Highly trans- stereoselective synthesis of bicyclic isoxazolidines via copper-catalyzed triple cascade catalysis

Article abstract of DOI:10.1021/jo400215e

A triple cascade was developed using a simple copper catalyst to trans-selectively access bicyclic isoxazolidines in a one-pot synthesis. This strategy features the in situ generation of nitrones and subsequent trapping by [3 + 2] cycloaddition. In this method, copper serves three catalytic functions: as a Lewis acid for the ene reaction, as an organometallic for aerobic oxidation, and as a Lewis acid for an endo-selective [3 + 2] cycloaddition. The successful merging of aerobic oxidation and Lewis acid catalysis demonstrated efficient cascade synergy.

Full text of DOI:10.1021/jo400215e

Note
pubs.acs.org/joc
Highly trans-Stereoselective Synthesis of Bicyclic Isoxazolidines via
Copper-Catalyzed Triple Cascade Catalysis
Hu Chen,† Zhaofeng Wang,† Yingnan Zhang,‡ and Yong Huang*,†
†Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
University, Shenzhen 518055, China
‡Division of Food-Borne Diseases Surveillance, China National Center for Food Safety Risk Assessment, Beijing 100021, China
S
* Supporting Information
ABSTRACT: A triple cascade was developed using a simple
copper catalyst to trans-selectively access bicyclic isoxazolidines
in a one-pot synthesis. This strategy features the in situ
generation of nitrones and subsequent trapping by [3 + 2]
cycloaddition. In this method, copper serves three catalytic
functions: as a Lewis acid for the ene reaction, as an
organometallic for aerobic oxidation, and as a Lewis acid for
an endo-selective [3 + 2] cycloaddition. The successful merging
of aerobic oxidation and Lewis acid catalysis demonstrated
efficient cascade synergy.
Scheme 1. Double Allylic Oxidation [3 + 2] Strategy to
Bicyclic Heterocycles
ascade and synergistic catalysis has recently re-emerged as
Ca powerful strategy for the rapid construction of
sophisticated molecular architectures.1 Much of the work in
this field has concentrated on the nucleophilic reaction
paradigm. Cascades involving redox catalytic cycles have been
lacking, despite recent advances in transition-metal-catalyzed
oxidative C−H activation2 and aerobic oxidation reactions.3
Cascades tethering these privileged functionalization methods,
preferably using a simple catalyst, are highly desirable for the
direct conversion of cheap industrial hydrocarbon feedstocks to
molecules with rich functionalities. However, one-pot trans-
formations involving hydrocarbons are challenging because
strong oxidants are often required, which can lead to
uncontrollable domino reaction pathways and catalyst quench-
ing. One such example is the nitrones, a class of highly reactive
functional groups that enable a number of chemical trans-
formations.4 Despite their versatile synthetic utilities, the use of
nitrones requires a separate preparation step that typically
involves the condensation of aldehydes and hydroxyamines.5
The synthesis of nitrones via direct aerobic oxidation of more
readily available olefins has not been successful. In this report,
we describe a catalytic cascade involving double allylic C−H
oxidation6 leading to in situ nitrone formation7 and a highly
endo-selective [3 + 2] cycloaddition8 using a simple,
commercially available copper catalyst to access pharmacolog-
ically valuable [5,5] bicyclic isoxazolidines in one pot with high
trans-diastereocontrol (Scheme 1). This novel method for in
situ nitrone generation via aerobic oxidation may enable
versatile applications tethered to this chemistry.
been reported for molecules containing this bicyclic scaffold
(Figure 1). In addition, via reductive cleavage of the N−O
bond, isoxazolidines allow quick access to γ-amino alcohols,
another important class of biologically relevant moieties.12 We
envisioned that a one-pot catalytic cascade involving aerobic
oxidation and [3 + 2] cycloaddition would be an ideal way to
access this class of important pharmacophores from simple
olefins. This strategy necessitated straightforward conversion of
an allyl group to the corresponding nitrone, which would be
further trapped by a dipolarophile in situ to yield the desired
bicyclic. Recently, Read de Alaniz, Jiao, and our group reported
Bicyclic isoxazolidines are widely found in natural products,
pharmaceutically valuable agents, and synthetic intermediates.
A number of biologically desirable properties, such as
antibacterial,9 antiamnestic,10 and antistress11 activities, have
Received: January 31, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
documented in the early literature.15 Often, products with
various oxidation stages were formed unselectively.16 The
reaction temperature and solvent were carefully examined, and
the highest cascade conversion was observed at 50−60 °C in
highly polar aprotic solvents. It has been reported that
nitrosobenzenes are prone to self-dimerization to afford
azoxybenzene in the presence of a transition metal.17 Substrate
ratios were studied in detail. Acceptable conversions were
achieved when the amount of nitrosobenzene was increased to
2 equiv, and >80% yields were obtained with 4 equiv of PhNO.
We tested various ligands in an effort to improve trans/cis-
selectivity. The employment of nitrogen-based bidentate
ligands significantly improved the trans-selectivity with some-
what compromised yields. Although the coupling constants for
the trans- and cis-isomers were quite similar, the relative
stereochemistries of both the cis- and trans-isomers of 2a were
unambiguously assigned based on their single-crystal X-ray
diffractions.
The substrate scope was explored, and the results are
summarized in Table 2. This protocol tolerated various
electron-rich and electron-deficient substituents on the allylic
aromatic rings, including heteroaromatics. For nonaromatic
substrates, oxidation led to various products, and selective
nitrone trapping was unsuccessful. Both alkyl and aryl
maleimides smoothly underwent this aerobic oxidation−
cycloaddition cascade. The N-alkylated maleimides led to
higher trans/cis-selectivity than their arylated counterparts. The
trans-selectivity for this transformation was uniformly high, and
dihydro-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione scaf-
folds containing three continuous stereogenic centers were
prepared in moderate to good yields. In general, the reaction
rates were not affected by electronic and steric modulation of
the substrates, and clean conversions were observed across the
board. Other dipolarophiles were briefly examined. The yields
involving maleic anhydrides and other ester-activated olefins
were significantly lower.
Figure 1. Natural products and biological agents containing bicyclic
isoxazolidines.
the aerobic dehydrogenation of hydroxyamines (to nitroso
compounds) and hydrazines (to hydrazones) by either Pd or
Cu catalysis.13 Inspired by this development, we decided to
investigate an ene reaction between allyl benzenes and
nitrosobenzenes,14 a key step for olefin oxidation. The
corresponding hydroxyamines generated would be further
dehydrogenated to afford transient nitrone species. Rapid [3
+ 2] dipolar addition using maleimides would render the
desired bicyclic isoxazolidines. This cascade combines tran-
sition-metal-catalyzed allylic oxidation and Lewis-acid-catalyzed
cycloaddition reactions, a strategy that conceptually echoes
White’s allylic dehydrogenation−cycloaddition cascade.6d
We initially studied a reaction cascade involving allylbenzene,
nitrosobenzene, and various electron-deficient olefins using
transition metals. In agreement with our previous studies,13c
most metals yielded messy mixtures, with the exception of
copper. The reaction involving N-methylmaleimide led to the
bicyclic isoxazolidine product in clean conversion using
Cu(OAc)2. Further optimization of the reaction conditions
revealed the features described below (Table 1). First, copper
proved to be the most efficient metal for this overall cascade.
Second, catalyst turnover was only achieved in the presence of
air or oxygen (Table 1, entries 1−3). Third, moderate trans-
selectivity was observed in the absence of a ligand due to poor
intrinsic endo/exo [3 + 2] cycloaddition. The direct oxidation of
olefins using nitrosobenzenes under heating has been
Isoxazolidine 2a could be opened reductively under Zn/
AcOH conditions, yielding a γ-amino alcohol 3a in 81% yield.
Upon treatment with NBS, the two most reactive nucleophilic
sites on 2a (i.e., p-aniline and the double bond) were
differentiated with complete selectivity. With 1 equiv of NBS,
a
Table 1. Reaction Condition Optimization for 2a
b
b
entry
sol
oxd
L
T/°C
yield (trans/cis)
entry
sol
oxd
L
T/°C
yield (trans/cis)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
DCM
Ar
50
50
50
80
50
50
50
50
13% (2.4:1)
21% (3.2:1)
28% (2.5:1)
trace (−)
36% (2.1:1)
5% (−)
9
10
11
12
13
14
15
DMSO
DMF
NMP
NMP
NMP
NMP
NMP
O2
O2
O2
O2
O2
O2
O2
50
50
50
50
50
50
50
38% (2.5:1)
36% (2.3:1)
39% (2.3:1)
84% (2.5:1)
52% (16:1)
60% (11:1)
69% (12:1)
air
O2
O2
O2
O2
O2
O2
1,10-phen
c
dzf
9% (−)
9% (−)
bpy
DCE
a
b
Substrate ratio (1a/1b/1c) for entries 1−6 1:1:1; for entries 7−11 1:2:2; for entries 12−15 1.5:4:1. Isolated yields. The trans/cis ratio was
c
measured by crude NMR integration. 4,5-Diazafluorenone.
B
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 2. Copper-Catalyzed Synthesis of Bicyclic Isoxazolidines
a
Isolated yield reflecting trans only; trans/cis ratio determined by crude NMR integration.
the p-position of the aniline was preferentially brominated at 60
°C in 96% yield. By increasing the amount of NBS to 2 equiv, a
bromine onium-mediated electrophilic cyclization occurred
following the initial aniline bromination. This led to a
structurally sophisticated novel pentacyclic scaffold (4b) in
95% yield (Scheme 2). The presence of two chemically
orthogonal bromine atoms (e.g., aryl bromide and alkyl
bromide) opens the door to further versatile molecular
manipulations.
subjected to a stand-alone [3 + 2] cycloaddition compared to
the one-pot cascade. The much higher yields observed under
cascade conditions indicated rapid nitrone trapping through
sequential [3 + 2] dipolar cycloaddition, resulting in an efficient
synergistic system. Nitrones generated in situ are best suited for
a one-pot cascade without isolation. The first ene reaction is
likely catalyzed by copper. Mixing allyl benzene and nitro-
sobenzene under Ar only resulted in nitrosobenzene dimeriza-
tion as a major side reaction. Only trace amount of allylic
oxidation was observed. On the other hand, the addition of
Cu(OAc)2 and bpy resulted in significantly less nitrosobenzene
decomposition under otherwise identical conditions. These
results indicated that copper is critical for controlling the
oxidation pathways and that the subsequent cascade improved
the overall chemoselectivity.
Scheme 2. Derivatization of Bicyclic Isoxazolidines
The proposed overall cascade mechanism is outlined in
Scheme 4. Presumably, a nitroso-ene reaction catalyzed by
copper generates the corresponding allylic hydroxylamine
species.18 The subsequent oxidation by another molecule of
nitrone or by copper-catalyzed direct aerobic oxidation leads to
the nitrone intermediate. The lack of catalyst turnover in the
absence of air or oxygen suggests that aerobic oxidation might
be the major pathway. Copper, which serves as a Lewis acid,
catalyzes the final [3 + 2] cycloaddition. The high trans-
selectivity is likely attributable to a square planar metal complex
that involves s-cis copper maleimide.19 The long styrenyl
substituent of nitrone is oriented away from the dipolarophile
(Scheme 4).
In summary, we have developed a simple copper system that
catalyzes a cascade reaction to access pharmacologically
attractive bicyclic isoxazolidines with high trans-diastereoselec-
tivity. The experimental evidence supports a nitroso-ene/
aerobic dehydrogenation cascade to generate a nitrone
intermediate, followed by subsequent copper-catalyzed [3 +
2] cycloaddition. Copper’s extended three-fold catalytic
function includes acting as a tethering Lewis acid for the ene
This cascade was believed to proceed through the nitrone
intermediate, as evidenced by the sequential experiments.
Nitrone 5a was obtained in 11% isolated yield when the
reaction was conducted in the absence of maleimides (Scheme
3, eq a). The low yield was attributed to nitrone decomposition
in the absence of a dipolarophile. Similar yields and trans-
selectivities were observed when purified nitrone 5a was
C
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 3. Stepwise Execution of the Cascade
rubber septum, degassed, flushed with molecular oxygen three times,
and stirred at 50 °C under an oxygen balloon overnight. The mixture
was cooled to room temperature and diluted with water (10 mL) and
ethyl acetate (10 mL). The organic layer was separated, and the
aqueous phase was extracted twice with ethyl acetate. The combined
extract was washed with water (10 mL) and brine (10 mL), dried over
sodium sulfate, filtered, and evaporated to dryness. The residue was
purified by flash silica gel column chromatography (ethyl acetate/
petroleum ether) to afford an analytically pure product.
Scheme 4. Proposed Reaction Mechanism and Explanation
for trans-Selective Cycloaddition
(3S,3aS,6aR)-5-Methyl-2-phenyl-3-((E)-styryl)dihydro-2H-pyrrolo-
[3,4-d]isoxazole-4,6(5H,6aH)-dione (2a): ethyl acetate/petroleum
ether = 1:5, 65% yield (0.109 g, dr = 7:1), yellow solid, mp 152−
154 °C; 1H NMR (CDCl3, 400 MHz) δ 7.38−7.19 (m, 7H), 7.02 (d, J
= 8.0 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.17
(dd, J = 16.0, 7.5 Hz, 1H), 5.06 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 7.2
Hz, 1H), 3.68 (d, J = 7.2 Hz, 1H), 2.81 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 175.0, 173.9, 147.0, 135.7, 133.9, 128.9, 128.7, 128.3,
126.6, 124.8, 122.9, 115.7, 76.0, 68.2, 55.3, 25.0; HRMS (ESI) found
335.1367, calcd for C20H18N2O3 ([M + H]+) 335.1396; IR (KBr)
1709, 1597, 1493, 1435, 1381, 1284, 1132, 1029, 968, 760, 737, 694,
625, 496.
(3R,3aS,6aR)-5-Methyl-2-phenyl-3-((E)-styryl)dihydro-2H-pyrrolo-
[3,4-d]isoxazole-4,6(5H,6aH)-dione (cis-2a): ethyl acetate/petroleum
1
ether = 1:4, yellow solid, mp 166−167 °C; H NMR (CDCl3, 400
reaction, as an organometallic in the allylic dehydrogenation,
and as a Lewis acid for the highly trans-selective [3 + 2] nitrone
cycloaddition. These results represent a rare triple cascade
catalysis involving both transition metal and Lewis acid
catalysis.
MHz) δ 7.38−7.26 (m, 7H), 7.23 (t, J = 4.4 Hz, 2H), 7.13 (t, J = 7.2
Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.09 (dd, J = 15.9, 8.6 Hz, 1H),
5.06 (d, J = 7.5 Hz, 1H), 4.16 (t, J = 8.3 Hz, 1H), 3.79 (t, J = 7.8 Hz,
1H), 3.11 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.4, 173.0,
146.9, 136.2, 136.0, 128.7, 128.6, 128.4, 126.8, 125.6, 121.8, 120.1,
76.0, 71.7, 53.4, 25.1; HRMS (ESI) found 335.1384, calcd for
C20H18N2O3 ([M + H]+) 335.1396; IR (KBr)1715, 1645, 1489, 1435,
1383, 1285, 1141, 1051, 968, 746, 694.
(3S,3aS,6aR)-3-(4-Fluorostyryl)-5-methyl-2-phenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2b): ethyl acetate/petro-
leum ether = 1:5, 51% yield (0.090 g, dr = 9:1), brown solid, mp 154−
156 °C; 1H NMR (CDCl3, 400 MHz) δ 7.29 (dd, J = 8.7, 5.4 Hz, 2H),
7.26−7.21 (m, 2H), 6.98 (ddd, J = 17.9, 11.2, 6.1 Hz, 5H), 6.73 (d, J =
16.0 Hz, 1H), 6.08 (dd, J = 16.0, 7.5 Hz, 1H), 5.05 (d, J = 7.5 Hz, 1H),
5.00 (d, J = 7.3 Hz, 1H), 3.67 (d, J = 7.3 Hz, 1H), 2.81 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 174.9, 173.9, 147.0, 132.7, 128.9, 128.2,
128.2, 124.5, 122.9, 115.7, 115.7, 115.5, 76.1, 68.2, 55.2, 25.0; HRMS
(ESI) found 353.1298, calcd for C20H17FN2O3 ([M + H]+) 353.1301;
IR (KBr) 1705, 1599, 1508, 1435, 1383, 1285, 1227, 1159, 1132, 1031,
970, 758, 694.
(3S,3aS,6aR)-2,5-Diphenyl-3-((E)-styryl)dihydro-2H-pyrrolo[3,4-
d]isoxazole-4,6(5H,6aH)-dione (2c): ethyl acetate/petroleum ether =
1:5, 57% yield (0.113 g, dr = 13:1), yellow solid, mp 116−117 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.35 (dq, J = 12.3, 7.5 Hz, 7H), 7.30−7.26
(m, 2H), 7.25 (d, J = 6.5 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.99 (t, J =
7.4 Hz, 1H), 6.85 (d, J = 15.9 Hz, 1H), 6.81−6.71 (m, 2H), 6.27 (dd, J
= 15.9, 6.8 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 5.13 (d, J = 7.5 Hz, 1H),
3.90−3.81 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 174.1, 172.7,
147.9, 135.8, 133.4, 131.1, 129.3, 129.0, 128.9, 128.7, 128.3, 126.7,
126.2, 125.3, 123.0, 115.2, 68.5, 55.4; HRMS (ESI) found 397.1539,
calcd for C25H20N2O3 ([M + H]+) 397.1552; IR (KBr) 1721, 1717,
1595, 1495, 1385, 1196, 1030, 968, 758, 692, 623.
EXPERIMENTAL SECTION
■
General Methods and Materials. All reactions were performed
under an oxygen atmosphere (balloon) with dry solvents under
anhydrous conditions. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received. The chromatography solvents were technical grade and
distilled prior to use. Flash chromatography was performed using
200−300 mesh silica gel with the indicated solvent system according
to standard techniques. Analytical thin-layer chromatography (TLC)
was performed on precoated, glass-backed silica gel plates. The
developed chromatogram was visualized by UV absorbance (254 nm).
The 1H NMR and 13C NMR data were recorded on 400 MHz nuclear
resonance spectrometers, unless otherwise specified. The chemical
shifts (δ) in parts per million are reported relative to the residual
signals of chloroform (1H 7.26 ppm or 13C 77.16 ppm). Multiplicities
are described as s (singlet), br s (broad singlet), d (doublet), t
(triplet), q (quartet), and m (multiplet), and coupling constants (J)
are reported in hertz (Hz). 13C NMR spectra were recorded with total
proton decoupling. HRMS (ESI) analysis with a quadrupole time-of-
flight (QqTOF) mass spectrometer yielded ion mass/charge (m/z)
ratios in atomic mass units. IR spectra were measured as dry films
(KBr) and are reported in terms of frequency (cm−1) and intensity of
absorption.
General Procedure for the Three-Component Reaction.
Cu(OAc)2 (9.1 mg, 0.05 mmol, 0.1 equiv) and bipyridine (9.4 mg,
0.06 mmol, 0.12 equiv) were weighed in a test tube, and NMP (3 mL)
was added. The mixture was stirred under air until the copper salt
completely dissolved (ca. 1 h). Allylbenzene (0.75 mmol, 1.5 equiv),
nitrosobenzene (2 mmol, 4.0 equiv), and maleimide (0.5 mmol, 1.0
equiv) were sequentially added. The test tube was capped with a
(3S,3aS,6aR)-3-(4-Methoxystyryl)-2,5-diphenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2d): ethyl acetate/petro-
leum ether = 1:5, 54% yield (0.115 g, dr > 20:1), orange solid, mp
136−138 °C; 1H NMR (CDCl3, 500 MHz) δ 7.34 (ddd, J = 13.7, 8.9,
D
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6.2 Hz, 5H), 7.29−7.22 (m, 2H), 7.15−7.08 (m, 2H), 6.99 (d, J = 7.4
Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.82−6.72 (m, 3H), 6.12 (dd, J =
15.9, 6.9 Hz, 1H), 5.27 (d, J = 6.9 Hz, 1H), 5.12 (d, J = 7.5 Hz, 1H),
3.83 (dd, J = 7.5, 0.4 Hz, 1H), 3.81 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 174.2, 172.8, 159.8, 148.0, 132.9, 131.1, 129.3, 129.0, 128.9,
128.6, 127.9, 126.2, 123.0, 122.9, 115.2, 114.2, 68.6, 55.5, 55.3; HRMS
(ESI) found 427.1650, calcd for C26H22N2O4 ([M + H]+) 427.1658;
IR (KBr) 3487, 3063, 1721, 1607, 1512, 1456, 1383, 1302, 1250, 1196,
1031, 692, 501.
76.2, 68.4, 55.3, 42.8; HRMS (ESI) found 429.1636, calcd for
C26H21FN2O3 ([M + H]+) 429.1614; IR (KBr) 1715, 1684, 1508,
1489, 1456, 1396, 1339, 1227, 1777, 1159, 756, 692, 669, 419.
(3S,3aS,6aR)-5-Benzyl-3-(4-methoxystyryl)-2-phenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2j): ethyl acetate/petro-
1
leum ether = 1:5, 48% yield (0.106 g, dr = 9:1), orange oil; H NMR
(CDCl3, 500 MHz) δ 7.32−7.13 (m, 9H), 7.00 (d, J = 7.8 Hz, 2H),
6.92 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 15.9 Hz,
1H), 6.00 (dd, J = 15.9, 7.7 Hz, 1H), 4.98 (t, J = 6.5 Hz, 2H), 4.49 (d,
J = 1.8 Hz, 2H), 3.78 (s, 3H), 3.65 (d, J = 7.4 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 174.8, 173.6, 159.8, 146.9, 134.9, 133.5, 128.8,
128.7, 128.6, 128.0, 127.9, 122.9, 122.5, 115.9, 114.1, 76.1, 68.6, 55.4,
55.3, 42.8; HRMS (ESI) found 441.1808, calcd for C27H24N2O4 ([M +
H]+) 441.1814; IR (KBr) 1717, 1684, 1559, 1541, 1508, 1396, 1339,
1250, 1175, 1030, 750, 690, 669, 419.
(3S,3aS,6aR)-2,5-Diphenyl-3-((E)-4-(trifluoromethyl)styryl)-
dihydro-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2e): ethyl
acetate/petroleum ether = 1:5, 57% yield (0.133 g, dr = 15:1), pale
yellow solid, mp 126−127 °C; 1H NMR (CDCl3, 500 MHz) δ 7.58 (d,
J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.40−7.31 (m, 3H), 7.26
(dd, J = 7.0, 1.6 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.00 (t, J = 7.4 Hz,
1H), 6.90 (d, J = 15.9 Hz, 1H), 6.80−6.68 (m, 2H), 6.36 (dd, J = 15.9,
6.6 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 5.15 (d, J = 7.5 Hz, 1H), 3.94−
3.80 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 173.9, 172.6, 147.8,
139.3, 132.1, 131.0, 129.4, 129.1, 129.0, 128.0, 126.9, 126.2, 125.7,
125.7, 125.2, 123.2, 115.2, 68.3, 55.3; HRMS (ESI) found 465.1421,
calcd for C26H19F3N2O3 ([M + H]+) 465.1426; IR (KBr) 1717, 1495,
1385, 1325, 1196, 1165, 1122, 1067, 1016, 758, 690, 617, 424.
(3S,3aS,6aR)-3-(4-Fluorostyryl)-2,5-diphenyldihydro-2H-pyrrolo-
[3,4-d]isoxazole-4,6(5H,6aH)-dione (2f): ethyl acetate/petroleum
ether = 1:5, 56% yield (0.116 g, dr = 10:1), yellow solid, mp 174−
176 °C; 1H NMR (CDCl3, 400 MHz) δ 7.37 (dd, J = 6.6, 5.1 Hz, 5H),
7.29 (t, J = 8.0 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.03 (dd, J = 17.2,
8.4 Hz, 3H), 6.84 (d, J = 15.9 Hz, 1H), 6.80−6.73 (m, 2H), 6.20 (dd, J
= 15.9, 6.8 Hz, 1H), 5.31 (d, J = 6.7 Hz, 1H), 5.15 (d, J = 7.5 Hz, 1H),
3.86 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 174.1, 172.8,
163.9, 161.5, 147.9, 132.2, 131.9, 131.0, 129.3, 129.1, 129.0, 128.3,
128.2, 126.2, 124.9, 123.1, 115.78, 115.6, 115.1, 76.7, 68.4, 55.3;
HRMS (ESI) found 415.1459, calcd for C25H19FN2O3 ([M + H]+)
415.1458; IR (KBr) 1719, 1597, 1508, 1454, 1385, 1227, 1198, 970,
758, 692, 619.
(3S,3aS,6aR)-3-((E)-2-Methylstyryl)-2,5-diphenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2g): ethyl acetate/petro-
leum ether = 1:5, 63% yield (0.130 g, dr = 10:1), pale yellow solid, mp
175−177 °C; 1H NMR (CDCl3, 400 MHz) δ 7.40 (q, J = 4.9 Hz, 4H),
7.30−7.26 (m, 2H), 7.18 (dt, J = 17.1, 7.3 Hz, 5H), 7.11−6.98 (m,
2H), 6.93−6.73 (m, 2H), 6.13 (dd, J = 15.8, 7.1 Hz, 1H), 5.31 (d, J =
7.1 Hz, 1H), 5.17 (d, J = 7.5 Hz, 1H), 3.89 (d, J = 7.5 Hz, 1H), 2.36 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ 174.2, 172.9, 147.8, 135.8,
135.0, 131.7, 131.0, 130.4, 129.2, 129.1, 129.0, 128.2, 126.4, 126.2,
126.2, 125.8, 123.0, 115.4, 68.7, 55.3, 19.8; HRMS (ESI) found
411.1706, calcd for C26H22N2O3 ([M + H]+) 411.1709; IR (KBr)
1716, 1647, 1597, 1491, 1383, 1263, 1196, 754, 691, 669, 651, 621.
(3S,3aS,6aR)-5-Benzyl-2-phenyl-3-((E)-4-(trifluoromethyl)styryl)-
dihydro-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2h): ethyl
acetate/petroleum ether = 1:5, 61% yield (0.146 g, dr = 37:1),
brown solid, mp 61−62 °C; 1H NMR (CDCl3, 500 MHz) δ 7.54 (d, J
= 8.2 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.30−7.24 (m, 5H), 7.21 (dd,
J = 8.5, 7.5 Hz, 2H), 7.01 (d, J = 7.8 Hz, 2H), 6.94 (t, J = 7.4 Hz, 1H),
6.76 (d, J = 16.0 Hz, 1H), 6.25 (dd, J = 16.0, 7.5 Hz, 1H), 5.03 (d, J =
7.5 Hz, 1H), 5.00 (d, J = 7.3 Hz, 1H), 4.49 (d, J = 1.7 Hz, 2H), 3.66
(d, J = 7.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 174.5, 173.4,
146.8, 139.2, 134.8, 132.6, 128.9, 128.7, 128.6, 128.0, 127.6, 126.8,
125.6, 125.6, 125.6, 123.2, 115.8, 76.2, 68.3, 55.2, 42.8; HRMS (ESI)
found 479.1574, calcd for C27H21F3N2O3 ([M + H]+) 479.1583; IR
(KBr) 1715, 1489, 1396, 1325, 1169, 1123, 1067, 1016, 970, 758, 695,
669.
(3S,3aS,6aR)-5-Benzyl-3-(2-methylstyryl)-2-phenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2k): ethyl acetate/petro-
1
leum ether = 1:5, 54% yield (0.115 g, dr = 9:1), brown oil; H NMR
(CDCl3, 400 MHz) δ 7.32−7.22 (m, 8H), 7.18−7.05 (m, 3H), 7.02
(d, J = 7.8 Hz, 2H), 6.97−6.86 (m, 2H), 5.98 (dd, J = 15.8, 7.9 Hz,
1H), 4.99 (t, J = 7.3 Hz, 2H), 4.54 (d, J = 4.5 Hz, 2H), 3.67 (d, J = 7.4
Hz, 1H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 174.7, 173.6,
146.8, 135.7, 135.1, 134.9, 132.5, 130.3, 128.8, 128.7, 128.5, 128.1,
128.0, 126.1, 126.0, 125.9, 123.0, 116.2, 75.9, 68.8, 55.2, 42.8, 19.7;
HRMS (ESI) found 425.1859, calcd for C27H24N2O3 ([M + H]+)
425.1865; IR (KBr) 1717, 1489, 1456, 1396, 1339, 1175, 1020, 968,
752, 692, 669, 419.
(3S,3aS,6aR)-5-Benzyl-2-phenyl-3-styryldihydro-2H-pyrrolo[3,4-
d]isoxazole-4,6(5H,6aH)-dione (2l): ethyl acetate/petroleum ether =
1:5, 55% yield (0.113 g, dr = 17:1), yellow solid, mp 147−148 °C; 1H
NMR (CDCl3, 400 MHz) δ 7.36−7.20 (m, 13H), 7.03 (d, J = 7.8 Hz,
2H), 6.95 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 15.9 Hz, 1H), 6.17 (dd, J =
16.0, 7.7 Hz, 1H), 5.03 (dd, J = 7.4, 2.5 Hz, 2H), 4.52 (s, 2H), 3.69 (d,
J = 7.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 174.7, 173.6, 146.8,
135.7, 134.8, 134.0, 128.8, 128.7, 128.6, 128.6, 128.3, 128.0, 126.6,
124.7, 123.0, 115.9, 76.0, 68.4, 55.3, 42.8; HRMS (ESI) found
411.1721, calcd for C26H22N2O3 ([M + H]+) 411.1709; IR (KBr)
1715, 1645, 1634, 1489, 1395, 1339, 1175, 1020, 968, 752, 692, 669,
418.
(E)-2-(2-(5-Methyl-4,6-dioxo-2-phenylhexahydro-2H-pyrrolo[3,4-
d]isoxazol-3-yl)vinyl)phenyl 4-Methylbenzenesulfon-ate (2m): ethyl
acetate/petroleum ether = 1:4, 53% yield (0.134 g, dr = 15:1), pale
yellow solid, mp 162−164 °C; 1H NMR (CDCl3, 400 MHz) δ 7.74 (d,
J = 8.3 Hz, 2H), 7.38−7.28 (m, 3H), 7.28−7.14 (m, 5H), 7.07 (dd, J =
7.7, 1.6 Hz, 1H), 7.01−6.91 (m, 3H), 6.73 (d, J = 16.1 Hz, 1H), 6.08
(dd, J = 16.1, 7.1 Hz, 1H), 4.95 (t, J = 7.2 Hz, 2H), 3.59 (d, J = 7.3 Hz,
1H), 2.76 (s, 3H), 2.41 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ
174.8, 173.8, 147.0, 146.9, 145.5, 129.9, 129.7, 129.1, 128.9, 128.4,
127.6, 127.2, 126.9, 123.1, 122.9, 115.4, 76.1, 67.7, 54.8, 24.9, 21.6;
HRMS (ESI) found 505.1429, calcd for C27H25N2O6S ([M + H]+)
505.1433; IR (KBr) 1790, 1707, 1597, 1489, 1456, 1435, 1375, 1285,
1194, 1180, 1163, 1082, 1034, 970, 880, 770, 719, 694, 669, 662, 561.
(3S,3aS,6aR)-5-Methyl-2-phenyl-3-((E)-2-(pyridin-3-yl)vinyl)-
dihydro-2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2n): ethyl
acetate/petroleum ether = 1:3, 66% yield (0.111 g, dr > 20:1), yellow
1
solid, mp 153−154 °C; H NMR (DMSO-d, 500 MHz) δ 7.52−7.37
(m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.1 Hz, 2H), 7.11 (d, J
= 8.6 Hz, 1H), 6.55 (d, J = 1.0 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H), 4.64
(t, J = 11.1 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 11.0 Hz,
1H), 4.00 (d, J = 7.4 Hz, 1H), 2.93 (s, 3H); 13C NMR (DMSO-d, 125
MHz) δ 174.7, 173.7, 149.1, 148.3, 146.9, 133.1, 130.4, 128.9, 127.3,
123.5, 123.1, 115.6, 75.9, 68.0, 55.0, 25.0; HRMS (ESI) found
336.1340, calcd for C19H17N3O3 ([M + H]+) 336.1348; IR (KBr)
1869, 1843, 1825, 1717, 1705, 1558, 1541, 1506, 1435, 1418, 1339,
1287, 1134, 1026, 670, 419.
(3S,3aS,6aR)-5-Benzyl-3-(4-fluorostyryl)-2-phenyldihydro-2H-
pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (2i): ethyl acetate/petro-
leum ether = 1:5, 53% yield (0.114 g, dr = 15:1), pale yellow solid, mp
1
104−105 °C; H NMR (CDCl3, 400 MHz) δ 7.37−7.21 (m, 12H),
7.03 (d, J = 7.8 Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 15.9 Hz,
1H), 6.17 (dd, J = 16.0, 7.7 Hz, 1H), 5.03 (dd, J = 7.4, 2.5 Hz, 2H),
4.52 (s, 2H), 3.69 (d, J = 7.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
174.6, 173.5, 163.9, 161.4, 146.8, 134.8, 132.8, 131.9, 131.9, 128.9,
128.7, 128.6, 128.2, 128.2, 128.0, 124.5, 123.0, 115.9, 115.7, 115.5,
4-((E)-2-((3S,3aS,6aR)-5-Methyl-4,6-dioxo-2-phenylhexahydro-
2H-pyrrolo[3,4-d]isoxazol-3-yl)vinyl)benzonitrile (2o): ethyl acetate/
1
petroleum ether = 1:5, 46% yield (0.083 g, dr > 20:1), yellow oil; H
NMR (CDCl3, 500 MHz) δ 7.58 (s, 1H), 7.52 (dd, J = 7.8, 1.5 Hz,
2H), 7.43−7.36 (m, 1H), 7.29−7.23 (m, 2H), 7.01 (dd, J = 8.7, 1.0
E
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 2H), 6.95 (dd, J = 10.6, 4.2 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H),
6.23 (dd, J = 16.0, 7.3 Hz, 1H), 5.07 (d, J = 7.2 Hz, 1H), 5.00 (d, J =
7.3 Hz, 1H), 3.67 (d, J = 7.2 Hz, 1H), 2.79 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 174.7, 173.7, 146.9, 137.0, 131.7, 131.5, 130.7, 130.0,
129.5, 129.0, 127.7, 123.2, 118.4, 115.6, 113.0, 76.1, 67.9, 55.0, 25.1;
HRMS (ESI) found 360.1342, calcd for C21H17N3O3 ([M + H]+)
360.1343; IR (KBr) 1792, 1715, 1699, 1558, 1489, 1456, 1384, 1285,
1132, 1031, 970, 762, 689, 669.
yellow solid, mp 192−193 °C; 1H NMR (400 MHz, DMSO) δ 7.52−
7.37 (m, 3H), 7.35 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 7.1 Hz, 2H), 7.11
(d, J = 8.6 Hz, 1H), 6.55 (d, J = 1.0 Hz, 1H), 5.07 (d, J = 7.3 Hz, 1H),
4.64 (t, J = 11.1 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 11.0
Hz, 1H), 4.00 (d, J = 7.4 Hz, 1H), 2.93 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 175.5, 175.4, 141.2, 139.7, 135.5, 131.9, 130.9, 129.6,
129.4, 128.2, 119.9, 76.3, 66.6, 54.7, 53.6, 52.2, 25.3; HRMS (ESI)
could not be obtained for this particular compound under either
positive or negative ionization; IR (KBr) 1715, 1705, 1684, 1558,
1541, 1506, 1472, 1456, 1435, 1339, 1281, 1136, 1040, 764, 750, 669,
419.
(E)-N-((E)-3-(2-(Tosyloxy)phenyl)allylidene)aniline oxide (5a):
ethyl acetate/petroleum ether = 1:1, yellow solid, mp 133−134 °C;
1H NMR (CDCl3, 400 MHz) δ 7.83−7.73 (m, 3H), 7.70 (d, J = 7.7
Hz, 3H), 7.50 (s, 4H), 7.35−7.27 (m, 4H), 7.15−7.00 (m, 2H), 2.40
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 147.5, 147.4, 146.0, 136.0,
132.3, 131.8, 130.2, 130.2, 129.9, 129.2, 128.6, 127.6, 126.8, 123.4,
121.3, 120.6, 21.7; HRMS (ESI) found 394.1101, calcd for
C22H19NO4S ([M + H]+) 394.1113; IR (KBr) 1867, 1844, 1749,
1717, 1684, 1558, 1541, 1506, 1457, 1275, 1260, 764, 750, 669, 419.
Derivatization of the Product (Synthesis of 3a, 4a, and 4b).
Synthesis of 3a: To a solution of 2a (90 mg, 0.3 mmol) in DCM (7
mL) were added powdered Zn (294 mg, 4.5 mmol) and glacial acetic
acid (1.0 mL). The reaction mixture was stirred vigorously at 40 °C for
24 h. The mixture was neutralized carefully with saturated aqueous
NaHCO3 solution and was extracted three times using DCM. The
combined organic layer was washed with brine, dried over Na2SO4,
concentrated under reduced pressure, and purified by flash silica gel
column chromatography (ethyl acetate/petroleum ether = 2:1) to give
compound 3a.
(3R,4S)-3-Hydroxy-1-methyl-4-((S,E)-3-phenyl-1-(phenylamino)-
allyl)pyrrolidine-2,5-dione (3a): ethyl acetate/petroleum ether = 2:1,
81% yield (0.082 g), yellow solid, mp 188−189 °C; 1H NMR (CDCl3,
400 MHz) δ 7.35−7.27 (m, 4H), 7.23 (dt, J = 6.8, 3.1 Hz, 1H), 7.17 (t,
J = 7.9 Hz, 2H), 6.73 (dd, J = 17.7, 7.8 Hz, 3H), 6.62 (d, J = 16.0 Hz,
1H), 6.28 (dd, J = 16.0, 6.3 Hz, 1H), 4.89 (s, 1H), 4.81 (d, J = 8.4 Hz,
1H), 4.56 (d, J = 8.4 Hz, 1H), 3.47 (br s, 1H), 3.39 (dd, J = 8.4, 3.0
Hz, 1H), 2.90 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 178.3, 175.8,
146.4, 136.4, 132.2, 129.3, 128.6, 127.8, 127.7, 126.5, 118.7, 114.6,
68.4, 55.1, 50.0, 24.7; HRMS (ESI) found 337.1538, calcd for
C20H20N2O3 ([M + H]+) 337.1552; IR (KBr) 1697, 1601, 1541, 1506,
1456, 1435, 1387, 1281, 1123, 970, 750, 692, 669, 419.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of new compounds. X-ray data
for compounds 2a, cis-2a, 4b, and 5b. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: huangyong@pkusz.edu.cn. Homepage: http://scbb.
pkusz.edu.cn/huang.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is financially supported by grants of the National
Basic Research Program of China (2010CB833201), Shenzhen
special funds for the development of biomedicine, Internet, new
energy and material industries (JC201104210111A,
JC201104210112A, and SW201110018), Shenzhen innovation
funds (GJHZ20120614144733420), and the Shenzhen Peacock
Program (KQTD201103). Shenzhen Municipal Development
and Reform Commission is thanked for the drug screening and
preclinical efficacy evaluation of public service platform.
Synthesis of 4a: To a solution of 2a (90 mg, 0.3 mmol) in MeCN
(1 mL) was added 1 equiv of NBS (53 mg, 0.3 mmol). The reaction
mixture was stirred at 60 °C for 24 h. The mixture was quenched with
saturated NaHCO3 solution and was extracted three times using ethyl
acetate. The combined organic layer was washed with brine, dried over
Na2SO4, concentrated under reduced pressure, and purified by flash
silica gel column chromatography (petroleum ether/ethyl acetate =
5:1) to give compound 4a.
(3S,3aS,6aR)-2-(4-Bromophenyl)-5-methyl-3-((E)-styryl)dihydro-
2H-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (4a): ethyl acetate/
petroleum ether = 1:5, 96% yield (0.118 g), yellow solid, mp 125−127
°C; 1H NMR (MeOD, 400 MHz) δ 7.36 (d, J = 8.0 Hz, 4H), 7.30 (t, J
= 7.3 Hz, 2H), 7.25 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 6.79
(d, J = 16.0 Hz, 1H), 6.21 (dd, J = 16.0, 7.8 Hz, 1H), 5.11 (dd, J =
14.9, 7.5 Hz, 2H), 3.83 (d, J = 7.2 Hz, 1H), 2.81 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 174.8, 167.1, 146.3, 138.1, 134.3, 132.7, 132.3,
129.3, 128.2, 127.3, 125.6, 114.8, 110.6, 98.3, 67.9, 49.9, 39.5, 24.5;
HRMS (ESI) found 411.0349, calcd for C20H17BrN2O3 ([M − H]−)
411.0344; IR (KBr)1790, 1709, 1485, 1435, 1381, 1284, 1134, 1072,
1034, 1003, 968, 826, 694, 623, 501, 419.
REFERENCES
■
(1) (a) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2012, 3, 633.
(b) Zhu, J. P. In Multicomponent Reactions, 1st ed.; Bienayme,
Wiley-VCH: Weinheim, Germany, 2005. (c) Bruggink, A.; Schoevaart,
B.; Kieboom, T. Org. Process Res. Dev. 2003, 7, 622.
́
H., Ed.;
(2) (a) Ackermann, L. Chem. Rev. 2011, 111, 1315. (b) Arockiam, P.
B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(c) Patureau, F. W.; Wencel-Delord, F.; Glorius, F. Aldrichimica Acta
2012, 45, 31. (d) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc.
Chem. Res. 2012, 45, 788.
(3) (a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int.
Ed. 2011, 50, 11062. (b) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res.
2012, 45, 851. (c) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev.
2012, 41, 3381. (d) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3464.
(4) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 1998. (b) Brown,
R. C. N-Oxides and Nitrones in Organic Chemistry of Aliphatic
Compounds; Oxford Clarendon Press: Oxford, 1994.
(5) Sandler, S. R.; Karo, W. Organic Functional Group Preparations,
2nd ed.; Academic Press: San Diego, CA, 1989; Vol. 3, p 351.
(6) For recent reviews on allylic C−H oxidation reactions, see:
(a) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921−2944.
(b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. For
related examples, see: (c) Vermeulen, N. A.; Delcamp, J. H.; White, M.
C. J. Am. Chem. Soc. 2010, 132, 11323−11328. (d) Stang, E. M.;
White, M. C. J. Am. Chem. Soc. 2011, 133, 14892. (e) Qin, C.; Jiao, N.
J. Am. Chem. Soc. 2010, 132, 15893−15895. (f) Dong, S.; Qin, T.;
Hamel, E.; Beutler, J. A.; Porco, J. A., Jr. J. Am. Chem. Soc. 2012, 134,
19782. (g) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011, 133,
Synthesis of 4b: To a solution of 2a (90 mg, 0.3 mmol) in MeCN
(1 mL) was added 2 equiv of NBS (106 mg, 0.6 mmol). The reaction
mixture was stirred at 60 °C for 24 h. The mixture was quenched with
saturated NaHCO3 solution and was extracted three times using ethyl
acetate. The combined organic layer was washed with brine, dried over
Na2SO4, concentrated under reduced pressure, and purified by flash
silica gel column chromatography (ethyl acetate/petroleum ether =
5:1) to give compound 4b.
(5R,6S,6aR,6bS,9aR)-3,6-Dibromo-8-methyl-5-phenyl-6,6a,8,9a-
tetrahydropyrrolo[3′,4′:4,5]isoxazolo[2,3-a]quinoline-7,9(5H,6bH)-
dione (4b): ethyl acetate/petroleum ether = 1:5, 95% yield (0.140 g),
F
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
12584. (h) Young, A. J.; White, M. C. Angew. Chem., Int. Ed. 2011, 50,
6824.
(7) Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 473.
(8) For examples on selective [3 + 2] dipolar cycloaddition of
nitrones, see: (a) Jiao, P.; Nakashima, D.; Yamamoto, H. Angew.
Chem., Int. Ed. 2008, 47, 2411. (b) Kano, T.; Hashimoto, T.; Maruoka,
K. J. Am. Chem. Soc. 2005, 127, 11926. (c) Desimoni, G.; Faita, G.;
Mella, M.; Boiocchi, M. Eur. J. Org. Chem. 2005, 1020. (d) Mita, T.;
Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457. (e) Viton,
F.; Bernardinelli, G.; Kuendig, E. P. J. Am. Chem. Soc. 2002, 124, 4968.
(f) Jensen, K. B.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1999, 64,
2353.
(9) Chakraborty, B.; Samanta, A.; Sharma, P. K.; Chhetri, M. S.;
Kafley, S.; Banerjee, A.; Sinha, C. J. Chem. Pharm. Res. 2010, 2, 727.
(10) Agirbas, H.; Guner, S.; Budak, F.; Keceli, S.; Kandemirli, F.;
Shvets, N.; Kovalishynd, V.; Dimoglo, A. Bioorg. Med. Chem. 2004, 12,
1629.
(11) Badru, R.; Anand, P.; Singh, B. Eur. J. Med. Chem. 2012, 48, 81.
(12) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767.
(13) Recently, Read de Alaniz reported copper-catalyzed aerobic
oxidation of hydroxyl amines to nitroso products and an ene tethered
cascade: (a) Frazier, C. P.; Engelking, J. R.; Read de Alaniz, J. J. Am.
Chem. Soc. 2011, 133, 10430. (b) Frazier, C. P.; Bugarin, A.; Engelking,
J. R.; Read de Alaniz, J. Org. Lett. 2012, 14, 3620. For copper-
catalyzed dehydrogenation of hydrazines to hydrazones, see: (c) Gao,
W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012, 3, 883.
(d) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174−6177.
(14) (a) Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131. (b) Leach,
A. G.; Houk, K. N. J. Am. Chem. Soc. 2002, 124, 14820. (c) Seymour,
C. A.; Greene, F. D. J. Org. Chem. 1982, 47, 5226.
(15) Kliegel, W. Tetrahedron Lett. 1969, 10, 2627.
(16) Knight, G. T.; Pepper, B. Chem. Commun. 1971, 1507.
(17) Alper, H.; Vasapollo, G. Tetrahedron Lett. 1987, 28, 6411.
(18) (a) Baruah, J. B.; Samuelson, A. G. Tetrahedron 1991, 47, 9449.
(b) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994,
116, 2742.
(19) NOE studies by Corey et al. have shown that maleimides
preferred to coordinate to Lewis acids in an s-cis manner to minimize
stereoelectronic interaction. See: Corey, E. J.; Sarshar, S.; Lee, D. H. J.
Am. Chem. Soc. 1994, 116, 12089.
G
dx.doi.org/10.1021/jo400215e | J. Org. Chem. XXXX, XXX, XXX−XXX