3-Halomethylated cyclic nitronates: Synthesis and nucleophilic substitution

Article abstract of DOI:10.1016/j.tet.2011.04.078

A method for the introduction of a halogen atom into the methyl group attached to the C-3 atom of five- and six-membered cyclic nitronates (isoxazoline N-oxides and oxazine N-oxides, respectively) has been studied. The process involves silylation of start

Full text of DOI:10.1016/j.tet.2011.04.078

Tetrahedron 67 (2011) 4584e4594
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3-Halomethylated cyclic nitronates: synthesis and nucleophilic substitution
,
,
a
a
Andrey A. Mikhaylov a b, Alexander D. Dilman a , Marina I. Struchkova , Yulia A. Khomutova ,
*
Alexander A. Korlyukovc, Sema L. Ioffe a , Vladimir A. Tartakovsky
,
a
*
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russian Federation
b Higher Chemical College of the Russian Academy of Sciences, Miusskaya sq. 9, 125047 Moscow, Russian Federation
c A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilova str. 28, Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the introduction of a halogen atom into the methyl group attached to the C-3 atom of five-
and six-membered cyclic nitronates (isoxazoline N-oxides and oxazine N-oxides, respectively) has been
studied. The process involves silylation of starting 3-methyl-substituted cyclic nitronates followed by
halogenation of the resulting N-(silyloxy)enamines. While five- and six-membered cyclic enamines
behave similarly toward elemental bromine and iodine, their reactions with NBS give different products,
that were rationalized by stereoelectronic effects. The obtained halogenated nitronates were coupled
with various nucleophiles affording new nitronates functionalized at the C-3 position.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 February 2011
Received in revised form 7 April 2011
Accepted 21 April 2011
Available online 28 April 2011
Keywords:
Halogenation
Nucleophilic substitution
5,6-Dihydro-4H-oxazine N-oxides
Isoxazoline N-oxides
a
-Halogenated cyclic nitronates
1. Introduction
O
O
A, Y = SiMe3
N
N
Y
B, Y = Alk
R1
R2
Nitronates represent an interesting class of compounds with
diverse reactivity.1 Despite the fact that nitronates are usually
considered merely as derivatives of nitro compounds, their chem-
istry is evolving into a separate subject, given the increasing
number of studies in recent years.2
C, Y, R2 = (CH2)n, n = 1, 2
O
O
O
O
O
O
Nu
N
N
Hal
Nu
Currently, two types of nitronates have been studied in detail,
namely, silyl- and alkylnitronates (Fig. 1). The silicon derivatives A
are moisture-sensitive and, preferably, should be generated in situ
and immediately utilized in further transformations. On the other
hand, the alkyl nitronate fragment is hydrolytically stable and tol-
erates a wide variety of functional groups. The only disadvantage of
the latter, is that nitronates B with a conventional alkyl substituent
at oxygen (e.g., Y¼Me, Et) possess limited stability,1a and, as
a consequence, much more stable cyclic nitronates C are mainly
investigated.
D
E
F
Fig. 1. Nitronates.
nitronates F.3 The latter sequence would constitute a convenient
method for the preparation of functionalized cyclic nitronates, for
which other strategies of synthesis may be unproductive. Herein
we report the full description of these processes.
Recently we communicated an approach for the synthesis of
halomethyl-substituted derivatives E by halogenation of the methyl
group in cyclic nitronates D, and demonstrated that the halogen can
be substituted by some nucleophiles to give a wide range of
2. Results and discussion
Starting cyclic nitronates 1 and 2 were obtained from readily
available nitro ethane according to literature procedures4e6
(Scheme 1). Subsequent silylation of 1 or 2 was performed
according to improved literature procedures4 leading to N-(sily-
loxy)enamines 3 in high yields.7 Compounds 3 were either used
just after preparation or stored in hexane solution at ꢀ30 ꢁC.
* Corresponding authors. Fax: þ7 499 135 53 28; e-mail address: adil25@mail.ru
(A.D. Dilman).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.078

A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4585
Table 1
R2
R5
R3
R4
R1
Halogenation of enamines 3 with X2
R1
Base
R2
R5
R3
O
R1
( )n
R1
( )n
R1
R2
R5
R2
R5
NO2
N
X2, Et3N/AcOH
CH2Cl2, –78 °C
X
O
O
R4
NO2
O
S
N
1
N
R3
O
O
R3
O
OTMS
R4
R4
CH2
3
6
R1
#
3
n
R1
R2
R3
R4
R5
X2
6
Yield, %a
1. Br2
R3
N
1
2
3
5
6
7
8
9
3a
3b
3c
3d
3e
3e
3f
1
1
1
1
0
0
0
0
0
Ph
Me
OBz
Ph
H
H
H
H
Ph
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
Me
H
H
H
H
H
d
d
d
d
d
I2
I2
I2
I2
6a-I
6b-I
6c-I
6d-I
81
45
81
86
68
85
95
87
83
O
R4
O
2.
R3
R4
2
e(CH2)4e
R1
( )n
d
d
d
d
d
Ph
Ph
4-BrC6H4
CO2Me
H
I2
6e-I
R1
Br2
Br2
Br2
Br2
6e-Br
6f-Br
6g-Br
6h-Br
R2
R5
R2
R5
R3
TMSX/Et3N
X = Br, OTf
( )n
3g
3h
N
R3
O
O
10
N
R4
1 or 2
O
OTMS
R4
a
Isolated yield.
n = 0, 1
3
89–97%
Scheme 1.
reasonable yields. Though introduction of iodine is preferable in
terms of subsequent nucleophilic substitution, five-membered
iodo-nitronates (and in some cases six-membered, e.g., 6b-I)
exhibited limited stability, decomposing even in their crystalline
state, that decreased their yield, as well as hampered isolation and
characterization. For that reason five-membered N-(silyloxy)en-
amines 3eeh were subjected mainly to bromination, which pro-
ceeded smoothly, providing the corresponding bromo-nitronates
6eeh-Br (entries 7e10).
2.1. Halogenation of N-(silyloxy)enamines 3
Two halogenating systems were considereddelemental halo-
gen and N-halosuccinimide. The general pathway is shown in
Scheme 2. After addition of halonium ion Xþ to the C]C, the in-
termediate iminium cation 4 may either add the counterion Yꢀ to
give adduct 5 or expel trimethylsilyl cation leading to nitronate 6.
The adduct 5 may also transform to 6, although the efficiency of this
step likely depends on the nature of Y.8 When elemental bromine or
iodine is used for halogenation, both pathways for the formation of
6 are indistinguishable since they are expected to proceed very fast
furnishing bromo- or iodosilane as by-products. Importantly, the
halosilane by-product may cause decomposition of the starting
N-(silyloxy)enamines 3,9 and therefore a basic scavenger has to be
present in the mixture to trap the halosilane.
Halogenation of alkoxy-substituted enamines 3i,j led to ring-
opened products, that is, the corresponding a-nitro alkenes 8 and
9, respectively (Scheme 3).
Ph
Ph
O
I2 Et N Ac H
/
O
,
3
N
N
O2
TM
O S
O
X
Y
MeO
O
3i
8
85
%
( )n
N
Y
Ph
O
Ph
R
R
O
OTMS
X
H
H
H
5
X
Y
( )n
( )n
c
H
O
I2 Et N A
/
,
3
Y
TMS
X
N
N
O2
N
N
O
TM
O
S
R
O
OTMS
R
O
OTMS
H
O
3j
9
56
%
3
4
Y
( )n
Scheme 3.
Y
TMS
N
O
O
Bromination of six-membered enamines 3aed,i,j with N-bro-
mosuccinimide (NBS) proceeded similarly to their reactions with
bromine (Table 2). Here again either bromo-nitronates 6aed-Br or
nitro alkene 8 was produced.
6
X
X
( )n
( )n
( )n
Surprisingly, the reaction of five-membered enamine 3e with
NBS did not furnish the expected halo-nitronate 6e-Br. Instead, the
product 10a arising from the addition of NBS to the C,C-double
bond was obtained as mixture of two isomers with cis-orientation
of silyloxy and succinimido substituents in all cases (Table 3).11
Similar products were formed in reactions of enamines 3e0 and
3f0 bearing a tert-butyldimethylsilyloxy group.12 Notably, com-
pounds 10 did not show any signs of elimination of silylsuccinimide
(see Scheme 2, conversion of 5 to 6) even after refluxing in aceto-
nitrile for 3 h.13
N
N
NO2
R'O
R'O
O
4'
OTMS
O
OTMS
O
7
8
Scheme 2.
If the starting N-(silyloxy)enamines contain the 6-alkoxy group,
the intermediates 40 may undergo ring cleavage to generate oxo-
carbenium species 7, which eventually, after stabilization and
elimination of TMSeX, would afford nitro alkenes 8.10
Enamines 3 were treated with bromine or iodine in dichloro-
methane at ꢀ78 ꢁC in the presence of triethylamine and acetic acid
as a scavenger of the halosilane by-product (Table 1). Halogen-
substituted products 6 were isolated after chromatography, in
To explain the difference between reactivity of five- and six-
membered enamines with NBS it is necessary to consider stereo-
electronic requirements for halogenation of 3. Thus, for effective

4586
A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
Table 2
Halogenation of enamines 3 (n¼1) with NBS
No.
3
R1
R2
R3
R4
R5
Product
Yield, %
1
2
3
4
5
6
3a
3b
3c
3d
3i
Ph
H
H
H
Me
Me
Me
Me
Me
Me
H
Me
eO(CH2)2e
H
H
H
H
H
6a-Br
6b-Br
6c-Br
6d-Br
8
93
66
80
86
57
da
Me
OBz
Ph
Ph
Ph
e(CH2)4e
H
H
OMe
H
3j
9
a
Mixture of unidentified products.
Table 3
Addition of NBS to five-membered cyclic enamines 3
O
O
NBS
O
Br
O
Br
N
N
N
N
+
N
–78 to –30 °C
CH2Cl2
OSiR'3
R
O
R
OSiR'3
R
OSiR'3
O
O
3e, 3e , 3f
'
'
10
#
3
R
SiR03
10
Yield of 10, %
dra
1
2
3
3e
3e0
3f0
Ph
Ph
SiMe3
10a
10b
10c
76
84
91
1.8:1
1.6:1
1.6:1
SitBuMe2
SitBuMe2
p-BreC6H4
a
The relative configuration was assigned by 2D-NOESY for 10b and 10c; the as-
signment of 10a was made by analogy.
stabilization of positive charge arising upon addition of an elec-
trophile at the C]C bond, the nitrogen lone pair should have a co-
planar arrangement with the p-orbitals as shown for conformation
11 in Fig. 2. In this case, iminium ion 12 bearing planar nitrogen is
formed. This is likely to be realized for six-membered N-(silyloxy)
enamines, since according to structural data,4 they exist in con-
formation 13 with an axial lone pair, which is well disposed for
overlap with the C]C bond.
Fig. 3. The molecular structure of 3f0 Non-hydrogen atoms are presented by thermal
ellipsoids at 50% probability. Hydrogen atoms are omitted for clarity.
Br
Br
OSiR3
present we may tentatively propose that divergent behavior of five-
and six-membered enamines is associated with a difference of their
reactive conformations 13 versus. 14.15
O
R3SiO
O
N
N
11
12
2.2. Nucleophilic substitution
O
Nitronates 6 were treated with various types of nucleophilic
reagents to give products of substitution of halogen (Table 4).
Potassium phthalimide, thiophenolate and malonate, as well as
sodium benzenesulfinate, gave nitronates 15 in high yields. The
reactions were typically carried out in DMF as solvent at 0 ꢁC to
room temperature, and were complete within 30 min. However,
reaction of iodo-nitronate 6d-I with malonate proceeded much
cleaner when the sodium salt was used in tetrahydrofuran as sol-
vent and mixing the reagents at ꢀ40 ꢁC. 2-Lithio-1,3-dithiane also
proved to be a suitable nucleophile affording the desired product in
92% yield (entry 5).
When nitronate 6a-I was reacted with lithium phenyl-
acetylenide in tetrahydrofuran, instead of the expected substitution
product we obtained a mixture of oxime 16 and iodoacetylene 17 in
good yields (Scheme 4). The mechanism of this process likely im-
plies initial attack of the acetylenide nucleophile on the iodine16 to
generate anionic species 18, which undergoes the cleavage of the
endocyclic NeO bond followed by recyclization of nitrosoalkene
19.17 We also attempted to substitute the iodine by fluoride in re-
action of 6a-I with silver(I) fluoride in DMF. However, only product
20, originating from the substitution of iodine by the molecule of
DMF with subsequent hydrolysis, was observed.
O
N
OSiR3
N
OSiR3
13
14
Fig. 2. Stereoelectronic effects of halogenation.
To gain some insight into the structure of five-membered en-
amines 3eeh, compound 3f0 was studied in greater detail. In the
solid state, as revealed by single crystal X-ray diffraction analysis
(Fig. 3), the silyloxy group is located in a pseudo-axial orientation.
Therefore, the nitrogen lone pair occupies a pseudo-equtorial po-
sition as depicted for structure 14, that renders inefficient its
overlap with the C]C bond. At the same time, as is evident from
NMR spectra of 3f0, in solution it exists as an equilibrium of two
species with the ratio ca. 6:1 that may correspond either to a con-
formational change of the cycle or to nitrogen lone pair inversion
(or a combination of both).14 Furthermore, this equilibrium raises
the questions on the relative reactivities of these species, as well as
the relative rates of this stereodynamic process and bromination of
3f0. While these questions require detailed mechanistic studies, at

A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4587
Table 4
Nucleophilic substitution
R1
R1
R2
R2
Nu M
R5 ( )
R5 ( )
X
Nu
n
n
N
N
R3
O
O
R3
O
O
R4
R4
6
15
#
6
X
N
R1
R2
R3
R4
R5
NuꢀMþ
PhthalNK
4-MeC6H4S K
(MeO2C)2CH K
PhSO2Na
Conds.a
15
Yield of 15, %
1
2
3
4
6a-I
6a-I
6a-I
6a-I
I
I
I
I
1
1
1
1
Ph
Ph
Ph
Ph
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
i
15a
15b
15c
15d
82
87
88
ii
ii
i
100
S
Li
S
5
6a-Br
Br
1
Ph
H
Me
Me
H
iii
15e
92
6
7
8
9
10
11
12
6c-I
6d-I
6d-I
6e-Br
6f-Br
6g-Br
6h-Br
I
I
I
Br
Br
Br
Br
1
1
1
0
0
0
0
OBz
Ph
Ph
H
H
H
H
Me
Me
H
H
H
H
H
H
H
d
d
d
d
(MeO2C)2CH K
(MeO2C)2CH Na
PhSO2Na
(MeO2C)2CH Na
(MeO2C)2CH Na
(MeO2C)2CH Na
(MeO2C)2CH Na
ii
iv
i
iv
iv
iv
iv
15f
15g
15h
15i
15j
15k
15l
93
97
99
84
93
76
95
e(CH2)4e
e(CH2)4e
d
d
d
d
Ph
4-BrC6H4
CO2Me
H
Me
H
Ph
a
i: PhthalNK (1.4 equiv) or PhSO2Na (1.1 equiv), DMF, 0 ꢁCdrt, 15 min. ii: NuH (1.25 equiv), tBuOK (1.1 equiv), DMF, ꢀ40e0 ꢁC, 30 min. iii: NuH (1.25 equiv), BuLi
(1.05 equiv), THF, ꢀ40e0 ꢁC, 2 h. iv: NuH (1.25 equiv), NaH (1.1 equiv), THF, ꢀ40e0 ꢁC, 1 h.
cyclic nitronates bearing a functionalized substituent at the C-3
position.
Ph
O
Ph OH
N
Ph
Li
I
Ph
I
+
4. Experimental section
4.1. General
N
THF, –50 °C
I
O
O
16, 88%
17, 90%
6a-I
Ph
All reactions were performed in oven-dried (150 ꢁC) glassware
under argon. The following solvents and reagents were distilled
from the indicated drying agents: CH2Cl2, Et3N (CaH2); THF (Na,
benzophenone ketyl); DMF (P2O5, under vacuum). NMR spectra
were recorded on a Bruker AM-300 or AC-200 instruments and
referenced to residual solvent peak. Chemical shifts are reported in
Ph
Ph
O
N
N
O
O
Li
OLi
O
18
19
ppm (d); multiplicities are indicated by s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) and br (broad). Coupling con-
stants, J, are reported in Hertz. The ratios of stereoisomers were
derived from the relative integral intensities of the characteristic
signals in the 1H NMR spectra. IR spectra were recorded on a Bruker
VECTOR 22 instrument in the range 400e4000 cmꢀ1. Elemental
analyses were performed by the Analytical Laboratory of the In-
stitute of Organic Chemistry. HRMS data were obtained on Bruker
microTOFF instrument. Melting points were determined on Kofler
melting point apparatus and are uncorrected.
Ph
O
Ph
AgF
O
I
N
N
DMF, –30 °C
O
O
O
6a-I
20, 77%
Scheme 4.
4.2. Iodination of enamines 3
3. Conclusions
Et3N (116 mL, 1.15 mmol) and AcOH (63 mL, 1.10 mmol) were
The halogenation of five- and six-membered cyclic N-(silyloxy)
enamines 3 has been studied. Reactions with elemental bromine
or iodine provide 3-halomethylsubstituted cyclic nitronates 6,
whereas the outcome of treatment with NBS depends on the ring
size. While six-membered cyclic enamines afford halogenated
nitronates 6, five-membered enamines add NBS across the C,C-
double bond. The halogenated nitronates 6 undergo facile nucle-
ophilic substitution of the halogen with a series of nucleophiles
furnishing a range of 3-functionalized cyclic nitronates 15. Given
that various cyclic nitronates can be readily obtained from nitro
ethane and other simple molecules, the described methodology
can be considered as a base for a new strategy of assembling of
mixed in CH2Cl2 (1.0 mL). The resulting solution was cooled to
ꢀ78 ꢁC (acetone/dry ice), and a solution of enamine 3 (1.00 mmol)
in CH2Cl2 (2.0 mL) was added, followed by dropwise addition of
a solution of I2 (264 mg, 1.05 mmol) in CH2Cl2 (2.0 mL) over 5 min
under intensive stirring. The mixture was stirred for 10 min at
ꢀ78 ꢁC and 30 min at ꢀ30 ꢁC, poured into EtOAc (25 mL)/soln of
100 mg of Na2S2O3 in 20 mL of H2O. The aqueous layer was sepa-
rated and back-extracted with EtOAc (2ꢂ10 mL). The combined
organic phase was washed with brine (20 mL) and dried over
Na2SO4. Solvents were evaporated in vacuo at 35 ꢁC, and the resi-
due was purified by column chromatography on silica gel (EtOAc/
hexane, 1/5/1/3).

4588
A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4.3. Bromination of enamines 3 with bromine (method A)
Et3N (116 L, 1.15 mmol) and AcOH (63 L, 1.10 mmol) were
mixed in CH2Cl2 (1.0 mL). The resulting solution was cooled to
ꢀ78 ꢁC (acetone/dry ice), and a solution of enamine 3 (1.00 mmol)
in CH2Cl2 (2.0 mL) was added, followed by dropwise addition of
(EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
d
¼1.26
[d, 3J¼7.0, 3H, CH3(8)], 1.36 and 1.39 [2s, 6H, CH3(6,7)], 1.67 [dd,
3J¼10.6, 2J¼13.6, 1H, HaxC(2)],1.98 [dd, 3J¼7.3, 2J¼13.6, 1H, HeqC(2)],
2.84e298 [m, 1H, CHax(3)],4.18 [d, 2J¼10.3, 1H, CH2(5)], 4.50 [d,
m
m
2J¼10.3,1H, CH2(5)]. 13C NMR (75.47 MHz, 300 K, CDCl3):
¼18.2 (C-
d
8), 23.1, 27.8, 26.8 (C-3, C-6, C-7), 28.0 (C-5), 40.1 (C-2), 82.4 (C-1),
123.5 (C-4). Anal. Calcd for C8H14BrNO2: C, 40.70; H, 5.87; N, 5.85.
Found: C, 40.70; H, 5.98; N, 5.93.
a solution of Br2 (51 mL, 1.05 mmol) in CH2Cl2 (2.0 mL) over 5 min
with intensive stirring. The mixture was stirred for 10 min at
ꢀ78 ꢁC and poured into EtOAc (25 mL)/soln of 10 mg of Na2SO3 in
20 mL of H2O. The aqueous layer was separated and back-extracted
with EtOAc (2ꢂ10 mL). The combined organic phase was washed
with brine (20 mL) and dried over Na2SO4. Solvents were evapo-
rated in vacuo at 35 ꢁC and the residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1/5/1/3).
O
10
9
11
12
8
O
5
3
4
2
1
I
N
6
O
O
7
4.4. Bromination of enamines 3 with NBS (method B)
4.4.5. 4-Benzoyloxy-3-(iodomethyl)-6,6-dimethyl-5,6-dihidro-4H-
[1,2]-oxazine 2-oxide (6c-I). Yield 315 mg (81%), mp¼78e80 ꢁC
(Et2O/hexane, 2/1) with decomposition, Rf¼0.62 (EtOAc/hexane, 1/
NBS (198 mg, 1.10 mmol) was added in one portion to a pre-
cooled (ꢀ78 ꢁC, acetone/dry ice) stirred solution of enamine 3
(1.00 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred for
10 min at ꢀ78 ꢁC and for 30 min at ꢀ30 ꢁC upon which the pre-
cipitate of NBS dissolved. The mixture was allowed to warm to
room temperature. [In the case of six-membered derivatives 3,
methanol (0.5 mL) was added to hydrolize N-silylsuccinimide and
the mixture was stirred for 10 min at room temperature.] Solvents
were evaporated in vacuo at 40 ꢁC, and the residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1/5/1/3 was
used for isolation of all compounds 6 and 8; EtOAc/hexane,
1/10/1/5 was used for isolation of nitrosoacetals 10).
1). 1H NMR (300.13 MHz, 300 K, CDCl3):
d
¼1.47 and 1.56 [2s, 6H,
CH3(6,7)], 2.16 [dd, 3J¼4.4, 2J¼14.7, 1H, HeqC(2)], 2.43 [dd, 3J¼7.0,
2J¼14.7, 1H, HaxC(2)], 4.14 [d, 2J¼9.5, 1H, CH2(5)], 4.29 [d, 2J¼9.5, 1H,
CH2(5)], 6.04 [dd, 3J¼4.4, 7.0, 1H, CHeq(3)], 7.48 [t, 3J¼7.7, 2H,
CH(11)], 7.62 [t, 3J¼7.7, 1H, CH(12)], 8.06 [d, 3J¼7.7, 2H, CH(10)]. 13
C
NMR (75.47 MHz, 300 K, CDCl3):
d
¼ꢀ1.4 (C-5), 25.4 and 26.3 (C-6
and C-7), 37.7 (C-2), 64.7 (C-3), 82.7 (C-1), 119.2 (C-4), 128.7 and
129.9 (C-10 and C-11), 129.0 (C-9), 133.9 (C-12), 165.6 (C-8). IR (KBr,
cmꢀ1): 1722 (
n, C]O), 1594 (n, C]N), 1267, 1250, 1109, 710. Anal.
Calcd for C14H16 INO4: C, 43.21; H, 4.14; N, 3.60. Found: C, 43.71; H,
4.43; N, 3.42.
4.4.1. 3-(Iodomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-[1,2]-
oxazine 2-oxide (6a-I). Yield 278 mg (81%), mp¼96e97 ꢁC (Et2O)
with decomposition, Rf¼0.53 (EtOAc/hexane, 1/1).3
O
10
9
11
12
8
O
5
3
4
2
1
4.4.2. 3-(Bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-
[1,2]-oxazine 2-oxide (6a-Br). By method B, yield 277 mg (93%),
mp¼101e102 ꢁC (Et2O/CH2Cl2, 1/1) with decomposition, Rf¼0.47
(EtOAc/hexane, 1/1).3
Br
N
6
O
O
7
8
4.4.6. 4-Benzoyloxy-3-(bromomethyl)-6,6-dimethyl-5,6-dihidro-4H-
[1,2]-oxazine 2-oxide (6c-Br). By method B, Yield 272 mg (80%),
mp¼91e92 ꢁC (Et2O/hexane, 2/1), Rf¼0.61 (EtOAc/hexane, 1/1). 1H
5
3
4
2
1
I
N
6
O
O
NMR (300.13 MHz, 300 K, CDCl3):
d¼1.48 and 1.57 [2s, 6H, CH3(6 or
7
7)], 2.18 [dd, 3J¼4.4, 2J¼14.7, 1H, HeqC(2)], 2.45 [dd, 3J¼7.0, 2J¼14.7,
1H, HaxC(2)], 4.32 [d, 2J¼10.3, 1H, CH2(5)], 4.43 [d, 2J¼10.3, 1H,
CH2(5)], 6.02 [dd, 3J¼4.4, 7.0, 1H, CHeq (3)], 7.48 [t, 3J¼7.7, 2H,
4.4.3. 3-(Iodomethyl)-4,6,6-trimethyl-5,6-dihydro-4H-[1,2]-oxazine
2-oxide (6b-I). Yield 128 mg (45%), crystalline solid but rapidly
decomposes at room temperature, Rf¼0.37 (EtOAc/hexane, 1/1).
This compound has a short lifetime in chloroform solution. 1H NMR
CH(11)], 7.62 [t, 3J¼7.7, 1H, CH(12)], 8.05 [d, 3J¼7.7, 2H, CH(10)]. 13
C
NMR (75.47 MHz, 300 K, CDCl3):
d
¼25.2 and 26.2 (C-6 and C-7),
26.1 (C-5), 37.6 (C-2), 64.8 (C-3), 82.8 (C-1), 118.1 (C-4), 128.8 and
129.9 (C-10 and C-11), 129.0 (C-9), 133.9 (C-12), 165.6 (C-8). IR (KBr,
(300.13 MHz, 300 K, CDCl3):
d
¼1.27 [d, 3J¼7.0, 3H, CH3(8)], 1.35 and
cmꢀ1): 1716 (
n, C]O), 1590 (n, C]N), 1321, 1264, 1105, 1096, 1027,
1.37 [2s, 6H, CH3(6,7)], 1.68 [dd, 3J¼10.6, 2J¼13.6, 1H, HaxC(2)], 1.99
[dd, 3J¼7.0, 2J¼13.6, 1H, HeqC(2)], 2.88e3.04 [m, 1H, CHax(3)], 4.08
[d, 2J¼9.2, 1H, CH2(5)], 4.56 [d, 2J¼9.2, 1H, CH2(5)]. 13C NMR
879, 711. Anal. Calcd for C14H16BrNO4: C, 49.14; H, 4.71; N, 4.09.
Found: C, 49.30; H, 4.90; N, 4.01.
(75.47 MHz, 300 K, CDCl3):
d
¼0.1 (C-5), 18.6 (C-8), 23.8, 27.9, 28.1
13
12
(C-3, C-6, C-7), 40.4 (C-2), 82.6 (C-1), 124.9 (C-4).
11
10
8
5
3
4
H 3
5
6
4
2
7
8
Br
I
2
1
1
N
6
N
O
O
O
O
7
9
H
4.4.4. 3-(Bromomethyl)-4,6,6-trimethyl-5,6-dihydro-4H-[1,2]-ox-
azine 2-oxide (6b-Br). By method B, yield 155 mg (66%),
mp¼70e71 ꢁC (Et2O/hexane, 1/1) with decomposition, Rf¼0.38
4.4.7. rel-(4R,4aS,8aS)-3-(Iodomethyl)-4-phenyl-4a,5,6,7,8,8a-hex-
ahydro-4H-benzo[e]-[1,2]-oxazine 2-oxide (6d-I). Yield 318 mg
(86%), mp¼131e132 ꢁC (EtOAc/hexane, 5/1) with decomposition,

A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4589
Rf¼0.62 (EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
1281, 1241, 896, 832, 708, 627. Anal. Calcd for C10H10BrNO2: C,
46.90; H, 3.94; N, 5.47. Found: C, 46.89; H, 4.12; N, 5.42.
d
¼1.31e1.91 [m, 8H, CH2(6), CH2(7), CH2(8) and CH2(9)], 2.04 [dd,
3J¼3.3, 14.7, 1H, CH(2)], 3.54 [d, 2J¼9.2, 1H, CH2(5)], 3.77 [br s, 1H,
CH(3)], 4.51 [d, 2J¼9.2, 1H, CH2(5)], 4.66 [br s, 1H, CH(1)], 7.17 [d,
3J¼7.0, 2H, CH (11)], 7.27e7.42 [m, 3H, CH(12) and CH(13)]. 13C NMR
4
Br
2
3
6
1
7
5
N
(75.47 MHz, 300 K, CDCl3):
d
¼3.2 (C-5), 19.9, 24.3, 26.9 and 28.7
O
8
O
(C-6, C-7, C-8 and C-9), 39.3 and 46.7 (C-2 and C-3), 76.7 (C-1),120.5
(C-4), 127.8 and 129.3 (C-11 and C-12), 127.9 (C-13), 141.2 (C-10).
Anal. Calcd for C15H18INO2: C, 48.53; H, 4.89; N, 3.77. Found: C,
48.32; H, 4.97; N, 3.76.
Br
13
12
4.4.11. 3-Bromomethyl-5-(4-bromophenyl)isoxazoline 2-oxide (6f-
Br). By method A, yield 319 mg (95%), mp¼117e118 ꢁC (hexane)
with decomposition, Rf¼0.41 (EtOAc/hexane, 1/1). 1H NMR
11
10
(300.13 MHz, 300 K, CDCl3):
d
¼3.20 [dd, 3J¼7.3, 2J¼16.9, 1H,
H 3
5
6
4
7
8
CH2(2)], 3.65 [dd, 3J¼9.6, 2J¼16.9, 1H, CH2(2)], 4.26 [s, 2H, CH2(4)],
5.63 [dd, 3J¼7.3, 9.6, 1H, CH(1)], 7.29 [d, 3J¼8.7, 2H, CH(6)], 7.56 [d,
Br
2
1
N
O
O
3J¼8.7, 2H, CH(7)]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼22.5 (C-
9
H
2), 38.8 (C-4), 76.6 (C-1), 111.6 (C-3), 123.2 (CBr), 127.4 and 132.3 (C-
6 and C-7), 137.3 (C-5). Anal. Calcd for C10H9Br2NO2: C, 35.85; H,
2.71; N, 4.18. Found: C, 35.99; H, 2.61; N, 3.86.
4.4.8. rel-(4R,4aS,8aS)-3-(Bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-4H-benzo[e]-[1,2]-oxazine 2-oxide (6d-Br). By method B,
yield 279 mg (86%), mp¼118e120 ꢁC (Et2O), Rf¼0.64 (EtOAc/hex-
4
Br
2
3
ane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
d¼1.29e1.93 [m, 8H,
7
1
CH2(6), CH2(7), CH2(8) and CH2(9)], 2.05 [dd, 3J¼3.3, 15.0, 1H,
CH(2)], 3.62 [d, 2J¼9.9, 1H, CH2(5)], 3.72 [br s, 1H, CH(3)], 4.64 [d,
2J¼9.9, 1H, CH2(5)], 4.66 [br s, 1H, CH(1)], 7.18 [d, 3J¼6.9, 2H,
CH(11)], 7.28e7.42 [m, 3H, CH(12) and CH(13)].
H3C
MeO2C
N
O
O
6
5
13C NMR (75.47 MHz, 300 K, CDCl3):
d¼19.9, 24.3, 27.0, and 28.6
(C-6, C-7, C-8, and C-9), 29.1 (C-5), 39.3 and 46.7 (C-2 and C-3), 76.8
(C-1), 119.2 (C-4), 127.8 and 129.3 (C-11 and C-12), 127.9 (C-13),
140.8 (C-10). Anal. Calcd for C15H18 BrNO2: C, 55.57; H, 5.60; N, 4.32.
Found: C, 55.81; H, 5.81; N, 4.32.
4.4.12. 3-Bromomethyl-5-methyl-5-methoxycarbonylisoxazoline 2-
oxide (6g-Br). By method A, yield 219 mg (87%), mp¼44e45 ꢁC
(Et2O), Rf¼0.39 (EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K,
CDCl3):
d
¼1.71 [s, 3H, CH3(7)], 3.15 [d, 2J¼17.1, 1H, CH2(2)], 3.58 [d,
2J¼17.1, 1H, CH2(2)], 3.83 [s, 3H, CH3(6)], 4.15 [d, 2J¼11.2, 1H,
4
I
2
3
CH2(4)], 4.23 [d, 2J¼11.2, 1H, CH2(4)]. 13C NMR (75.47 MHz, 300 K,
6
1
7
5
CDCl3):
d
¼22.5 (C-4), 23.0 (C-7), 40.7 (C-2), 55.4 (C-6), 77.4 (C-1),
N
O
O
111.8 (C-3), 171.0 (C-5). Anal. Calcd for C7H10BrNO4: C, 33.35; H,
4.00; N, 5.56. Found: C, 33.42; H, 4.20; N, 5.52.
8
7
8
4.4.9. 3-Iodomethyl-4-phenylisoxazoline 2-oxide (6e-I). Prepared
according to a slightly modified iodination procedure: Et2O was
used for extraction instead of EtOAc, and the product was crystal-
lized from Et2O after evaporation. Yield 206 mg (68%),
mp¼48e49 ꢁC (Et2O/hexane, 1/1) with decomposition, Rf¼0.50
6
4
Br
5
2
3
1
N
O
O
(EtOAc/hexane, 1/1). 1H NMR (200.13 MHz, 300 K, CDCl3):
d¼3.29
[dd, 3J¼7.7, 2J¼16.5, 1H, CH2(2)], 3.67 [dd, 3J¼9.5, 2J¼16.5, 1H,
CH2(2)], 4.09 [d, 2J¼7.0, 1H, CH2(4)], 4.14 [d, 2J¼7.0, 1H, CH2(4)], 5.63
[dd, 3J¼7.7, 9.5, 1H, CH(1)], 7.29e7.52 [m, 5H, Ph]. 13C NMR
4.4.13. 3-Bromomethyl-4-phenylisoxazoline 2-oxide (6h-Br). By
method A, yield 213 mg (83%), mp¼49 ꢁC (Et2O), Rf¼0.53 (EtOAc/
(50.32 MHz, 300 K, CDCl3):
113.3 (C-3), 125.7 and 128.9 (C-6, C-7, and C-8), 138.0 (C-5).
d
¼ꢀ5.7 (C-4), 38.7 (C-2), 76.9 (C-1),
hexane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
d
¼3.74 [dd,
2J¼11.0, J¼0.7, 1H, CH2(4)], 4.36 [d, 2J¼11.0, 1H, CH2(4)], 4.40 [t,
3Jz2J¼7.3, 1H, CH2(1)] 4.70 [dd, 3J¼7.0, 9.9, 1H, CH(2)], 4.87 [dd,
2J¼7.7, 3J¼9.9, 1H, CH2(1)], 7.25e7.34 [m, 2H] and 7.37e7.47 [m, 3H]
4
Br
2
3
(Ph). 13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼21.6 (C-4), 49.5 (C-2),
6
1
7
5
N
71.5 (C-1), 114.9 (C-3), 127.8 and 129.7 (C-6 and C-7), 128.9 (C-8),
137.1 (C-5). Anal. Calcd for C10H10BrNO2: C, 46.90; H, 3.94; N, 5.47.
Found: C, 47.27; H, 4.34; N, 5.36.
O
O
8
4.4.10. 3-Bromomethyl-5-phenylisoxazoline 2-oxide (6e-Br). By
method A, yield 218 mg (85%), mp¼51e52 ꢁC (EtOAc), Rf¼0.58
4.4.14. 5-Nitro-4-phenylhex-5-ene-2-one (8). Yield 186 mg (85%),
colorless liquid, Rf¼0.44 (EtOAc/hexane, 1/1). 1H NMR (300.13 MHz,
(EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
d¼3.26
300 K, CDCl3):
d
¼2.11 [s, 3H, CH3], 3.04 [d, 3J¼7.3, 2H, CH2], 4.78 [td,
[dd, 3J¼7.3, 2J¼16.5, 1H, CH2(2)], 3.64 [dd, 3J¼9.5, 2J¼16.5, 1H,
CH2(2)], 4.27 [s, 2H, CH2(4)], 5.67 [ddd, 3J¼7.3, 9.5, J¼0.4,1H, CH(1)],
4J¼2.2, 3J¼7.3, 1H, CHPh], 5.59 [br s, 1H] and 6.54 [br d, 4J¼2.2, 1H]
(CH2]), 7.20e7.35 [m, 5H, Ph]. 13C NMR (75.47 MHz, 300 K, CDCl3):
7.35e7.47 [m, 5H, Ph]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d¼22.7
d
¼30.3 (CH3), 40.7 (CHPh), 47.9 (CH2), 117.5 (CH2]), 127.6 (CHp-Ph),
127.7 and 129.0 (both CHPh), 138.9 (Ci-Ph), 160.2 (CNO2), 204.7 (CO).
IR (thin layer from CHCl3, cmꢀ1): 1718 (
, C]O), 1525 (nas, NO2),
(C-2), 38.8 (C-4), 76.4 (C-1), 111.8 (C-3), 125.8 and 129.1 (C-6 and C-
7), 129.2 (C-8), 138.2 (C-5). IR (KBr, cmꢀ1): 1634 (
, C]N), 1315,
n
n

4590
A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
1495, 1454, 1421, 1342 (ns, NO2), 1167, 949, 756, 701. HRMS (ESI):
calcd for C12H13NO3 (MþNa) 242.0788. Found 242.0786.
3.51 [d, 2J¼11.0, 1H, CH2(4)], 3.59 [dd, 4J¼2.2, 3J¼10.3, 2J¼13.6, 1H,
CH2(2)], 4.55 [dd, 4J¼2.2,2J¼11.0, 1H, CH2(4)], 5.20 [dd, 3J¼7.0,
10.3, 1H, CH(3)], 7.28e7.48 [m, 5H, Ph]. 13C NMR (75.47 MHz,
H
5
300 K, CDCl3):
d
¼ꢀ0.1 (C-9), 27.7 and 28.8 (br, C-7 and C-8), 32.0
H
10
9
and 37.7 (C-2 and C-4), 84.1 (C-1), 90.5 (C-3), 126.3 and 128.3
(C-11 and C-12), 127.9 (C-13), 139.8 (C-10), 175.7 and 176.6 (C-5
and C-6).
O2N
8
4
11
6
H
2
3H
7
Compound 10b (mixture of 10b-
a and 10b-b, dr 1.6:1). Yield
1
nOe
O
H
395 mg (84%), colorless oil, gradually decomposes at room tem-
perature, Rf¼0.67 (EtOAc/hexane, 1/1).
OH
4.4.15. rel-(2R,3R)-3-((R)-2-Nitro-1-phenylallyl)tetrahydrofuran-2-
ol (9). Yield 134 mg (56%), mp¼142e143 ꢁC (EtOAc/Et2O, 1/2),
Rf¼0.34 (EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K, DMSO-
8
7
6
5
O
2
O
Br
N
4
d6, COSY, NOESY):
d
¼1.63e1.83 [m, 1H, CH2(6)], 1.96e2.10 [m, 1H,
1
CH2 (6)], 2.67e2.85 [m, 1H, CH (2)], 3.77 [dd, 3J¼8.2, 2J¼16.0, 1H,
CH2(7)], 3.95 [tdd, 3J¼2.8, 9.6, 2J¼16.0, 1H, CH2(7)], 4.26 [d, 3J¼11.4,
1H, CH(3)], 4.68 [t, 3J¼4.1, 1H, CH(1)], 6.07 [d, 3J¼4.1, 1H, OH], 6.30
14
Me9
3
13
15
16
N
Me10
OSi
O
11
12
Me
[br s, 1H, CH2(5)], 6.57 [br s, 1H, CH2(5)], 7.20e7.37 [m, 5H, Ph]. 13
C
Me
Me
NMR (75.47 MHz, 300 K, DMSO-d6, HSQC):
47.0 (C-2), 65.7 (C-7), 95.9 (C-1), 119.0 (C-5), 127.0 (C-11), 128.3 (C-9
and C-10), 139.7 (C-8), 160.2 (C-4). IR (KBr, cmꢀ1): 3360 (
, OH),
d¼27.4 (C-6), 45.5 (C-3),
n
1532 (nas, NO2), 1408,1340 (ns, NO2),1264,1088,1072, 988, 956, 896,
772, 712. HRMS (ESI): calcd for C13H15NO4 (MþNa) 272.0893. Found
272.0895.
Nitrosoacetals 10aec were obtained according to method B.
They were isolated as mixtures of diastereoisomers, and their rel-
ative configurations were determined by 2D-NOESY measurements
(see Supplementary data).
4.4.18. 1-{rel-(2S,3S,5R)-3-Bromomethyl-2-(tert-butyldimethylsily-
loxy)-5-phenylisoxazolidine-3-yl}-pyrrolidine-2,5-dione (10b-
). 1H
a
NMR (300.13 MHz, 300 K, CDCl3):
d
¼0.14 and 0.26 [2s, 6H,
2CH3(9,10)], 0.89 [s, 9H, 3CH3(12)], 2.60 [dd, 3J¼5.5, 2J¼13.6, 1H,
CH2(2)], 2.66e2.81 [m, 4H, CH2(7) and CH2(8)], 3.29 [d, 2J¼11.0,
1H, CH2(4)], 4.23 [ddd, 4J¼1.8, 3J¼9.5, 2J¼13.6, 1H, CH2(2)], 4.67
[dd, 4J¼1.8, 2J¼11.0, 1H, CH2(4)], 5.65 [dd, 3J¼5.5, 9.5, 1H, CH(3)],
Compound 10a (mixture of 10a-a and 10a-b, dr 1.8:1). Yield
7.26e7.50 [m, 5H, Ph]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d¼ꢀ5.2
325 mg (76%), colorless oil, rapidly decomposes at room tempera-
and ꢀ4.7 (C-9 and C-10), 17.8 (C-11), 25.8 (3C-12), 27.8 and 28.8
(br, C-7 and C-8), 35.8 and 36.3 (C-2 and C-4), 80.2 (C-1), 91.5 (C-
3), 126.3 (C-16), 128.2 and 128.8 (C-14 and C-15), 138.7 (C-13),
175.8 and 176.8 (br, C-5 and C-6). 29Si (59.63 MHz, 300 K, CDCl3):
ture, Rf¼0.62 (EtOAc/hexane, 1/1). IR (for mixture of isomers, thin
layer from CHCl3, cmꢀ1): 1784 (
n, C]O), 1724 (n, C]O), 1433, 1356,
1251, 1165, 1132, 877, 845, 756, 700.
8
7
d¼28.6.
6
5
O
2
O
N
N
4
8
7
1
Br
11
3
6
10
9
12
13
5
O
2
OSiMe3
O
N
N
4
O
1
Br
14
9
3
13
15
16
Me
10
OSi
Me
O
11
4.4.16. 1-{rel-(2S,3S,5R)-3-Bromomethyl-5-phenyl-2-(trimethylsily-
loxy)isoxazolidine-3-yl}-pyrrolidine-2,5-dione (10a-
). 1H NMR
12
Me
Me
a
Me
(300.13 MHz, 300 K, CDCl3):
d
¼0.20 [s, 9H, 3CH3(9)], 2.62 [dd,
3J¼5.5, 2J¼13.6, 1H, CH2(2)], 2.67e2.85 [m, 4H, CH2(7) and CH2(8)],
3.30 [d, 2J¼10.6, 1H, CH2(4)], 4.17 [ddd, 4J¼1.8, 3J¼9.5, 2J¼13.6, 1H,
CH2(2)], 4.64 [dd, 4J¼1.8, 2J¼10.6, 1H, CH2(4)], 5.64 [dd, 3J¼5.5, 9.5,
1H, CH(3)], 7.28e7.48 [m, 5H, Ph]. 13C NMR (75.47 MHz, 300 K,
4.4.19. 1-{rel-(2S,3S,5S)-3-Bromomethyl-2-(tert-butyldimethylsily-
loxy)-5-phenylisoxazolidine-3-yl}-pyrrolidine-2,5-dione (10b-
). 1H
NMR (300.13 MHz, 300 K, CDCl3):
¼0.11 and 0.13 [2s, 6H,
b
d
CDCl3):
d
¼ꢀ0.2 (C-9), 27.7 and 28.8 (br, C-7 and C-8), 35.9 and 36.6
2CH3(9,10)], 0.80 [s, 9H, 3CH3(12)], 2.67e2.85 [m, 4H, CH2(7) and
CH2(8)], 3.36 [dd, 3J¼6.6, 2J¼13.2, 1H, CH2(2)], 3.51 [d, 2J¼11.0, 1H,
CH2(4)], 3.77 [dd, 4J¼2.2, 3J¼10.3, 2J¼13.2, 1H, CH2(2)], 4.63 [dd,
4J¼2.2,2J¼11.0, 1H, CH2(4)], 5.22 [dd, 3J¼6.6, 10.3, 1H, CH(3)],
(C-2 and C-4), 80.1 (C-1), 91.3 (C-3), 126.3 (C-13), 128.2 and 128.6
(C-11 and C-12), 138.6 (C-10), 175.7 and 176.6 (br, C-5 and C-6).
8
7
7.26e7.50 [m, 5H, Ph]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼ꢀ5.1
6
5
O
2
O
N
N
4
and ꢀ4.0 (C-9 and C-10), 17.6 (C-11), 25.8 (3C-12), 27.8 and 28.7
(br, C-7 and C-8), 31.8 and 36.7 (C-2 and C-4), 83.8 (C-1), 90.9 (C-
3), 126.3 and 128.3 (C-14 and C-15), 127.8 (C-16), 139.6 (C-13),
175.8 and 176.9 (C-5 and C-6). 29Si (59.63 MHz, 300 K, CDCl3):
1
Br
11
3
10
OSiMe39
12
13
O
d¼27.9.
Compound 10c (mixture of 10c-
a and 10c-b, dr 1.6:1). Yield
4.4.17. 1-{rel-(2S,3S,5S)-3-Bromomethyl-5-phenyl-2-(trimethylsily-
loxy)isoxazolidine-3-yl}-pyrrolidine-2,5-dione (10a-
). 1H NMR
499 mg (91%), mp¼107e110 ꢁC (hexane, for 1.26:1 mixture of 10c-
b
a
and 10c-
b
). Rf¼0.72 (EtOAc/hexane, 1/1). Anal. Calcd for
(300.13 MHz, 300 K, CDCl3):
d
¼0.15 [s, 9H, 3CH3(9)], 2.67e2.85
C20H28Br2N2O4Si: C, 43.85; H, 5.15; Br, 29.14; N, 5.11; Si, 5.12. Found:
C, 44.19; H, 5.32; Br, 29.15; N, 5.12; Si, 5.12.
[m, 4H, CH2(7) and CH2(8)], 3.40 [dd, 3J¼7.0, 2J¼13.6, 1H, CH2(2)],

A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4591
8
7
4.6. Reaction of halomethylnitronates with
dimethylmalonate in DMF (Table 4, typical procedure ii)
6
5
O
2
O
Br
N
N
4
1
Dimethylmalonate (72 mL, 0.63 mmol) was added to the stirred
14
9
solution of t-BuOK (52 mg, 0.56 mmol) in DMF (1.3 mL) at 0 ꢁC. The
reaction mixture was stirred for 10 min at 0 ꢁC, cooled to ꢀ40 ꢁC,
and nitronate 6a-I (175 mg, 0.51 mmol) was added. The reaction
mixture was stirred for 15 min at ꢀ40 ꢁC, and the temperature was
allowed to rise to 0 ꢁC over 15 min. The reaction mixture was
poured into Et2O (20 mL)/water (20 mL), the aqueous layer was
separated and washed with Et2O (2ꢂ10 mL). The combined organic
phases were dried over Na2SO4. The solvents were evaporated in
vacuo at 40 ꢁC and residue was subjected to column chromatog-
raphy on silica (EtOAc/hexane, 1/3) to give nitronate 15b as color-
less flakes (156 mg, 88%).
3
13
15
Me
10
OSi
Me
Br 16
O
11
12
Me
Me
Me
4.4.20. 1-{rel-(2S,3S,5R)-3-Bromomethyl-5-(4-bromophenyl)-2-
(tert-butyldimethylsilyloxy)-isoxazolidine-3-yl}-pyrrolidine-2,5-di-
one (10c-
a
). 1H NMR (300.13 MHz, 300 K, CDCl3):
d¼0.13 and 0.24
[2s, 6H, 2CH3(9,10)], 0.88 [s, 9H, 3CH3(12)], 2.66 [dd, 3J¼5.0, 2J¼11.4,
1H, CH2(2)], 2.60e2.81 [m, 4H, CH2(7) and CH2(8)], 3.19 [d, 2J¼11.0,
1H, CH2(4)], 4.23 [ddd, 4J¼1.8, 3J¼9.6, 2J¼11.4, 1H, CH2(2)], 4.66 [dd,
4J¼1.8, 2J¼11.0, 1H, CH2(4)], 5.58 [dd, 3J¼5.0, 9.6, 1H, CH(3)], 7.24 [d,
2J¼8.2, 2H, CH(14)], 7.52 [d, 2J¼8.2, 2H, CH(15)]. 13C NMR
4.7. Reaction of nitronate 6a-Br with 2-lithio-2,3-dithiane
(Table 4, procedure iii)
n-BuLi (287 mL, 2.5 M solution in hexanes) was added to a stirred
(75.47 MHz, 300 K, CDCl3):
d
¼ꢀ5.2 and ꢀ4.7 (C-9 and C-10),17.8 (C-
solution of 1,3-dithiane (93 mg, 0.77 mmol) in THF (2.5 mL) at
ꢀ20 ꢁC. The reaction mixture was stirred for 10 min, cooled to
ꢀ60 ꢁC, and nitronate 6a-Br (200 mg, 0.67 mmol) was added. The
reaction mixture was kept for 1 h at ꢀ60 ꢁC, then was allowed to
warm up to room temperature and poured into Et2O (15 mL)/water
(15 mL). The aqueous layer was separated and extracted with Et2O
(2ꢂ5 mL). The combined organic phases were washed with water
(10 mL), brine (15 mL) and dried over Na2SO4. The solvents were
evaporated in vacuo at 40 ꢁC, and the residue was subjected to
column chromatography on silica gel (EtOAc/hexane, 1/3) to give
nitronate 15e as colorless flakes (208 mg, 92%).
11), 25.7 (C-12), 27.8 and 28.8 (br, C-7 and C-8), 35.6 and 36.4 (C-2
and C-4), 79.5 (C-1), 91.4 (C-3), 122.2 (C-16), 127.9 and 132.0 (C-14
and C-15), 137.8 (C-13), 176.4 and 177.8 (br, C-5 and C-6). 29Si NMR
(59.63 MHz, 300 K, CDCl3):
d
¼28.9.
8
7
6
5
O
2
O
Br
N
N
4
1
Me9
14
15
3
13
10
OSi
Me
Br 16
O
11
12
4.8. Reaction of halomethylnitronates with
dimethylmalonate in DMF (Table 4, typical procedure iv)
Me
Me
Me
NaH (37 mg, 60% suspension in mineral oil, 0.93 mmol) was
added to a stirred solution of dimethylmalonate (115 mL,1.01 mmol)
in THF (2.0 mL) at 0 ꢁC. The reaction mixture was stirred for 20 min
at 0 ꢁC, cooled to ꢀ40 ꢁC, and nitronate 6d-I (300 mg, 0.81 mmol)
was added. The reaction mixture was stirred for 30 min at ꢀ40 ꢁC,
and the temperature was allowed to rise to 0 ꢁC over 15 min. The
reaction mixture was poured into Et2O (20 mL)/water (20 mL),
the aqueous layer was separated and washed with Et2O (2ꢂ10 mL).
The combined organic phases were dried over Na2SO4. The solvents
were evaporated in vacuo at 40 ꢁC and residue was subjected to the
column chromatography (EtOAc/hexane, 1/3) to give nitronate 15g
as colorless prisms (295 mg, 97%).
4.4.21. 1-{rel-(2S,3S,5R)-3-Bromomethyl-5-(4-bromophenyl)-2-
(tert-butyldimethylsilyloxy)-isoxazolidine-3-yl}-pyrrolidine-2,5-di-
one (10c-
b
). 1H NMR (300.13 MHz, 300 K, CDCl3):
d
¼0.11 and 0.12
[2s, 6H, 2CH3(9,10)], 0.80 [s, 9H, 3CH3(12)], 2.55e2.82 [m, 4H,
CH2(7) and CH2(8)], 3.36 [dd, 3J¼6.4, 2J¼13.8, 1H, CH2(2)], 3.47 [d,
2J¼11.0, 1H, CH2(4)], 3.73 [dd, 4J¼1.8, 3J¼9.6, 2J¼13.8, 1H, CH2(2)],
4.62 [dd, 4J¼1.8,2J¼11.0,1H, CH2(4)], 5.17 [dd, 3J¼6.4, 9.6,1H, CH(3)],
7.34 [d, 2J¼8.2, 2H, CH(14)], 7.46 [d, 2J¼8.2, 2H, CH(15)]. 13C NMR
(75.47 MHz, 300 K, CDCl3):
d
¼ꢀ5.1 and ꢀ4.0 (C-9 and C-10), 17.6 (C-
11), 25.7 (C-12), 27.8 and 28.9 (br, C-7 and C-8), 31.7 and 36.7 (C-2
and C-4), 83.1 (C-1), 90.9 (C-3), 122.2 (C-16), 129.5 and 131.5 (C-14
and C-15), 138.8 (C-13), 176.4 and 176.9 (C-5 and C-6). 29Si NMR
Nitronates 15a (yield 82%), 15b (yield 87%), and 15c (yield 88%)
have been described.3
(59.63 MHz, 300 K, CDCl3):
d
¼28.3.
11
10
4.5. Reaction of halomethylnitronates with PhSO2Na (Table 4,
typical procedure i)
9
15
14
8
5
3
4
2
1
12
S
13
Nitronate 6a-I (207 mg, 0.60 mmol) was added to the stirred
suspension of sodium benzenesulfinate (118 mg, 0.72 mmol) in
DMF (1.5 mL) at 0 ꢁC. The temperature was allowed to rise to room
temperature and the reaction mixture was stirred for 15 min until
all the precipitate was dissolved. Then the reaction mixture was
poured into Et2O (15 mL)/water (20 mL). The aqueous layer was
separated and back-extracted with Et2O (2ꢂ6 mL). The combined
organic phase was washed with water (20 mL), brine (20 mL), and
dried over Na2SO4. The solvents were evaporated in vacuo at 40 ꢁC,
and the residue dried under high vacuum (0.03 Torr) to give pure
white crystalline nitronate 15d (215 mg, 100%).
O2
N
6
O
O
7
4.8.1. 6,6-Dimethyl-4-phenyl-3-[(phenylsulfonyl)methyl]-5,6-dihy-
dro-4H-[1,2]-oxazine 2-oxide (15d). Yield 215 mg (100%),
mp¼119e121 ꢁC (Et2O), Rf¼0.33 (EtOAc/hexane, 1/1). 1H NMR
(300.13 MHz, 300 K, CDCl3):
d
¼1.40 and 1.52 [2 s, 6H, CH3(6,7)],
2.02 [t, 3Jz2J¼14.7, 1H, HaxC(2)], 2.22 [dd, 3J¼7.8, 2J¼13.7, 1H,
HeqC(2)], 3.51 [d, 2J¼14.2, 1H, CH2(5)], 4.24 [dd, 3J¼7.8, 11.0, 1H,

4592
A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
CHax(3)], 4.79 [d, 2J¼14.2, 1H, CH2(5)], 7.22 [d, 3J¼7.7, 2H, CH (9)],
7.26e7.41 [m, 3H, CH(10) and CH(11)], 7.54 [t, 3J¼7.3, 2H, CH(14)],
7.65 [t, 3J¼7.3, 1H, CH(15)], 7.94 [d, 3J¼7.3, 2H, CH(13)]. 13C NMR
C
19H23NO8: C, 58.01; H, 5.89; N, 3.56. Found: C, 58.10; H, 5.85;
N, 3.68.
(75.47 MHz, 300 K, CDCl3):
d
¼22.2 and 27.8 (C-6 and C-7), 40.9 and
18
17
16
41.7 (C-2 and C-5), 83.1 (C-1), 115.4 (C-4), 128.3 (C-11), 128.0, 128.1,
129.2, 129.5 (all CHPh), 134.2 (C-15), 139.4 and 140.4 (C-8 and C-12).
IR (KBr, cmꢀ1): 1598 (
n, C]N), 1317, 1295, 1281, 1162, 1152, 705, 525.
15
7
8
5
H
11
3
6
4
CO2Me
12
13
Anal. Calcd for C19H21NO4S: C, 63.49; H, 5.89; N, 3.90. Found: C,
63.45; H, 6.04; N, 4.04.
2
1
N
CO2Me
O
O
9
10
14
H
15
14
4.8.4. Dimethyl {2-[rel-(4R,4aS,8aS)-4-phenyl-2-oxo-4a,5,6,7,8,8a-
hexahydro-4H-benzo[e]-[1,2]-oxazin-3-yl]methyl}malonate
(15g). Obtained according to the procedure iv. Yield 285 mg (97%),
mp¼127e128 ꢁC (EtOAc/hexane, 1/3), Rf¼0.43 (EtOAc/hexane, 1/1).
13
12
5
3
4
6
S
7
1H NMR (300.13 MHz, 300 K, CDCl3):
d
¼1.19e1.87 [m, 8H, (CH2)4,],
2
1
N
S
1.93e2.05 [m, 1H, CH(2)], 2.44 [t, 3Jz2J¼11.9, 1H, CH2(5)], 3.01 [dd,
3J¼3.2,2J¼13.7, 1H, CH2(5)], 3.64 [br s, 1H, CH(3)], 3.69 and 3.76 [2s,
6H, CH3(8,10)], 4.41 [dd, 3J¼3.2, 10.5, 1H, CH(6)], 4.62 [br s, 1H,
CH(1)], 7.15 [d, 3J¼6.4, 2H, CH(16)], 7.25e7.42 [m, 3H, CH(17) j
8
10
O
O
9
11
CH(18)]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼20.0, 24.7, 27.3 and
28.7 (C-11, C-12, C-13 and C-14), 31.7 (C-5), 39.6 and 45.9 (C-2 and
C-3), 49.7 (C-6), 52.6 and 52.8 (C-8 and C-10), 75.8 (C-1),120.1 (C-4),
127.7 (C-18),127.8 and 129.3 (C-16 and C-17),141.2 (C-15),169.0 and
169.5 (C-7 and C-9). HRMS (ESI): calcd for C20H25NO6 (MþH)
376.1755. Found 376.1745.
4.8.2. 6,6-Dimethyl-3-((1,3-dithian-2-yl)methyl)-4-phenyl-5,6-
dihydro-4H-[1,2]-oxazine 2-oxide (15e). Yield 208 mg (92%),
mp¼155e157 ꢁC (Et2O), Rf¼0.37 (EtOAc/hexane, 1/1). 1H NMR
(300.13 MHz, 300 K, CDCl3):
d
¼1.42 and 1.57 [2s, 6H, CH3(10,
11)], 1.80e2.18 [m, 4H, CH2(2) and CH2(8)], 2.27 [dd, 3J¼11.0,
2J¼14.2, 1H, CH2(5)], 2.78e2.88 [br m, 4H, CH2(7) and CH2(9)],
3.08 [dd, 3J¼5.0, 2J¼14.2, 1H, CH2(5)], 3.91 [dd, 3J¼8.2, 10.5, 1H,
CHax(3)], 4.68 [dd, 3J¼5.0, 11.0, 1H, CH(6)], 7.19 [d, 3J¼6.9, 2H,
CHo-Ph], 7.29e7.41 [m, 3H, CHPh]. 13C NMR (75.47 MHz, 300 K,
13
12
11
16
15
17
10
CDCl3):
d
¼22.6 and 27.9 (C-10 and C-11), 25.6 (C-8), 29.0 and
H 3
5
6
9
4
7
8
29.1 (C-7 and C-9), 36.0 and 41.8 (C-2 and C-5), 40.9 and 43.9
(C-3 and C-6), 82.0 (C-1), 122.2 (C-4), 127.8 (C-15), 128.1 and
129.4 (C-13 and C-14), 140.0 (C-12). Anal. Calcd for C17H23NO2S2:
C, 60.50; H, 6.87; N, 4.15; S, 19.00. Found: C, 60.47; H, 7.20; N,
3.93; S, 18.99.
14
O2
S
2
1
N
O
O
H
4.8.5. rel-(4R,4aS,8aS)-3-(phenylsulfonyl)methyl-4-ahenyl-4a,5,6,7,8,8a-
hexahydro-4H-benzo[e]-[1,2]-oxazine 2-oxide (15h). Obtained similar
to 15d according to the procedure i from 300 mg, 0.81 mmol of
6d-I. Yield 309 mg (99%), white flakes, mp¼174e175 ꢁC (Et2O/
pentane, 3/1) with decomposition, Rf¼0.37 (EtOAc/hexane, 1/1). 1H
O
15
14
16
13
O
7
8
5
3
4
17
CO2CH3
6
NMR (300.13 MHz, 300 K, CDCl3):
d¼1.25e2.07 [m, 9H, CH2(6),
2
CH2(7), CH2(8), CH2(9) and CH(2)], 3.56 [d, 2J¼14.2, 1H, CH2(5)],
4.00 [br s, 1H, CH(3)], 4.62 [br s, 1H, CH(1)], 4.82 [d, 2J¼14.2, 1H,
CH2(5)], 7.14 [d, 3J¼7.7, 2H, CH (11)], 7.30e7.41 [m, 3H, CH(12) and
CH(13)], 7.57 [t, 3J¼7.3, 2H, CH(16)], 7.68 [t, 3J¼7.3, 1H, CH(17)], 7.97
1
N
CO2CH3
11
9
O
O
10
12
[d, 3J¼7.3, 2H, CH(15)]. 13C NMR (75.47 MHz, 300 K, CDCl3):
¼20.0,
d
24.3, 27.4, and 28.4 (C-6, C-7, C-8 and C-9), 39.7 and 47.7 (C-2 and
C-3), 57.4 (C-5), 76.9 (C-1), 113.1 (C-4), 127.9 (C-13), 128.0, 128.2,
129.2, 129.4 (all CHPh), 134.3 (C-17), 139.9 and 140.6 (C-10 and
C-14). Anal. Calcd for C21H23NO4S: C, 65.43; H, 6.01; N, 3.63. Found:
C, 65.39; H, 6.07; N, 3.75.
4.8.3. Dimethyl [2-(4-benzoyloxy-6,6-dimethyl-2-oxo-5,6-dihydro-
4H-[1,2]-oxazin-3-yl)-methyl]malonate (15f). Obtained similar to
15b according to the procedure ii from 215 mg, 0.55 mmol of
6c-I. Yield 201 mg (93%), colorless needles, mp¼91e92 ꢁC
(Et2O/hexane, 3/1), Rf¼0.29 (EtOAc/hexane, 1/1). 1H NMR
(300.13 MHz, 300 K, CDCl3):
d
¼1.43 and 1.53 [2s, 6H, CH3(11,
12)], 2.10 [dd, 3J¼4.4, 2J¼14.7, 1H, HeqC(2)], 2.38 [dd, 3J¼6.6,
2J¼14.7, 1H, HaxC(2)], 2.91 [dd, 3J¼9.9, 2J¼14.3, 1H, CH2(5)], 3.04
[dd, 3J¼5.1, 2J¼14.3, 1H, CH2(5)], 3.68 and 3.73 [2s, 6H,
CH3(8,10)], 4.29 [dd, 3J¼5.1, 9.9, 1H, CH(6)], 5.94 [dd, 3J¼4.4, 6.6,
1H, CHeq(3)], 7.46 [t, 3J¼7.7, 2H, CH(16)], 7.60 [t, 3J¼7.7, 1H,
CH(17)], 8.01 [d, 3J¼7.7, 2H, CH(15)]; 13C NMR (75.47 MHz,
6
7
CO2CH3
4
5
2
3
11
CO2CH3
12
13
1
8
9
N
O
10
O
300 K, CDCl3):
d
¼25.3 and 25.7 (C-11 and C-12), 28.6 and 37.5
(C-2 and C-5), 45.9 (C-6), 52.8 and 52.9 (C-8 and C-10), 66.6 (C-
3), 81.7 (C-1), 118.5 (C-4), 128.7 and 129.8 (C-15 and C-16), 129.2
(C-14), 133.7 (C-17), 165.5 (C-13), 168.9 and 169.3 (C-7 and C-9).
4.8.6. Dimethyl 2-(2-oxido-5-phenylisoxazolin-3-ylmethyl)malonate
(15i). Obtained similar to 15g according to the procedure iv from
330 mg, 1.29 mmol of 6e-Br. Yield 331 mg (84%), white flakes,
mp¼40e41 ꢁC (Et2O/CHCl3, 2/1), Rf¼0.37 (EtOAc/hexane, 1/1). 1H
IR (KBr, cmꢀ1): 1750 (
1613 (
n
, C]O), 1733 (
, C]N), 1323, 1289, 1260, 1225, 1108, 715. Anal. Calcd for
n, C]O), 1717 (n, C]O),
n
NMR (300.13 MHz, 300 K, CDCl3):
d
¼2.94 [d, 3J¼7.3, 2H, CH2(4)],

A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
4593
3.14 [dd, 3J¼7.8, 2J¼17.0, 1H CH2(2)], 3.55 [dd, 3J¼9.2, 2J¼17.0, 1H
CH2(2)], 3.69 and 3.76 [2s, 6H; CH3(7,9)], 4.00 [t, 3J¼7.3, 1H, CH(5)],
5.60 [dd, 3J¼7.8, 3J¼9.2, CH(1)], 7.38 [br s, 5H, Ph]; 13C NMR
13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼24.4 (C-4), 46.5 and 51.9 (C-
2 and C-5), 52.9 and 53.0 (C-7 and C-9), 71.5 (C-1), 115.5 (C-3), 127.7
and 129.5 (C-11 and C-12), 128.6 (C-13), 137.8 (C-10), 168.5 and
168.8 (C-6 and C-8). HRMS (ESI): calcd for C15H17NO6 (MþNa)
330.0948. Found 330.0950.
(75.47 MHz, 300 K, CDCl3):
d
¼25.4 (C-4), 41.5 (C-2), 46.7 (C-5), 52.9,
and 53.0 (C-7 and C-9), 76.2 (C-1), 112.6 (C-3), 125.6 and 128.9 (C-11
and C-12), 128.8 (C-13), 138.7 (C-10), 168.6 (C-6 and C-8). IR (KBr,
CCDC-812034 (for 3f0) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
cmꢀ1): 1754 (
n, C]O), 1738 (n, C]O), 1648 (n, C]N), 1438, 1309,
1275, 1141, 869, 703. Anal. Calcd for C15H17NO6: C, 58.63; H, 5.58; N,
4.56. Found: C, 58.29; H, 5.46; N, 4.52.
6
7
CO2CH3
4
Acknowledgements
5
2
3
11
CO2CH3
12
1
We are grateful to the Presidium of Russian Academy of Sciences
(program # 7), the Ministry of Science (project MD-1151.2011.3),
and the Federal program ‘Scientific and educational personnel of
innovative Russia’ (project 02.740.11.0258). We also thank Dr. I.P.
Yakovlev for assistance with measuring and interpretation of IR
spectra.
8
9
N
O
10
O
Br 13
4.8.7. Dimethyl 2-(2-oxido-5-phenylisoxazolinyl-3-ylmethyl)malo-
nate (15j). Obtained similar to 15g according to the procedure iv
from 150 mg, 0.45 mmol of 6f-Br. Yield 161 mg (93%), white solid,
mp¼27 ꢁC (Et2O), Rf¼0.39 (EtOAc/hexane, 1/1). 1H NMR
Supplementary data
(300.13 MHz, 300 K, CDCl3):
d
¼2.91 [d, 3J¼7.3, 2H, CH2(4)], 3.08 [dd,
3J¼7.3, 2J¼17.4, CH2(2)], 3.55 [dd, 3J¼9.6, 2J¼17.4, CH2(2)], 3.69 and
Synthesis of starting compounds, characterization data for
compounds 16, and 20, copies of 2D-NOESY spectra. Supplemen-
tary data associated with this article can be found in online version
at doi:10.1016/j.tet.2011.04.078.
3.75 [2s, 6H; CH3(7,9)], 3.97 [t, 3J¼7.3, 1H, CH(5)], 5.54 [t, 3Jz3J¼8.7,
CH(1)], 7.25 [d, 3J¼8.3, 2H, CH(11)], 7.52 [d, 3J¼8.3, 2H, CH(12)]. 13
C
NMR (75.47 MHz, 300 K, CDCl3):
d
¼25.4 (C-4), 41.5 (C-2), 46.7 (C-5),
53.0 and 53.1 (C-7 and C-9), 75.5 (C-1), 112.3 (C-3), 122.8 (C-13),
127.4 and 132.2 (C-11 and C-12), 137.9 (C-10), 168.6 (C-6 and C-8).
Anal. Calcd for C15H16BrNO6: C, 46.65; H, 4.18; N, 3.63; Found: C,
46.69; H, 4.45; N, 3.48.
References and notes
1. (a) Ioffe, S. L. In Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis: Novel
Strategies in Synthesis, 2nd ed.; Feuer, H., Ed.; John Wiley: Chichester, UK, 2008;
pp 435e748; (b) Denmark, S. E.; Cottell, J. J. In Synthetic Applications of 1,3-Di-
polar Cycloaddition Chemistry toward Heterocycles and Natural Products; Padwa,
A., Pearson, W. H., Eds.; Wiley: Chichester, United Kingdom, 2002; Vol. 59,
pp 83e167; (c) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996, 96, 137e165.
2. (a) Creech, G. S.; Kwon, O. J. Am. Chem. Soc. 2010, 132, 8876e8877; (b) Shi, Z.;
Tan, B.; Leong, W. W. Y.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett. 2010, 12,
5402e5405; (c) Duan, H.; Sun, X.; Liao, W.; Petersen, J. L.; Shi, X. Org. Lett. 2008,
10, 4113e4116; (d) Wilson, J. E.; Casarez, A. D.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 11332e11334; (e) Smirnov, V. O.; Ioffe, S. L.; Tishkov, A. A.;
Khomutova, Y. A.; Nesterov, I. D.; Antipin, M. Y.; Smit, W. A.; Tartakovsky, V. A.
J. Org. Chem. 2004, 69, 8485e8488; (f) Romashov, L. V.; Khomutova, Y. A.;
Danilenko, V. M.; Ioffe, S. L.; Lesiv, A. V. Synthesis 2010, 407e414; (g) Smirnov,
V. O.; Khomutova, Y. A.; Tishkov, A. A.; Ioffe, S. L. Izv. Akad. Nauk, Ser. Khim.
2006, 1983e1992; [ Russ. Chem. Bull. Int. Ed. 2006, 55, 2061e2070 ]; (h) Nes-
terov, I. D.; Lesiv, A. V.; Ioffe, S. L.; Antipin, M. Y. Mendeleev Commun. 2004,
280e281; (i) Bokach, N. A.; Ioffe, S. L.; Dolgushin, F. M.; Antipin, M. Y.; Tarta-
kovskii, V. A.; Kukushkin, V. Y. Inorg. Chem. Commun. 2009, 12, 173e176; (j)
Smirnov, V. O.; Khomutova, Y. A.; Ioffe, S. L. Mendeleev Commun. 2008, 18,
255e257.
3. Mikhaylov, A. A.; Dilman, A. D.; Kunetsky, R. A.; Khomutova, Y. A.; Struchkova,
M. I.; Korlyukov, A. A.; Ioffe, S. L.; Tartakovsky, V. A. Tetrahedron Lett. 2010, 51,
1038e1040.
4. For synthesis of oxazine N-oxides 1: Tishkov, A. A.; Lesiv, A. V.; Khomutova, Y.
A.; Strelenko, Y. A.; Nesterov, I. D.; Antipin, M. Y.; Ioffe, S. L.; Denmark, S. E.
J. Org. Chem. 2003, 68, 9477e9480.
5. For synthesis of isoxazoline N-oxides 2 from 1-bromonitroethane: (a) Kunetsky,
R. A.; Dilman, A. D.; Ioffe, S. L.; Struchkova, M. I.; Strelenko, Y. A.; Tartakovsky,
V. A. Org. Lett. 2003, 5, 4907e4909; (b) Kunetsky, R. A.; Dilman, A. D.; Struch-
kova, M. I.; Belyakov, P. A.; Tartakovsky, V. A.; Ioffe, S. L. Synthesis 2006,
2265e2270.
6
7
CO2Me
4
5
2
3
H31C2
CO2Me
1
8
9
N
O
O
MeO2C
11
10
4.8.8. Dimethyl 2-(2-oxido-5-methyl-5-methoxycarbonylisoxazoline-
3-ylmethyl)malonate (15k). Obtained similar to 15g according to
the procedure iv from 214 mg, 0.85 mmol of 6g-Br. Yield 195 mg
(76%), colorless oil, Rf¼0.41 (EtOAc/hexane, 1/1). 1H NMR
(300.13 MHz, 300 K, CDCl3):
d
¼1.57 [s, 3H, CH3(12)], 2.79 [d, 3J¼7.3,
2H, CH2(4)], 3.00 [d, 2J¼17.4, 1H, CH2(2)], 3.42 [d, 2J¼17.4, 1H,
CH2(2)], 3.67 [s, 6H, CH3(7,9)], 3.72 [s, 3H, CH3(11)], 3.85 [t, 3J¼7.3,
1H, CH(5)]. 13C NMR (75.47 MHz, 300 K, CDCl3):
d
¼22.8 (C-12), 25.1
(C-4), 43.0 (C-2), 46.5 (C-5), 52.8 (C-7 and C-9), 53.0 (C-11), 79.0 (1),
112.3 (3), 168.3 (C-6 and C-8), 171.3 (C-10). HRMS (ESI): calcd for
C12H17NO8 (MþNa) 326.0846. Found 326.0846.
13
6
7
CO2CH3
12
4
5
2
3
11
6. For synthesis of isoxazoline N-oxides 2 from nitroalkenes and dime-
thylsulfoxonium methylide: Clagett, M.; Gooch, A.; Graham, P.; Holy, N.; Mains,
B.; Strunk, J. J. Org. Chem. 1976, 41, 4033e4035.
7. The use of TMSOTf was found to be advantageous for the silylation of nitro-
nates, which do not contain alkoxy substituent (R3 or R4), see Supplementary
data for details.
8. For example, species 5 with X¼Br (n¼0) cannot be identified, whereas if X¼F
(n¼0) the transformation of 5 to 6 takes place only after heating in acetonitrile,
see. Ref. 5.
10
CO2CH3
1
8
9
N
O
O
4.8.9. Dimethyl 2-(2-oxido-4-phenylisoxazolin-3-ylmethyl)malonate
(15l). Obtained similar to 15g according to the procedure iv from
204 mg, 0.77 mmol of 6h-Br. Yield 232 mg (95%), colorless oil,
Rf¼0.40 (EtOAc/hexane, 1/1). 1H NMR (300.13 MHz, 300 K, CDCl3):
9. Tabolin, A. A.; Lesiv, A. V.; Khomutova, Y. A.; Nelyubina, Y. V.; Ioffe, S. L. Tetra-
hedron 2009, 65, 4578e4592.
10. (a) For ring-chain tautomerism of cations 40, see Ref. 2g. (b) For the halogenation
of N,N-bis(silyloxy)enamines affording nitroalkenes, see: Kunetsky, R. A.; Dil-
man, A. D.; Struchkova, M. I.; Tartakovsky, V. A.; Ioffe, S. L. Tetrahedron Lett. 2005,
46, 5203e5205.
d
¼2.62 [dd, 3J¼9.6, 2J¼15.1, 1H, CH2(4)], 2.84 [ddd, J¼1.3, 3J¼5.5,
2J¼15.1, 1H, CH2(4)], 3.69 and 3.74 [both s, 6H, CH3(7 and 9)], 3.96
[dd, 3J¼5.5, 9.6,1H, CH(5)], 4.33 [dd, 3J¼6.4, 2J¼7.3,1H, CH2(1)], 4.55
[t, 3Jz2J¼6.4, 1H, CH(2)], 4.76 [dd, 2J¼7.3, 3J¼9.6, 1H, CH2(1)],
7.23e7.30 [m, 2H, CH(11)], 7.35e7.43 [m, 3H, CH(12) and CH(13)];
11. Similar stereochemistry was observed for the addition of C-nucleophiles to
analogous iminium cations derived from five-membered nitronates, see:

4594
A.A. Mikhaylov et al. / Tetrahedron 67 (2011) 4584e4594
Smirnov, V. O.; Sidorenkov, A. S.; Khomutova, Y. A.; Ioffe, S. L.; Tartakovsky, V. A.
Eur. J. Org. Chem. 2009, 3066e3074.
14. For studies of stereodynamic processes of six-membered N-(silyloxy)enamines,
see Khomutova, Y. A.; Smirnov, V. O.; Mayr, H.; Ioffe, S. L. J. Org. Chem. 2007, 72,
9134e9140.
15. Concerning the reaction of five-membered enamines with NBS, the in-
termediate generation of the bromonium ion can be proposed. In this case, the
exclusive formation of products 10 with cis-arrangement of succinimido and
silyloxy groups may be explained by generation of the bromonium ion on the
face anti to the pseudoaxial silyloxy substituent followed by SN2 ring-opening
with succinimide.
16. The lithiumeiodine exchange with lithium acetylenides was described, see
Blackmore, I. J.; Boa, A. N.; Murray, E. J.; Dennis, M.; Woodward, S. Tetrahedron
Lett. 1999, 40, 6671e6672.
17. The rearrangement of anion 18 to 19 upon treatment of N-(silyloxy)enamines 3
with fluoride anion has been reported, see Ref. 9.
12. Analogous addition of NBS or NIS to C]C bond of enamines has been de-
scribed, see: (a) Coe, J. W. Org. Lett. 2000, 2, 4205e4208; (b) Lavilla, R.; Coll, O.;
Kumar, R.; Bosch, J. J. Org. Chem. 1998, 63, 2728e2730; (c) Cano, M. C.; Con-
treras, F. G.; Sanz, A. M. J. Heterocycl. Chem. 1980, 17, 1265e1271.
13. The addition of NBS to enamines 3 can give products 10 with NeC(imide)e
CH2eBr fragment or alternative regioisomers with NeC(Br)eCH2-imide frag-
ment. The assignment for structure 10 follows from: (a) The alternative
regioisomer would contain R3SieOeNeCeBr fragment which could readily
eliminate R3SiBr to give five-membered nitronates, see Ref. 5a; (b) The
observed 13C chemical shifts of exocyclic CH2-group correspond to CH2Br (ca.
36 ppm), rather than to CH2-imido (ca. 55 ppm, based on ACD/Labs
prediction).