Stereoselective electrophilic cyclisation of O-homoallyl hydroxylamine derivatives

Article abstract of DOI:10.1055/s-2002-34385

Electrophilic cyclisations of various O-homoallyl hydroxylamine derivatives are discussed. Non-protected O-homoallyl hydroxylamines undergo oxidative cyclisations to isoxazolines. The new isoxazoline synthesis comprises an initial electrophilic cyclisatio

Full text of DOI:10.1055/s-2002-34385

PAPER
2117
Stereoselective Electrophilic Cyclisation of O-Homoallyl Hydroxylamine
Derivatives
C
B
yclizationof
H
o
i
moally
r
l
H
ydr
o
g
xylamine
D
e
i
rivative
t
s
Janza, Armido Studer*
Fachbereich Chemie , Universität Marburg, Hans-Meerwein-Straße, 35032 Marburg, Germany
Fax +49(6421)2825629; E-mail: studer@mailer.uni-marburg.de
Received 18 June 2002
Dedicated to Prof. Dr. Dieter Seebach on the occasion of his 65th birthday.
alkoxyamines described herein were prepared in an anal-
ogous manner. We first studied the electrophilic cyclisa-
Abstract: Electrophilic cyclisations of various O-homoallyl hy-
droxylamine derivatives are discussed. Non-protected O-homoallyl
hydroxylamines undergo oxidative cyclisations to isoxazolines.
2
tion of 1 using tert-butyl hypochlorite (1 equiv) in CH Cl2
The new isoxazoline synthesis comprises an initial electrophilic cy- at room temperature (Scheme 1). Isoxazoline 2 was ob-
clisation to form intermediate isoxazolidines, which are subse- tained in 24% yield along with unreacted starting materi-
quently oxidized to isoxazolines. Cyclisations can be conducted
al. The desired isoxazolidine 3 was not identified. Thus,
with various electrophiles (t-BuOCl, PhSeBr, NBS and NIS). Oxi-
oxidation of isoxazolidine 3 with t-BuOCl is faster than
dation can be suppressed if the starting O-homoallyl hydroxy-
the electrophilic cyclisation of alkoxyamine 1. Isoxazoli-
lamines are N-sulfonylated. The electrophilic cyclisation then
dine 3 is obviously readily chlorinated to provide N-chlor-
provides N-sulfonylated isoxazolidines with moderate cis-selectiv-
ity (up to 7:1). Electrophilic cyclisation of N-acylated O-homoallyl
oalkoxyamine 4, which upon HCl-elimination eventually
12
hydroxylamines provides isoxazolines or isoxazolidines depending leads to the isolated isoxazoline 2. With 3 equivalents of
on the reaction conditions (reagents). The t-BuOCl-mediated cycli- t-BuOCl the highest yield of the electrophilic 5-exo-cycli-
sation affords isoxazolines via an oxidative cyclisation, whereas the
sation/oxidation product was obtained (69%).
NIS-induced reaction provides the 5-exo-cyclisation product with
We further tested, whether the electrophilic cyclisation/
oxidation can also be performed with other electrophiles.
We found that the reaction of alkoxyamine 1 with phe-
high stereoselectivity (cis:trans = 13:1).
Key words: stereoselective synthesis, electrophilic additions, isox-
azolidines, isoxazolines, oxidative cyclisations
nylselenyl bromide (3 equiv) in acetonitrile in the pres-
13
ence of Na CO3
at room temperature provides
2
isoxazoline 5 in 59% yield. A slightly better yield was ob-
tained for the oxidative cyclisation of 1 using N-bromo-
succinimide (NBS, CH Cl , r.t. 6, 61%). The analogous
Electrophilic cyclisations of alkenes containing internal
nucleophiles are well established for the preparation of
heterocycles in synthetic organic chemistry. Various
1
2
2
reaction with N-iodosuccinimide (NIS) provided iodide 7
45%). However, the reaction was not clean anymore,
electrophiles have been successfully used to induce these
cyclisations and the nucleophilic moiety can also be readi-
ly varied. Thus, a large number of different heterocycles
can be prepared using this approach. N-Heterocycles,
which occur in numerous natural products, have been syn-
thesized via electrophilic cyclisations using N-centered
(
and iodide 7 could not be isolated in analytically pure
form.
Thus, the oxidative cylisation can be readily performed
with different electrophilic reagents providing isoxazo-
lines bearing interesting functional groups. Phenylse-
lenides and alkyl halides are useful compounds for further
synthetic manipulations. Isoxazolines are interesting
compounds in organic synthesis, which are generally pre-
pared by nitrile oxide cycloaddition reactions.14 Our
method provides a new approach to this important class of
compounds.15
2
3
4
5
nucleophiles. Carbamates, ureas, hydrazines, amines,
6
7
amides and oximes were used as N-nucleophiles in these
studies. There are also some reports on the cyclisation of
8
O-allyl hydroxylamines.
Recently, we initiated a program towards the study of
stereoselective 5-exo-cyclisation reactions using
9
alkoxyaminyl radicals. During these studies we observed
In order to suppress the oxidation, we decided to decrease
the basicity of the nitrogen atom of the initially formed
isoxazolidine. To this end, the alkoxyamine 1 was sulfo-
that O-homoallyl hydroxylamine derivatives undergo
electrophilic cyclisations with good to excellent selectivi-
1
0
ties. Herein, we disclose our first results on this subject.
nylated using benzenesulfonyl chloride and Et N in THF
3
Alkoxyamine 1 was readily prepared from the corre-
sponding alcohol using the Mitsunobu reaction with N-
to give N-alkoxysulfonamide 8 (84%). We first tested its
electrophilic cyclisation using t-BuOCl. However, the re-
action appeared to be very slow. We therefore studied oth-
er electrophilic chlorine sources and were pleased to find
hydroxyphthalimide/diisopropyl azodicarboxylate/Ph P
3
1
1
and subsequent hydrazinolysis (85%). All the other
that upon using NaOCl in CHCl in the presence of acetic
3
1
6
acid smooth cyclisation occurred (r.t., 24 h). As expect-
ed, oxidation was completely suppressed, and the cyclisa-
tion product 9 was formed in 61% yield as a 4.4:1 cis/
Synthesis 2002, No. 14, Print: 07 10 2002.
Art Id.1437-210X,E;2002,0,14,2117,2123,ftx,en;C03202SS.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2
118
B. Janza, A. Studer
PAPER
NH2
O
O
Ph
O
t-BuOCl
CH2Cl2, rt
O
S
O
Ph
O
N
S
Cl
NH
N
X
O
O
see Table
69%
1
2
H
Cl
8
9 (X = Cl)
10 (X = SePh)
N
Cl
N
Cl
O
O
11 (X = Br)
2 (X = I)
1
t-BuOCl
-
t-BuOH
Scheme 2 Stereoselective electrophilic cyclisation of N-alkoxysul-
fonamide 8
3
4
Table 1 Cyclisation of N-Alkoxysulfonamide 8 under Different
Conditions
O
N
5
6
7
(X = SePh, 59%)
(X = Br, 61%)
(X = I, 45%, not pure)
X
Entry
Reagent
NaOCl
PhSeBr
NBS
NIS
Temp.
r.t.
Product
cis:trans
4.4:1
3.8:1
4.8:1
5.0:1
6.3:1
7.0:1
5.0:1
5.1:1
Yield (%)
1
2
3
4
5
9
10
11
12
61
73
79
Scheme 1 Electrophilic cyclisation/oxidation of alkoxyamine 1
r.t.
trans mixture of isomers (Scheme 2, Table 1, entry 1).
The selectivity was determined by H NMR spectroscopy.
The relative configuration of the major isomer was unam-
biguously assigned by NOE experiments. We then tested
the Se-induced electrophilic cyclisation using PhSeBr
r.t.
1
r.t.
70
-a
NIS
–20 °C 12
–68 °C 12
6
NIS
-b
(
1.5 equiv) in acetonitrile in the presence of Na CO at
2 3
room temperature. The cyclisation product 10 was isolat-
ed in 73% yield (cis/trans = 4.4:1, entry 2). The relative
configuration was assigned in analogy to chloride 9. An
even better yield was obtained for the NBS-mediated cy-
clisation. Bromide 11 was isolated in 79% with a 4.8:1 di-
astereoisomer ratio (entry 3). In contrast to the oxidative
cyclisation described above, the NIS-induced reaction
worked well for the sulfonylated alkoxyamine 8. Iodide
7c
I2
r.t.
r.t.
12
12
74
69
8d
I2
a
b
c
d
9
9% conversion after 36 h, product not isolated.
60% conversion after 3 d, product not isolated.
Reaction conducted in CHCl in the presence of aq NaHCO
Reaction conducted in MeCN.
.
3
3
1
2
2 was isolated in 70% yield (dr = 5.0:1, NIS, CH Cl , r.t.,
4 h, entry 4). Reactions performed with elemental iodine
2 2
atom of the acylated isoxazolidine 14 is nucleophilic
enough to be chlorinated with t-BuOCl to form intermedi-
ate 15. HCl-elimination then affords the acyliminium ion
instead of NIS provided similar results (entries 7 and 8).
We also tested whether the selectivity can be further in- 16, which eventually provides isoxazoline 2. We believe
creased upon decreasing the reaction temperature. At that the N-atom of the acylated isoxazolidine 14 is slightly
–
20 °C, the reaction took 36 hours for completion and the pyramidalized and has therefore enhanced nucleophilici-
selectivity could be slightly increased (dr = 6.3:1, entry ty.
1
7
5
). The same cyclisation was also conducted at –68 °C.
After 3 days only 60% conversion was obtained, and io-
dide 12 was formed as a 7.0:1 cis/trans mixture of isomers
O
O
NH
t-BuOCl (3.5 equiv)
O
N
(
entry 6). Since the cyclisation at –68 °C was not efficient
CH2Cl2, rt, 24 h
Cl
anymore, cyclisations at even lower temperatures were
not performed.
55%
We next decided to study the influence of the substituent
at the nitrogen atom on the stereoselectivity of the cycli-
sation. The acylated alkoxyamine 13 was readily prepared
1
3
2
O
O
O
O
from alkoxyamine 1 (AcCl, THF, Et N, 0 °C, 92%). To
3
N
Cl
Cl
Cl
Cl
our surprise, reaction with t-BuOCl in CH Cl at room
N
N
2
2
O
O
temperature for 24 hours afforded the oxidative cyclisa-
tion product 2 (40%) along with unreacted starting ma-
1
terial (60%, as determined by H NMR spectroscopy).
1
4
15
16
None of the desired isoxazolidine 14 was identified. We
repeated the reaction using 3.5 equivalents of the electro-
phile under otherwise identical conditions. Isoxazoline 2
was isolated in 55% yield (Scheme 3). Obviously the N-
Scheme 3 Oxidative cyclisation of acylated alkoxyamine 13 with t-
BuOCl
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclization of Homoallyl Hydroxylamine Derivatives
2119
To suppress the oxidation, we decided to decrease the re- We also studied the influence of the substituent R (see
activity of the electrophile. Indeed, with NIS the oxidative Scheme 5) on the diastereoselectivity of the NIS-mediat-
cyclisation product 7 was not formed anymore, and iodide ed cyclisation (1,3-stereoinduction). As for the phenyl
1
8
1
7 was isolated in 65% yield (Scheme 4). We were very substituted derivative discussed above, the methyl substi-
pleased to observe that the cyclisation occurred with high tuted alkoxyamine 22 and the cyclohexyl substituted con-
selectivity (cis:trans = 12.5:1). The two isomers were gener 23 provided the corresponding cyclisation products
readily separated using flash chromatography [ cis-17 in good yields with high selectivity [
24 (63%,
(
76%); trans-17 (6%)]. The relative configuration of dr = 11.3:1), 25 (75%, dr = 10.8:1)]. The relative con-
the major isomer was assigned by NOE experiments.
figuration of the major isomer was assigned in analogy to
iodide 17. Thus, for all R-substituents tested so far, a sim-
ilar high 1,3-stereoinduction was obtained.
We suggest the following model to explain the stere-
ochemical outcome of the cyclisation: Initial iodonium
ion formation is probably not stereoselective. Thus, the di-
astereoisomeric intermediates 18 and 19 are formed in
equal amounts. The cyclisations are supposed to occur
through chair type conformations as depicted in
Scheme 4. 1,3-Diaxial interaction in the case of diastere-
oisomer 18 increases the activation energy for the forma-
tion of the trans isomer. Since the initial iodonium ion
formation is reversible, the ‘non-productive’ isomer 18
can readily be converted back to the starting olefin 13.
O
O
O
NH
N
I
O
NIS,CH Cl
2
2
R
R
2
2 (R = CH3)
24 (63%, cis:trans = 11.3:1, R = CH3)
25 (75%, cis:trans = 10.8:1, R = C6H11)
23 (R = C6H11)
Scheme 5 NIS-induced stereoselective 5-exo-cyclisations
O
In conclusion, we have presented a new approach for the
preparation of isoxazolines starting from O-homoallyl hy-
droxylamine derivatives. The starting alkoxyamines are
readily prepared from the corresponding alcohols. The
new isoxazoline synthesis comprises an initial electro-
philic cyclisation reaction to form intermediate isoxazo-
lidines, which are subsequently oxidized to isoxazolines.
The oxidative cyclisation can be conducted with various
reagents such as t-BuOCl, PhSeBr, NBS and NIS and are
easy to perform at ambient temperature. Our method nice-
ly complements the traditional isoxazoline syntheses. Fur-
thermore, we have shown that the oxidation can be
suppressed if the starting O-homoallyl hydroxylamines
are N-sulfonylated. The electrophilic cyclisation can
again be performed with various electrophiles to afford N-
sulfonylated isoxazolidines with moderate cis-selectivi-
ties (up to 7:1).
NIS, CH2Cl2
rt, 24 h
N
I
O
1
3
82%
Ph
1
7 (cis:trans = 12.5:1)
O
O
I
O
+I
-I
O
N
H
H
I
Ph
N
H
Ph
13 + I2
-I
+I
H
H
H
1
8
19
minor pathway
major pathway
O
O
I
N
I
N
O
O
Electrophilic cyclisations using N-acylated O-homoallyl
hydroxylamines provided very interesting results. The t-
BuOCl-mediated cyclisation afforded isoxazolines via an
oxidative cyclisation. However, with the milder NIS as
electrophile, oxidation could be suppressed, and the 5-
exo-cyclisation product was obtained with high stereo-
control (cis:trans = 13:1). Lower selectivities were ob-
tained for the PhSeBr and NBS-mediated cyclisations.
Thus, upon switching the electrophile, one can chose be-
tween an oxidative cyclisation (t-BuOCl isoxazolines)
or a conventional highly stereoselective electrophilic cy-
Ph
Ph
trans-17
cis-17
O
NBS, CH2Cl2
rt, 24 h, or
N
X
O
13
PhSeBr, CH3CN
Na2CO3, rt
Ph
2
2
0 (82%, cis:trans = 4.2:1, X = SePh)
1 (77%, cis:trans = 4.7:1, X = Br)
Scheme 4 Stereoselective cyclisation of olefin 13
clisation (NIS
isoxazolidines) starting from the same
olefin. Isoxazolidines as well as isoxazolines are very use-
ful compounds in synthetic organic chemistry.
We also tested Se- and Br-induced cyclisations. The Se-
mediated cyclisation using PhSeBr as electrophile oc-
curred with lower selectivity (cis:trans = 4.2:1, 82%). The
NBS-mediated cyclisation of 13 afforded a similar result.
Bromide 21 was formed as a 4.7:1 cis:trans-mixture of di-
astereoisomers in 77% yield. The diastereoisomers can be
readily separated.
1H NMR, 13C NMR and NOESY spectra were recorded on a Bruker
DRX-500, DRX-400, ARX-300 or ARX-200 spectrometer. IR
spectra were recorded on a Bruker IFS-200 or a Nicolet
MagnaIR 750 spectrometer. Mass spectra were recorded as EI-MS
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York

2
120
B. Janza, A. Studer
PAPER
on a Varian CH7 and as HRMS on a MAT 95S instrument. Elemen-
tal analyses were performed on a Heraeus CHN-Rapid analyser.
Solvents were purified by standard methods. Air and moisture sen-
sitive compounds were handled under argon using Schlenk tech-
niques.
13C NMR (50 MHz, CDCl3): = 155.89 (C), 140.76 (CH), 133.24
(CH), 129.26 (CH), 128.57 (CH), 128.51 (CH), 128.02 (C), 127.75
(C), 125.74 (CH), 82.32 (CH), 43.84 (CH ), 22.64 (CH ).
2
2
+
MS (EI): m/z = 317 [M] , 211, 160, 142, 129, 117, 115, 91, 77.
Anal. Calcd for C H NOSe (316.26): C, 60.76; H, 4.78; N, 4.43.
1
6
15
Found: C, 60.70; H, 4.94; N, 4.65.
O-(1-Phenylbut-3-enyl)hydroxylamine (1)
1
-Phenylbut-3-ene-1-ol (1.44 g, 9.72 mmol), Ph P (2.96 g, 11.25
3
3
-Bromomethyl-5-phenylisoxazoline (6)
According to GP 1, from 1 (0.2 g, 1.2 mmol) and N-bromosuccin-
imide (0.66 g, 3.7 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
mmol) and N-hydroxyphthalimide (1.83 g, 11.25 mmol) were dis-
solved in THF (60 mL). The solution was cooled to 10 °C, and di-
isopropyl azodicarboxylate (2.6 g, 11.25 mmol) was added over 30
min. The mixture was allowed to warm to r.t. and stirred for 4 h. Hy-
drazine monohydrate (1.05 mL, 22 mmol) was added and the stir-
2
2
1
:9) afforded 6; yield: 180 mg (61%).
IR (film): 3442, 2966, 1680, 1609, 1494, 1343, 1224, 918, 759, 624
cm .
ring was continued for further 30 min. After addition of H O, the
–1
2
mixture was extracted with methyl tert-butyl ether (MTBE)–pen-
tane (1:1). The organic layer was separated and dried (MgSO4).
Evaporation of the solvent and purification by flash chromatogra-
phy (FC) [MTBE–pentane, 1:9] afforded 1; yield: 1.35 g (85%).
1H NMR (200 MHz, CDCl3): = 7.42–7.25 (m, 5 Harom), 5.65 (dd,
J = 11.1, 8.3 Hz, 1 H, HCON), 4.20 (s, 2 H, CH Br), 3.54 (dd,
2
J = 17.1, 10.9 Hz, 1 H, CH ), 3.11 (dd, J = 16.8, 8.5 Hz, 1 H, CH ).
2
2
13C NMR (50 MHz, CDCl
): = 154.59 (C), 140.17 (CH), 128.75
–
1
3
IR (film): 3317, 1641, 1583, 1454, 1182, 916, 702 cm .
(
CH), 128.37 (C), 125.80 (CH), 83.31 (CH), 42.65 (CH ) 23.65
2
1
H NMR (200 MHz, CDCl ): = 7.39–7.29 (m, 5 Harom), 5.87–5.67
3
(CH2).
(
m, 1 H, CH =CH), 5.22 (br s, 2 H, NH ), 5.12–5.00 (m, 2 H,
2
2
+
MS (EI): m/z = 241 [M] , 211, 160, 148, 129, 104, 91, 78, 43.
CH=CH ), 4.56 (dd, J = 7.4, 6.0 Hz, 1 H, HCON), 2.68–2.33 (m, 2
2
+
1081BrNO, 243.0083. Found:
H, CH2).
HRMS: m/z [M ] Calcd for C10
H
13C NMR (50 MHz, CDCl3): = 141.29 (C), 134.36 (CH), 128.43
243.0079.
(
(
CH), 127.75 (CH), 126.69 (CH), 117.02 (CH ), 86.57 (CH), 40.51
CH2).
2
3
-Iodomethyl-5-phenylisoxazoline (7)
According to GP 1, from 1 (0.2 g, 1.2 mmol) and N-iodosuccinim-
ide (0.83 g, 3.7 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
+
MS (EI): m/z = 163 [M] , 131, 116, 105, 91, 77, 65, 53.
2
2
1
:9) afforded 7; yield: 196 mg (containing starting material and oth-
Anal. Calcd for C H NO (163.22): C, 73.59; H, 8.03; N, 8.58.
Found: C, 73.28; H, 8.25; N, 8.87.
1
0
13
er impurities).
1H NMR (200 MHz, CDCl3): = 7.39–7.25 (m, 5 Harom), 5.60 (dd,
J = 11.0, 8.5 Hz, 1 H, HCON), 4.10 (s, 2 H, CH I), 3.58 (dd,
J = 16.8, 11.0 Hz, 1 H, CH ), 3.15 (dd, J = 17.0, 8.3 Hz, 1 H, CH ).
13C NMR (50 MHz, CDCl3):
Isoxazolines 2, 5, 6, and 7; General Procedure (GP 1)
2
2
O-(1-Phenylbut-3-enyl)hydroxylamine (1) was dissolved in CH Cl2
2
2
or MeCN. A solution of the electrophile in CH Cl or MeCN was
2
2
= 155.59 (C), 140.18 (CH), 128.74
added at r.t. After stirring at r.t. for 24 h, sat. aq Na S O was added.
2
2
3
(
(
CH), 128.36 (CH), 127.48 (C), 82.98 (CH), 43.79 (CH ), 43.16
CH2).
2
The organic layer was separated, washed with sat. aq NaHCO and
3
brine, and dried (MgSO ). After evaporation of the solvent, the
4
crude product was purified by FC.
N-(1-Phenylbut-3-enyloxy)benzenesulfonamide (8)
O-(1-Phenylbut-3-enyl)hydroxylamine (1; 0.4 g, 2.5 mmol) and
3
-Chloromethyl-5-phenylisoxazoline (2)
Et N (0.34 mL, 2.5 mmol) were dissolved in THF (10 mL). The so-
3
According to GP 1, from 1 (0.2 g, 1.2 mmol) and tert-butyl hy-
pochlorite (0.38 g, 3.6 mmol) in CH Cl (15 mL). FC (MTBE–pen-
tane, 1:9) afforded 2; yield: 161 mg (69%).
lution was cooled to 0 °C, and benzenesulfonyl chloride (0.33 mL,
2
2
2
.5 mmol) was added. The mixture was allowed to warm to r.t. and
stirred for 3 d. After addition of H O, the mixture was extracted with
2
–
1
IR (film): 3448, 1740, 1618, 1493, 1456, 1262, 922, 759, 699 cm .
1H NMR (200 MHz, CDCl3): = 7.28–7.23 (m, 5 Harom), 5.59 (dd,
J = 11.2, 8.5 Hz, 1 H, HCON), 4.27 (s, 2 H, CH Cl), 3.45 (dd,
Et O. The organic layer was separated, washed with H O and brine,
2
2
and dried (MgSO ). Evaporation of the solvent and purification by
4
FC (MTBE–pentane, 1:10) afforded 8; yield: 640 mg (84%).
IR (KBr): 3207, 1449, 1385, 1347, 1173, 751, 684 cm–1.
2
J = 17.3, 11.3 Hz, 1 H, CH ), 3.01 (dd, J = 17.2, 8.5 Hz, 1 H, CH ).
2
2
13C NMR (50 MHz, CDCl3): = 154.54 (C), 140.21 (CH), 128.76
1
H NMR (200 MHz, CDCl ): = 7.94–7.89 (m, 2 Harom), 7.65–7.52
3
(
(
CH), 128.36 (C), 125.64 (CH), 83.09 (CH), 42.42 (CH ), 37.74
CH2).
2
(m, 3 Harom), 7.34–7.23 (m, 5 Harom), 6.79 (s, 1 H, NH), 5.86–5.66
(m, 1 H, CH =CH), 5.12–4.99 (m, 3 H, HCO, CH=CH ), 2.67–2.38
(m, 2 H, CH2).
2
2
+
MS (EI): m/z = 195 [M] , 160, 142, 128, 117, 104, 89, 78, 42.
1
3
+
C NMR (50 MHz, CDCl ): = 139.47 (C), 139.66 (C), 133.74
HRMS: m/z [M ] Calcd for C H ClNO, 195.0451. Found:
3
1
0
10
(
1
CH), 133.69 (CH), 128.96 (CH), 128.62 (CH), 128.42 (CH),
1
95.0459.
28.29 (CH), 127.11 (CH), 117.66 (CH ), 88.07 (CH), 39.62 (CH ).
2
2
3
-Phenylselenylmethyl-5-phenylisoxazoline (5)
+
MS (EI): m/z =: 262 [M – allyl] , 131, 91, 77, 41.
According to GP 1, from 1 (0.2 g, 1.2 mmol), phenylselenyl bro-
mide (0.87 g, 3.7 mmol) and Na CO (300 mg) in MeCN (25 mL).
FC (MTBE–pentane, 1:9) afforded 5; yield: 252 mg (59%).
Anal. Calcd for C H NO S (303.38): C, 63.34; H, 5.65; N, 4.62.
Found: C, 63.00; H, 5.32; N, 4.28.
1
6
17
3
2
3
–
1
IR (film): 3058, 2924, 1578, 1496, 1437, 1335, 899, 739, 699 cm .
N-Phenylsulfonylisoxazolidines 9–12 and N-Acetylisoxazoli-
dines 17, 20, 21, 24, and 25; General procedure (GP 2)
The alkoxysulfonamide 8 or alkoxyacetamide 13, 22, 23 was dis-
1
H NMR (200 MHz, CDCl ): = 7.89–7.46 (m, 2 Harom), 7.32–7.15
3
(
m, 8 Harom), 5.51 (dd, J = 11.0, 8.3 Hz, 1 H, HCON), 3.85 (d,
solved in CH Cl , CHCl or MeCN. A solution of the electrophile
J = 13.0 Hz, 1 H, CH SePh), 3.70 (d, J = 12.7 Hz, 1 H, CH SePh),
3
H, CH2).
2
2
3
2
2
in CH Cl or MeCN was added at r.t. After stirring at r.t. for 24 h,
.44 (dd, J = 16.4, 11.0 Hz, 1 H, CH ), 3.04 (dd, J = 16.8, 8.1 Hz, 1
2
2
2
sat. aq Na S O was added. The organic layer was separated,
2
2
3
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclization of Homoallyl Hydroxylamine Derivatives
2121
washed with sat. aq NaHCO and brine, and dried (MgSO ). After
evaporation of the solvent the crude product was purified by FC.
1H NMR (200 MHz, CDCl3): (cis-isomer) = 8.04–7.92 (m, 2
Harom), 7.67–7.51 (m, 3 Harom), 7.35–7.25 (m, 5 Harom), 5.12 (dd,
J = 10.5, 5.7 Hz, 1 H, HCON), 4.74–4.59 (m, 1 H, HCN), 3.79 (dd,
3
4
2
-Benzenesulfonyl-3-chloromethyl-5-phenylisoxazolidine (9)
J = 10.1, 4.7 Hz, 1 H, BrCH ), 3.52 (dd, J = 9.5, 9.5 Hz, 1 H,
2
According to GP 2, from 8 (0.2 g, 0.66 mmol), NaOCl (13% in H O,
BrCH ), 2.97–2.84 (m, 1 H, CH ), 2.33–2.18 (m, 1 H, CH );
2
2
2
2
0
.4 mL, 0.7 mmol) and glacial AcOH (0.11 mL, 1.9 mmol) in
(trans-isomer) = 8.04–7.52 (m, 2 Harom), 7.67–7.59 (m, 3 Harom),
7.35–7.25 (m, 5 Harom), 5.20 (dd, J = 11.5, 5.8 Hz, 1 H, HCON),
4.59–4.43 (m, 1 H, HCN), 3.70 (dd, J = 10.1, 4.8 Hz, 1 H, BrCH2),
3.52–3.02 (m, 1 H, BrCH ), 2.68–2.58 (m, 1 H, CH ), 2.20–2.08 (m,
CHCl (5 mL). FC (MTBE–pentane, 1:9) afforded 9; yield: 140 mg
3
(61%) as a mixture of two diastereoisomers [dr (cis/trans) = 4.4: 1].
1
The ratio was determined by H NMR spectroscopy of the crude
product.
2
2
1 H, CH2).
–
1
13
IR (KBr): 3066, 1698, 1453, 1330, 1214, 1156, 768, 728, 611 cm .
C NMR (50 MHz, CDCl ): (both isomers) = 135.73 (C), 135.53
3
1H NMR (500 MHz, CDCl3): (cis-isomer) = 7.95–7.93 (m, 2
Harom), 7.65–7.36 (m, 3 Harom), 7.30–7.11 (m, 5 Harom), 5.10 (dd,
J = 12.8, 9.6 Hz, 1 H, HCON), 4.58 (m, 1 H, HCN), 3.85 (dd,
(CH), 134.14 (CH), 129.19 (CH), 129.15 (CH), 128.98 (CH),
1
8
3
28.64 (CH), 128.54 (CH), 127.12 (C), 126.85 (CH), 83.74 (CH),
2.36 (CH), 62.23 (CH), 60.85 (CH), 42.43 (CH ), 39.64 (CH ),
2
2
4.74 (CH ), 33.00 (CH ).
2
2
J = 10.9, 4.8 Hz, 1 H, ClCH ), 3.59 (dd, J = 10.9, 8.5 Hz, 1 H,
2
+
ClCH ), 2.83–2.78 (m, 1 H, CH ), 2.28–2.18 (m, 1 H, CH );
MS (EI): m/z = 383 [M] , 288, 257, 242, 211, 141, 131, 104, 91, 77,
2
2
2
(
trans-isomer) = 7.95–7.93 (m, 2 Harom), 7.65–7.36 (m, 3 Harom),
40.
7
4
3
2
.30–7.11 (m, 5 Harom), 4.95 (dd, J = 10.6, 2.8 Hz, 1 H, HCON),
.44–4.41 (m, 1 H, HCN), 3.74 (dd, J = 11.3, 5.1 Hz, 1 H, ClCH2),
.64 (dd, J = 6.8, 4.6 Hz, 1 H, ClCH ), 2.66–2.63 (m, 1 H, CH ),
Anal. Calcd for C H BrNO S (382.27): C, 50.27; H, 4.22; N, 3.66.
found: C, 49.86; H, 3.95; N, 3.36.
1
6
16
3
2
2
.41–2.38 (m, 1 H, CH2).
2
-Benzenesulfonyl-3-iodomethyl-5-phenylisoxazolidine (12)
13C NMR (50 MHz, CDCl3): (cis-isomer) = 135.89 (C), 134.14
CH), 129.24 (CH), 129.16 (CH), 128.98 (CH), 128.67 (CH),
26.87 (CH), 83.66 (CH), 60.93 (CH), 46.54 (CH ), 41.35 (CH ).
According to GP 2, from 8 (0.1 g, 0.33 mmol) and N-iodosuccinim-
(
1
ide (0.083 g, 0.33 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
2
2
9:1) afforded 12: 99 mg (70%) as a mixture of two diastereoisomers
2
2
1
+
[dr (cis/trans) = 5.0: 1]. The ratio was determined by H NMR spec-
MS (EI): m/z =142 [PhSO ] , 107, 79, 44.
2
troscopy of the crude product.
IR (KBr): 3445, 1454, 128, 1160, 883, 766 cm–1.
Anal. Calcd for C H ClNO S (337.82): C, 56.89; H, 4.77; N, 4.15.
Found: C, 56.72; H, 5.01; N, 3.97.
1
6
16
3
1H NMR (200 MHz, CDCl3): (cis-isomer) = 8.03–7.99 (m, 2
Harom), 7.71–7.53 (m, 3 Harom), 7.32–7.26 (m, 5 Harom), 5.13 (dd,
J = 10.5, 5.5 Hz, 1 H, HCON), 4.65–4.56 (m, 1 H, HCN), 3.61 (dd,
J = 9.8, 4.3 Hz, 1 H, ICH ), 3.37 (dd, J = 9.5, 9.5 Hz, 1 H, ICH ),
2
-Benzenesulfonyl-5-phenyl -3-phenylselenylmethylisoxazoli-
dine (10)
According to GP 2, from 8 (0.1 g, 0.33 mmol), phenylselenyl bro-
mide (0.12 g, 0.5 mmol) and Na CO (100 mg) in MeCN (25 mL).
2
2
3.00–2.87 (m, 1 H, CH ), 2.56–2.10 (m, 1 H, CH ); (trans-
2
3
2
2
FC (MTBE–pentane, 1:9) afforded 10: 110 mg (73%) as a mixture
of two diastereoisomers [dr (cis/trans) = 3.8: 1]. The ratio was de-
termined by H NMR spectroscopy of the crude product.
isomer) = 8.04–7.52 (m, 2 Harom), 7.67–7.59 (m, 3 Harom), 7.35–7.25
(m, 5 Harom), 5.21 (dd, J = 11.2, 5.7 Hz, 1 H, HCON), 4.55–4.42 (m,
1
1 H, HCN), 3.55–3.50 (m, 1 H, ICH ), 3.35 (dd, J = 10.0, 10.0 Hz,
2
–
1
1 H, ICH
13C NMR (50 MHz, CDCl
1
8
2
), 2.67–2.58 (m, 1 H, CH
): = 135.74, 135.58, 134.12 (CH),
29.21 (CH), 129.15 (CH), 128.99 (C), 128.65 (CH), 126.87 (CH),
3.91 (CH), 61.21 (CH), 44.14 (CH ), 8.62 (CH ).
2
), 2.26–2.06 (m, 1 H, CH ).
2
IR (film): 3026, 1671, 1448, 1361, 1171, 741, 691, 599 cm .
1H NMR (200 MHz, CDCl3): (cis-isomer) = 7.89–7.77 (m, 2
Harom), 7.63–7.44 (m, 5 Harom), 7.33–7.21 (m, 8 Harom), 4.95 (dd,
J = 10.5, 5.8 Hz, 1 H, HCON), 4.52–4.40 (m, 1 H, HCN), 3.56 (dd,
3
2
2
+
J = 12.5, 4.5 Hz, 1 H, SeCH ), 3.12 (dd, J = 12.6, 9.2 Hz, 1 H,
MS (EI): m/z = 429 [M] , 288, 257, 131, 104, 91, 77, 40.
2
SeCH ), 2.90–2.77 (m, 1 H, CH ), 2.24–2.09 (m, 1 H, CH );
2
2
2
Anal. Calcd for C H INO S (429.27): C, 44.77; H, 3.76; N, 3.26.
Found: C, 44.38; H, 4.07; N, 3.13.
1
6
16
3
(
trans-isomer) = 7.81–7.79 (m, 2 Harom), 7.63–7.44 (m, 5 Harom),
7
4
3
1
.33–7.21 (m, 8 Harom), 5.16 (dd, J = 15.5, 5.7 Hz, 1 H, HCON),
.40–4.30 (m, 1 H, HCN), 3.46 (dd, J = 12.8, 4.8 Hz, 1 H, SeCH2),
.16–3.02 (m, 1 H, SeCH ), 2.60–2.45 (m, 1 H, CH ), 2.16–2.13 (m,
N-Acetylalkoxyamines 13, 22, and 23; General Procedure (GP
2
2
3
)
H, CH2).
The alkoxyamine and Et N were dissolved in THF and cooled to
3
13C NMR (50 MHz, CDCl3): (cis-isomer) = 136.11 (C), 135.46
0 °C. AcCl was added and stirring was continued for 30 min at 0 °C.
After addition of H O, the mixture was extracted with Et O. The or-
(
(
CH), 133.90 (CH), 133.03 (CH), 132.73 (C), 129.53 (C), 129.28
CH), 129.18 (CH), 129.02 (CH), 128.91 (CH), 128.81 (CH),
2
2
ganic layer was separated, washed with H O and brine, and dried
2
1
6
28.56 (CH), 127.28 (CH), 127.06 (CH), 126.81 (CH), 83.42 (CH),
1.00 (CH), 43.15 (CH ), 32.51 (CH ).
(MgSO ). After evaporation of the solvent the crude product was
purified by recrystallization or FC.
4
2
2
+
MS (EI): m/z = 317 [M – SO Ph] , 117, 106, 91, 73, 57, 43.
2
N-(1-Phenylbut-3-enyloxy)acetamide (13)
According to GP 3, from 1 (1.47 g, 9 mmol), Et N (1.23 mL, 9
mmol) and AcCl (0.59 mL, 9 mmol) in THF (15 mL). Recrystalli-
Anal Calcd for C H NO SSe (458.43): C, 57.64; H, 4.62; N, 3.06.
Found: C, 58.00; H, 4.91; N, 2.89.
22
21
3
3
zation (MTBE–pentane, 1:1) afforded 13; yield: 1.56 g (92%).
2
-Benzenesulfonyl-3-bromomethyl-5-phenylisoxazolidine (11)
IR (KBr): 3447, 3143, 2945, 1660, 1528, 1358, 1071, 999, 925, 760,
According to GP 2, from 8 (0.1 g, 0.33 mmol) and N-bromosuccin-
imide (0.066 g, 0.33 mmol) in CH Cl (15 mL). FC (MTBE–pen-
tane, 1:9) afforded 11; yield: 99 mg (79%) as a mixture of two
diastereoisomers [dr (cis/trans) = 4.8: 1]. The ratio was determined
by H NMR spectroscopy of the crude product.
–
1
7
02 cm .
2
2
1H NMR (200 MHz, CDCl3): (mixture of rotamers) = 8.30 (br s,
1 H, NH, rotamer A), 7.79 (br s, 1 H, NH, rotamer B), 7.27–7.26 (m,
1
5 Harom, rotamer A + B), 5.74–5.66 (m, 1 H, CH =CH, rotamer A +
2
–
1
B), 5.05–4.58 (m, 3 H, HCO, CH=CH , rotamer A + B), 2.69–2.66
2
IR (KBr): 3442, 1495, 1292, 1155, 886, 766, 617 cm .
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York

2
122
B. Janza, A. Studer
PAPER
(
(
1
m, 1 H, CH , rotamer A), 2.50–2.39 (m, 1 H, CH , rotamer B), 1.95
1H NMR (200 MHz, CDCl3): (cis-isomer) = 7.45–7.40 (m, 5
Harom), 4.91 (dd, J = 10.6, 6.0 Hz, 1 H, HCON), 4.84–4.72 (m, 1 H,
2
2
br s, 1 H, CH , rotamer B), 1.68 (br s, 1 H, CH , rotamer A).
3
3
3
HCN), 3.74 (dd, J = 10.0, 4.0 Hz, 1 H, BrCH
2
), 3.51 (dd, J = 9.9,
C NMR (50 MHz, CDCl ): (mixture of rotamers) = 167.60 (C,
3
8
.0 Hz, 1 H, BrCH ), 2.99–2.86 (m, 1 H, CH ), 2.41–2.25 (m, 1 H,
2
2
rotamer A + B), 139.33 (C, rotamer A + B), 133.17 (CH, rotamer A
B), 128.34 (CH, rotamer A + B), 118.15 (CH , rotamer B), 117.54
CH ), 2.19 (s, 3 H, CH ); (trans-isomer) = 7.37–7.27 (m, 5 Harom),
2
3
+
2
5
3
.35 (dd, J = 5.6, 5.6 Hz, 1 H, HCON), 4.81–4.80 (m, 1 H, HCN),
(CH , rotamer A), 88.52 (CH, rotamer B), 86.47 (CH, rotamer A),
2
.74 (dd, J = 9.9, 3.4 Hz, 1 H, BrCH ), 3.53 (dd, J = 9.0, 9.0 Hz, 1
2
3
9.44 (CH , rotamer A + B), 19.59 (CH , rotamer A + B).
3 2
H, BrCH ), 2.74–2.71 (m, 2 H, CH ), 1.89 (s, 3 H, CH ).
2
2
3
+
MS (EI): m/z = 205 [M] , 164, 131, 116, 105, 91, 77, 43.
1
3
C NMR (50 MHz, CDCl ): (cis-isomer) = 172.07 (C), 135.73
3
+
HRMS: m/z [M ] Calcd for C H NO , 205.1102. Found:
2
1
2
15
2
(C), 129.09 (CH), 128.77 (CH), 126.69 (CH), 83.81 (CH), 57.60
CH), 42.05 (CH ), 34.48 (CH ), 20.41 (CH ); δ (trans-
05.1093.
(
2
3
2
isomer) = 137.15 (C), 129.02 (CH), 128.87 (CH), 126.82 (CH),
1.67 (CH), 57.08 (CH), 38.85 (CH ), 33.63 (CH ), 20.63 (CH ).
2
-Acetyl-3-iodomethyl-5-phenylisoxazolidine (17)
8
2
3
2
According to GP 2, from 13 (0.2 g, 1.0 mmol) and N-iodosuccin-
imide (0.25 g, 1.1 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
1
+
MS (EI): m/z = 283 [M] , 243, 209, 186, 148, 129, 104, 91, 43.
2
2
+
:1) afforded cis-17; yield: 250 mg (76%) and trans-17; yield: 20
HRMS: m/z [M ] Calcd for C H BrNO , 283.0208. Found:
1
2
14
2
mg (6%) [dr (cis/trans) = 12.5: 1].
283.0203.
–
1
IR (film): 3038, 1745, 1668, 1385, 1336, 1032, 761, 699 cm .
N-(1-Methylbut-3-enyloxy)acetamide (22)
According to GP 3, from O-(1-methylbut-3-enyl)hydroxylamine
1
H NMR (200 MHz, CDCl ): (cis-isomer) = 7.45–7.39 (m, 5
3
Harom), 4.92 (dd, J = 8.6, 5.8 Hz, 1 H, HCON), 4.71–4.57 (m, 1 H,
(150 mg, 1.49 mmol), Et N (0.21 mL, 1.49 mmol) and AcCl (0.12
3
HCN), 3.56 (dd, J = 9.8, 3.7 Hz, 1 H, ICH ), 3.35 (dd, J = 9.5, 8.6
2
mL, 1.49 mmol) in THF (10 mL). FC (MTBE–pentane, 8:2) afford-
ed 22; yield: 130 mg (52%).
IR (film): 3197, 1669, 1523, 1373, 1084, 993 cm–1.
Hz, 1 H, ICH ), 3.02–2.89 (m, 1 H, CH ), 2.29–2.14 (m, 1 H, CH ),
2
2
2
2
.18 (s, 3 H, CH ); (trans-isomer) = 7.44–7.27 (m, 5 Harom), 5.35
3
(
(
dd, J = 6.6, 5.5 Hz, 1 H, HCON), 4.76–4.63 (m, 1 H, HCN), 3.58
dd, J = 9.8, 3.7 Hz, 1 H, ICH ), 3.34 (dd, J = 9.2, 9.2 Hz, 1 H,
1H NMR (300 MHz, CDCl3): (mixture of rotamers) = 9.53 (br s,
1 H, NH, rotamer A), 8.99 (br s, 1 H, NH, rotamer B), 5.87–5.73 (m,
1 H, CH =CH, rotamer A + B), 5.13–5.08 (m, 2 H, CH=CH , rota-
2
ICH ), 2.84–2.70 (m, 1 H, CH ), 2.66–2.54 (m, 1 H, CH ), 1.88 (s,
2
2
2
3
H, CH3).
2
2
13C NMR (50 MHz, CDCl3): (cis-isomer) = 171.69 (C), 135.70
mer A + B), 4.03–4.02 (m, 1 H, HCO, rotamer A), 3.91 (br s, 1 H,
HCO, rotamer B), 2.48–2.44 (m, 1 H, CH , rotamer A + B), 2.28–
2
(
(
C), 129.10 (CH), 128.78 (CH), 126.72 (CH), 83.97 (CH), 57.88
CH), 43.92 (CH ), 20.48 (CH ), 9.03 (CH ).
2
.23 (m, 1 H, CH , rotamer A + B), 2.06 (s, 1 H, H CCO, rotamer
2
3
2
3
2
B), 1.93 (s, 1 H, H CCO, rotamer A), 1.24 (br s, 1 H, CH , rotamer
3
3
+
MS (EI): m/z = 331 [M] , 289, 257, 231, 162, 148, 130, 104, 91, 43.
A + B).
+
HRMS: m/z [M ] Calcd for C H INO , 331.0069. Found:
13C NMR (75 MHz, CDCl3): (mixture of rotamers) = 168.37 (C,
rotamer A + B), 133.91 (CH, rotamer A), 133.39 (CH, rotamer B),
1
2
14
2
3
31.0075.
1
17.96 (CH , rotamer B), 117.33 (CH , rotamer A), 81.83 (CH, rot-
2
2
2
-Acetyl-5-phenyl -3-phenylselenylmethylisoxazolidine (20)
amer B), 80.76 (CH, rotamer A), 38.94 (CH , rotamer A + B), 19.75
3
According to GP 2, from 13 (0.2 g, 1.0 mmol), phenylselenyl bro-
mide (0.36. g, 1.0 mmol) and Na CO (300 mg) in MeCN (15 mL).
FC (MTBE–pentane, 1:1) afforded cis-20; yield: 240 mg (66%) and
trans-20; yield: 57 mg (16%) [dr (cis/trans) = 4.2: 1].
(CH , rotamer A), 19.47 (CH , rotamer B), 17.89 (CH , rotamer A
2
2
3
2
3
+ B).
+
MS (EI): m/z = 143 [M ], 102, 84, 68, 58, 41.
–
1
IR (film): 2935, 1666, 1386, 1034, 739, 698 cm .
N-(1-Cyclohexylbut-3-enyloxy)acetamide (23)
1
According to GP 3, from O-(1-cyclohexylbut-3-enyl)hydroxy-
lamine (100 mg, 0.6 mmol), Et N (0.083 mL, 0.6 mmol) and AcCl
H NMR (200 MHz, CDCl ): (cis-isomer) = 7.59–7.55 (m, 2
3
Harom), 7.40–7.39 (m, 5 Harom), 7.28–7.25 (m, 3 Harom), 4.86 (dd,
J = 15.8, 9.0 Hz, 1 H, HCON), 4.76–4.70 (m, 1 H, HCN), 3.49 (dd,
J = 18.8, 6.4 Hz, 1 H, PhSeCH ), 3.10 (dd, J = 18.6, 12.8 Hz, 1 H,
3
(
0.043 mL, 0.6 mmol) in THF (5 mL). FC (MTBE–pentane, 1:2) af-
forded 23; yield: 120 mg (95%).
2
PhSeCH ), 2.96–2.86 (m, 1 H, CH ), 2.32–2.17 (m, 1 H, CH ), 2.10
IR (film): 2927, 1749, 1673, 1449, 1373, 888 cm–1.
1H NMR (300 MHz, CDCl3): = 7.93 (br s, 1 H, NH), 6.05–5.76
2
2
2
(s, 3 H, CH3); (trans-isomer) = 7.60–7.58 (m, 2 Harom), 7.46–7.7
(
m, 8 Harom), 5.33–5.29 (m, 1 H, HCON), 4.88–4.70 (m, 1 H, HCN),
(
m, 1 H, CH =CH), 5.17–5.08 (m, 2 H, CH=CH ), 3.66–3.60 (m, 1
2
2
3
2
.53–3.49 (m, 1 H, PhSeCH ), 3.12–3.02 (m, 1 H, PhSeCH ), 2.70–
2
2
H, HCO), 2.43–2.32 (m, 2 H, CH ), 2.10–1.06 (m, 14 H).
2
.57 (m, 2 H, CH ), 1.85 (s, 3 H, CH ).
2
3
13C NMR (50 MHz, CDCl
): = 135.22 (CH), 117.61 (CH ), 89.85
13C NMR (50 MHz, CDCl3): (cis-isomer) = 132.44 (CH), 129.19
3
2
(
CH), 39.61 (CH ), 34.04 (CH ), 28.52 (CH ), 28.47, 26.44 (CH ),
3
2
2
2
(
(
CH), 128.99 (CH), 128.75 (CH), 127.06 (CH), 126.73 (CH), 83.77
CH), 57.27 (CH), 42.89 (CH ), 31.71 (CH ), 20.44 (CH ).
2
6.21 (CH ), 19.96.
2
2
3
2
+
+
MS (EI): m/z = 211 [M ], 170, 152, 137, 95, 81, 55.
MS (EI): m/z = 361 [M] , 286, 204, 164, 148, 129, 104, 91, 56, 43.
+
HRMS: m/z [M ] Calcd for C H SeNO , 361.0581. Found:
1
8
19
2
2-Acetyl-3-iodomethyl-5-methylisoxazolidine (24)
According to GP 2, from 22 (114 g, 0.8 mmol) and N-iodosuccin-
3
61.0581.
imide (198 g, 0.88 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
2
2
2
-Acetyl-3-bromomethyl-5-phenylisoxazolidine (21)
7
:3) afforded cis-24; yield: 125 mg (58%) and trans-24; yield: 11
According to GP 2, from 13 (0.2 g, 1.0 mmol) and N-bromosuccin-
imide (0.180 g, 1.0 mmol) in CH Cl (15 mL). FC (MTBE–pentane,
1
mg (5%) [dr (cis/trans) = 11.3: 1].
IR (film): 2977, 1662, 1395, 1223, 1104, 1037 cm–1.
2
2
:1) afforded cis-21; yield: 180 mg (64%) and trans-21; yield: 38
1
mg (13%) [dr (cis/trans) = 4.7: 1].
H NMR (300 MHz, CDCl ): (cis-isomer) = 4.54–4.48 (m, 1 H,
3
–
1
HCN), 4.09–4.01 (m, 1 H, HCON), 3.50–3.47 (m, 1 H, ICH
2
), 3.23–
IR (film): 3445, 1666, 1375, 912, 734 cm .
3
.17 (m, 1 H, ICH ), 2.77–2.65 (m, 1 H, CH ), 2.12 (s, 3 H,
2
2
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclization of Homoallyl Hydroxylamine Derivatives
2123
H CCO), 1.80–1.67 (m, 1 H, CH ), 1.39 (d, J = 5.9, 3 H, CH );
I.; Prange, T.; Salazar, J. A.; Suárez, E. J. Chem. Soc., Chem.
Commun. 1989, 450.
3
2
3
(
trans-isomer) = 4.83–4.67 (m, 1 H, HCN) 4.19–4.09 (m, 1 H,
HCON), 3.41–3.15 (m, 2 H, ICH ), 2.01 (s, 3 H, H CCO), 1.99–
(4) (a) Tiecco, M.; Testaferri, L.; Marini, F.; Bagnoli, L.; Santi,
C.; Temperini, A. Tetrahedron 1997, 53, 4441. (b) Ternon,
M.; Outurquin, F.; Paulmier, C. Tetrahedron 2001, 57,
2
3
1
.76 (m, 2 H, CH ), 1.18 (d, J = 6.2, 3 H, CH ).
2
3
1
3
C NMR (75 MHz, CDCl ): (cis-isomer) = 78.67 (CH), 57.77
3
10259.
(
CH), 43.26 (CH ), 20.33 (CH ), 17.26 (CH ), 8.95 (CH ).
2
3
3
2
(
5) (a) Wilson, S. R.; Sawicki, R. A. J. Org. Chem. 1979, 44,
+
MS (EI): m/z = 269 [M ], 227, 162, 128, 86, 43.
287. (b) Tokuda, M.; Yamada, Y.; Suginome, H. Chem. Lett.
1988, 1289. (c) Raner, K. D.; Ward, A. D. Aust. J. Chem.
1991, 44, 1749. (d) Ferraz, H. M. C.; de Oliveira, E. O.;
2
-Acetyl-3-iodomethyl-5-cyclohexylisoxazolidine (25)
According to GP 2, from 23 (0.1 g, 0.47 mmol) and N-iodosuccin-
imide (0.118 g, 0.52 mmol) in CH Cl (15 mL). FC (MTBE–pen-
Payret-Arrua, M. E.; Brandt, C. A. J. Org. Chem. 1995, 60,
7357.
2
2
tane, 1:1) afforded cis-25; yield: 108 mg (68%) and trans-25; yield:
0 mg (6%) [dr (cis/trans) = 10.8: 1].
(
(
6) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681.
7) (a) Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu,
J.; Thornton-Pett, M. J. Chem. Soc., Chem. Commun. 1993,
1
–
1
IR (film): 3194, 2927, 1665, 1450, 1083, 991 cm .
1340. (b) Tiecco, M.; Testaferri, L.; Tingoli, M.; Bagnoli, L.
1H NMR (300 MHz, CDCl3): (cis-isomer) = 4.52–4.50 (m, 1 H,
J. Chem. Soc., Chem. Commun. 1995, 235. (c) Tiecco, M.;
Testaferri, L.; Tingoli, M.; Bagnoli, L.; Santi, C.
Tetrahedron 1995, 51, 1277. (d) Tiecco, M.; Testaferri, L.;
Marini, F.; Sternativo, S.; Santi, C.; Bagnoli, L.; Temperini,
A. Tetrahedron: Asymmetry 2001, 12, 3053.
HCN), 3.63–3.62 (m, 1 H, HCON), 3.48–3.46 (m, 1 H, ICH ), 3.21–
2
3
1
.15 (m, 1 H, ICH ), 2.62–2.54 (m, 1 H, CH ), 2.10 (s, 3 H, CH ),
2
2
3
.99–1.95 (m, 1 H, CH ), 1.84–1.03 (m, 11 H); (trans-isomer)
2
=
4.52–4.39 (m, 1 H, HCN), 4.00–3.95 (m, 1 H, HCON), 3.55–3.52
(
(
1
m, 1 H, ICH ), 3.253.19 (m, 1 H, ICH ), 2.38–2.20 (m, 2 H), 2.11
2
2
(
8) (a) Tiecco, M.; Testaferri, L.; Tingoli, M.; Santi, C.
Tetrahedron Lett. 1995, 36, 163. (b) Tiecco, M.; Testaferri,
L.; Tingoli, M.; Marini, F. J. Chem. Soc., Chem. Commun.
1995, 237.
s, 3 H, CH ), 1.961.92 (m, 1 H, CH ), 1.75–0.96 (m, 10 H).
3
2
3
C NMR (50 MHz, CDCl ): (cis-isomer) = 87.08 (CH), 57.44
3
(
(
CH), 40.39 (CH ), 39.56 (CH ), 29.82 (CH ), 28.68 (CH ), 26.11
3 2 2 2
CH ), 25.65 (CH ), 25.36 (CH ), 20.21 (CH), 9.17 (CH ); (trans-
(9) Janza, B. unpublished results.
2
2
2
2
isomer) = 84.44 (CH), 56.70 (CH), 40.61 (CH ), 37.21 (CH ),
(10) To the best of our knowledge, there is only one report
describing the electrophilic cyclisation of
homoallyloxyamines, see Ref.
(11) (a) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc.
3
2
2
2
9.92 (CH ), 28.57 (CH ), 26.10 (CH ), 25.67 (CH ), 25.43 (CH ),
0.79 (CH), 7.81 (CH2).
2 2 2 2 2
8
b
+
MS (EI) m/z = 337 [M] , 295, 252, 186, 154, 110, 67, 43.
1
1
972, 94, 679. (b) Grochowski, E.; Jurczak, J. Synthesis
976, 682. (c) Ishikawa, T.; Kawakami, M.; Fukui, M.;
Yamashita, A.; Urano, J.; Saito, S. J. Am. Chem. Soc. 2001,
23, 7734.
12) Similar electrophilic cyclisation/oxidation reactions have
Acknowledgement
1
We thank the Fonds der Chemischen Industrie for supporting our
research.
(
been observed in Se-induced 5-endo-type cyclisations of
4
b
hydrazines, see Ref.
13) Ternon, M.; Outurquin, F.; Paulmier, C. Tetrahedron 2001,
7, 10259.
(
(
References
5
14) Caramella, P.; Grünager, P. 1,3-Dipolar Cycloaddition
Chemistry, Vol. 1; Wiley-Interscience: New York, 1984,
(
1) (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.
b) Frederickson, M.; Grigg, R. Org. Prep. Proced. Int.
(
291.
1997, 29, 33. (c) Robin, S.; Rousseau, G. Tetrahedron 1998,
54, 13681. (d) Wirth, T. Angew. Chem., Int. Ed. 2000, 39,
3740. (e) Tiecco, M. Top. Curr. Chem. 2000, 208, 7.
(
15) Nitrile oxides can formally be regarded as aldol products,
see: Curran, D. P. Adv. Cycloadd. 1988, 1, 129.
16) Fuller, A. E.; Hickinbottom, W. J. J. Chem. Soc. 1965, 3228.
17) Glover, S. A. Tetrahedron 1998, 54, 7229.
18) All the cyclisations were performed using racemic olefins. In
the schemes only one enantiomer is shown.
(
(
(
(2) (a) Cooper, M. A.; Ward, D. A. Tetrahedron Lett. 1992, 33,
5999. (b) Cooper, M. A.; Ward, A. D. Tetrahedron Lett.
1994, 35, 5065.
(
3) (a) Balko, T. W.; Brinkmeyer, R. S.; Terando, N. H.
Tetrahedron Lett. 1989, 30, 2045. (b) Betancor, C.; León, E.
Synthesis 2002, No. 14, 2117–2123 ISSN 0039-7881 © Thieme Stuttgart · New York