Palladium-catalyzed cascade one-pot synthesis of 5-arylmethylisoxazolidines from N-homoallylhydroxylamines with aryl bromides

Article abstract of DOI:10.1016/j.tet.2007.12.014

A novel method for the synthesis of 5-arylmethylisoxazolidines via palladium-catalyzed reactions of aryl bromides with N-homoallylhydroxylamines is described. This reaction effects intramolecular C-O bond formation with concomitant intermolecular formatio

Full text of DOI:10.1016/j.tet.2007.12.014

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1641e1647
www.elsevier.com/locate/tet
Palladium-catalyzed cascade one-pot synthesis of 5-
arylmethylisoxazolidines from N-homoallylhydroxylamines
with aryl bromides
Dahong Jiang a,b, Jinsong Peng a,b, Yuanwei Chen a,
*
a Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, China
Received 30 October 2007; received in revised form 6 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
A novel method for the synthesis of 5-arylmethylisoxazolidines via palladium-catalyzed reactions of aryl bromides with N-homoallylhydroxyl-
amines is described. This reaction effects intramolecular CeO bond formation with concomitant intermolecular formation of a CeC bond
in moderate to good yields. Moderate to excellent diastereoselectivities are observed for the formation of the isoxazolidines. The catalytic
system has a tolerance to a wide variety of functional groups.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cascade reaction of O-homoallylhydroxylamines with aryl
iodides.11
The synthesis of isoxazolidine derivatives has received
much attention due to the prevalence of this moiety in biolo-
gically active molecules and natural products.1 They also serve
as precursors for b-amino alcohols,2 b-amino ketones,3
b-amino acids,4 and 3-isoxazolidones.5 The 1,3-dipolar cyclo-
addition of nitrones with alkenes was among these important
reactions for the construction of substituted isoxazolidines.6
However, one of today’s challenges in this field is to control
the regio-, diastereoselectivity and expand the scope of the
reactions to the unactivated alkenes.7 To avoid these problems
in 1,3-dipolar cycloaddition, a number of different synthetic
methods have been devised for the preparation, including reac-
tion of N-benzylhydroxylamines with a,b-unsaturated esters,8
reaction of hemiaminals with a,b-unsaturated esters bearing
a leaving group on its d-C,9 Pd(II)-catalyzed cyclofunctionali-
zation of O-homoallylhydroxylamines,10 and Pd(0)-catalyzed
We have a long-standing and continuing interest in this
field. In our laboratory, we recently developed a new method
for the stereoselective synthesis of substituted isoxazolidines
via Pd-catalyzed sequential reaction of aryl bromides with
O-homoallylhydroxylamines (Eq. 1) in high yields (up to
90%) and furthermore, selective diarylation of O-homoallyl-
hydroxylamines with different aryl bromides was also
achieved in one-pot process by an in situ modification of the
palladium catalyst via phosphine ligands exchange (Eq. 2).12
We have found that transformations of O-homoallylhydroxyl-
amine substrates provide cis-3,5-disubstituted products with
excellent levels of diastereoselectivities. To evaluate the scope
of this methodology, we set out to examine the reactions of
aryl bromides with N-homoallylhydroxylamines containing
a less nucleophilic oxygen atom. Herein we describe our
preliminary studies on the stereoselective synthesis of 5-aryl-
methylisoxazolidines via Pd(0)-promoted cascade reaction of
N-homoallylhydroxylamines with aryl bromides.13 These
studies illustrate the potential utility of this methodology for
the construction of various substituted isoxazolidines.
* Corresponding author.
E-mail address: chenyw@cioc.ac.cn (Y. Chen).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.014

1642
D. Jiang et al. / Tetrahedron 64 (2008) 1641e1647
1 mol % Pd2(dba)3
find that this transformation provided the 5-arylmethylisoxazo-
Ar
ONH2
Ph
2 mol % Xantphos 1
Ph
Ph
(1)
(2)
lidine 8a in 69% yield, though moderate diastereoselectivity
was observed (36:64, cis/trans ratio). To optimize the reaction
conditions, we judiciously screened the ligand, base, and cata-
lyst loading. Some results from that study are summarized in
Table 1. To our disappointment, an attempted survey of ligands
failed to improve the diastereoselectivity (entries 2e9, Table 1).
Noteworthy was that when DPE-phos and BINAP were em-
ployed as ligands, the major product was reversed to cis-diaste-
reomer (entries 2 and 9), which was also observed by Wolfe in
his recent work.13 Balancing the yield and the diastereoselectiv-
ity, the Xantphos 1 was selected as the ligand for the subsequent
studies. An attempt to decrease the reaction temperature pro-
vided no detectable amounts of the 5-arylmethylisoxazolidine
8a. NaO-t-Bu was proved to be clearly superior to other bases,
as Et3N, Cs2CO3, K2CO3, and K3PO4 gave no desired product
while the starting materials simply remained unchanged
(entries 10, 11, 13, and 14). This yield was further improved
to 84% by adding 2 mol % of Pd2(dba)3 and 4 mol % of Xant-
phos to the reaction mixture (entry 12). However, further in-
crease of the catalyst loading gave decreased yield (entry 17).
Use of THF as solvent resulted in a significantly lower yield
to those obtained in toluene (entry 18). It is worth to note that
either palladium or ligand was required for isoxazolidine for-
mation: stirring a mixture of N-benzyl-N-homoallylhydroxyl-
amine 3, bromobenzene, and NaO-t-Bu in toluene in the
+
2 ArBr
N
2.4 equiv NaOtBu
90 °C for 3h, toluene
O
Ar
3,5-cis : >50:1
1) Ar1Br, 1.5 mol% Pd2(dba)3
3 mol% 2, NaOtBu, Toluene
40 °C - 60 °C
Ar2
ONH2
Ph
O
N
2) Ar2Br, Xantphos 1
Ar1
90 °C
3,5-cis : >50:1
P(t-Bu)2
O
PPh2
PPh2
1
2
2. Results and discussion
In order to determine the feasibility of this process, we first
examined the reaction of N-benzyl-N-homoallylhydroxyl-
amine14 3 with 1.2 equiv of bromobenzene in the presence of
NaO-t-Bu (1.2 equiv) and catalytic amounts of Pd2(dba)3
(1 mol %) and Xantphos 1 (2 mol %). These reaction conditions
were derived from our earlier studies on Pd-catalyzed synthesis
of N-aryl-3-arylmethylisoxazolidines.12a We were pleased to
Table 1
Optimization of the reaction conditions in the synthesis of 8aa
Ph
Br
cat. Pd/L, base
solvent, 3-5 h
Ph
+
Ph
N
OH
N
Ph
O
8a
3
Entry
Ligand
mol % Pd2(dba)3
/mol % ligand
Base
Solvent
Yieldb (%)
Cis/transc
1
Xantphos 1
DPE-phos
dppe
1:2
1:2
1:2
1:2
1:4
2:4
2:8
2:4
2:4
1:2
1:2
2:4
2:4
2:4
2:0
0:4
4:8
2:4
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
Et3N
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
69
40
0d
11
57
77
38
52
68
0d
0d
84
0d
0d
0d
0d
56
44
36:64
63:37
d
2
3
4
dppb
Ph3P
nd
5
47:53
47:53
47:53
45:55
60:40
d
6
Ph3P
Ph3P
7
8
dppf
BINAP
9
10
11
12
13
14
15
16
17
18
Xantphos 1
Xantphos 1
Xantphos 1
Xantphos 1
Xantphos 1
d
Cs2CO3
d
NaO-t-Bu
K2CO3
K3PO4
37:63
d
d
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
d
d
Xantphos 1
Xantphos 1
Xantphos 1
35:65
37:63
DPE-phos¼bis(2-diphenylphosphinophenyl)ether, dppe¼1,2-bis(diphenylphosphino)ethane, dppb¼1,4-bis(diphenylphosphino)butane, dppf¼1,10-bis(diphenyl-
posphino)ferrocene.
a
Conditions: 1.0 equiv of hydroxylamine, 1.2 equiv of PhBr, 1.2 equiv of base, solvent (0.1 M), 90 ꢀC.
Isolated yield of 8a.
The cis/trans ratio of 8a was based on 1H NMR analysis.
Complete recovery of starting material.
b
c
d

D. Jiang et al. / Tetrahedron 64 (2008) 1641e1647
1643
Table 2
Palladium-catalyzed synthesis of 5-arylmethylisoxazolidines from corresponding hydroxylamines with aryl bromidesa
R2
R2
Ar
cat. Pd2(dba)3/Xantphos
R1
+
ArBr
N
N
NaOt-Bu, Toluene, 90 °C
O
R1
OH
Entry
1
Hydroxylamine
Ar
Ph
Product
Cis/transb
37:63
Yieldc (%)
3 (R1¼benzyl, R2¼Ph)
8a
69
84d
58
2
3
3
3
p-MeePh
8b
8c
32:68
45:55
78d
18
p-NO2ePh
32d
93d
87d
58d
40d
58d
73
4
5
6
7
8
9
3
p-Biphenyl
8d
8e
8f
23:77
42:58
40:60
41:59
62:38
d
3
2,4-Dimethylphenyl
p-CH3COePh
p-CHOePh
3
3
8g
8h
9a
3
o-Biphenyl
p-MeePh
4 (R1¼benzyl, R2¼H)
75d
76
10
11
12
13
14
15
16
17
a
4
4
4
o-ClePh
p-MeOePh
p-NO2ePh
p-CNePh
o-i-PrePh
Ph
9b
9c
d
d
78
11
9d
d
d
5 (R1¼cyclohexyl, R2¼H)
10a
10b
11
71
5
d
0
82
6 (R1¼cyclohexyl, R2¼Ph)
30:70
0:100
0:100
7 (R1¼R2¼e(CH2)4e)
Pyridin-3-yl
o-ClePh
12a
12b
72
85
7
Conditions: 1.0 equiv of hydroxylamine, 1.2 equiv of ArBr, 1 mol % of Pd2(dba)3, 2 mol % of Xantphos, 1.2 equiv of NaO-t-Bu, toluene (0.1 M), 90 ꢀC.
The cis/trans ratio was based on 1H NMR analysis.
b
c
d
Isolated yield. In the case of entries 1e8, it was an isolated yield of two isomers. In the case of entry 12, we were unable to isolate pure cyclized compound 9d.
Catalyst loading was 2 mol % of Pd2(dba)3 and 4 mol % of Xantphos instead.
absence of palladium or ligand produced no desired isoxazol-
idine after 5 h at 90 ꢀC (entries 15 and 16).
(entries 6, 7, 10, 13, and 17) and the heteroaryl bromide also
afforded the corresponding product in good yield (entry 16).
Stereo-hindered o-methyl (entry 5), o-phenyl (entry 8), and
o-chloro (entries 10 and 17) substituted aryl bromides had
little influence on the yield. On the contrary, o-isopropyl-
phenyl bromide failed to undergo the palladium-catalyzed cas-
cade conversion (entry 14), presumably due to the large
blocking group at the o-position of the aryl bromide.
In the cascade transformations of N-homoallylhydroxyl-
amine substrates bearing substituents at the position a to nitro-
gen atom, moderate diastereoselectivities were observed
(entries 1e8, Table 2). However, in the case of conversion of
the cyclohydroxylamine 7, a single diastereoisomer15 was
obtained (entries 16 and 17). The stereochemistry of a number
of the isoxazolidine products were determined by NOESY stud-
ies. For example, the stereochemistry of the major isomer of 8a
was confirmed to be trans because no correlation between the
protons H-3 and H-5 was observed in its NOESY experimental
data, while a distinct correlation between the two protons was
With the optimized reaction conditions in hand, we
prepared a wide range of 5-arylmethylisoxazolidines (Table
2). A number of N-homoallylhydroxylamines and aryl
bromides underwent the intramolecular ring closure with gen-
eration of a CeO bond, a CeC bond, and a stereocenter in
a single step to form the 5-benzylisoxazolidines. In contrast
to the conversion of O-homoallylhydroxylamines to 3-arylme-
thylisoxazolidine derivatives,12a the high yields were obtained
with both electron-neutral and electron-rich aryl bromides
(entries 1, 2, 4, 9, 11, and 15), though electron-deficient aryl
bromides slightly reduced the yields (entries 6, 7, and 13).
However, nitrophenyl bromide served as less effective sub-
strate to form isoxazolidines (entries 3 and 12); in the case
of entry 3, a large amount of the imine 13 (Fig. 1) as by-
product was detected after stirring at 90 ꢀC for 5 h and in
the case of entry 12, the yield was very low, generating lots
of complex mixtures that we have not further investigated.
Several functional groups are tolerated under these conditions
O
N
H
H
H
H
N
Figure 2. The 1H NOESY experimental data showing a distinct correlation
between the protons H-3 and H-5 of the minor isomer of 8a.
Figure 1. Imine 13.

1644
D. Jiang et al. / Tetrahedron 64 (2008) 1641e1647
detected in the NOESYexperimental data of the minor isomer of
8a (Fig. 2).
1H NMR spectra, multiplicities and abbreviations used are as
follows: Ar¼aromatic, Ph¼phenyl, d¼doublet, dd¼doublet
of doublets, m¼multiplet, q¼quartet, s¼singlet, t¼triplet.
High-resolution mass spectra were recorded on a Bruker
BIOTOF Q mass spectrometer.
The suggested mechanism of this reaction, taking the trans-
formation of the N-homoallylhydroxylamine 3 to isoxazolidine
8a, as an example, is shown in Scheme 1. Oxidative addition of
phenyl bromide to Pd(0) would lead to 14, which would be
transformed to 15 in the presence of NaO-t-Bu and hydroxyl-
amine 3. A syn insertion of the alkene into the PdeO bond
would give 16, which would undergo CeC bond forming
reductive elimination to afford the desired compound 8a and re-
generate the Pd(0) catalysis. The reason for transformations of
N-homoallylhydroxylamines bearing a substituent at 1-position
with low level of diastereoselectivities was not clear yet.
4.2. General procedure for the preparation of N-homoallyl-
hydroxylamine substrates
A solution of nitrone (1 equiv) in dry ether (0.25 M) was
stirred at room temperature as allylmagnesium bromide in ether
(0.30 M) was added. The resulting white suspension was stirred
for 1 h, and saturated ammonium chloride was added at 0 ꢀC.
The ether layer was separated from the aqueous layer, which
was extracted twice with ether. The combined ether layers
were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by flash chromatography on silica gel, eluting
with 5e10% ethyl acetateepetroleum ether.
Ph
N
O
PhBr
Ph
Ph
Ph
L-Pd(0)
8a
Ph
4.2.1. Compound 3
1H NMR (300 MHz, CDCl3) d 7.26e7.38 (m, 10H), 6.25 (br,
1H), 5.52e5.68 (m, 1H), 4.92e5.02 (m, 2H), 3.72e3.78 (m,
2H), 3.57 (d, J¼13.3 Hz, 1H), 2.89e2.92 (m, 1H), 2.58e2.61
(m, 1H). 13C NMR (75 MHz, CDCl3) d 139.8, 138.2, 135.5,
129.4, 128.9, 128.3, 128.2, 127.5, 127.2, 116.6, 71.8, 61.4, 38.2.
Ph
Br
N
O
L
Pd
L-Pd
14
Ph
16
3, NaOt-Bu
Ph
4.2.2. Compound 4
NaBr
Ph
1H NMR (300 MHz, CDCl3) d 7.29e7.36 (m, 5H), 7.00 (br,
1H), 5.76e5.82 (m, 1H), 5.01e5.11 (m, 2H), 3.78 (s, 2H), 2.74
(t, J¼7.2 Hz, 2H), 2.31e2.38 (m, 2H). 13C NMR (75 MHz,
CDCl3) d 136.9, 136.2, 129.9, 128.3, 127.5, 115.7, 64.8, 58.7, 31.4.
Ph
O
N
Pd
L
15
Scheme 1. Proposed catalytic cycle.
4.2.3. Compound 5
1H NMR (300 MHz, CDCl3) d 6.40 (br, 1H), 5.78e5.87
(m, 1H), 4.97e5.10 (m, 2H), 2.77 (t, J¼7.2 Hz, 2H), 2.49e2.55
(m, 1H), 2.32e2.39 (m, 2H), 1.93e1.95 (m, 2H), 1.78e1.80 (m,
2H), 1.55e1.63 (m, 1H), 1.17e1.28 (m, 5H). 13C NMR
(75 MHz, CDCl3) d 136.6, 115.6, 65.7, 54.7, 31.6, 28.7, 26.0, 25.4.
3. Conclusion
We developed a new, palladium-catalyzed route to 5-benzy-
lisoxazolidines via intramolecular CeO bond formation and in-
termolecular C-arylation in a single step with concomitant
formation of one new stereocenter. The chemistry developed
herein together with our previous work should be thus particu-
larly useful in the diversity-oriented synthesis of isoxazolidines.
Studies on the mechanism of the diastereoselectivities as well as
the applications of this methodology to the synthesis of complex
molecules are currently undergoing.
4.2.4. Compound 6
1H NMR (300 MHz, CDCl3) d 7.25e7.33 (m, 5H),
5.61e5.63 (m, 1H), 4.89e5.01 (m, 2H), 4.40 (br, 1H), 3.98
(dd, J¼9.0, 5.2 Hz, 1H), 2.77e2.83 (m, 1H), 2.52e2.58
(m, 1H), 2.44e2.52 (m, 1H), 1.85e1.90 (m, 2H), 1.71e1.75
(m, 2H), 1.52e1.56 (m, 1H), 1.35e1.39 (m, 2H), 1.10e1.12 (m,
3H). 13C NMR (75 MHz, CDCl3) d 140.4, 135.9, 128.8, 128.1,
127.1, 116.2, 66.8, 61.0, 30.1, 26.0, 25.2, 24.8.
4. Experimental
4.1. General
4.2.5. Compound 7
Chemicals and solvents were all purchased from commer-
cial supplies and purified by standard techniques. NMR spectra
were recorded on a Bruker-300 MHz spectrometer; 13C NMR
spectra were recorded at 75 MHz. Chemical shifts (d) are given
in parts per million (ppm) downfield relative to CDCl3. Coup-
ling constants are given in hertz (Hz). In assignment of the
1H NMR (300 MHz, CDCl3) d 8.31 (br, 1H), 5.69e5.77 (m,
1H), 4.95e5.02 (m, 2H), 3.22e3.26 (m, 1H), 2.73e2.79
(m, 1H), 2.43e2.47 (m, 1H), 2.28e2.29 (m, 1H), 1.97e2.01 (m,
1H), 1.75e1.79 (m, 1H), 1.51e1.63 (m, 3H), 1.09e1.11
(m, 2H). 13C NMR (75 MHz, CDCl3) d 135.6, 116.6, 66.8,
59.6, 37.8, 30.6, 25.7, 23.5.

D. Jiang et al. / Tetrahedron 64 (2008) 1641e1647
1645
4.3. General procedure for the palladium-catalyzed cascade
synthesis of 5-arylmethylisoxazolidines
J¼13.6, 5.1 Hz, 1H), 2.76 (dd, J¼13.6, 7.5 Hz, 1H),
2.27e2.37 (m, 5H). 13C NMR (75 MHz, CDCl3) d 140.1,
137.8, 135.8, 134.7, 129.3, 129.0, 128.5, 128.1, 127.9, 127.7,
127.5, 127.0, 77.6, 69.9, 60.1, 43.8, 40.4, 21.0. HRMS-ESI
(m/z): [MþNa]þ calcd for C24H25NNaO, 366.1828; found,
366.1826.
A flame-dried two-neck round-bottomed flask equipped with
a reflux condenser was cooled under a stream of nitrogen and
charged with N-homoallylhydroxylamine (1 equiv), Pd2(dba)3
(1 mol %), Xantphos (2 mol %), and NaO-t-Bu (1.2 equiv).
The flask was purged with nitrogen and a solution of aryl bro-
mide (1.2 equiv) in toluene (5 mL) was added through syringe.
The mixturewas heated to 90 ꢀC with stirring until the hydroxyl-
amine was consumed completely as judged by TLC. The re-
action mixture was cooled to room temperature, followed by
the addition of saturated ammonium chloride and ethyl acetate.
The organic layer was separated and the aqueous layer was ex-
tracted with ethyl acetate (2ꢁ10 mL). The combined organic
layer was dried over anhydrous MgSO4, filtrated, and concen-
trated in vacuo to give the crude product, which was then puri-
fied by chromatography on silica gel.
4.3.5. (ꢂ)-(3,5-trans)-2-Benzyl-3-phenyl-5-(4-nitrobenzyl)-
isoxazolidine (8c)
1H NMR (300 MHz, CDCl3) d 8.13 (d, J¼8.7 Hz, 2H),
7.27e7.40 (m, 12H), 4.47e4.51 (m, 1H), 3.93 (d, J¼14.0 Hz,
1H), 3.72 (d, J¼14.0 Hz, 1H), 3.67e3.69 (m, 1H), 2.96e3.10
(m, 2H), 2.32e2.39 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 146.8, 145.7, 130.3, 129.1, 128.7, 128.1, 127.8, 127.7,
127.2, 125.6, 123.4, 122.6, 76.5, 69.8, 59.8, 43.9, 40.6.
HRMS-ESI (m/z): [MþH]þ calcd for C23H23N2O3, 375.1703;
found, 375.1717.
4.3.6. (ꢂ)-(3,5-trans)-2-Benzyl-3-phenyl-5-(4-phenyl-
benzyl)isoxazolidine (8d)
4.3.1. (ꢂ)-(3,5-cis)-3-Phenyl-2,5-diphenylmethyl-
isoxazolidine (8a)
1H NMR (300 MHz, CDCl3) d 7.52e7.58 (m, 4H),
7.29e7.44 (m, 15H), 4.49e4.52 (m, 1H), 3.96 (d, J¼14.2 Hz,
1H), 3.78 (d, J¼14.2 Hz, 1H), 3.76e3.78 (m, 1H), 3.10 (dd,
J¼13.7, 5.4 Hz, 1H), 2.86 (dd, J¼13.7, 7.1 Hz, 1H),
2.29e2.39 (m, 2H). 13C NMR (75 MHz, CDCl3) d 140.9,
140.0, 139.2, 137.7, 136.9, 129.8, 129.4, 129.0, 128.8, 128.7,
128.6, 128.5, 128.1, 127.7, 127.5, 126.9, 77.4, 69.9, 60.0,
43.8, 40.5. HRMS-ESI (m/z): [MþNa]þ calcd for C29H27NNaO,
428.1985; found, 428.2010.
1H NMR (300 MHz, CDCl3) d 7.17e7.47 (m, 15H),
4.43e4.48 (m, 1H), 4.03 (d, J¼14.0 Hz, 1H), 3.93 (dd, J¼8.4,
8.1 Hz, 1H), 3.84 (d, J¼14.0 Hz, 1H), 3.23 (dd, J¼13.5,
7.0 Hz, 1H), 2.76e2.86 (m, 2H), 2.16e2.18 (m, 1H). 13C
NMR (75 MHz, CDCl3) d 140.3, 138.5, 137.9, 129.4, 128.8,
128.6, 128.2, 128.0, 127.5, 127.4, 126.9, 126.1, 77.8, 70.6,
60.0, 45.1, 41.8. HRMS-ESI (m/z): [MþH]þ calcd for
C23H24NO, 330.1727; found, 330.1729.
4.3.2. (ꢂ)-(3,5-trans)-3-Phenyl-2,5-diphenylmethyl-
isoxazolidine (8a)
4.3.7. (ꢂ)-(3,5-trans)-2-Benzyl-3-phenyl-5-(2,4-dimethyl-
benzyl)isoxazolidine (8e)
1H NMR (300 MHz, CDCl3) d 7.29e7.44 (m, 15H),
4.51e4.56 (m, 1H), 4.00 (d, J¼14.1 Hz, 1H), 3.82 (d,
J¼14.1 Hz, 1H), 3.77 (dd, 1H), 3.11 (dd, J¼13.7, 5.3 Hz,
1H), 2.86 (dd, J¼13.7, 7.3 Hz, 1H), 2.31e2.43 (m, 2H). 13C
NMR (75 MHz, CDCl3) d 140.0, 137.7, 129.4, 128.9, 128.5,
128.3, 128.2, 128.0, 127.7, 127.5, 127.0, 126.3, 77.4, 69.9,
60.0, 43.8, 40.8. HRMS-ESI (m/z): [MþH]þ calcd for
C23H24NO, 330.1727; found, 330.1729.
1H NMR (300 MHz, CDCl3) d 7.26e7.46 (m, 10H),
6.96e7.06 (m, 3H), 4.48e4.51 (m, 1H), 4.02 (d, J¼13.9 Hz,
1H), 3.85 (d, J¼13.9 Hz, 1H), 3.78e3.85 (m, 1H), 3.08 (dd,
J¼14.3, 5.2 Hz, 1H), 2.81 (dd, J¼14.3, 6.7, 1H), 2.37e2.40
(m, 2H), 2.32 (s, 3H), 2.25 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 140.3, 137.7, 136.3, 135.8, 133.0, 131.0, 129.8,
129.0, 128.5, 128.0, 127.7, 127.5, 127.0, 126.4, 77.0, 69.9,
60.1, 44.0, 37.6, 20.7, 19.7. HRMS-ESI (m/z): [MþNa]þ calcd
for C25H27NNaO, 380.1985; found, 380.1987.
4.3.3. (ꢂ)-(3,5-cis)-2-Benzyl-3-phenyl-5-(4-methylbenzyl)-
isoxazolidine (8b)
4.3.8. (ꢂ)-(3,5-trans)-2-Benzyl-3-phenyl-5-(4-acetylbenzyl)-
isoxazolidine (8f)
1H NMR (300 MHz, CDCl3) d 7.26e7.46 (m, 10H), 7.03e7.05
(m, 4H), 4.38e4.43 (m, 1H), 4.00 (d, J¼14.1 Hz, 1H), 3.91 (dd,
J¼7.9, 7.9 Hz, 1H), 3.81 (d, J¼14.1 Hz, 1H), 3.16 (dd, J¼13.5,
6.9 Hz, 1H), 2.73e2.79 (m, 2H), 2.32 (s, 3H), 2.12e2.18 (m,
1H). 13C NMR (75 MHz, CDCl3) d 140.3, 138.0, 135.6, 135.5,
129.2, 128.9, 128.8, 128.6, 128.0, 127.7, 127.5, 126.9, 78.0,
70.6, 60.1, 45.1, 41.4, 21.0. HRMS-ESI (m/z): [MþNa]þ calcd
for C24H25NNaO, 366.1828; found, 366.1826.
1H NMR (300 MHz, CDCl3) d 7.89(d, J¼8.4, 2H), 7.26e7.38
(m, 12H), 4.47e4.49 (m, 1H), 3.98 (d, J¼13.9 Hz, 1H), 3.74 (d,
J¼13.9 Hz, 1H), 3.71e3.73 (m, 1H), 3.06 (dd, J¼13.1, 5.9 Hz,
1H), 2.89 (dd, J¼13.1, 6.5 Hz, 1H), 2.59 (s, 3H), 2.30e2.36
(m, 2H). 13C NMR (75 MHz, CDCl3) d 197.8, 143.6, 139.7,
137.6, 135.5, 129.7, 129.0, 128.6, 128.4, 128.1, 127.7, 127.5,
127.1, 76.8, 69.9, 59.8, 43.8, 40.8, 26.5. HRMS-ESI (m/z):
[MþNa]þ calcd for C25H25NNaO2, 394.1778; found, 394.1796.
4.3.4. (ꢂ)-(3,5-trans)-2-Benzyl-3-phenyl-5-
(4-methylbenzyl)isoxazolidine (8b)
4.3.9. (ꢂ)-4-(((3,5-trans)-2-Benzyl-3-phenylisoxazolidin-5-
yl)methyl)benzaldehyde (8g)
1H NMR (300 MHz, CDCl3) d 9.99 (s, 1H), 7.80 (d,
J¼8.1 Hz, 2H), 7.29e7.41 (m, 12H), 4.49e4.51 (m, 1H), 3.97
1H NMR (300 MHz, CDCl3) d 7.26e7.39 (m, 10H),
7.11e7.12 (m, 4H), 4.44e4.48 (m, 1H), 3.95 (d, J¼14.1 Hz,
1H), 3.76 (d, J¼14.1 Hz, 1H), 3.73e3.75 (m, 1H), 3.04 (dd,

1646
D. Jiang et al. / Tetrahedron 64 (2008) 1641e1647
(d, J¼13.7 Hz, 1H), 3.73 (d, J¼13.7 Hz, 1H), 3.69e3.73 (m,
1H), 3.08 (dd, J¼12.8, 6.1 Hz, 1H), 2.95 (dd, J¼12.8, 6.2 Hz,
1H), 2.32e2.37 (m, 2H). 13C NMR (75 MHz, CDCl3) d 192.0,
145.2, 139.6, 137.5, 134.8, 130.2, 129.7, 129.0, 128.6, 128.1,
127.7, 127.5, 127.1, 77.1, 69.9, 59.8, 43.8, 40.9. HRMS-ESI
(m/z): [MþNa]þ calcd for C24H23NNaO2, 380.1621; found,
380.1623.
1H), 2.80 (br, 1H), 2.31e2.42 (m, 3H), 1.93e2.09 (m, 2H),
1.58e1.90 (m, 4H), 1.21e1.23 (m, 5H). 13C NMR (75 MHz,
CDCl3) d 144.5, 132.0, 130.1, 119.0, 110.1, 76.2, 64.9, 52.3,
41.6, 34.4, 31.0, 25.0, 24.5. HRMS-ESI (m/z): [MþH]þ calcd
for C17H23N2O, 271.1805; found, 271.1808.
4.3.15. (ꢂ)-(3,5-trans)-5-Benzyl-2-cyclohexyl-3-phenyli-
soxazolidine (11)
1H NMR (300 MHz, CDCl3) d 7.21e7.44 (m, 10H),
4.35e4.38 (m, 1H), 4.18e4.20 (m, 1H), 3.14 (dd, J¼13.7,
6.4 Hz, 1H), 2.74 (dd, J¼13.7, 6.9 Hz, 1H), 2.67e2.71 (m,
1H), 2.03e2.16 (m, 2H), 1.75e1.79 (m, 2H), 1.64e1.68 (m,
2H), 1.16e1.18 (m, 6H). 13C NMR (75 MHz, CDCl3)
d 143.1, 138.5, 129.2, 128.4, 128.3, 128.1, 126.3, 126.2,
78.0, 67.4, 64.5, 46.4, 40.4, 31.1, 29.6, 25.9. HRMS-ESI (m/z):
[MþH]þ calcd for C22H28NO, 322.2165; found, 322.2164.
4.3.10. (ꢂ)-(3,5-cis)-2-Benzyl-3-phenyl-5-(2-phenylbenzyl)-
isoxazolidine (8h)
1H NMR (300 MHz, CDCl3) d 7.18e7.42 (m, 19H),
4.23e4.27 (m, 1H), 3.92 (d, J¼14.1 Hz, 1H), 3.79 (dd, J¼8.4,
8.1 Hz, 1H), 3.72 (d, J¼14.1 Hz, 1H), 3.15 (dd, J¼13.8,
7.2 Hz, 1H), 2.91 (dd, J¼13.8, 6.2 Hz, 1H), 2.55e2.59 (m,
1H), 1.90e1.95 (m, 1H). 13C NMR (75 MHz, CDCl3) d 142.1,
141.8, 140.1, 137.9, 135.9, 130.7, 130.0, 129.4, 128.9, 128.5,
128.1, 128.0, 127.5, 127.4, 127.2, 126.9, 126.8, 126.1, 77.2,
70.5, 59.8, 44.9, 38.5. HRMS-ESI (m/z): [MþNa]þ calcd for
C29H27NNaO, 428.1985; found, 428.2007.
4.3.16. (ꢂ)-(2,3b-trans)-2-(Pyridin-3-ylmethyl)-piperidino-
[1,2-b]isoxazolidine (12a)
1H NMR (300 MHz, CDCl3) d 8.45 (s, 1H), 8.41 (d,
J¼3.9 Hz, 1H), 7.56 (d, J¼7.8 Hz, 1H), 7.16e7.20 (m, 1H),
4.16e4.23 (m, 1H), 3.38e3.41 (m, 1H), 3.04 (dd, J¼13.8,
8.0 Hz, 1H), 2.69 (dd, J¼13.8, 5.3 Hz, 1H), 2.38e2.39 (m,
2H), 2.31e2.33 (m, 1H), 1.87e1.90 (m, 1H), 1.63e1.73 (m,
4H), 1.38e1.46 (m, 1H), 1.19e1.22 (m, 1H). 13C NMR
(75 MHz, CDCl3) d 150.4, 147.5, 136.8, 134.4, 123.2, 76.2,
67.3, 55.1, 41.0, 40.0, 29.1, 24.6, 23.6. HRMS-ESI (m/z):
[MþNa]þ calcd for C13H18N2NaO, 241.1311; found, 241.1308.
4.3.11. (ꢂ)-2-Benzyl-5-(4-methylphenylmethyl)-
isoxazolidine (9a)
1H NMR (300 MHz, CDCl3) d 7.27e7.41 (m, 5H),
7.10e7.13 (m, 4H), 4.30e4.46 (m, 1H), 3.96e4.05 (m, 1H),
3.75e3.96 (m, 1H), 3.15e3.20 (m, 1H), 3.01 (dd, J¼13.7,
5.9 Hz, 1H), 2.74 (dd, J¼13.7, 7.1 Hz, 1H), 2.33 (s, 3H),
2.20e2.28 (m, 1H), 1.96e2.02 (m, 1H), 1.82e1.96 (m, 1H).
13C NMR (75 MHz, CDCl3) d 137.2, 135.7, 135.0, 129.2,
129.0, 128.9, 128.2, 127.2, 78.1, 62.0, 54.1, 40.7, 33.3, 21.0.
HRMS-ESI (m/z): [MþH]þ calcd for C18H22NO, 268.1696;
found, 268.1709.
4.3.17. (ꢂ)-(2,3b-trans)-2-(2-Chlorophenylmethyl)-
piperidino[1,2-b]isoxazolidine (12b)
1H NMR (300 MHz, CDCl3) d 7.28e7.31 (m, 2H),
7.08e7.18 (m, 2H), 4.31e4.36 (m, 1H), 3.39e3.42 (m, 1H),
3.12 (dd, J¼13.6, 7.7 Hz, 1H), 2.94 (dd, J¼13.6, 5.7 Hz,
1H), 2.28e2.40 (m, 2H), 2.17e2.24 (m, 1H), 1.86e1.90
(m, 1H), 1.66e1.75 (m, 4H), 1.36e1.41 (m, 1H), 1.15e1.22
(m, 1H). 13C NMR (75 MHz, CDCl3) d 136.5, 133.9, 131.6,
129.1, 127.5, 126.5, 74.7, 67.2, 55.1, 40.8, 40.4, 29.0, 24.6,
23.6. HRMS-ESI (m/z): [MþH]þ calcd for C14H19ClNO,
252.1150; found, 252.1159.
4.3.12. (ꢂ)-2-Benzyl-5-(2-chlorophenylmethyl)-
isoxazolidine (9b)
1H NMR (300 MHz, CDCl3) d 7.27e7.39 (m, 7H),
7.15e7.17 (m, 2H), 4.46e4.52 (m, 1H), 3.96 (br, 1H), 3.86
(br, 1H), 3.11 (dd, J¼13.9, 6.8 Hz, 1H), 3.08e3.15 (m, 1H),
2.99 (dd, J¼13.9, 6.0 Hz, 1H), 2.81e2.86 (m, 1H), 2.35 (br,
1H), 1.97e2.03 (m, 1H). 13C NMR (75 MHz, CDCl3)
d 137.2, 136.0, 134.1, 131.7, 129.3, 129.1, 128.3, 127.7,
127.3, 126.6, 76.2, 62.0, 54.1, 38.6, 33.5. HRMS-ESI (m/z):
[MþH]þ calcd for C17H19ClNO, 288.1150; found, 288.1139.
Acknowledgements
4.3.13. (ꢂ)-2-Benzyl-5-(4-methoxyphenylmethyl)-
The authors thank the 100-talent program of Chinese Acad-
emy of Sciences and Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences for financial support of this
work. The authors also want to thank Mr. Yuan Shixue for ben-
eficial discussion and unrestricted support.
isoxazolidine (9c)
1H NMR (300 MHz, CD3OD) d 7.27e7.36 (m, 5H), 7.13 (d,
J¼8.5 Hz, 2H), 6.82 (d, J¼8.5 Hz, 2H), 4.45 (br, 1H), 3.99 (br,
1H), 3.81e3.82 (m, 1H), 3.75 (s, 3H), 3.07 (br, 1H), 2.74e2.89
(m, 3H), 2.38 (br, 1H), 1.97e2.01 (m, 1H). 13C NMR (75 MHz,
CD3OD) d 159.7, 133.2, 131.4, 130.6, 129.3, 128.5, 116.9,
114.7, 79.3, 62.5, 55.6, 54.6, 41.0, 34.0. HRMS-ESI (m/z):
[MþNa]þ calcd for C18H21NNaO2, 306.1465; found, 306.1460.
References and notes
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4.3.14. (ꢂ)-2-Cyclohexyl-5-(4-cyanophenylmethyl)-
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