General method for the synthesis of isoxazoline N-oxides from aliphatic nitro compounds

Article abstract of DOI:10.1055/s-2006-942428

A method for the synthesis of isoxazolines N-oxides from primary aliphatic nitro compounds and olefins based on the 1,3-dipolar cycloaddition of intermediate 1-halo-substituted silyl nitronates, followed by halosilane elimination has been described. The n

Full text of DOI:10.1055/s-2006-942428

PAPER
2265
General Method for the Synthesis of Isoxazoline N-Oxides from Aliphatic
Nitro Compounds
S
ynthesis of Isox
o
azoline
N
-O
x
m
ides an A. Kunetsky, Alexander D. Dilman,* Marina I. Struchkova, Pavel A. Belyakov, Vladimir A. Tartakovsky,
Sema L. Ioffe
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
Fax +7(495)1355328; E-mail: adil25@mail.ru
Received 26 April 2006
the approach shown on Scheme 1. First of all we decided
to improve previously reported procedure3 by using
cheaper silylating reagent Me3SiCl at step 2 and perform-
ing the process at higher concentration (1 M) of the nitro
Abstract: A method for the synthesis of isoxazolines N-oxides
from primary aliphatic nitro compounds and olefins based on the
1,3-dipolar cycloaddition of intermediate 1-halo-substituted silyl
nitronates, followed by halosilane elimination has been described.
The nature of the halogen atom plays a key role in determining the substrate. Under these conditions the reaction can be car-
stability and reactivity of all intermediates of this process. Bromoni-
ried out with only 1.5 equivalents of the alkene (Table 1).
tro compounds can be conveniently used in reactions with terminal
Importantly, these modifications allow increasing the re-
alkenes, while fluorinated derivatives must be employed for internal
action scale up to 50 mmol of a-bromonitro compounds
olefins.
and facilitating isolation of target products 2. However,
the refined protocol does not solve the major problem of
extending the scope of the method and offers little con-
Key words: aliphatic nitro compounds, silyl nitronates, 1-halo-
substituted nitro compounds, 1,3-dipolar cycloaddition
cerning sluggish rate limiting step.
To address the latter issue we first analyzed the influence
In contrast to the six-membered nitronates, which proved
of the halogen atom on the energy surface of [3+2] cy-
to be valuable intermediates in organic synthesis,1 their
cloaddition event. For this purpose we calculated the free
lower homologs, five-membered nitronates 2 (isoxazoline
N-oxides), have much narrower synthetic applications.
This is primarily associated with the lack of convenient
energy of activation for the cycloaddition of ethylene to
model silyl nitronates in the gas phase (Table 2).4
It can be concluded from these data that the rate of cy-
cloaddition increases in the order I < Cl ~ Br << F. Ac-
cordingly, to accelerate the step 3 (see Scheme 1) it is
necessary to employ poorly studied and difficult-to-pre-
pare a-fluoronitro compounds.5 For their synthesis we
used the fluorination of nitro compounds with Select-
fluor.6 1-Nitroheptane (1a, R = n-C6H13) and phenylnitro-
methods for their synthesis. Indeed, there has been only
one well known strategy towards isoxazoline N-oxides
based on the cyclization of g-functionalized nitro com-
pounds,2 while the latter require tedious preparation them-
selves.
Recently we reported completely different approach to
isoxazoline N-oxides starting from simple primary ali-
phatic nitro compounds and terminal olefins (Scheme 1).3
The method includes bromination of nitro compounds 1
Table 1 Synthesis of Isoxazoline N-Oxides from Bromonitro Com-
(step 1), silylation of a-bromo derivatives (step 2), cy- poundsa
cloaddition of bromosilyl nitronates with alkenes (step 3),
and elimination of bromosilane from N-silyloxyisoxazoli-
dine (step 4). Steps 2–4 proceed within one synthetic op-
eration.
Nitro
Compound
Alkene
Product
2
Yield of 2
(%)b
O
O
NO2
Br
NO2
Br
NO2
Br
NO2
Br
2a 62
2b 65
MeO2C
O
N
The major disadvantage of this procedure is very slow cy-
cloaddition (step 3) requiring up to one month at room
temperature, which precludes employment of less reactive
internal olefins, thereby rendering 4-substituted isoxazo-
line N-oxides inaccessible by this method. There are also
additional shortcomings such as the need for large excess
of alkene (up to five equiv) and utilization of expensive si-
lylating reagent t-BuMe2SiCl.
OMe
Ph
O
Ph
Ph
Ph
O
N
2c
60
O
O
O
O
Ph
Ph
N
N
The major focus of the present work is to reduce the reac-
tion time of cycloaddition in order to broaden the scope of
2d 50
Ph
Ph
a Reactions performed in CH2Cl2 for 3–7 days at r.t.
b Isolated yield.
SYNTHESIS 2006, No. 13, pp 2265–2270
Advanced online publication: 23.06.2006
DOI: 10.1055/s-2006-942428; Art ID: C01806SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

2266
R. A. Kunetsky et al.
PAPER
NO2
O
OSit-BuMe2
Br
NO2
Br
Br2/KOH
step 1
R2
step 3
t-BuMe2SiCl, Et3N
N
R1
R1
– Et3N·HCl
step 2
R1
1
R2
R2
O
O
OSit-BuMe2
O
For R1, R2 see Table 1.
N
N
– t-BuMe2SiBr
step 4
Br
R1
R1
2
Scheme 1
analogous bromosilyl nitronate,3 thereby corroborating
computational results. Thus, the employment of a-fluo-
ronitro compounds dramatically reduces the time of cy-
cloaddition step. However, two other problems emerge.
First is the instability of fluorosilyl nitronates mentioned
above, while the second problem is the enhanced stability
of 3-fluoro-N-silyloxyisoxazolidines. The latter fact was
somewhat surprising, given that analogous 3-bromo-N-si-
lyloxyisoxazolidines cannot even be observed by NMR
spectroscopy owing to rapid elimination of bromosilane.3
In other words; the elimination of fluorosilane (step 4) be-
comes the rate limiting step.7
Table 2 Calculated Activation Energies (in kcal/mol, at 298.15 K)
and Relative Rate Constantsa
H2C CH2
O
O
N
+
N
O
OSiMe3
X
N
OSiMe3
X
X
OSiMe3
≠
X
H
F
DH≠
15.5
11.1
14.0
13.4
15.2
DG≠
DGX≠–DGH
0.0
k(X)/k(H)
27.5
23.0
26.0
25.1
27.1
1
2051
14
–4.5
To cope with the instability of fluorosilyl nitronates 4a,b
we used the procedure allowing to maintain their station-
ary concentration at low level during the cycloaddition
process. This can be achieved by performing the silylation
in a solvent of low polarity. In particular, silylation of ni-
tro compound 3a in pentane in the presence of excess ole-
fin (10 equiv) during seven days furnished cycloadduct 5a
in 75% yield determined by NMR spectroscopy of reac-
tion mixture (Equation 2). It should be pointed out that in
dichloromethane under otherwise identical conditions no
product 5a could be isolated.
Cl
Br
Ib
–1.6
–2.4
57
–0.4
2
a Calculated at the level B3LYP/6-31G(d) unless otherwise men-
tioned.
b Combined basis set was used: LanL2DZ for iodine, 6-31G(d) for all
other atoms.
ethane (1b) were selected as model substrates, which were
fluorinated to afford a-fluoronitro alkanes 3a,b.
NO2
O
OSiMe3
Me3SiCl, Et3N
N
Initial experiments on silylation of 3a,b provided unex-
pected results. Thus, in contrast to stable and distillable
1-bromosilyl nitronates, fluorosilyl nitronates 4a,b were
found to be very unstable. Even in dilute solutions they
can be stored for only few hours at room temperature,
whereas upon concentration the rate of decomposition
significantly increases, and the process becomes autocat-
alytic leading to intractable mixtures. Nevertheless, silyl
nitronates 4a,b were characterized by NMR spectroscopy
(Equation 1).
+
C6H13
F
Pentane, r.t., 7 d
F
3a
n-C6H13
5a
Equation 2
The elimination of fluorosilane from 3-fluoro-N-silyloxy-
isoxazolidines 5 proved to be more challenging. Com-
pounds 5b and 5b¢ were produced from 3b and styrene as
diastereomeric mixtures (ca. 1:1) and were characterized
by NMR analysis. Attempted chromatographic purifica-
tion was thwarted because of their noticeable
decomposition8 (Equation 3).
Rewardingly, the cyloaddition of silyl nitronates 4a,b to
styrene proceeded within 2 hours at ambient temperature,
which is about two orders of magnitude faster than for
O
NO2
Ph
OSiR3
O
OSiMe3
NO2
Ph
N
R3SiCl, Et3N
CH2Cl2, 1 d, r.t.
DBU, Me3SiCl
–20 °C, CCl4
N
Ph
F
R
F
F
R
F
3b
Ph
3a R = n-C6H13
3b R = Bn
4a 90%, 1H, 13C, 19F NMR
4b 77%, 1H NMR
5b SiR3 = SiMe3, 79%
5b' SiR3 = Sit-BuMe2, 70%
Equation 1
Equation 3
Synthesis 2006, No. 13, 2265–2270 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoxazoline N-Oxides
2267
Screening of conditions for the elimination of fluorosilane lation in non-polar solvent in the presence of alkene, and
was carried out with compound 5b. No elimination could 2) elimination of fluorosilane in refluxing acetonitrile.
be effected by means of Lewis acids [10 mol% BF3·OEt2,
Taking into account high reactivity of 1-fluorosilyl ni-
LiClO4, Zn(OTf)2] nor in the presence of silicon-specific
tronates in cycloaddition, we studied their reactions with
Lewis bases (10 mol% KF/18-crown-6 or Bu4NOAc).
internal olefins, which were inert with 1-bromosilyl
However, heating solutions of 5b to 80 °C effected the de-
nitronates3 (Table 3). The desired products 2d–i were ob-
sired transformation with the rate increasing in the order
tained in acceptable yields using cyclopentene, nor-
of solvents benzene < dichloroethane < acetonitrile. In
bornene, indene, and methyl crotonate as alkenes. At the
more polar media (DMF, DMSO) the decomposition of
same time, less reactive dipolarophiles, such as
5b was observed. The optimal conditions involved reflux-
ing of 3-fluoro-N-silyloxyisoxazolidines in acetonitrile
for one hour (Equation 4).
cyclohexene9 could not be involved in this process.
Despite efficiency of utilization a-fluoronitro compounds,
these derivatives appear to be quite expensive substances
and use of a-bromonitro compounds is recommended for
the preparation of isoxazoline N-oxides from terminal ole-
fins.
In summary, in this work and in previous report3 we stud-
ied in detail and optimized a method for the synthesis of
five-membered cyclic nitronates from aliphatic nitro com-
pounds and olefins. The presented approach renders these
derivatives readily available, thereby paving the way for
development of their chemistry.
O
Ph
O
Ph
OSiMe3
MeCN, ∆, 1 h
O
N
N
– Me3SiF
F
90%
2d
Ph
5b
Ph
Equation 4
As follows from the data discussed above, the proposed
scheme for the synthesis of five-membered nitronates 2
from a-fluoronitro compounds includes two steps: 1) sily-
Table 3 Synthesis of Isoxazoline N-Oxides from Fluoronitro Compounds
NO2
R2
O
R2
O
OSiMe3
O
Me3SiCl, Et3N
MeCN, ∆, 1 h
N
N
+
R2
R1
F
pentane, r.t., 7 d
1
F
R1
5
R1
2
Entry
1
Nitro Compound
Alkene
Product
2
Yield of 2 (%)a
NO2
O
2d
82
Ph
O
Ph
N
N
Ph
F
Ph
2
2e
2f
65
66
83
82
51c
NO2
H
H
O
O
n-C6H13
F
n-C6H13
H
3b
NO2
O
O
N
Ph
F
Ph
O
H
4
2g
2h
2i
NO2
H
O
N
n-C6H13
n-C6H13
n-C6H13
F
n-C6H13
O
H
5
H
NO2
O
N
F
n-C6H13
O
H
6
CO2Me
NO2
O
MeO2C
N
F
n-C6H13
a Isolated yield.
b Cyclopentene was used as solvent, reaction time 2 d.
c The diminished yield is due to partial decomposition at the step of fluorosilane elimination.
Synthesis 2006, No. 13, 2265–2270 © Thieme Stuttgart · New York

2268
R. A. Kunetsky et al.
PAPER
All reactions were performed under argon. CH2Cl2, MeCN, and
pentane were distilled from CaH2. Petroleum ether used had a bp of
60–70 °C. Column chromatography was carried out employing
Merck silica gel (Kieselgel 60, 230–400 mesh). Precoated silica gel
plates F 254 were used for TLC visualizing with UV and methanolic
anisaldehyde/H2SO4 solution.
1H NMR (200 MHz, CDCl3): d = 0.90 (t, 3J = 6.6, 3 H, CH3), 1.19–
1.62 (m, 8 H, 4 CH2), 1.94–2.33 (m, 2 H, CH2CF), 5.80 (ddd,
2JH,F = 50.8 Hz, 3J = 5.4, 5.4 Hz, 1 H, CHF).
13C NMR (50 MHz, CDCl3): d = 14.0 (CH3), 22.4 (CH2), 22.8
(4JH,F = 2.7 Hz, 3-CH2), 28.4 (CH2), 31.4 (CH2), 33.3 (3JH,F = 19.8
Hz, 2-CH2), 111.3 (1JH,F = 238.9 Hz, 1-CH2).
Isoxazoline N-Oxides 2a–d from a-Bromonitro Compounds;
General Procedure (Table 1)
1-Fluoro-2-phenylnitroethane (3b)11
Yield: 83%; bp 53–56 °C/0.3 Torr.
Et3N (2.09 mL, 15 mmol) was added to a solution of a-bromonitro
compound (10 mmol) and Me3SiCl (1.52 mL, 12 mmol) in CH2Cl2
(20 mL) at 0 °C, and the mixture was stirred for 1 h. Alkene (15
mmol) was added, the mixture was kept for a certain time (3 d for
2a, 7 d for 2b–d), and Et3N (2.80 mL, 20 mmol) and H2O (50 mL)
were added at 0 °C. After stirring for additional 15 min, the organic
phase was separated, the aqueous phase was washed with CH2Cl2
(2 × 10 mL). Combined organic phases were dried (Na2SO4), con-
centrated, and purified either by recrystallization or chromatogra-
phy on silica gel (Table 1).
1H NMR (200 MHz, CDCl3): d = 3.27–3.64 (m, 2 H, CH2), 5.96
(ddd, 2JH,F = 50.8 Hz, 3J = 6.4, 3.9 Hz, 1 H, CHF), 7.16–7.52 (m, 5
H, C6H5).
2
13C NMR (50 MHz, CDCl3): d = 39.6 (d, JC,F = 19.8 Hz, CH2),
2
110.8 (d, JC,F = 241.1 Hz, CHF), 128.3 (CHarom), 129.1 (CHarom),
129.6 (CHarom).
Silyl Nitronates 4a,b
A solution of a-fluoronitro compound 4a or 4b (113 mg, 0.69
mmol) was slowly added to a solution of DBU (120 mL, 0.80 mmol)
and Me3SiCl (for 4a) or t-BuMe2SiCl (for 4b) (0.76 mmol) in CCl4
(2 mL) at –20 °C. After stirring at –20 °C for 10 min, the cooling
bath was removed, and the mixture was allowed to warm to r.t. The
precipitate of DBU·HCl was removed by filtration under argon and
the filtrate was charged directly into NMR tube. The yield was de-
termined relative to internal standard (methyl benzoate).
5-Methoxycarbonyl-3-methylisoxazoline N-Oxide (2a)3
Chromatography on silica gel, eluting from hexane–EtOAc (1:1) to
EtOAc; yield: 62%.
3-Methyl-5-phenylisoxazoline N-Oxide (2b)3
Recrystallization from Et2O; mp 77–78 °C; yield: 65%.
3-Ethyl-5-phenylisoxazoline N-Oxide (2c)3
Recrystallization from Et2O; mp 52–55 °C; yield: 60%.
Trimethylsilyl 1-Fluoroheptanenitronate (4a)
1H NMR (200 MHz, CDCl3): d = 0.41 [s, 9 H, Si(CH3)3], 1.01 (t,
3J = 6.8 Hz, 3 H, CH3), 1.28–1.61 (m, 6 H, 3 CH2), 1.64–1.88 (m, 2
3
H, CH2CH2CF), 2.73 (td, JH,F = 15.1 Hz, 3J = 7.3 Hz, 2 H,
3-Benzyl-5-phenylisoxazoline N-Oxide (2d)
Product 2d can be isolated by chromatography eluting with hexanes
to hexanes–EtOAc (10:1 to 1:1); Rf 0.44 (hexanes–EtOAc, 1:1). Re-
crystallization from Et2O; mp 51–53 °C; yield: 50%.
CH2CH2CF).
13C NMR (50 MHz, CDCl3): d = 0.1 [Si(CH3)3], 13.9 (CH3), 22.3
(CH2), 24.4 (4JH,F = 2.3 Hz, 4-CH2), 26.7 (3JH,F = 19.9 Hz, 3-CH2),
29.7 (2JH,F = 139.3 Hz, 2-CH2).
19F NMR (188 MHz, CDCl3): d = –108.81.
1H NMR (300 MHz, CDCl3): d = 2.97 (ddt, J = 16.9, J = 8.1,
2
3
2
3
4J = 1.5 Hz, 1 H, CHAHB), 3.36 (dd, J = 16.9, J = 9.6 Hz, 1 H,
CHAHB), 3.72 (d, 2J = 15.4 Hz, 1 H, CHAHBPh), 3.80 (d, 2J = 15.4
Hz, 1 H, CHAHBPh), 5.57 (dd, 3J = 8.1, 9.6 Hz, 1 H, CHO), 7.14–
7.50 (m, 10 H, 2 C6H5).
Trimethylsilyl 1-Fluoro-2-phenylethanenitronate (4b)
1H NMR (200 MHz, CDCl3): d = 0.26 [s, 9 H, Si(CH3)3], 3.82 (d, 2
H, 3JH,F = 16.2 Hz, CH2), 6.96–7.32 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 32.5, 40.5 (2 CH2), 75.8 (CHO),
114.8 (CN), 125.6, 127.4, 128.7, 128.9, 129.0 (CHarom), 134.9 and
138.7 (Carom).
Isoxazoline N-Oxides 2d–i and 3-Fluoro-N-silyloxyisoxazo-
lidines 5b,b¢ from a-Fluoronitro Compounds; General Proce-
dure (Equation 3 and Table 3)
Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C,
75.55; H, 6.17; N, 5.41.
Me3SiCl (165 mL, 1.3 mmol) and Et3N (210 mL, 1.5 mmol) were
added to a mixture of fluoronitro compound 3 (1 mmol), appropriate
alkene (1.5 mmol) and pentane (0.25 mL) at 0 °C, and the mixture
was kept with occasional stirring for 7 d [reaction conditions for
5b,b¢: CH2Cl2 (2 mL), 1 d, r.t.]. The solvent was removed in vacu-
um. To remove traces of Me3SiCl and Et3N, benzene (3 mL) was
added and then evaporated in vacuum. The residue was again dilut-
ed with benzene (10 mL), filtered through Celite, and concentrated
to afford a viscous oil, which consists of 3-fluoro-N-silyloxyisox-
azolidine 5 along with traces of isoxazoline N-oxide. The crude 5
(see Table 3) was refluxed in a solution of MeCN (7 mL) for 1 h (the
progress of the reaction can be monitored by TLC), concentrated,
and the residue purified by flash chromatography on silica gel elut-
ing with hexanes–EtOAc.
a-Fluoronitro Compounds 3a,b
Solid KOH (85%, 2.30 g, 34.5 mmol) was added to a mixture of the
respective nitro compound 1a (R = n-C6H13)/1b (R = Bn) (30
mmol), MeCN (15 mL) and H2O (30 mL) at 0 °C. The mixture was
vigorously stirred until complete dissolution of starting nitro com-
pound (ca. 30 min), and then cooled to such a temperature to pro-
vide partial precipitation of the nitronate (ca. –5 °C to –15 °C).
CH2Cl2 (60 mL, pre-cooled to –78 °C) and Selectfluor (12.30 g,
34.5 mmol) were successively added (since commercial Selectfluor
sticks to the glass, it can be conveniently weighed on a filter paper
and added into the reaction flask rapidly in one portion). The cool-
ing bath was removed, and the mixture was vigorously stirred al-
lowing the temperature to rise to 10 °C, at which point petroleum
ether (60 mL) was added. The mixture was filtered through Celite,
the phases were separated, and the aqueous phase was extracted
with CH2Cl2–hexanes (1:1, 60 mL). The combined organic phases
were dried (Na2SO4), concentrated, and the residue was distilled in
vacuum.
3-Benzyl-3-fluoro-5-phenyl-2-trimethylsilyloxyisoxazolidine
(5b) (Two Isomers 1:1)
1H NMR (300 MHz, CDCl3): d = 0.31 [s, 9 H, Si(CH3)3 of both iso-
mers], 2.06 (ddd, 1 H, J = 5.2, 14.0, 20.6 Hz, CH of isomer A),
2.43–2.72 (m, 2 H, CH2 of isomer B), 2.96 (ddd, 1 H,
J = 9.6, 14.0, 37.5 Hz, CH of isomer A), 3.22–3.42 (m, 2 H, CH2Ph
of both isomers), 5.34 (dd, J = 7.4, 9.6 Hz, CHO of isomer B), 5.53
1-Fluoro-1-nitroheptane (3a)10
Yield: 84%; bp 95–100 °C/25–30 Torr.
Synthesis 2006, No. 13, 2265–2270 © Thieme Stuttgart · New York

PAPER
Synthesis of Isoxazoline N-Oxides
2269
(dd, J = 5.2, 9.6 Hz, CHO of isomer A), 7.18–7.52 (m, 10 H, C6H5
of both isomers).
13C NMR (50 MHz, CDCl3): d = 14. 1 (CH3), 22.5, 22.9, 25.2, 25.7,
27.4, 29.2, 31.5, 32.5, 39.4, 42.0, 55.0 (CH2, CH and 2 CCN), 79.9
(CHO), 117.0 (C=N).
3-Benzyl-2-tert-butyldimethyl-3-fluoro-5-phenylsilyloxyisox-
azolidine (5b¢) (Two Isomers 1:1)
Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found: C,
70.57; H, 9.68; N, 6.03.
1H NMR (300 MHz, CDCl3): d = 0.28 (s, 3 H, SiCH3), 0.30 (s, 3 H,
SiCH3), 0.33 (s, 6 H, 2 SiCH3), 1.01 (s, 9 H, t-C4H9), 1.04 (s, 9 H, t-
C4H9), 2.05 (ddd, 1 H, J = 5.1, 13.8, 20.6 Hz, CH of isomer A),
2.36–2.75 (m, 2 H, CH2 of isomer B), 2.97 (ddd, 1 H, J = 9.6, 13.8,
37.1 Hz, CH of isomer A), 3.24–3.40 (m, 2 H, CH2Ph of both iso-
mers), 5.34 (dd, J = 7.4, 9.6 Hz, CHO of isomer B), 5.52 (dd,
J = 5.2, 9.6 Hz, CHO of isomer A), 7.16–7.55 (m, 10 H, C6H5 of
both isomers).
3-Hexyl-6,7-benzo-1-oxa-2-azabicyclo[3.3.04,8]oct-2,3-ene
N-Oxide (2h)
Chromatography: hexanes–EtOAc (10:1 to 1:1); Rf 0.56 (hexanes–
EtOAc, 1:1).
3
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H, CH3),
1.18–1.43 (m, 8 H, 4 CH2), 1.45–1.70 (m, 2 H, CH2CH2CN), 2.12–
2.31 (m, 1 H, CHAHBCN), 2.38–2.58 (m, 1 H, CHAHBCN), 3.10 (dd,
Chromatography in toluene–hexanes (from 1:5 to 1:1) [Rf 0.44 (tol-
uene–hexanes 1: 3)] afforded the isomer A.
3
2J = 17.5 Hz, J = 2.2 Hz, 1 H, CHAHBPh), 3.26 (dd, 2J = 17.5 Hz,
3J = 8.1 Hz, 1 H, CHAHBPh), 4.15 (br t, 3J = 8.8 Hz, 1 H, CHCN),
5.90 (d, 3J = 8.8 Hz, 1 H, CHO), 7.19–7.38 (m, 3 H, CHarom), 7.46
(d, 3J = 7.4 Hz, 1 H, CHarom).
Isomer A of 5b¢
1H NMR (200 MHz, CDCl3): d = 0.30 (s, 3 H, SiCH3), 0.35 (s, 3 H,
SiCH3), 1.06 (s, 9 H, t-C4H9), 2.07 (ddd, 1 H, J = 5.1, 13.8, 20.6 Hz,
CH), 2.99 (ddd, 1 H, J = 9.6, 13.8, 37.1 Hz, CH), 3.35–3.46 (m, 2
H, CH2Ph), 5.54 (dd, J = 5.2, 9.6 Hz, CHO), 7.16–7.59 (m, 10 H,
C6H5).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.5, 24.9, 25.5, 29.1,
31.4, 35.1 (all CH2), 48.2 (CHCN), 81.5 (CHO), 118.2 (C=N),
125.0, 126.2, 127.7, 129.9 (CHarom), 139.1, 140.7 (Carom).
Anal. Calcd for C16H21NO2: C, 74.10; H, 8.16; N, 5.40. Found: C,
74.20; H, 8.38; N, 5.42.
13C NMR (50 MHz, CDCl3): d = –4.8 (SiCH3), –4.7 (SiCH3), 18.0
(CMe3), 26.0 [C(CH3)3], 40.0 (d, JC,F = 21.0 Hz, CH2) 42.5 (d,
JC,F = 24.3 Hz, CH2), 81.5 (CHO), 118.8 (d, JC,F = 198.6 Hz, CF),
126.9, 127.18, 127.22, 128.0, 128.2, 128.3, 130.0 (d, JC,F = 1.4 Hz)
(all CHarom), 135.3 (Carom), 139.3 (Carom).
3-Hexyl-5-methoxycarbonyl-4-methylisoxazoline N-Oxide (2i)
Chromatography: hexanes to hexanes–EtOAc (1:1); Rf 0.70 (hex-
anes–EtOAc, 1:1).
3
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H, CH3),
3-Hexyl-1-oxa-2-azabicyclo[3.3.04,8]oct-2,3-ene N-Oxide (2e)
Chromatography: hexanes to hexanes–EtOAc (1:1); Rf 0.40 (hex-
anes–EtOAc, 1:1).
1.15–1.70 (m, 8 H, 4 CH2), 1.36 (d, 3J = 6.8 Hz, 3 H, CH3), 2.11–
2.54 (m, 2 H, CH2CN), 3.37–3.54 (m, 1 H, CHCN), 3.80 (s, 3 H,
CH3O), 4.53 (d, 3J = 4.9 Hz, 1 H, CHO).
3
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H, CH3),
13C NMR (50 MHz, CDCl3): d = 14.0, 17.1 (2 CH3), 22.4, 24.7,
25.1, 28.9, 31.3 (all CH2), 44.3, 52.9, 77.6 (CHO, CH3O and
CHCN), 117.7 (C=N), 169.6 (C=O).
1.19–1.95 (m, 13 H, CH and 6 CH2), 2.00–2.27 (m, 2 H, CHAHBCN
and CH), 2.36–2.54 (m, 1 H, CHAHBCN), 3.56–3.73 (m, 1 H,
CHCN), 4.90–5.08 (m, 1 H, CHO).
Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C,
59.30; H, 8.52; N, 5.73.
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.5, 23.6, 25.2, 25.5,
29.1, 30.6, 31.5 (7 CH2), 34.8 (CH2CN), 50.0 (CHCN), 79.6 (CHO),
118.4 (C=N).
Acknowledgment
Anal. Calcd for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.26; H, 10.13; N, 6.74.
This work was supported by the Russian Foundation for Basic Re-
search (project 05-03-32733).
3-Benzyl-1-oxa-2-azabicyclo[3.3.04,8]oct-2,3-ene N-Oxide (2f)
Chromatography: hexanes–EtOAc (5:1 to 1:1); Rf 0.38 (hexanes–
EtOAc, 1:1).
References
1H NMR (300 MHz, CDCl3): d = 1.30–1.73 (m, 5 H) and 1.80–2.01
(m, 1 H) (CH2CH2CH2), 3.33–3.51 (m, 2 H, CHCN and CHAHBPh),
3.65 (d, 2J = 15.4 Hz, 1 H, CHAHBPh), 4.74–4.85 (m, 1 H, CHO),
7.05–7.25 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 23.0, 29.8, 31.3, 34.2 (3 CH2 and
CHCN), 49.1 (CH2Ph) 79.4 (CHO), 116.8 (C=N), 126.6 (CHarom),
128.2, (CHarom), 128.3 (CHarom), 134.9 (Carom).
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EtOAc, 1:1).
3
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H, CH3),
1.03–1.81 (m, 14 H, 7 CH2), 2.11–2.29 (m, 1 H, CHAHBCN), 2.33–
2.47 (m, 2 H) and 2.48–2.60 (m, 1 H, CHAHBCN and 2 CH), 3.10
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Synthesis 2006, No. 13, 2265–2270 © Thieme Stuttgart · New York

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R. A. Kunetsky et al.
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Synthesis 2006, No. 13, 2265–2270 © Thieme Stuttgart · New York