 4.95 (d, 1H, Jϭ9.0 Hz), 6.88—7.54 (m, 9H). HR-MS m/z;
311.1523 (Calcd for C19H21NO3: 311.1521).
Ethyl 4-(2-Bromophenylamino)-2-hydroxy-4-phenylbutanoate (5kA: Di-
astereomer A): 1H-NMR (CDCl3) d: 1.26 (t, 3H, Jϭ7.2 Hz), 2.06—2.35 (m,
2H), 4.19 (q, 2H, Jϭ7.2 Hz), 4.60 (dd, 1H, Jϭ6.0, 8.1 Hz), 4.74—4.80 (m,
1H), 6.39 (d, 1H, Jϭ8.7 Hz), 6.46—6.52 (m, 1H), 7.12—7.42 (m, 7H). HR-
MS m/z; 377.0633 (Calcd for C18H20NO3Br: 377.0627).
Ethyl 4-(2-Bromophenylamino)-2-hydroxy-4-phenylbutanoate (5kA: Di-
astereomer B): 1H-NMR (CDCl3) d: 1.27 (t, 3H, Jϭ7.2 Hz), 2.06—2.35 (m,
2H), 4.19 (q, 2H, Jϭ7.2 Hz), 4.66 (dd, 1H, Jϭ3.9, 8.1 Hz), 4.74—4.80 (m,
1H), 6.40 (d, 1H, Jϭ8.7 Hz), 6.46—6.52 (m, 1H), 7.12—7.42 (m, 7H). HR-
MS m/z; 377.0630 (Calcd for C18H20NO3Br: 377.0627).
Ethyl 3-(2-Bromophenylamino)-2-(hydroxymethyl)-3-phenylpropanoate
(6kA: Diastereomer A): 1H-NMR (CDCl3) d: 1.21 (t, 3H, Jϭ7.2 Hz), 2.95—
3.05 (m, 1H), 3.74—3.85 (m, 2H), 3.81—4.22 (m, 2H), 4.12 (q, 2H,
Jϭ7.2 Hz), 4.87 (d, 1H, Jϭ7.2 Hz), 6.41—7.41 (m, 9H). HR-MS m/z;
377.0622 (Calcd for C18H20NO3Br: 377.0627).
Ethyl (3R*,4S*)-2-(4-Methylphenyl)-3-phenylisoxazolidin-4-carboxylate
(4؅mA): 1H-NMR (CDCl3) d: 1.20 (t, 3H, Jϭ7.2 Hz), 2.27 (s, 3H), 3.54
(ddd, 1H, Jϭ6.0, 6.6, 8.1 Hz), 4.12 (q, 2H, Jϭ7.2 Hz), 4.32 (dd, 1H, Jϭ6.9,
8.4 Hz), 4.37 (dd, 1H, Jϭ7.8, 8.4 Hz), 4.93 (d, 1H, Jϭ5.7 Hz), 6.88—7.54
(m, 9H). HR-MS m/z; 311.1523 (Calcd for C19H21NO3: 311.1521).
Ethyl (3R*,5S*)-2-(4-Chlorophenyl)-3-phenylisoxazolidin-5-carboxylate
(3nA): 1H-NMR (CDCl3) d: 1.26 (t, 3H, Jϭ7.2 Hz), 2.71 (dt, 1H, Jϭ6.3,
12.6 Hz), 3.07 (dt, 1H, Jϭ8.4, 12.6 Hz), 4.18 (q, 2H, Jϭ7.2 Hz), 4.56 (dd,
1H, Jϭ6.3, 8.4 Hz), 4.76 (dd, 1H, Jϭ6.3, 8.4 Hz), 6.89—7.53 (m, 9H). HR-
MS m/z; 331.0970 (Calcd for C18H18NO3Cl: 331.0975).
Ethyl (3R*,5R*)-2-(4-Chlorophenyl)-3-phenylisoxazolidin-5-carboxylate
1
(3؅nA): H-NMR (CDCl3) d: 1.24 (t, 3H, Jϭ7.2 Hz), 2.69 (dt, 1H, Jϭ7.2,
12.6 Hz), 2.94 (ddd, 1H, Jϭ5.4, 7.2, 12.6 Hz), 4.22 (q, 2H, Jϭ7.2 Hz), 4.67
(t, 1H, Jϭ7.2 Hz), 4.76 (dd, 1H, Jϭ5.4, 7.2 Hz), 6.89—7.53 (m, 9H). HR-
MS m/z; 331.0968 (Calcd for C18H18NO3Cl: 331.0975).
Ethyl 3-(2-Bromophenylamino)-2-(hydroxymethyl)-3-phenylpropanoate
(6kA: Diastereomer B): 1H-NMR (CDCl3) d: 1.16 (t, 3H, Jϭ7.2 Hz), 2.95—
3.05 (m, 1H), 3.74—3.85 (m, 1H), 3.81—4.22 (m, 2H), 4.16 (q, 2H,
Jϭ7.2 Hz), 4.82 (d, 1H, Jϭ6.9 Hz), 6.41—7.41 (m, 9H). HR-MS m/z;
377.0625 (Calcd for C18H20NO3Br: 377.0627).
Ethyl (3R*,4R*)-2-(4-Chlorophenyl)-3-phenylisoxazolidin-4-carboxylate
(4nA): 1H-NMR (CDCl3) d: 0.90 (t, 3H, Jϭ7.2 Hz), 3.61—3.80 (m, 1H),

920
Vol. 50, No. 7
Similarly, the following g-aminoalcohols were obtained in yields shown
with silica gel using a mixed solvent of chloroform and ethanol to give bu-
tanoates (5kA), propanoates (6kA) and 4؅kA in 61% (224 mg), 14%
(51 mg), and 13% (37 mg) yields, respectively.
Similarly, ethyl 2-hydroxy-2-methyl-4-(4-methylphenylamino)-4-
phenylbutanoate (8mN) was obtained from 3mN.
Ethyl 2-Hydroxy-2-methyl-4-(4-methylphenylamino)-4-phenylbutanoate
(8mN): 1H-NMR (CDCl3) d: 1.28 (t, 3H, Jϭ7.2 Hz), 1.45 (s, 3H), 2.14 (dd,
1H, Jϭ9.6, 14.7 Hz), 2.18 (s, 3H), 2.30 (dd, 1H, Jϭ3.9, 14.7 Hz), 4.13 (q,
1H, Jϭ7.2 Hz), 4.16 (q, 1H Jϭ7.2 Hz), 4.37 (dd, 1H, Jϭ3.9, 9.6 Hz), 6.45
(d, 2H, Jϭ8.4 Hz), 6.89 (d, 2H, Jϭ8.4 Hz), 7.19—7.31 (m, 5H). HR-MS
m/z; 327.1832 (Calcd for C20H25NO3: 327.1834).
in Table 4 from the reaction of 1k—m with 2A or 2N.
Ethyl 4-(2-Bromo-4-methylphenylamino)-2-hydroxy-4-phenylbutanoate
1
(5mA: Diastereomer A): H-NMR (CDCl3) d: 1.27 (t, 3H, Jϭ7.2 Hz), 2.15
(s, 3H), 2.12—2.35 (m, 2H), 4.13 (dd, 1H, Jϭ7.2, 12.0 Hz), 4.19 (q, 2H,
Jϭ7.2 Hz), 4.71—4.76 (m, 1H), 6.39 (d, 1H, Jϭ8.1 Hz), 6.79 (d, 1H,
Jϭ8.1 Hz), 7.20—7.37 (m, 6H). HR-MS m/z; 391.0780 (Calcd for
C19H22NO3Br: 391.0783).
Ethyl 4-(2-Bromo-4-methylphenylamino)-2-hydroxy-4-phenylbutanoate
1
(5mA: Diastereomer B): H-NMR (CDCl3) d: 1.27 (t, 3H, Jϭ7.2 Hz), 2.15
(s, 3H), 2.12—2.35 (m, 2H), 4.19 (q, 2H, Jϭ7.2 Hz), 4.32 (dd, 1H, Jϭ3.0,
9.0 Hz), 4.71—4.76 (m, 1H), 6.34 (d, 1H, Jϭ8.1 Hz), 6.79 (d, 1H,
Jϭ8.1 Hz), 7.20—7.37 (m, 6H). HR-MS m/z; 391.0791 (Calcd for
C19H22NO3Br: 391.0783).
References
1) Padwa A. (ed.), “1,3-Dipolar Cycloaddition Chemistry,” Interscience,
New York, 1984.
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York, 1977, pp. 369—532.
Ethyl 3-(2-Bromo-4-methylphenylamino)-2-(hydroxymethyl)-3-phenyl-
propanoate (6mA: Diastereomer A): 1H-NMR (CDCl3) d: 1.22 (t, 3H,
Jϭ7.2 Hz), 2.14 (s, 3H), 2.92—3.02 (m, 1H), 3.74—3.85 (m, 2H), 4.14 (q,
2H, Jϭ7.2 Hz), 4.81—4.86 (m, 1H), 6.34 (d, 1H, Jϭ8.1 Hz), 6.79 (d, 1H,
Jϭ8.1 Hz), 7.22—7.33 (m, 6H). HR-MS m/z; 391.0795 (Calcd for
C19H22NO3Br: 391.0783).
3) Carruthers W., “Cycloaddition Reaction in Organic Synthesis,” Perga-
mon Press, New York, 1990, pp. 269—331.
Ethyl 3-(2-Bromo-4-methylphenylamino)-2-(hydroxymethyl)-3-phenyl-
propanoate (6mA: Diastereomer B): 1H-NMR (CDCl3) d: 1.16 (t, 3H,
Jϭ7.2 Hz), 2.14 (s, 3H), 2.92—3.02 (m, 1H), 3.74—3.85 (m, 1H), 3.96 (dd,
1H, Jϭ3.6, 12.0 Hz), 4.16 (q, 2H, Jϭ7.2 Hz), 5.12 (d, 1H, Jϭ3.9 Hz), 6.31
(d, 1H, Jϭ7.8 Hz), 6.78 (d, 1H, Jϭ8.1 Hz), 7.22—7.33 (m, 6H). HR-MS
m/z; 391.0789 (Calcd for C19H22NO3Br: 391.0783).
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Ethyl 4-(2-Bromo-4-chlorophenylamino)-2-hydroxy-4-phenylbutanoate
1
(5nA: Diastereomer A): H-NMR (CDCl3) d: 1.27 (t, 3H, Jϭ7.2 Hz), 2.19
(ddd, 1H, Jϭ3.9, 9.3, 14.4 Hz), 2.31 (ddd, 1H, Jϭ3.0, 8.1, 14.4 Hz), 3.00
(br s, 1H), 4.19 (q, 2H, Jϭ7.2 Hz), 4.24—4.33 (m, 1H), 4.73 (dd, 1H, Jϭ3.9,
8.1 Hz), 5.60 (br s, 1H), 6.30 (d, 1H, Jϭ8.7 Hz), 6.94 (dd, 1H, Jϭ2.4,
8.7 Hz), 7.20—7.36 (m, 5H), 7.39 (d, 1H, Jϭ2.4 Hz). HR-MS m/z; 411.0240
(Calcd for C18H19NO3BrCl: 411.0237).
Ethyl 4-Methyl-2,3-diphenylisoxazolidin-4-carboxylate (4kN): 1H-NMR
(CDCl3) d: 1.03 (s, 3H), 1.24 (t, 3H, Jϭ6.9 Hz), 3.93 (d, 1H, Jϭ8.4 Hz),
4.16 (q, 2H, Jϭ7.2 Hz), 6.80—7.50 (m, 10H). HR-MS m/z; 311.1518 (Calcd
for C19H21NO3: 311.1521).
Ethyl 4-(2-Bromophenylamino)-2-hydroxy-2-methyl-4-phenylbutanoate
(5kN: Diastereomer A): mp. 126—128 °C (from ethanol); 1H-NMR (CDCl3)
d: 1.23 (t, 3H, Jϭ7.2 Hz), 1.45 (s, 3H), 2.23 (dd, 1H, Jϭ9.0, 14.4 Hz), 2.33
(dd, 1H, Jϭ4.8, 14.4 Hz), 3.72 (br s, 1H), 4.06 (q, 1H, Jϭ7.2 Hz), 4.11 (q,
1H, Jϭ7.2 Hz), 4.43 (dd, 1H, Jϭ4.8, 9.0 Hz), 5.50 (br s, 1H), 6.32 (dd, 1H,
Jϭ1.5, 8.1 Hz), 6.49 (dt, 1H, Jϭ1.5, 7.5 Hz), 6.95 (ddd, 1H, Jϭ1.5, 7.5,
8.1 Hz), 7.20—7.31 (m, 5H), 7.38 (dd, 1H, Jϭ1.5, 7.5 Hz). IR (KBr) cmϪ1
:
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3486, 3323, 1730. HR-MS m/z; 391.0780 (Calcd for C19H22NO3Br:
391.0783). Anal. Calcd for C19H22NO3Br: C, 57.53; H, 5.74; N, 3.63. Found:
C, 57.35; H, 5.88; N, 3.86.
Ethyl 4-(2-Bromo-4-methylphenylamino)-2-hydroxy-2-methyl-4-phenyl-
butanoate (5mN: Diastereomer A): 1H-NMR (CDCl3) d: 1.24 (t, 3H,
Jϭ7.2 Hz), 1.45 (s, 3H), 2.18 (s, 3H), 2.21 (dd, 1H, Jϭ9.3, 14.7 Hz), 2.32
(dd, 1H, Jϭ4.5, 14.7 Hz), 4.02—4.17 (m, 2H), 4.41 (dd, 1H, Jϭ4.5, 9.3 Hz),
6.26 (d, 1H, Jϭ8.1 Hz), 6.76 (d, 1H, Jϭ8.1 Hz), 7.19—7.31 (m, 6H). HR-
MS m/z; 405.0935 (Calcd for C20H24NO3Br: 405.0940).
Ethyl 4-(2-Bromo-4-chlorophenylamino)-2-hydroxy-2-methyl-4-phenyl-
butanoate (5nN: Diastereomer A): 1H-NMR (CDCl3) d: 1.24 (t, 3H,
Jϭ7.2 Hz), 1.44 (s, 3H), 2.22 (dd, 1H, Jϭ9.3, 14.7 Hz), 2.32 (ddd, 1H,
Jϭ0.6, 4.5, 14.7 Hz), 3.63 (s, 1H), 4.00—4.20 (m, 2H), 4.32—4.40 (m, 1H),
5.63 (d, 1H, Jϭ4.2 Hz), 6.20 (d, 1H, Jϭ8.7 Hz), 6.90 (dd, 1H, Jϭ2.4,
8.7 Hz), 7.20—7.35 (m, 5H), 7.38 (d, 1H, Jϭ2.4 Hz). HR-MS m/z; 425.0388
(Calcd for C19H21NO3BrCl: 425.0393).
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Chem., 56, 4473—4481 (1991).
Ethyl 4-(4-Chlorohenylamino)-2-hydroxy-2-methyl-4-phenylbutanoate
(8nN): 1H-NMR (CDCl3) d: 1.26 (t, 3H, Jϭ7.2 Hz), 1.43 (s, 3H), 2.09—
2.37 (m, 2H), 4.00—4.20 (m, 2H), 4.29 (dd, 1H, Jϭ4.2, 9.6 Hz), 6.39 (d,
2H, Jϭ8.7 Hz), 6.99 (d, 2H, Jϭ8.7 Hz), 7.20—7.40 (m, 5H). HR-MS m/z;
347.1281 (Calcd for C19H22NO3Cl: 347.1288).
Treatment of 2-Arylisoxazolidines with Lewis Acid. Typical Proce-
dure To a benzene solution (25 ml) of a mixture of 3kA, 3؅ka, 4kA, and
4؅kA (288 mg, 1.0 mmol; 26 : 44 : 14 : 16 mixture, respectively), was added
magnesium bromide etherate (260 mg, 1.0 mmol), and the mixture was
heated to reflux for 3 h under nitrogen atmosphere with vigorous stirring.
After cooling, water was added and extracted with chloroform several times.
The combined organic solution was dried with anhydrous magnesium sul-
fate, from which the solvents were evapolated by rotary evapolator. Viscous
yellow oily residue was passed through the column chromatography packed
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