Amine nucleophilic addition to nitroalkene as a new practical approach for the synthesis of fully substituted isoxazoline-N-oxide

Article abstract of DOI:10.1016/j.tet.2011.01.085

The secondary amine nucleophilic addition to the nitroalkene was used to generate the active nitronate intermediate, followed by the sequential addition to aldehyde and ylide, giving the fully substituted isoxazoline-N-oxide in one-pot fashion. Mechanisti

Full text of DOI:10.1016/j.tet.2011.01.085

Tetrahedron 67 (2011) 4402e4411
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Amine nucleophilic addition to nitroalkene as a new practical approach for the
synthesis of fully substituted isoxazoline-N-oxide
Cheng Zhong, Lekh Nath S. Gautam, Dawei Wang, Novruz G. Akhmedov, Jeffrey L. Petersen,
*
Xiaodong Shi
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The secondary amine nucleophilic addition to the nitroalkene was used to generate the active nitronate
intermediate, followed by the sequential addition to aldehyde and ylide, giving the fully substituted
isoxazoline-N-oxide in one-pot fashion. Mechanistic studies revealed the equilibrium nature of the diene
intermediates, which provide the foundation for the asymmetric synthesis of this interesting
heterocycles.
Received 5 December 2010
Received in revised form 26 January 2011
Accepted 26 January 2011
Available online 2 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoline-N-oxide
Cascade reaction
Lewis base catalysis
Multi-component-reaction
Stereoselectivity
1. Introduction
H
H
H
O
N
H
R
R
NO2
N
R
N
R
NO2
N
O
O
LB catalyst
R
R
In the last 3 years, our group reported the application of the
secondary amines as nucleophilic catalysts for the activation of
nitroalkene as a new reaction mode in promoting multiple-com-
ponent cascade reactions (Scheme 1).1 Two key features of this
strategy were (A) Lewis base activation allowed the nitroalkene,
a popular electrophile in literature, to serve as the nucleophile for
R
R
R
E+
N
H
H
O
O
N
NO2
N
R
N
O
N
R
E
β
-elimination
R
E
E
the sequential addition; and (B) the introduction of the b-hydrogen
elimination provided irreversible step for the effective catalyst
turnover. With this method, the first intermolecular cross conjugate
additions between two different Michael receptors were achieved.
Recently, we further extended the cascade by reacting the
amine-activated nitroalkene with aldehyde to form highly reactive
nitroalkene intermediate. Further reaction with the third compo-
nent gave substituted heterocyclic compounds, such as 1,2,3-tri-
azoles1b,2 and dihydrofuran,3 in one-pot (Scheme 2). These
transformations were efficient and provided the functional group
enriched products from simple starting materials.
O
O
R'
R
R
L-proline 20%
DMSO
X
+
X
R1
R'H2C
NO2
R1
NO2
X: ketone or ester;
70-90% yield
both cyclic and acyclic
Scheme 1. Intermolecular catalytic cascade reaction promoted by secondary amine
nucleophilic addition to nitroalkene.
especially for potential asymmetric catalysis, it is important to
understand how different substrates interact with each other and
which is the rate determination step in the overall transformation.
In this study, we report the investigation of amine catalyzed
nitroalkeneealdehyde-ylide condensation in the synthesis of fully
substituted isoxazoline-N-oxide, which provided us some mecha-
nistic insight regarding the amine catalyzed nitroalkene activation.
It is clear that this type of multiple-component condensation
can be very useful in complex molecule synthesis. Given the
complicate nature of these reactions, to further extend this strategy,
* Corresponding author. E-mail address: xiaodong.shi@mail.wvu.edu (X. Shi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.085

C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
4403
R
R
and vinyl ester for the synthesis of isoxazoline N-oxides in a one-
pot fashion.15
-
N
N
N3
As shown in Scheme 4, reactions between b-alkyl nitroalkene and
vinyl ester gave the diene intermediate A in the presence of proline
catalyst. Sequential conjugate addition by the second nitro carbanion
led to the di-nitro intermediate B and intramolecular cyclization gave
the substituted isoxazoline-N-oxide as single trans isomer.
NH
R'
R
NO2
R
R
N
H
up to 89% yields
R
R
NO2
R'
O
LB catalyst
R
O
O
O
R
R'
H
R
OR
R'
O
OR
N
O
NO2
R2
OAc
R2
20% Proline, 1 equiv. NaOAc
DMSO, rt, 10 h
R2
O
+
R1
up to 95% yields,
R1
R3
R1
single trans isomer
R3
single trans isomers
Scheme 2. Intermolecular catalytic cascade reaction promoted by secondary amine
nucleophilic addition to nitroalkene.
55 - 88% yields
OAc
O2N
R1
O
The isoxazoline-N-oxide and its derivatives4 are one particularly
interesting class of heterocyclics,5 which play a predominant role in
chembiology research and medicinal chemistry research, due to
their structural uniqueness and the significant biological proper-
ties.6 Despite of the potential in pharmaceutical industry,7 the
isoxazoline-N-oxide and its derivatives have also been widely used
as practical synthetic building blocks, which could be readily con-
verted into useful intermediates for stereoselective preparation of
complex molecules8 and natural product total synthesis.9 Some
representative syntheses of this heterocycles are summarized in
Scheme 3.
O
O2N
R2
N
N
H
H
N
R3
R3
H
R2
R1
R1
A
R2
N
NO2
O
R2 R1
Nu-LG
1
O
R2
O
R2
N O R1
N
3
5
R2
-NO2-
R1
R3
R1
R3
4
R2
R1
limitations:
NO2
B
a) only aliphatic functionality on C4;
b) identical vinyl groups on C3 and C5;
c) poor enantioselectivity.
Scheme 4. Cascade isoxazoline-N-oxide synthesis through Lewis base and its
A Intramolecular cyclization
limitations.
O
NO2 LG
O
N
This cascade approach provided a new strategy to produce ac-
tive diene intermediate A in situ, which allowed the preparation of
isoxazoline N-oxide without going through the challenging nitro-
nate intermediate synthesis. However, despite the high efficiency,
this process suffered from some obvious limitations: (a) the C-4
substitution was limited to aliphatic groups; (b) two identical vinyl
groups on C-3 and C-5 positions, and; (c) poor enantioselectivity
(<15% ee was observed). Considering the unique mechanism and
high efficiency, it is expected that successful strategies in over-
coming the above-mentioned limitations will lead to the discovery
of concise synthesis of the isoxazoline motifs. Moreover, in-
vestigation of how each component involved in the process will
lead to the needed mechanistic insight, which is critical for further
extension of this attractive multiple-component process. Herein,
we report the investigation of this reaction with the focuses on the
role of Lewis base catalyst, effective reaction intermediates and
factors that controlled the reaction chemo- and stereo-selectivity.
isoxazoline-N-oxide
B Intermolecular [3+2] cycloaddition
RO
O
RO
O
[3+2]
N
N
+
isoxazolidine
C Nucleophilic addition of activated nitroalkene
O
O
N
ROOC
NO2
R
COOR
NR3
COOR
+
30-79% yields
ROOC
R
Scheme 3. Literature reported synthesis.
As reported in literature, the conventional strategy for the
preparation of isoxazoline frameworks was from the intra-
molecular 5-exo-tet cyclization of aliphatic nitro compounds
(Scheme 3A).10 But the lack of practical preparation the specific
nitro group containing starting materials compromised the generic
application of this method, which also tended to give low overall
yields and limited substrate scope. Further efforts were made in
developing intermolecular [3þ2] cycloaddition as an alternative
approach (Scheme 3B).11 However, most of these studies focused on
the preparation of nitronate12, which made the overall strategy less
practical. Recent research of Tang and co-workers revealed a suc-
cessful ylide addition to carbonyl-activated nitroalkene, giving the
isoxazoline-N-oxides with decent yields and excellent diaster-
eoselectivity (Scheme 3C).13 Although with high efficiency and mild
reaction conditions, the requirement of specific nitroalkenes could
limit the substrate scope for further application. Thus, up-to-date,
practical synthesis of isoxazoline-N-oxides is still considered as one
big challenge and new efficient methodologies are highly
desirable.14
2. Results and discussions
2.1. Synthesis of isoxazoline-N-oxides through one-pot
condensation of nitroalkenes and aldehydes
The key step for the isoxazoline-N-oxide synthesis was the
formation of diene intermediate A. Besides the previously reported
nitroalkene-vinyl ester condensation approach,17a the diene could
also be prepared through the Lewis based mediated Henry process
between nitroalkene 1 and aldehyde 2. Thus, the desired homo-
isoxazoline-N-oxide 3a would be prepared through a more general
method with good variety on the C-4 position. The reactions be-
tween 1a and benzaldehyde 2a were then investigated. As expec-
ted, isoxazoline-N-oxide 3a was obtained as a single diastereomer.
The reaction condition optimization is summarized in Table 1.
Similar to the previous reported cases, the reaction did not go
well when only proline or only weak base NaOAc was applied
(entries 1e2). The major side reaction was the polymerization of 1a.
Based on the amine-catalyzed nitroalkene developed in our lab,
we recently discovered an interesting method using nitroalkene

4404
C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
Table 1
Table 2
,b
One-pot synthesis of homo-isoxazoline-N-oxide by Lewis base activated nitro-
Substrate scope of one-pot homo isoxazoline-N-oxide synthesisa
alkeneealdehyde condensationa
O
O
1
O
4
O
N
O
O
O
O
O
O
N
O2N
N
NO2
Ph
5
N
N
O
L-proline
Ph
Ph
+
Ph
Ph
Ph
Ph
3
H
Ph
Ph
Ph
Ph
Ph
Ph
O
Ph
Ph
single diasteromer
Active diene intermediate
N
1a
2a
NO2
3d, 95%
A
3a
3a, 92%
3b, 85%
3c, 91%
SOL
DMSO Proline
DMSO
DMSO Proline
DMSO Proline
DMSO Proline
DMSO Proline
DMSO Otherse
LB (20%)
Additive
t (h) Conv.b (%) Yieldc (%)
O
O
N
O
O
O
O
O
1
2
3
4
5
6
7
8
9
d
12
12
3
3
3
12
3
12
12
46
79
>95
>95
84
89
>95
23
11
<5
N
O
N
N
Ph
d
NaOAc (1.0 equiv)
NaOAc (1.0 equiv)
K2CO3 (0.5 equiv)
NaOtBu (1.0 equiv)
Et3N (1.0 equiv)
K2CO3 (0.5 equiv)
K2CO3 (0.5 equiv)
BF3eTHF (1.0 equiv)
K2CO3 (0.5 equiv)
K2CO3 (0.5 equiv)
Ph
NO2
Ph
Ph
87d
92d
70d
65d
<50
19
Ph
Ph
Ph
Ph
3h, 57%
Ph
3e, 86%
3f, 93%
3g, 61%
THF
THF
Proline
Proline
O
O
O
O
N
35
Trace
13e49
43
N
O
O
N
10 Othersf Proline
11 MeOH Proline
3e12 45e90
12
3
Ph-p-Cl
Ph
>95
>95
Ph
p-Cl-Ph
Ph
12 DMSO Pyrrolidine K2CO3 (0.5 equiv)
88
N
Ph
N
N
a
Cl
General reaction condition: 1a (2.2 equiv), 2a (1.0 equiv, 0.1 M) and catalysts
were mixed in solvents. The reactions were monitored by TLC.
Ph-p-Cl
3i, 81%
3j, 57%
3k, 95%
b
Based on the consumption of 2a.
NMR yield with 1,3,5-trimethoxybenzene as internal standard.
Isolated yield.
Other Lewis bases include DMAP, DABCO, NMI, Ph3P.
c
O
O
N
d
O
O
O
O
N
N
e
Ph-p-Cl
f
Ph-p-Cl
Ph-p-Cl
Other solvents include EtOAc, DCM, Toluene, MeCN, iPrOH.
p-Cl-Ph
O
N
p-Cl-Ph
p-Cl-Ph
N
The desired product 3a was received in good yield when both
proline and NaOAc were used and reaction finished within 3 h
(entry 3), which provided another strong support for our proposed
proline nucleophilic addition to nitroalkene mechanism. Strong
base, such as NaOtBu, caused significant polymerization of 1a and
0.5 equiv of K2CO3 was identified as the optimal choice with min-
imum polymerization (entries 4e6). To investigate the reaction
mechanism, the allylic nitro compound 1a0 was prepared separately
and applied into the optimal reaction conditions. As shown in
Scheme 5, a slower reaction was observed (took 12 h for starting
materials consumption) with much lower yield (32% yield while
>95% starting material was consumed). This significant difference
between 1a and 1a0 as the starting materials provided strong evi-
dence for the proposed amine nucleophilic addition to nitroalkene
other than the alternative Brønsted base deprotonation path (for-
mation of nitro carbanion).
NO2
3l, 95%
3m, 87%
3n, 87%
O
O
O
O
N
O
N
O
N
NO2
OMe
3o, 94%
3p, 92%
3q, 90%
O
O
O
O
O
N
O
N
O
N
O
N
3r, 89%
3s, 64%
3t, 64%
O
O
O
N
N
O
O
N
20% L-Proline,
O
Me
O2N
0.5 equiv K2CO3
Me
polymerization
Me
+
3a
+
2a
O
O
of 1a'
Me
12 h, > 95% conv.
Ph
35% yield
1a'
NO2
3u,46%
OMe
3v, 74%
3w, 71%
Scheme 5. Reactivity difference between 1a and allylic nitro 1a0.
a
Reaction condition: 1a (2.2 equiv), 2 (1.0 equiv, 0.15 M) and ylide 4 (1.1 equiv)
were mixed DMSO. The reactions were monitored by TLC.
b
Isolated yield.
Other general nucleophilic catalysts, such as DMAP, DABCO,
NMI, etc. have also been tested, giving uncompetitive results (entry
7). These results highlighted the unique reaction nature of proline
nucleophilic addition to nitroalkenes: the problematic nitroalkene
polymerization associated with the Lewis base catalyzed mecha-
nism was successfully avoided by forming a rather stable H-bond
intermediate (Scheme 1). The pyrrolidine was also effective LB
catalyst for this transformation (entry 12, 88% yield) and proline
was selected in this study because of the practical nature (in-ex-
pensive and easy to handle). Solvent screening revealed DMSO as
the optimal solvent (entry 10). Various isoxazoline-N-oxides were
prepared under the optimal conditions, with different substitution
on C-4 position from corresponding aldehydes as shown in Table 2.
Among all these substrates, excellent diastereoselectivity was
achieved and only trans isomers were obtained. The aromatic al-
dehydes generallygave good to excellent yields, while slightly lower
yields were observed with aliphatic aldehydes (3g, 3h, 3t). This was
likely caused by the side reactions resulting from the formation of
enamines. These results generated skeptical thought that whether
our previously reported nitroalkeneevinyl ester condensation went
through the hydration of vinyl ester, forming the aliphatic aldehyde
in situ, followed by the similar Henry reaction to yield the corre-
sponding isoxazoline (Scheme 6A). To verify this concern, the vinyl
ester was treated with the proline under identical conditions
without addition of nitroalkene 1a. Interestingly, based on the NMR

C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
4405
Table 3
A
O
Substrate screening for three-component condensation in the synthesis of iso-
N O
xazoline-N-oxidea
O2N
OAc
20% L-Proline,1 equiv NaOAc
10 h, DMSO, rt
88% isolated yield
+
O
O
O
O
Nu
N
N
Ph
Ph
Ph
Proline (10%), K2CO3 (50%)
DMSO, r.t., 3~5 h
Ph
1a
3x
1a + 2a +
Nu LG
4
Ph
Ph
Ph
Ph
B
Homo product 3a
5
O
OAc
20% L-Proline,1 equiv NaOAc
24 h, DMSO, rt
H3C SO2Ph
4a
O
O
O
O
Br-
Br-
Br-
Br-
SMe2
H
PPh3
NMe3
SMe2
Ph
Ph
Ph
MeO
4f
H2N Ts
4b
No aldehyde formation;
4c
4d
4e
starting material completely recovered
Scheme 6. Vinyl ester condensation as alternative strategy for aliphatic aldehyde.
Entry
NueLG
Product
3a (%)
5 (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
76b
85b
58b
74b
<5b
<5b
<5
<5
study, no hydration product observed based on the NMR, which
supported our previously proposed [3þ2] mechanism between
Lewis based activated nitroalkene and vinyl ester (Scheme 6B). This
study was important since it revealed the possibility for thermal
[3þ2] process with the amine-activated nitroalkene, which would
likely lead to possible new cascade reactions through the Lewis
based catalyzed nitroalkene activation (currently under in-
vestigation in our lab). Moreover, considering the modest yields
with the aliphatic aldehydes, the vinyl ester condensation is likely
a better alternative route for the synthesis of the isoxazoline-N-
oxide derivatives with alkyl group on the C-4 position.
35b
18b
91c
92c
a
Reaction condition: 1a (1.0 equiv), 2a (1.0 equiv, 0.75 M), and catalysts were
mixed in solvents. The reactions were monitored by TLC.
b
NMR yields with 1,3,5-trimethoxybenzene as internal standard.
c
Isolated yield.
process: with the presence of alternative reaction paths (forma-
tion of homo-condensation product 3a and aldehyde epoxida-
tion), well-designed cascade process could direct the reaction
pathway to products that would not be achieved from the step-
wise approach (Scheme 8).
2.2. Three-component condensation to introduce different
substitute groups on C-3 and C-5 positions
As demonstrated by our previous work, the diene A was the key
intermediate for this cascade process. We postulated that an al-
ternative path involved the third component with the featured
functionality as NueLG (with nucleophile and leaving group on the
same molecule) could be the potential solution to introduce three
different components at the C-3, C-4, and C-5 positions (Scheme 7).
Based on this hypothesis, several ylides were prepared to react
with nitroalkene 1a and aldehyde 2a. The results are summarized
in Table 3.
O
O
N
O
N
O
R
O
R
R
R
R2
R
R1
R
R
NO2
R
O
O
N
O
O
O
O
O
S
R
R1
R2
R1
H
R2
R2
R
R1
Dominante product with excellent
chemoselectivity
Scheme 8. Achieving excellent chemoselectivity.
R
R
R
O
R
R
O
N
O
N
NO2
N
H
R'
Nu
Nu LG
NO2
+
With the optimal three-component conditions revealed, some
R'
R'
O
R
cat.
R"
representative isoxazoline-N-oxides were prepared as shown in
O
R'
"R
"R
Nu LG
Table 4.
"R
H
Scheme 7. Proposed alternative reaction path to introduce the third component in the
synthesis of isoxazoline-N-oxide.
2.3. Characterization of diene intermediate and cross
cyclizations
As shown in Table 3, application of 4a and 4b, under the pre-
viously developed optimal condition, produced only the homo-
isoxazoline-N-oxide 3a, which was probably due to the low
reactivity of the sulfonate nucleophiles (entries 1 and 2). The
phosphine ylide 4c and amine ylide 4d did generate the desired
product 5. However, the reaction suffered from the significant
competition of homo-condensation (entries 3 and 4). Interestingly,
application of sulfur ylides 4e and 4f gave compound 5 as the
dominant product in excellent yields (entries 5 and 6) with only
trace amount 3a observed.
Notably, it was well known that the reaction between aldehyde
2a and sulfur ylide 4e could produce the corresponding epoxides
in good yields.16 However, under the reported reaction condition,
no significant formation of epoxide was observed. This result
further highlighted the significance of the reported cascade
As discussed earlier, the nitro-diene A was the key intermediate
that accounted for the formation of the desired product. In-
terestingly, previous study had informed us that conducting the
reaction with the presence of D2O revealed effective deuterium
exchange on various positions, except the C-4 proton (Scheme 9).16
This result suggested that the C-4 stereogenic center was not
epimerizable under the reaction condition. Therefore, the absolute
stereochemistry of the products would be determined by the sec-
ond nucleophilic addition to the diene. This result raised the con-
cern for the asymmetric synthesis of the isoxazoline since the diene
intermediate was likely formed as Z/E isomer mixtures without
good stereochemistry control. To verify this concern, efforts were
the put in obtaining the diene intermediate. As show in Scheme 10,
diene A0 was successfully isolated as mixtures of isomers (Z/
E¼1:1.5, conformations were determined by 2D NMR).

4406
C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
Table 4
2.4. Asymmetric synthesis with chiral auxiliary
Representative isoxazoline-N-oxides from three-component condensationa
O
Enantioselective synthesis of isoxazoline derivatives is consid-
ered as one challenging task and few asymmetric syntheses of this
compound have been reported in literature.10,11 As shown in pre-
vious sections, the Lewis base catalyzed cascade approach gave
excellent diastereoselectivity, where only trans isomers were ob-
served in all cases. However, based on the reaction mechanism, the
chiral Lewis base was unlikely a feasible solution in pursuing
asymmetric synthesis due to the poor involvement of Lewis base
catalysts in the stereochemistry determining step (formation of the
C-4 stereogenic center). This was consistent with the observed low
ee (<15%) for all tested chiral secondary amines.18
O
NO2
N
Br-
R2
O
Proline (10%), K2CO3 (50%)
DMSO, rt, 2-4 h
R2
+
+
S
R1
H
Ph
Me
R1
Ph
5
1a
2
4
Entry
R1
C6H5
p-CH3eC6H4
2-Furyl
n-C3H7
i-C3H7
R2
eC(O)C6H5
Yieldb (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
91
92
73
62
52
92
p-NO2eC6H4
In previous section, one valid approach in achieving asymmetric
synthesis of fully substituted isoxazoline-N-oxides had been dis-
cussed, that is, to develop stereoselective nucleophilic addition of
chiral ylides to diene intermediates through dynamic kinetic res-
olution. Several readily available chiral ylides were then applied to
evaluate the stereoselectivity of these auxiliaries in this cascade
process. Detailed reaction condition screening is shown in Table 5.
The amine-based ylide 6a did not promote the hetero coupling
reaction (entry 1) very well, giving the homo coupling product 3a
(>85% yield) as the major product. Similar result was observed with
ketone ylide 6b (entry 2), which was likely caused by the reduced
nucleophilicity associated with more hindered chiral ylide (com-
paring with the simple ketone ylide 4, which gave the desired
hetero coupling product in excellent yields). The ester modified
ylide 6c did give the hetero coupling product 7 though with poor
yield (entry 3). Solvent screening indicated that MeOH was the
optimal solvent (entries 4e6). Further modification on the ylides
revealed 6d (R1¼Me and R2¼H) as the optimal auxiliary (entry 7)
and Cs2CO3 as preferred choice of base (entry 10), producing the
desired product 7a in excellent yield. In addition, to our great
7
8
2-Nap
p-NO2eC6H4
eCO2Et
5g
5h
88
92
9
p-CH3eC6H4
p-NO2eC6H4
p-OCH3eC6H4
p-Pyridinyl
eC(O)-p-BreC6H4
5i
5j
5k
5l
91
73
92
92
10
11
12
a
Reaction condition: 1a (1.1 equiv), 2 (1.0 equiv, 0.15 M) and ylide 4 (1.1 equiv)
were mixed DMSO. The reactions were monitored by TLC.
b
Isolated yield.
O
3
D
5
D
D
N
O
O2N
AcO
L-Proline 20%, NaOAc
DMSO/D2O 5:1, rt, 10 h
4
D
+
D
H
Ph
Ph
Ph
D3C
no D-exchange on C-4 position
Scheme 9. Deuterium exchange experiment.
NO2
NO2
O
Proline (10%), K2CO3 (50%)
DMSO/DCM, r.t., 5 h
65% yield
Table 5
+
CHO
Z/E = 1/1.5
Reaction condition screening of different auxiliaries for asymmetric isoxazoline-N-
O
oxide synthesisa
A'
1b (1.0 equiv)
2b (1.5 equiv)
O
R
S
O
O
O
N
O
O
O
NO2
O
O
N
N
+
+
R
R2
R2
NO2
Ph
H
Br-
Ph
Me
Ph
7
O
O
O
O
Ph
1a
2a
aux 6
Proline (10%)
K2CO3 (50%)
3s', 24%
3s, 26%
A'
OMe
N
+
DMSO, rt
NO2
O
O
N
O
N
aux 6b: R1=Me, R2=H, R3=Ph;
aux 6c: R1=Bn, R2=H, R3=OEt;
aux 6d: R1=Me, R2=H, R3=OEt;
aux 6e: R1=Bn, R2=Me, R3=OEt;
aux 6f: R1=Me, R2=Me, R3=OEt;
R1
S
O
OMe
N
R3
R2
O
O
O
Br-
aux 6a
Br-
EtO2C
1c
3b, 18%
3b', 6%
Temp (ꢀC) Time (h) Yield %b (ee %)c
Scheme 10. Cross condensation with nitro-diene.
Sol
LB (20%) Base
(1.0 equiv)
aux
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
Acetone
THF
MeOH
MeOH
MeOH
MeOH
L
L
L
L
L
L
L
L
L
L
L
L
-Proline K2CO3
aux 6a rt
aux 6b rt
aux 6c rt
aux 6c rt
aux 6c rt
aux 6c rt
aux 6d rt
aux 6e rt
aux 6f rt
aux 6d rt
aux 6d ꢁ25
aux 6d ꢁ40
12
12
6
6
24
6
6
6
6
6
<5 (n.d.)d
<5 (n.d.)d
19 (n.d.)
16 (n.d.)
13 (n.d.)
60e (36)
81e (75)
23 (40)
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline K2CO3
-Proline Cs2CO3
-Proline Cs2CO3
-Proline Cs2CO3
The formation of Z/E isomer mixture made the asymmetric
synthesis very challenging since it was hard to achieve good
enantioselectivity with two diastereomeric intermediates (Z/E iso-
mers) present in a similar ratio. The enantioselective synthesis of
the desired isoxazoline-N-oxides then relied on the different re-
activity of the two isomers, under the assumption that these two
isomers could inter-convert into each other (dynamic kinetic res-
olution).17 To investigate the diene’s reactivity, the cross-conden-
sation between diene A0 and nitroalkene 1c was performed.
Interestingly, mixtures of four different isoxazoline-N-oxides were
obtained in the crude NMR (Scheme 5), which indicated that the
equilibrium between nitroalkene A0 and starting materials (nitro-
alkene 1 and aldehyde 2). Therefore, it is feasible to control the C-4
stereogenic center with proper nucleophile with dynamic kinetic
resolution.
43 (59)
10 MeOH
11 MeOH
12 MeOH
54 (76)
48
60
87e (82)
62e (82)
a
General reaction condition: 1a (1.2 equiv), 2a (1.0 equiv, 0.15 M) and auxiliary 6
(1.1 equiv). Fast ester exchange happened under mild basic condition in MeOH, only
methyl ester was detected.
b
NMR yields with 1,3,5-trimethoxybenzene as internal standard.
Determined by chiral HPLC.
Major products were homo-isoxazoline 3a and the epoxide.
Isolated yield.
c
d
e

C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
4407
please, good enantioselectivity was also received (75% ee). Con-
sidering that diene intermediate gave low Z/E selectivity, the suc-
cess in obtaining good enantioselectivity supported the hypothesis
that chiral ylide nucleophile reacted with the diene intermediate
with good stereochemistry control and the asymmetric synthesis
achieved through dynamic kinetic resolution (DKR).
with a concentration of 0.1 M aldehyde. The resulting reaction
mixture was stirred at room temperature for 2e5 h monitored by
TLC. Upon the aldehyde was all consumed, the mixture was diluted
with EtOAc (100 mL). The organic phase was washed by HCl solu-
tion (1.0 M), saturated NaHCO3 (aq) and brine, and then dried over
anhydrous Na2SO4. The solvent was removed under reduced pres-
sure to give a residue. Flash silica gel chromatography was then
applied to give the product.
2.5. Influence of amine catalysts in stereoselectivity
4.1.1. 4-Phenyl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide (3a). Puri-
fied by flash chromatography (hexaneeEtOAc) as a colorless oil
Although the proline was simply identified as the secondary
amine Lewis base catalyst in the nitroalkene activation, it was in-
deed a chiral catalyst. One concern was whether the stereochem-
istry of amine catalysts influenced the reaction stereoselectivity.
Investigations of different chiral amines gave interesting results,
(yield: 92%); 1H NMR (600 MHz, CDCl3):
d¼7.37e7.34 (m, 5H),
7.22e7.17 (m, 4H), 7.15e7.12 (m, 2H), 6.85e6.81 (m, 4H), 6.17 (s, 1H),
5.67 (s, 1H), 5.53 (d, J¼7.8 Hz, 2H), 5.31 (d, J¼4.2 Hz, 1H), 4.15 (d,
J¼5.4 Hz, 1H); 13C NMR (150 MHz, CDCl3):
¼144.8, 138.7, 138.0,
d
where
D-proline and achiral pyrrolidine gave improved enantiose-
137.1, 135.9, 128.9, 128.7, 128.4, 128.0, 127.9, 127.8, 127.5, 127.1, 127.0,
121.8, 116.2, 115.0, 82.9, 56.7; HRMS Calculated for
[C25H21NO2þH]þ: 368.16450, found: 368.16474.
lectivity (Scheme 11).
O
O
O
N
LB-cat. 20%, 1 eq Cs2CO3
-25 oC, MeOH
1a
+
2a
+
aux 6d
4.1.2. 4-Furyl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide (3b). Puri-
fied by flash chromatography (hexaneeEtOAc) as a colorless oil
OMe
Ph
Ph
yield %
ee %
Cat.
(yield: 85%); 1H NMR (600 MHz, CDCl3):
d
¼7.41e7.33 (m, 5H),
87
82
L-Proline
7.30e7.29 (s, 1H), 7.23e7.17 (m, 3H), 6.93e6.91 (m, 2H), 6.19 (s, 1H),
6.16 (s, 1H), 5.82 (d, J¼3.0 Hz, 1H), 5.67 (s, 1H), 5.60 (s, 1H), 5.57 (s,
1H), 5.57e5.47 (m, 1H), 4.35 (d, J¼4.2 Hz, 1H); 13C NMR (150 MHz,
90
86
51
85
91
89
D-Proline
pyrrolidine
N-methyl-Glycine
CDCl3):
d
¼149.9, 144.2, 142.7, 137.9, 136.9, 135.8, 128.7, 128.4, 128.1,
Scheme 11. Influence from amine catalysts.
127.9, 127.3, 127.0, 121.6, 115.7, 113.6, 110.5, 108.0, 80.2, 50.3; HRMS
calculated for [C23H19NO3þH]þ: 358.14377, found: 358.14397.
The influence from the amine on the product stereochemistry,
though was subtle, provided interesting information regarding how
amine interact with nitroalkene. The amine Lewis base could remain
contact with thenitroalkene, either through H-bond oras ionpair (by
protonation). The exact mechanism remained uncertain at this mo-
ment. However, the application of chiral amines inprompting similar
cross conjugated addition was recently reported, which suggested
the critical role of amine Lewis base in stereoselective cascade pro-
cess. The asymmetric isoxazoline-N-oxide synthesis along with the
stereoselective total synthesis of Clausenamide have been recently
reported by our group, which were based on this full investigation.
4.1.3. 4-Pyridin-4-yl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide
(3c). Purifiedbyflashchromatography(hexaneeEtOAc)asyellowish
solid (yield: 91%); 1H NMR (600 MHz, CDCl3):
d¼8.42e8.41 (dd,
J¼4.8, 3.6 Hz,2H), 7.39e7.36 (m, 3H), 7.33e7.32 (m, 2H), 7.21e7.18(m,
1H), 7.15e7.12 (m, 2H), 6.80e6.78 (dd, J¼7.2, 1.8 Hz, 2H), 6.73e6.72
(dd, J¼4.2, 3.0 Hz, 2H), 6.30 (s, 1H), 5.68 (s, 1H), 5.58 (s, 1H), 5.56 (s,
1H), 5.27e5.26 (d, J¼4.2 Hz,1H), 4.13e4.12 (d, J¼3.6 Hz,1H); 13C NMR
(150 MHz, CDCl3):
d
¼150.31, 147.42,144.28, 137.8,136.8, 135.4,128.8,
128.6, 128.1, 128.0, 127.6, 127.0, 122.0, 115.5, 115.0, 82.0, 55.93; HRMS
calculated for [C24H20N2O2þNa]þ: 391.14170, found: 391.14190.
4.1.4. 4-p-Nitro-phenyl-3,5-bis-(1-phenylvinyl) isoxazoline-N-oxide
(3d). Purified by flash chromatography (hexaneeEtOAc) as a col-
3. Conclusion
orless oil (yield: 95%); 1H NMR (600 MHz, CDCl3):
d
¼8.03e8.01 (d,
The one-pot condensation of nitroalkeneealdehydeeylide
condensation was developed for the synthesis of fully substituted
isoxazoline-N-oxides. Broad substrates were tested, giving series
new isoxazoline-N-oxides with full characterization. Equilibrium
between the nitroalkene intermediate to the nitroalkene and al-
dehyde starting materials was confirmed through the cross con-
jugate addition. Combined with the observed enantioselective
synthesis through chiral auxiliary, the dynamic kinetic resolution
mechanismwas confirmed. The influence from chiral Lewis base on
the product stereochemistry revealed the important role of chiral
amine. Overall, these studies provided strong mechanistic in-
formation for the further extension of this highly efficient amine-
mediated nitroalkene activation cascade process for the synthesis
of complex organic molecules.
J¼9.0 Hz, 2H), 7.38e7.37 (m, 3H), 7.32e7.31 (m, 2H), 7.21e7.18 (t,
J¼7.8 Hz, 1H), 7.14e7.11 (t, J¼7.8 Hz, 2H), 6.93e6.92 (d, J¼8.4 Hz,
2H), 6.78e6.76 (d, J¼7.2 Hz, 2H), 6.34 (s, 1H), 5.69 (s, 1H), 5.59 (s,
1H), 5.56 (s, 1H), 5.28e5.27 (d, J¼3.6 Hz, 1H), 4.26e4.25 (d,
J¼4.2 Hz, 1H); 13C NMR (150 MHz, CDCl3):
¼147.5, 145.8, 144.2,
d
137.9, 136.9, 135.3, 128.9, 128.7, 128.2, 128.1, 127.6, 127.0, 124.1, 122.1,
115.6, 115.3, 82.2, 56.3; HRMS calculated for [C25H20N2O4þH]þ:
413.14958, found: 413.14967.
4.1.5. 4-o-Nitro-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide (3e). Puri-
fied by flash chromatography (hexaneeEtOAc) as a colorless oil
(yield: 86%); 1H NMR (600 MHz, CDCl3):
d
¼7.68e7.67 (d, J¼8.4 Hz,
1H), 7.62e7.60 (t, J¼7.8 Hz, 1H), 7.47e7.36 (m, 7H), 7.16e7.13 (t,
J¼7.2 Hz, 1H), 7.05e7.02 (t, J¼7.2 Hz, 2H), 6.47e6.46 (d, J¼7.8 Hz,
2H), 6.36 (s, 1H), 5.53 (s, 1H), 5.48 (s, 1H), 5.45 (s, 1H), 5.18 (d,
J¼3.6 Hz, 1H), 5.00 (d, J¼3.6 Hz, 1H); 13C NMR (150 MHz, CDCl3):
4. Experimental procedures
d
¼147.9, 145.2, 137.8, 137.5, 135.4, 133.9, 133.7, 129.5, 128.8, 128.6,
4.1. General procedure for preparation of homo-isoxazoline-
N-oxide (3)
128.4, 128.1, 128.0, 127.8, 127.3, 124.8, 121.8, 118.5, 115.9, 84.0, 50.6;
HRMS calculated [C25H20N2O4þH]þ: 413.14958, found: 413.14967.
The nitroalkene (1.1 mmol, 2.2 equiv) was added to a DMSO
4.1.6. p-Toulyl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide (3f). Puri-
fied by flash chromatography (hexaneeEtOAc) as a colorless oil
solution of aldehyde (0.5 mmol, 1.0 equiv),
L-Proline (25 mg,
0.22 mmol, 0.2 equiv), and K2CO3 (35 mg, 0.25 mmol, 0.5 equiv),
(yield: 93%); 1H NMR (600 MHz, CDCl3):
d¼7.36e7.33 (m, 5H),

4408
C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
7.21e7.18 (t, J¼7.2 Hz, 1H), 7.16e7.13 (m, 2H), 7.01 (d, J¼7.8 Hz, 2H),
6.85e6.83 (m, 2H), 6.76e6.75 (d, J¼8.4 Hz, 2H), 6.11 (s, 1H), 5.66 (s,
1H), 5.54e5.52 (d, J¼11.8 Hz, 2H), 5.29e5.28 (dd, J¼3.6, 3.0 Hz, 1H),
4.11 (d, J¼3.6 Hz, 1H), 2.29(s, 1H); 13C NMR (150 MHz, CDCl3):
56.5, 21.0; HRMS calculated for [C26H21NO2Cl2þH]þ: 450.10221,
found: 450.10252.
4.1.12. 4-p-Nitro-phenyl-3,5-bis (p-chloribenzylvinyl) isoxazoline-N-
oxide (3l). Purified by flash chromatography (hexaneeEtOAc) as
d¼144.88, 138.0, 137.7, 137.1, 135.9, 135.7, 129.6, 128.7, 128.3, 127.9,
127.7, 127.5, 127.0, 121.7, 116.2, 114.8, 83.0, 56.4, 21.0; HRMS calcu-
a colorless oil (yield: 95%); 1H NMR (600 MHz, CDCl3):
d¼8.10e8.09
lated for [C26H23NO2þH]þ: 382.18016, found: 382.18161.
(m, 2H), 7.38e7.36 (m, 2H), 7.29e7.26 (m, 2H), 7.15e7.13 (m, 2H),
7.04e7.03 (m, 2H), 6.73e6.71 (m, 2H), 6.21 (s,1H), 5.68 (s,1H), 5.56 (s,
2H), 5.25 (d, J¼4.2 Hz,1H), 4.20 (d, J¼4.2 Hz,1H); 13C NMR (150 MHz,
4.1.7. 4-Propyl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide (3g).
Purified by flash chromatography (hexaneeEtOAc) as a colorless
CDCl3):
d
¼147.8, 145.4, 143.0, 136.0, 135.1, 134.9, 134.4, 134.3, 129.2,
oil (yield: 61%); 1H NMR (600 MHz, CDCl3):
d¼7.38e7.34 (m, 5H),
128.8, 128.5, 128.3, 128.1, 124.3, 122.7, 116.7, 114.7,82.3, 56.3; HRMS
7.25e7.22 (m, 3H), 6.99e6.89 (dd, J¼6.0, 6.0 Hz, 2H), 6.27 (s, 1H),
5.71 (s, 1H), 5.63 (s, 1H), 5.43 (s, 1H), 5.09 (d, J¼2.4 Hz, 1H),
3.06e3.04 (m, 1H), 1.47e1.41 (m, 1H), 1.31e1.25 (m, 1H),
1.22e1.16 (m, 1H), 1.09e1.02 (m, 1H), 0.58e0.55 (t, J¼7.2 Hz, 3H);
calculated for [C25H18Cl2N2O4þH]þ: 481.07164, found: 481.07172.
4.1.13. 4-Furyl-3,5-bis (p-chloribenzylvinyl) isoxazoline-N-oxide
(3m). Purified by flash chromatography (hexaneeEtOAc) as a col-
13C NMR (150 MHz, CDCl3):
128.68, 128.28, 128.0, 127.4, 127.2, 121.4, 116.4, 115.1, 80.3, 49.5,
33.85, 18.68, 13.2; HRMS calculated for [C22H23NO2þH]þ:
334.18016, found: 334.18031.
d
¼145.81, 138.29, 137.88, 135.87,
orless oil (yield: 87%); 1H NMR (600 MHz, CDCl3):
d
¼7.36e7.32 (m,
5H), 7.19e7.17 (m, 2H), 6.87e6.85 (m, 2H), 6.23 (q, J¼3.0 Hz,1H), 6.07
(s, 1H), 5.89 (d, J¼3.0 Hz, 1H), 5.66 (s, 1H), 5.56 (s, 1H), 5.55 (s, 1H),
5.44 (d, J¼4.8 Hz, 1H), 4.31 (d, J¼4.8 Hz, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼149.5, 143.0, 142.9, 136.0, 135.2, 134.8, 134.6, 134.0, 129.0,
128.6, 128.4, 128.3, 122.0, 116.5, 113.2, 110.7, 108.3, 80.2, 50.3; HRMS
4.1.8. 4-Phenyl-ethyl-3,5-bis (1-phenylvinyl) isoxazoline-N-oxide
(3h). Purified by flash chromatography (hexaneeEtOAc) as a col-
calculated for [C24H20NO3Cl2þH]þ: 406.12048, found: 406.12060.
orless oil (yield: 57%); 1H NMR (600 MHz, CDCl3):
d
¼7.39e7.33 (m,
4.1.14. 4-20-Methyl-imidazole-3,5-bis (p-chloribenzylvinyl) isoxazo-
line-N-oxide (3n). Purifiedby flash chromatography(hexaneeEtOAc)
5H), 7.25e7.22 (m, 1H), 7.20e7.17 (m, 2H), 7.12e7.09 (m, 3H),
6.92e6.90 (m, 2H), 6.73e6.71 (dd, J¼8.4, 6.0 Hz, 2H), 6.24 (s, 1H),
5.68 (d, J¼1.2 Hz, 1H), 5.62 (t, J¼1.2 Hz, 1H), 5.41 (s, 1H), 5.16 (d,
J¼2.4 Hz, 1H), 3.09e3.07 (m, 1H), 2.51e2.46 (m, 1H), 2.35e2.30 (m,
1H), 1.80e1.74 (m, 1H), 1.69e1.63 (m, 1H); 13C NMR (150 MHz,
asa colorlessoil (yield: 87%); 1H NMR (600 MHz, CDCl3):
d¼7.27e7.25
(m, 3H), 7.17e7.13 (m, 4H), 6.96 (d, J¼1.2 Hz, 1H), 6.77e6.76 (m, 2H),
6.47 (d, J¼1.2 Hz,1H), 6.32 (s,1H), 5.65 (s,1H), 5.63e5.62 (d, J¼7.8 Hz,
1H), 5.52 (s, 1H), 4.29 (d, J¼7.2 Hz, 1H), 2.49 (s, 3H); 13C NMR
CDCl3):
d
¼145.7, 139.9, 138.1, 137.8, 135.7, 128.7, 128.36, 128.34,
(150 MHz, CDCl3):
d
¼143.1, 142.7, 136.7, 135.2, 134.6, 134.3, 133.9,
128.1, 127.9, 127.4, 127.3, 125.9, 121.6, 116.1, 115.6, 80.4, 49.3, 33.1,
31.6; HRMS calculated for [C27H25NO2þH]þ: 396.19581, found:
396.19613.
128.9,128.79,128.73,128.3,128.2,122.2,120.9,116.5,114.4, 81.2, 48.3,
31.3; HRMS calculated for [C23H19N3O2Cl2þH]þ: 440.09271, found:
440.09301.
4.1.9. 4-Methyl-imidazole-3,5-bis (1-phenylvinyl) isoxazoline-N-ox-
4.1.15. 4-Toulyl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide (3o). Puri-
fied by flash chromatography (hexaneeEtOAc) as a white solid
ide (3i). Purified by flash chromatography (hexaneeEtOAc) as
a
colorless oil (yield: 81%); 1H NMR (600 MHz, CDCl3):
(yield: 94%); 1H NMR (600 MHz, CDCl3):
d
¼7.16e7.15 (d, J¼7.8 Hz,
d
¼7.28e7.25 (m, 3H), 7.22e7.20 (m, 2H), 7.17e7.12 (m, 3H), 6.96
2H), 7.10e7.09 (m, 2H), 6.58 (t, J¼1.8 Hz, 2H), 4.51 (d, J¼4.2 Hz, 1H),
4.24 (d, J¼4.8 Hz, 1H), 2.34 (s, 3H), 2.25e1.95 (m, 8H), 1.80e1.41 (m,
(d, J¼1.2 Hz, 1H), 6.81e6.79 (m, 2H), 6.47 (s, 1H), 6.36 (d, J¼1.2 Hz,
1H), 5.67 (s, 1H), 5.64e5.64 (d, J¼6.6 Hz, 1H), 5.55 (s, 1H), 5.49 (s,
1H), 4.28e4.26 (d, J¼7.2 Hz, 1H), 2.19 (s, 3H); 13C NMR (150 MHz,
8H); 13C NMR (150 MHz, CDCl3):
d
¼137.5, 137.2, 134.3, 132.4, 129.8,
126.9, 126.1, 124.8, 118.3, 86.4, 55.0, 25.8, 24.8,22.8, 22.2, 22.19,
22.15, 21.3, 21.0; HRMS calculated for [C22H27NO2þH]þ: 338.21146,
found: 338.21159.
CDCl3):
d
¼144.0, 143.5, 138.8, 137.1, 135.2, 128.7, 128.6, 128.4, 128.1,
127.7, 127.4, 126.9, 121.9, 120.5, 115.4, 114.8, 81.1, 84.2, 30.9; HRMS
calculated for [C23H21N3O2þH]þ: 372.17065, found: 372.17094.
4.1.16. 4-p-Nitrophenyl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide
(3p). Purified by flash chromatography (hexaneeEtOAc) as a yel-
4.1.10. 4-N-Methyl-indole-3,5-bis (1-phenylvinyl) isoxazoline-N-ox-
ide (3j). Purified by flash chromatography (hexaneeEtOAc) as
low solid (yield: 92%); 1H NMR (600 MHz, CDCl3):
d
¼8.25e8.23 (m,
a colorless oil (yield: 53%); 1H NMR (600 MHz, CDCl3):
d¼7.41e7.39
2H), 7.42e7.40 (m, 2H), 6.47e6.45 (p, J¼4.2 Hz, 1H), 5.76 (s, 1H),
4.51 (d, J¼4.2 Hz, 1H), 4.41 (d, J¼4.2 Hz, 1H), 2.30e1.92 (m, 8H),
(m, 2H), 7.38e7.35 (m, 4H), 7.22e7.17 (m, 3H), 7.13e7.10 (t, J¼7.8 Hz,
2H), 7.04e7.02 (t, J¼7.8 Hz, 1H), 6.83e6.81 (m, 2H), 6.49 (s, 1H), 6.14
(d, J¼1.2 Hz,1H), 5.70 (s,1H), 5.56 (s,1H), 5.50 (d, J¼1.2 Hz,1H), 5.42
(d, J¼3.0 Hz, 1H), 5.45 (d, J¼3.6 Hz, 1H), 3.64 (s, 3H); 13C NMR
1.78e1.40 (m, 8H); 13C NMR (150 MHz, CDCl3):
133.1, 128.0, 127.3, 124.56, 124.53, 117.3, 85.7, 55.0, 25.8, 24.8, 22.7,
22.1, 22.09, 22.04, 21.2; HRMS calculated for [C21H24N2O4þH]þ:
369.18088, found: 369.18118.
d
¼147.6,147.4,133.7,
(150 MHz, CDCl3):
d
¼145.2, 138.2, 137.4, 137.1, 136.0, 128.9, 128.7,
128.3, 127.9, 127.6, 127.5, 127.19, 127.12, 125.7, 122.0, 121.6, 119.6,
118.8,115.7,114.6,111.5,109.3, 82.29, 48.9, 32.6; HRMS calculated for
[C28H24N2O2þH]þ:421.19105, found: 421.19143.
4.1.17. 4-p-Anisyl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide
(3q). Purified by flash chromatography (hexaneeEtOAc) as a white
solid (yield: 90%); 1H NMR (600 MHz, CDCl3):
d
¼7.26e7.11 (m, 2H),
4.1.11. 4-p-Toulyl-3,5-bis (p-chloribenzylvinyl) isoxazoline-N-oxide
(3k). Purified by flash chromatography (hexaneeEtOAc) as a col-
6.89e6.87 (m, 2H), 6.59e6.58 (m,1H), 5.73 (s,1H), 4.51 (d, J¼4.8 Hz,
1H), 4.23 (d, J¼4.2 Hz, 1H), 3.80 (s, 3H), 2.22e1.94 (m, 8H),
orless oil (yield: 95%); 1H NMR (600 MHz, CDCl3):
d¼7.35e7.33 (m,
1.73e1.44 (m, 8H); 13C NMR (150 MHz, CDCl3):
d¼159.1, 134.3,
2H), 7.30e7.28 (m, 2H), 7.15e7.13 (dt, J¼8.4, 4.8 Hz, 2H), 7.06e7.05
(d, J¼7.8 Hz, 2H), 6.81e6.79 (d, J¼7.8 Hz, 2H), 6.78e6.75 (dt, J¼8.4,
4.2 Hz, 2H), 6.04 (s, 1H), 5.64 (s, 1H), 5,53 (s, 1H), 5.49 (s, 1H), 5.25
(d, J¼4.2 Hz, 1H), 4.06 (d, J¼4.2 Hz, 1H), 2.31 (s, 3H); 13C NMR
132.5, 132.2, 128.1, 126.2, 124.8, 118.4, 114.5, 86.6, 55.2, 54.7, 25.8,
24.8, 22.8, 22.2, 22.1, 21.3; HRMS calculated for [C22H27NO3þH]þ:
354.20637, found: 354.20658.
(150 MHz, CDCl3):
133.9, 129.8, 129.0, 128.8, 128.3, 128.2, 127.0, 122.3, 115.8, 115.7, 83.0,
d
¼143.6, 138.1, 136.2, 135.48, 135.42, 134.9, 134.5,
4.1.18. 4-Furyl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide (3r).
Purified by flash chromatography (hexaneeEtOAc) as a colorless oil

C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
4409
(yield: 89%); 1H NMR (600 MHz, CDCl3):
d¼7.38 (s, 1H), 6.60e6.58
0.1 mmol, 0.2 equiv) and K2CO3 (35 mg, 0.25 mmol, 0.5 equiv) were
then added in and stir for 5 min. The aldehyde (0.5 mmol, 1.0 equiv)
and DMSO solution (0.2 M) were added drop wise through 5 min.
The resulting reaction mixture was stirred at room temperature for
1e5 h monitored by TLC. Upon the aldehyde was all consumed, the
mixture was diluted with EtOAc (100 mL). The organic phase was
washed by HCl solution (1.0 M), saturated NaHCO3 (aq) and brine,
and then dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure to give a residue. Flash silica gel chroma-
tography was then applied to give the product.
(m, 1H), 6.34 (m, 1H), 6.19 (d, J¼3.6 Hz, 1H), 5.81 (s, 1H), 4.72 (d,
J¼4.2 Hz, 1H), 4.43 (d, J¼4.2 Hz, 1H), 2.24e2.23 (t, J¼4.2 Hz, 2H),
2.17e2.12 (m, 3H), 2.06e2.04 (m, 2H), 1.98e1.92 (m, 1H), 1.76e1.48
(m, 8H); 13C NMR (150 MHz, CDCl3):
126.5,124.8,115.8,110.7,107.3, 83.2, 48.8, 25.9, 25.5, 24.8, 22.8, 22.3,
22.1, 22.0, 21.3; HRMS calculated for [C19H23NO3þH]þ: 314.17507,
found: 314.117533.
d
¼151.7, 142.4, 133.8, 132.2,
4.1.19. 4-Pyridin-4-yl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide
(3s). Purified by flash chromatography (hexaneeEtOAc) as an or-
ange solid (yield: 92%); 1H NMR (600 MHz, CDCl3):
d
¼8.61 (dd,
4.2.1. 4-Phenyl-3-(1-phenylvinyl)-5-(phenylketone)-isoxazoline-N-
oxide (5a). Purified by flash chromatography (hexaneeEtOAc) as
J¼4.8, 3.6 Hz, 2H), 7.17e7.16 (dd, J¼4.8, 3.0 Hz, 2H), 6.47 (m, 1H),
5.76 (s, 1H), 4.51 (d, J¼3.6 Hz, 1H), 4.28 (d, J¼4.2 Hz, 1H), 2.30e1.92
a colorless oil (yield: 91%); 1H NMR (600 MHz, CDCl3):
d¼7.97e7.95
(m, 8H), 1.78e1.40 (m, 8H); 13C NMR (150 MHz, CDCl3):
d¼150.6,
(m, 2H), 7.62e7.59 (tt, J¼7.2 Hz, 1H), 7.48e7.46 (t, J¼7.8 Hz, 2H),
7.26e7.21 (m, 6H), 7.06e7.02 (m, 4H), 6.29 (s, 1H), 5.60 (s, 1H), 5.55
(d, J¼3.6 Hz, 1H), 5.07 (d, J¼3.6 Hz, 1H); 13C NMR (150 MHz, CDCl3):
148.9, 133.7, 132.9, 127.0, 124.5, 122.0, 117.0, 85.4, 54.5, 25.8, 25.7,
24.8, 22.7, 22.1, 22.05, 22.0, 21.2; HRMS calculated for
[C20H24N2O2þH]þ: 325.19105, found: 325.19129.
d
¼192.4, 138.1, 137.9, 135.6, 134.3, 133.7, 129.4, 129.1, 128.9, 128.2,
128.1, 127.9, 127.8, 127.5, 122.3, 115.6, 81.0, 52.4; HRMS calculated
4.1.20. 4-n-Propyl-3,5-bis (cyclohexenyl) isoxazoline-N-oxide (3t). Pu-
rified by flash chromatography (hexaneeEtOAc) as a white solid
for [C22H27NO3þH]þ: 370.14377, found: 370.14390.
(yield: 64%); 1H NMR (600 MHz, CDCl3):
d
¼6.45e6.43 (m, 1H), 4.47
4.2.2. 4-p-Toulyl-3-(1-phenylvinyl)-5-(phenylketone)-isoxazoline-N-
oxide (5b). Purified by flash chromatography (hexaneeEtOAc) as
(d, J¼2.4 Hz, 1H), 3.13e3.11 (m, 1H), 2.52e2.48 (m, 1H), 2.29e1.88
(m, 6H),1.89e1.80 (m,1H),1.78e1.30 (m,13H), 0.95 (t, J¼7.2 Hz, 3H);
a colorless oil (yield: 92%); 1H NMR (600 MHz, CDCl3):
d¼7.97e7.95
13C NMR (150 MHz, CDCl3):
d
¼135.3, 131.6, 125.1, 124.9, 119.0, 82.9,
(m, 2H), 7.62e7.60 (tt, J¼6.0 Hz, 1H), 7.49e7.46 (t, J¼5.4 Hz, 2H),
7.26e7.23 (m, 3H), 7.08e7.05 (m, 4H), 6.93e6.92 (d, J¼7.8 Hz, 2H),
6.24 (s, 1H), 5.60 (s, 1H), 5.53 (d, J¼3.6 Hz, 1H), 5.01 (d, J¼3.6 Hz,
48.5, 34.1, 25.9, 25.5, 24.7, 22.8, 22.3, 22.16, 22.13, 21.4, 19.3, 13.9;
HRMS calculated for [C18H27NO2þH]þ: 390.21146, found: 290.21173.
1H), 2.30 (s, 3H); 13C NMR (150 MHz, CDCl3):
135.6, 135.1, 134.3, 133.7, 129.8, 129.3, 128.9, 128.1, 127.9, 127.7, 127.3,
122.2, 115.6, 81.2, 52.2, 21.0; HRMS calculated for [C25H21NO3þH]þ:
384.15942, found: 384.15955.
d
¼192.5, 138.1, 137.9,
4.1.21. 4-p-Nitro-phenyl-3,5-bis (1-furylvinyl)isoxazoline-N-oxide
(3u). Purified by flash chromatography (hexaneeEtOAc) as a col-
orless oil (yield: 46%); 1H NMR (600 MHz, CDCl3):
d
¼8.14e8.12 (m,
2H), 7.39 (d, J¼1.8 Hz, 1H), 7.11e7.09 (m, 2H), 6.76 (d, J¼1.8 Hz, 1H),
6.47 (q, J¼2.4 Hz, 1H), 6.39 (q, J¼2.4 Hz, 1H), 6.17e6.16 (d, J¼3.0 Hz,
1H), 5.96e5.65 (t, J¼3.6 Hz, 1H), 5.77 (s, 1H), 5.64 (d, J¼1.2 Hz, 1H),
5.61e5.60 (q, J¼3.6 Hz, 1H), 5.59 (s, 1H), 5.17 (dd, J¼2.4, 1.2 Hz, 1H),
4.2.3. 4-Furyl-3-(1-phenylvinyl)-5-(phenylketone)-isoxazoline-N-ox-
ide (5c). Purified by flash chromatography (hexaneeEtOAc) as
a colorless oil (yield: 73%); 1H NMR (600 MHz, CDCl3):
d
¼8.03e8.01
4.28 (d, J¼3.6 Hz, 1H); 13C NMR (150 MHz, CDCl3):
d¼150.2, 147.7,
(m, 2H), 7.65e7.62 (tt, J¼6.0, 2.4 Hz, 1H), 7.52e7.49 (t, J¼7.8 Hz, 2H),
7.34 (m, 1H), 7.31e7.25 (m, 3H), 7.18e7.16 (m, 2H), 6.28 (s, 1H),
6.23e6.22 (q, J¼3.6 Hz, 1H), 5.92 (d, J¼3.0 Hz, 1H), 5.70 (d, J¼4.2 Hz,
1H), 5.67 (s, 1H), 5.35 (d, J¼4.2 Hz, 1H); 13C NMR (150 MHz, CDCl3):
146.2, 142.8, 134.5, 129.3, 128.2, 126.4, 124.7, 124.0, 120.9, 116.0,
111.4, 110.2, 109.7, 107.6, 107.1, 79.6, 57.6, 46.2, 33.1, 29.6; HRMS
calculated for [C21H16N2O6þH]þ: 393.10811, found: 393.08662.
d
¼191.8, 186.8, 149.2, 143.0, 137.8, 135.5, 134.4, 133.7, 129.5, 128.9,
4.1.22. 4-p-Anisyl-3,5-bis (methylvinyl) isoxazoline-N-oxide (3v).
Purified by flash chromatography (hexaneeEtOAc) as a colorless oil
128.2, 128.1,127.6,122.1, 110.7,108.6, 78.1, 46.0; HRMS calculated for
[C22H17NO4þNa]þ: 382.10498, found: 382.10522.
(yield: 74%); 1H NMR (600 MHz, CDCl3):
d
¼7.16e7.13 (m, 2H),
6.90e6.88 (m, 2H), 5.67 (s, 1H), 5.23 (t, J¼1.8 Hz, 1H), 5.07 (s, 1H),
4.97 (s, 1H), 4.64 (d, J¼4.8 Hz, 1H), 4.26 (d, J¼4.8 Hz, 1H), 3.80 (s,
4.2.4. 4-Propyl-3-(1-phenylvinyl)-5-(phenylketone)-isoxazoline-N-
oxide (5d). Purified by flash chromatography (hexaneeEtOAc) as
3H), 1.92 (s, 3H), 1.85 (s, 3H); 13C NMR (150 MHz, CDCl3):
d¼159.4,
a colorless oil (yield: 62%); 1H NMR (600 MHz, CDCl3):
d
¼8.03e8.01
141.0, 131.6, 130.6, 128.2, 119.7, 117.8, 114.7, 113.8, 85.3, 55.2, 20.8,
16.9; HRMS calculated for [C16H19NO2þH]þ: 258.14886, found:
258.14896.
(m, 2H), 7.64e7.61 (tt, J¼6.0, 2.4 Hz, 1H), 7.52e7.50 (t, J¼7.8 Hz, 2H),
7.39e7.29 (m, 5H), 6.37 (s, 1H), 5.78 (s, 1H), 5.32 (d, J¼3.0 Hz, 1H),
4.06e4.04 (m, 1H), 1.56e1.50 (m, 1H), 1.47e1.41 (m, 1H), 1.31e1.30
(m, 2H), 0.75 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3):
¼193.6,
d
4.1.23. 4-20-Furyl-3,5-bis (methylvinyl) isoxazoline-N-oxide (3w). Pur-
ified by flash chromatography (hexaneeEtOAc) as a colorless oil
138.1, 135.6, 134.17, 134.12, 129.3, 128.8, 128.5, 128.2, 127.6, 122.0,
115.8, 78.6, 45.8, 33.3, 18.9, 13.4; HRMS calculated for
[C21H21NO3þH]þ: 336.15942, found: 336.16080.
(yield: 71%); 1H NMR (600 MHz, CDCl3):
d
¼7.40e7.39 (m, 1H),
6.36e6.35 (dd, J¼3.0, 1.8 Hz, 1H), 6.23 (d, J¼3.0 Hz, 1H), 5.68 (s, 1H),
5.26 (s, 1H), 5.14 (s, 1H), 5.01 (s, 1H), 4.84 (d, J¼4.8 Hz, 1H), 4.47 (d,
J¼4.8 Hz, 1H), 1.97 (s, 3H), 1.85e1.84 (s, 3H); 13C NMR (150 MHz,
4.2.5. 4-i-Propyl-3 (1-phenylvinyl) 5-(phenylketone) isoxazoline-N-
oxide (5e). Purified by flash chromatography (hexaneeEtOAc) as
CDCl3):
d
¼159.4, 141.0, 131.6, 130.6, 128.2, 119.7, 117.8, 114.7, 113.8,
a colorless oil (yield: 52%); 1H NMR (600 MHz, CDCl3):
d¼8.05e8.04
85.3, 55.2, 20.8, 16.9; HRMS calculated for [C13H15NO3þH]þ:
(m, 2H), 7.65e7.62 (m,1H), 7.53e7.51 (m, 2H), 7.39e7.25 (m, 5H), 7.36
(s,1H), 5.83(s,1H), 5.38(d, J¼2.4 Hz,1H), 4.02e4.01 (dd, J¼4.2,1.2 Hz,
1H),1.86e1.80 (m,1H), 0.95e0.89 (m, 3H), 0.82 (d, J¼6.6 Hz, 3H), 0.74
234.11247, found: 234.11261.
4.2. General procedure for preparation of three-component
isoxazoline-N-oxide (5)
(t, 3H); 13C NMR (150 MHz, CDCl3):
d
¼194.0,138.2,135.9,134.2,134.1,
129.4,128.8,128.5,128.3,127.6,122.2,115.0, 75.4, 51.6, 29.3,19.4,17.5;
HRMS calculated for [C21H21NO3þH]þ: 336.15942, found: 358.15967.
The nitroalkene (0.6 mmol, 1.2 equiv) was added to a solution of
the corresponding sulfur ylide (0.55 mmol, 1.1 equiv) DMSO (0.2 M
for nitroalkene) solution, till theylide is all dissolved. Proline (12 mg,
4.2.6. 4-p-Nitrophenyl-3-(1-phenylvinyl)-5-(phenylketone) isoxazo-
line-N-oxide (5f). Purified by flash chromatography (hexaneeEtOAc)

4410
C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
as
a
colorless oil (yield: 92%); 1H NMR (600 MHz, CDCl3):
(hexaneeEtOAc) as a colorless oil (yield: 92%); 1H NMR (600 MHz,
CDCl3):
d
¼8.08e8.06 (d, J¼7.2 Hz, 2H), 8.00e7.99 (d, J¼8.4 Hz, 2H), 7.66e7.63
d
¼8.41e8.40 (dd, J¼4.8, 3.0 Hz, 2H), 8.05e8.04 (dd, J¼7.2,
(t, J¼8.4 Hz, 1H), 7.52e7.50 (t, J¼7.8 Hz, 2H), 7.28e7.24 (m, 3H),
7.17e7.15 (m, 2H), 7.04e7.03 (d, J¼7.8 Hz, 2H), 6.46 (s,1H), 5.67 (s,1H),
5.48 (d, J¼4.2 Hz, 1H), 5.34 (d, J¼4.2 Hz, 1H); 13C NMR (150 MHz,
5.4 Hz, 2H), 7.66e7.63 (t, J¼8.4 Hz, 1H), 7.52e7.50 (t, J¼8.4 Hz, 2H),
7.26e7.20 (m, 6H), 7.14e7.13 (dd, J¼4.2, 3.0 Hz, 2H), 5.91 (s, 1H),
5.69 (s, 1H); 13C NMR (150 MHz, CDCl3):
d
¼182.5, 162.8, 162.4,
CDCl3):
d¼191.7, 147.6, 145.2, 138.0, 135.0, 134.7, 133.6, 129.5, 129.0,
149.5, 146.9, 137.0, 136.6, 136.3, 135.7, 135.4, 134.5, 130.2, 128.7,
128.6, 128.4, 126.7, 124.0, 121.8, 121.2; HRMS calculated for
[C23H17N2O3BrþH]þ: 449.04953, found: 449.04984.
128.6, 128.4, 128.3, 127.9, 124.2, 122.7, 114.9, 80.4, 51.5; HRMS calcu-
lated for [C24H18N2O5þH]þ: 415.12885, found: 415.21173.
4.2.7. 4-Napthyl-3-(1-phenylvinyl)-5-(ethyl ester)-isoxazoline-N-ox-
ide (5g). Purified by flash chromatography (hexaneeEtOAc) as
4.3. Procedure for diene intermediate A0 and the cross
condensation. (Scheme 10)
a colorless oil (yield: 88%); 1H NMR (600 MHz, CDCl3):
d
¼7.85e7.79
(m, 3H), 7.49e7.35 (m, 4H), 7.14e7.12 (m, 3H), 7.03 (d, J¼3.0, 2H),
6.33 (s,1H), 5.62 (s,1H), 4.81 (d, J¼3.0 Hz,1H), 4.64 (d, J¼3.0 Hz,1H),
4.37e4.33 (m, 2H), 1.37e1.35 (t, J¼7.2, 3H); 13C NMR (150 MHz,
The nitroalkene 1b (141 mg, 1.0 mmol, 1.0 equiv, 0.1 M) and
DMSO solution were added to a DCM solution of aldehyde
(1.5 mmol, 1.5 equiv, 0.15 M), L-proline (11 mg, 0.1 mmol, 0.1 equiv),
CDCl3):
d
¼169.3, 137.9, 135.5, 134.0, 133.0, 132.8, 130.3, 129.1, 129.0,
and K2CO3 (35 mg, 0.25 mmol, 0.5 equiv) mixture. Add the nitro-
alkene drop wise to the reaction mixtures in 5 min. The resulting
mixture was stirred at room temperature for 2 h. Upon the nitro-
alkene was all consumed, the mixture was diluted with EtOAc
(100 mL). The organic phase was washed by brine and then dried
over anhydrous Na2SO4. Flash silica gel chromatography was then
applied to give the Z/E isomers A0 as a mixture (143 mg, 65% yield),
128.1, 127.9, 127.6, 126.9, 126.0, 125.4, 122.4, 122.1, 78.1, 62.6, 49.1,
14.6; HRMS calculated for [C20H19NO4þH]þ: 388.15433, found:
388.15453.
4.2.8. 4-p-Nitrophenyl-3-(1-phenylvinyl)-5-(ethyl ester) isoxazoline-
N-oxide (5h). Purified by flash chromatography (hexaneeEtOAc) as
a colorless oil (yield: 92%); 1H NMR (600 MHz, CDCl3):
d
¼8.10e8.07
Z/E¼1/1.5. 1H NMR (600 MHz, CDCl3): set 1,
¼7.81 (s, 1H), 7.57 (d,
d
(m, 2H), 7.30e7.23 (m, 3H), 7.14e7.12 (m, 2H), 6.99e6.98 (m, 2H),
6.43 (s, 1H), 5.66 (s, 1H), 4.82e4.80 (dd, J¼10.2, 6.6 Hz, 2H),
4.39e4.35 (m, 2H), 1.39e1.36 (t, J¼7.2 Hz, 3H); 13C NMR (150 MHz,
J¼3.2 Hz, 1H) 6.85e6.86 (d, 1H), 6.52e6.53 (dd, J¼3.6 Hz, 1H),
5.95e5.96 (m, 1H), 2.17e2.24 (m, 4H), 1.72e1.83 (m, 3H), 1.62e1.65
(m, 1H); set 2,
d
¼7.43 (d, 1H), 6.49e6.50 (d, 1H), 6.41e6.42 (dd,
CDCl3):
d
¼168.2, 147.7, 144.7, 137.8, 134.8, 128.4, 128.3, 128.1, 127.7,
J¼3.6, 1.8 Hz, 1H), 6.15 (s, 1H), 5.86e5.88 (t, J¼7.2 Hz, 1H), 2.17e2.24
124.2, 122.5, 113.9, 62.7, 54.1, 14.0; HRMS calculated for
(m, 4H), 1.72e1.83 (m, 3H), 1.62e1.65 (m, 1H); 13C NMR (150 MHz,
[C20H18N2O6þH]þ: 383.12376, found: 383.12396.
CDCl3): set 1,
d
¼148.0, 146.1, 144.3, 133.8, 120.8, 117.1, 112.9, 112.0,
26.8, 25.5, 22.5, 21.5; set 2
d
¼149.0, 148.5, 147.2, 129.1, 128.0, 112.8,
4.2.9. 4-p-Toulyl-3-(1-phenylvinyl)-5-(p-bromophenyl ketone) iso-
xazoline-N-oxide (5i). Purified by flash chromatography (hex-
aneeEtOAc) as a colorless oil (yield: 91%); 1H NMR (600 MHz, CDCl3):
104.9, 29.7, 25.7, 24.5, 22.1; HRMS calculated for [C12H13NO3þH]þ:
220.09682, found: 220.09697.
The diene A0 (132 mg, 0.6 mmol, 1.0 equiv) was then mixed with
nitroalkene 1a (106 mg, 0.65 mmol, 1.1 equiv) in DMSO, with A0 as
0.1 M. Proline (14 mg, 0.12 mmol, 0.2 equiv) and K2CO3 (41 mg,
0.30 mmol, 0.5 equiv) were added in the solution. 2 h later, the
nitroalkene was all consumed, the mixture was diluted with EtOAc
(100 mL). The organic phase was washed brine and then dried over
anhydrous Na2SO4. Flash silica gel chromatography was then ap-
plied to give the crude product 3b (18%), 3b0 (6%), 3s (26%), 3s0
(24%). These four compounds could not be separated by
chromatography.
d
¼7.84e7.82 (m, 2H), 7.64e7.62 (m, 2H), 7.27e7.23 (m, 3H), 7.06e7.05
(m, 4H), 6.92e6.90 (d, J¼8.4 Hz, 2H), 6.25 (s, 1H), 5.60 (s, 1H), 5.45 (d,
J¼4.2 Hz,1H), 5.02 (d, J¼3.6 Hz, 1H), 2.30 (s, 3H); 13C NMR (150 MHz,
CDCl3):
d¼191.7, 138.2, 137.8, 135.5, 134.9, 132.5, 132.2, 130.8, 129.8,
128.1, 127.9, 127.7, 127.3, 122.4, 115.5, 81.1, 52.0, 21.0; HRMS calculated
for [C25H20NO3BrþH]þ: 462.06993, found: 462.07183.
4.2.10. 4-p-Nitrophenyl-3-(1-phenylvinyl)-5-(p-bromophenylke-
tone)-isoxazoline-N-oxide (5j). Purified by flash chromatography
(hexaneeEtOAc) as a colorless oil (yield: 73%); 1H NMR (600 MHz,
CDCl3):
d
¼8.09e8.06 (m, 2H), 8.00e7.99 (d, J¼7.2 Hz, 2H),
4.4. General procedure for preparation of three-component
isoxazoline-N-oxide (optical sample for Table 5)
7.66e7.63 (tt, J¼6.0, 2.4 Hz, 1H), 7.52e7.50 (t, J¼6.6 Hz, 2H),
7.30e7.24 (m, 2H), 7.17e7.15 (m, 2H), 7.04e7.03 (d, J¼4.8 Hz, 2H),
6.46 (s, 1H), 5.67 (s, 1H), 5.49 (d, J¼4.2 Hz, 1H), 5.35 (d, J¼4.2 Hz,
The nitroalkene 1a (114 mg, 0.7 mmol, 1.4 equiv) was added to
a solution of the sulfur ylide 4d (219 mg, 0.6 mmol, 1.2 equiv) in
MeOH (0.4 M for nitroalkene), till the ylide is all dissolved. The
mixture was cooled down to ꢁ25 ꢀC. Pyrrolidine (7 mg, 0.1 mmol,
0.2 equiv) and K2CO3 (35 mg, 0.25 mmol, 0.5 equiv) were then
added in and stir for 30 min. The aldehyde 2a (0.5 mmol, 1.0 equiv)
MeOH solution (0.4 M) was added drop wise through 10 min. The
resulting reaction mixture was stirred at ꢁ25 ꢀC for 48 h. The
mixture was then diluted with EtOAc (20 mL) and the water phase
was extracted with EtOAc (20 mLꢂ3). The organic phase was
washed by HCl solution (1.0 M), saturated NaHCO3 (aq) and brine,
and then dried over anhydrous Na2SO4. Flash silica gel chroma-
tography was then applied to give the product 7a (144 mg, 89%) as
1H); 13C NMR (150 MHz, CDCl3):
d
¼191.7, 147.6, 145.2, 138.0, 135.0,
134.7, 133.6, 129.5, 129.0, 128.6, 128.4, 128.3, 127.9, 124.2, 122.7,
114.9, 80.5, 51.5; HRMS calculated for [C25H20BrNO4þH]þ:
478.06485, found: 478.06495.
4.2.11. 4-p-Anisyl-3 (1-phenylvinyl) 5- (p-bromophenyl ketone) iso-
xazoline-N-oxide (5k). Purified by flash chromatography (hex-
aneeEtOAc) as a colorless oil (yield: 92%); 1H NMR (600 MHz,
CDCl3):
d
¼7.84e7.82 (d, J¼8.4 Hz, 2H), 7.64e7.62 (d, J¼9.0 Hz, 2H),
7.27e7.23 (m, 3H), 7.05e7.04 (m, 2H), 6.93e6.91 (d, J¼8.4 Hz, 2H),
6.77e6.76 (d, J¼6.6 Hz, 2H), 6.28 (s, 1H), 5.61 (s, 1H), 5.44 (d,
J¼3.6 Hz, 1H), 5.01 (d, J¼3.6 Hz, 1H), 3.77 (s, 3H); 13C NMR
(150 MHz, CDCl3):
d¼191.8, 159.5, 138.0, 135.5, 132.5, 132.2, 130.8,
clear oil. 1H NMR (600 MHz, CDCl3)
d
¼7.27e7.22 (m, 6H), 7.01e6.98
129.8, 128.6, 128.1, 128.0, 127.7, 122.4, 115.6, 114.5, 81.2, 55.2, 51.7;
HRMS calculated for [C25H20BrNO4þH]þ: 478.06485, found:
478.06498.
(m, 4H), 6.29 (s, 1H), 5.61 (s, 1H), 4.83 (d, J¼3.0 Hz, 1H), 4.65 (d,
J¼3.0 Hz, 1H), 3.89(s, 3H); 13C NMR (150 MHz, CDCl3): 169.4, 137.9,
137.7, 135.4, 129.1, 129.10, 128.7, 128.3, 128.1, 128.0, 127.7, 127.0,
122.3, 114.7, 78.2, 54.8, 53.1; HRMS calculated for [C19H17NO4þH]þ:
26
4.2.12. 4-Pyridin-4-yl-3-(1-phenylvinyl)-5-(p-bromophenyl ketone)
324.12303, found: 324.12316. [
a
]
104.5ꢀ (c 1.0 CHCl3). Enantio-
D
isoxazoline-N-oxide (5l). Purified by flash chromatography
meric excess was determined by HPLC with a Chiralcel OD-H

C. Zhong et al. / Tetrahedron 67 (2011) 4402e4411
4411
G.; Oikonomakos, N. G. Bioorg. Med. Chem. 2009, 17, 7368e7380; (c) Maurya, R.;
Gupta, P.; Ahmad, G.; Yadav, D. K.; Chand, K.; Singh, A. B.; Tamrakar, A. K.;
Srivastava, A. K. Med. Chem. Res. 2008, 17, 123e136; (d) Khan, M. O. F.; Lee, H. J.
Chem. Rev. 2008, 108, 5131e5145; (e) Pirrung, M. C.; Tumey, L. N.; Raetz, C. R. H.;
Jackman, J. E.; Snehalatha, K.; McClerren, A. L.; Fierke, C. A.; Gantt, S. L.; Rusche,
K. M. J. Med. Chem. 2002, 45, 4359e4370.
column;
l
¼254 nm; eluent: hexaneeisopropanol¼90/10; flow
rate: 1.0 mL/min; tminor¼10.352 min, tmajor¼12.964 min; ee%¼91%.
Acknowledgements
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We thank the NSF-CAREER (CHE-0844602), DOE (DE-FC26-
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