X=Y-ZH systems as potential 1,3-dipoles. Part 50:1 phenylselenyl halide induced formation of cyclic nitrones from alkenyl oximes

Article abstract of DOI:10.1016/S0040-4020(00)01012-7

Oximes possessing γ- δ or ω-alkenyl substituents are cyclised by phenylselenyl bromide, or by phenylselenyl chloride and an appropriate silver salt to the corresponding cyclic nitrones; the seleno nitrones undergo facially specific cycloaddition reactions with N-methylmaleimide; bis(alk-γ,δ-enyl) ketones undergo regiospecific cyclisation and stereospecific intramolecular cycloaddition to furnish spirocyclic products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)01012-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 10087±10096
XvY±ZH Systems as Potential 1,3-Dipoles. Part 50:1
Phenylselenyl Halide Induced Formation of Cyclic Nitrones
from Alkenyl Oximes
a
a
H. Ali Dondas,a Ronald Grigg,a, Maria Hadjisoteriou, Jasothara Markandu,
*
W. Anthony Thomasa and Peter Kennewellb
aSchool of Chemistry, The University of Leeds, Leeds LS2 9JT, UK
bRoussel Scienti®c Institute, King®sher Drive, Swindon SN3 5BZ, UK
Received 24 August 2000; revised 28 September 2000; accepted 19 October 2000
AbstractÐOximes possessing g-, d or v-alkenyl substituents are cyclised by phenylselenyl bromide, or by phenylselenyl chloride and an
appropriate silver salt to the corresponding cyclic nitrones; the seleno nitrones undergo facially speci®c cycloaddition reactions with
N-methylmaleimide; bis(alk-g,d-enyl) ketones undergo regiospeci®c cyclisation and stereospeci®c intramolecular cycloaddition to furnish
spirocyclic products. q 2000 Elsevier Science Ltd. All rights reserved.
Inter- and intra-molecular cycloaddition reactions of
nitrones have attracted much attention because they provide
a potentially ¯exible entry into the complex molecular
framework of natural products.2 Utilising oximes as nitrone
precursors in tandem nitrone generation-cycloaddition
protocols substantially enhances this ¯exibility. We have
recently introduced a range of such protocols3 most of
which have four distinct synthetic variants depending on
whether the nitrone forming step or the cycloaddition step
is inter- or intra-molecular (Table 1).
lidines, and the latter's potential for further synthetic manip-
ulation.
In this paper we report more fully on our studies concerned
with phenylselenyl halide.6 In a preliminary evaluation of
phenylselenyl halides7 it became clear that phenylselenyl
bromide in combination with silver tri¯ate, usually gave
rise to cleaner reactions and improved yields compared
with phenylselenyl chloride alone or phenylselenyl chloride
in combination with silver tetra¯uoroborate. We now report
full details of our studies of these processes. Subsequent to
our preliminary communication Tiecco et al. have published
similar observations using persulphate in combination with
diphenyl diselenide to generate the electrophilic phenyl-
selenyl species.8
Electrophile induced cyclisation reactions are a well estab-
lished strategy for the formation of hetero- and carbo-cyclic
systems.4 We have been exploring the generality of electro-
phile induced oxime-ole®n (alkyne) reactions as a source of
novel cascade nitrone formation-cycloaddition protocols
(Scheme 1).5
Oxime 1a (E/Z 2:1) reacted (CH2Cl2, 258C, 0.5 h) with
phenylselenyl bromide (1.0 mol) to give the cyclic nitrone
salt 2a. Treatment with anhydrous potassium carbonate
(1.1 mol) (CH2Cl2, 258C, 16 h) afforded the corresponding
nitrone 6a together with a trace of oxazine 3a. Heating the
nitrone 6a in acetonitrile (808C, 9 h) with N-methylmalei-
mide (NMM) (1 mol) afforded a 3:2 mixture (70% overall
Oximes are potentially ambident nucleophiles with either N
or O acting as the reactive site depending on the co-reagents,
solvent and pH of the reaction mixture. Nucleophilic nitro-
gen leads to the desired reaction (Scheme 1) whilst nucleo-
philic oxygen leads to oxime ethers (intermolecular process)
or oxazines (intramolecular process) (Scheme 2). Oximes
are attractive precursors of nitrones because of their ease of
preparation, their impressive diversity and range of molec-
ular complexity coupled with the corresponding features
present in the nitrone cycloaddition products, the isoxazo-
Table 1. Synthetic variants of oxime!nitrone!cycloaddition cascades
Class
Nitrone formation
Cycloaddition
1
2
3
4
Intermolecular
Intermolecular
Intramolecular
Intramolecular
Intermolecular
Intramolecular
Intermolecular
Intramolecular
Keywords: cyclic nitrones; alkenyl oximes; cycloaddition cascades.
* Corresponding author. Tel.: 144-(0)113-2336501; fax: 144-(0)113-
2336501; e-mail: r.grigg@chem.leeds.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01012-7

10088
H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
Scheme 1.
from 1a) of endo- and exo-cycloadducts 4a and 5a, respec-
tively. The diastereofacially speci®c cycloaddition of this
and all the nitrones in this paper accords with our obser-
vations on related cases.3,5 The stereochemistry of 4a and 5a
were assigned from nOe data (see Experimental). It is appar-
ent from this result that the ratio of nitrone 2a to oxazine 3a
does not re¯ect the E:Z ratio of the oxime. The nitrone:ox-
azine ratio is sensitive to the reagents and conditions as
shown by reaction of 1a with PhSeCl±AgOTf (CH2Cl2,
08C) to give 6a followed by treatment with potassium car-
bonate (CH2Cl2, 258C, 16 h) which affords a 2.5:1 mixture
of 6a and 3a in 76% combined yield. The relationship
between the E/Z-oxime ratio and the formation of 2 or 3
is summarised in Scheme 2.
The outcome of the electrophile induced cyclisation
depends on the relative values of k1, k21, k2 and k3 (Scheme
2). The cyclisation would be expected to be the rate limiting
steps for the more stable E-isomer whilst for the Z-isomer k1
or k3 may be rate limiting depending on factors that control
Scheme 2.

H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
10089
Scheme 3.
the relative rates of k1 versus k3. Clearly under the con-
ditions applied to the formation of 6a (above) k21.k3.
gave a 3:1 mixture (55%) of endo-4d and exo-5d cyclo-
adducts. Stereochemical assignments were again based on
nOe data (see Experimental). The conversions of oximes
1a±d into cycloadducts 4a±d and 5a,c,d constitute
examples of Class 3 processes (Table 1).
Oxime 1b (E/Z 1:1) reacted under analogous conditions to
give the corresponding nitrone salt 2b. Neutralisation and
1,3-dipolar cycloaddition afforded a single endo- cyclo-
adduct 4b (61% overall from 1b). In this case none of the
corresponding oxazine was observed. The stereochemistry
of 4b was assigned from nOe data (see Experimental). The
oxime 1c reacted under the same conditions to give a 3:2
mixture (72%) of endo- and exo-cycloadducts 4c and 5c,
respectively, but again no oxazine was detected. The stereo-
chemistry of 4c and 5c was assigned from nOe data (see
Experimental). These studies were then extended to the
generation of 7-membered cyclic nitrone 2d. 7-Octen-2-
one oxime 1d reacted with PhSeBr (CH3CN, 48 h, 258C)
to give nitrone salt 2d [the reaction could also be carried out
by heating in acetonitrile (508C, 4 h)] which upon treatment
with anhydrous K2CO3 and NMM (CH3CN, 258C, 16 h)
The cycloadditions occur trans to the CH2SePh substituent
for the cyclic nitrones 2a±d. This outcome points to stereo-
electronic effects in the cycloaddition transition state as
illustrated in Scheme 3 for the 6-membered nitrone.
In the more stable conformer A (partial MO only is shown
for clarity) attack on the face of nitrone anti to the equatorial
CH2SePh group involves axial C±C bond formation in the
transition state whilst in the less stable conformer B (partial
MO only is shown for clarity) attack anti to the axial
CH2SePh involves equatorial C±C bond formation as the
cycloaddition transition state develops towards product.
Similarly attack syn to the CH2SePh substituent in A
Scheme 4.

10090
H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
Scheme 5.
involves equatorial C±C bond formation whilst syn attack
on B is destabilised by developing axial±axial interactions
between the forming C±C bond and the CH2SePh moiety.
then K2CO3 afforded a 5:2 mixture of 10 and 13. Heating
this mixture (CH3CN, 908C, 5 h), afforded only 11 (35%
overall from 8) whilst nitrone 13 did not undergo cyclo-
addition. The failed intramolecular cycloaddition of 13
re¯ects the higher transition state energies involved in
forming a strained subsiduary 4-membered ring or a
[2.2.1]-bridged ring (Scheme 4).
Class 4 processes (intramolecular nitrone formation±intra-
molecular cycloaddition) have been explored with both
symmetrical and unsymmetrical ketoximes. We ®rst insti-
gated a study into the effect of ring size (5-versus
6-membered) as a controlling factor in de®ning the regio-
selectivity of nitrone formation. Dialkenyl oxime 8, in
which both the alkene moieties are terminal was investi-
gated ®rst. Electrophilic attack at bond A would lead, via
salt 9, to the 5-membered ring nitrone 10 via a 5-exo-tet
attack on the intermediate selenonium ion whilst electro-
philic attack at bond B would lead, via a 6-exo-tet process,
to 6-membered nitrone salt 12. Treating 8 with PhSeBr and
The stereochemistry of 11 was assigned on the basis of nOe
difference spectroscopy. Irradiation of the signal for Hc (d
2.97) resulted in a 5.2% enhancement of the signal for Hd (d
3.28), thus de®ning the cis-relationship between Hc and Hd
and the stereochemistry at the spiro centre, and 4.9%
enhancement of the signal at (d 4.05) which is therefore
assigned to Ha. The CHaHbO moiety gives rise to two
signals, one at d 4.05 (Ha) and the other at d 3.61(Hb).
Scheme 6. (i) NH2OH´HCl, CH3COONa, MeCN, H2O, 208C. (ii) PhSeBr, CH2Cl2, 258C, 0.5 . (iii) K2CO3, CH2Cl2, 258C, 16 h. (iv) CH3CN, 808C, 5 h.

H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
10091
Scheme 7.
A similar sequence of reactions was performed on the
unsymmetrical ketoxime 15. Regiospeci®c cyclisation
(CH3CN, 258C) to nitrone 16 occurred on treatment of 15
sequentially with phenylselenyl bromide and potassium
carbonate. Heating 16 in acetonitrile (808C, 4 h) afforded
a single cycloadduct 17 (61% from 15) via the anticipated
diastereofacially speci®c cycloaddition (Scheme 5). The
stereochemistry of the cycloadduct 17 was established by
1H NMR decoupling experiments and nOe studies (see
Experimental).
on heating in boiling acetonitrile afforded a single spiro-
cyclic cycloadduct 22 (65% overall from 19) (Scheme 6).
The stereochemistry of the cycloadduct 22 was
established by decoupling experiments and nOe studies
(see Experimental).
The unsymmetrical diketone 23 was prepared to study the
selectivity of electrophile mediated cascades of its oxime
24. Cyclisation of 24 in the presence of PhSeBr (CH3CN,
258C 2h) and anhydrous K2CO3 (CH3CN, 258C, 2 h), added
sequentially, gave a 2:1 mixture of nitrones 27 and 28,
respectively, via the nitrone salts 25 and 26. The nitrones
were not isolated but were trapped in an intramolecular
cycloaddition by heating the mixture of nitrones in aceto-
nitrile (808C, 4 h) to afford the corresponding cycloadducts
29 (47%) and 30 (25%) (isolated overall yield from 24). The
stereochemical assignment of 29 is based on nOe data.
Irradiation of the signal for Hb (d 2.14) resulted in a 7%
enhancement of the signal for Hc(d 2.88) and a 4%
enhancement of the signal for Me (d 1.20). The signal for
Ha (d, 3.69) showed zero enhancement. The result
established a cis-relationship between Hc, Hb and Me
The formation of both nitrone salts 9 and 12 from oxime 8
indicates comparable rates of cyclisation via the corre-
sponding 5- and 6- membered transition states with non-
selective selenonium ion formation at bonds A and B. The
addition of the terminal ethyl substituent in 15 creates a
more electron rich environment at the D9-alkene and
promotes regioselective selenonium ion formation. Studies
were next extended to the symmetrical diketone 18. Oxime
19 reacted (CH3CN, 258C, 16 h) with phenylselenyl
bromide to afford nitrone salt 20. Treatment of 20 with
anhydrous potassium carbonate afforded nitrone 21 which
Scheme 8.

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H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
together with the relative stereochemistry of the spiro centre
which is the outcome of the expected concerted diastereo-
facially speci®c cycloaddition of the E-alkene to the nitrone
27 (Scheme 7). The stereochemistry of 30 was also assigned
from nOe data (see Experimental).
164 (10), 140 (13), 127 (77), 112 941), 73 (97), 55, (47) and
41 (100). d: 1.61 (m, 4H, 2£CH2), 2.09 (m, 4H, CH2), 2.35
and 2.20 (2£m, 2£2H, 2£CH2), 5.00 (m, 4H, CHvCH2),
5.84 (m, 2H, CHvCH2) and 8.8 (brs, 1H, OH).
endo-2,8a-Dimethyl-6-phenylselenylmethyl-hexahydro-
dipyrrolo[1,2-b;30,40-d]isoxazole-1,3-dione (4a) and exo-
2,8a-dimethyl-6-phenylselenylmethyl-hexahydro-dipyr-
rolo[1,2-b;30,40-d]isoxazole-1,3-dione (5a)
It is clear from the results with oxime 24 that there is both a
much reduced and reversed regioselectivity of nitrone
formation in this case compared to the corresponding
result with oxime 15. Thus the expected selectivity for
selenonium ion formation at the more substituted double
bond of 24 is not observed. A possible explanation of these
results is that the transition state for the 6-exo-tet cyclisation
of the oxime moiety onto the selenonium ion 31!28
involves a developing destabilising A1,2-strain9 between
the N±O bond and the MeCHSePh moiety requiring a
higher activation energy for this process compared to that
for cyclisation of the oxime moiety onto selenonium ion
32!27 (Scheme 8).
PhSeBr (0.21 g, 0.88 mmol) was added to a stirred solution
of oxime 1a (0.1 g, 0.88 mmol) in dry dichloromethane
(10 mL) and the mixture was stirred at rt for 0.5 h, during
which time quantitative conversion of the oxime into the
corresponding nitrone salt 2a occurred. Anhydrous K2CO3
(0.12 g, 0.88 mmol) was added and the reaction mixture was
stirred overnight to liberate the nitrone (proton NMR
showed a trace amount of the oxazine 3a). The dichloro-
methane was removed under reduced pressure, the residue
taken up in dry CH3CN (10 mL), NMM (0.1 g, 0.88 mmol)
added and the mixture heated at 808C for 9 h. After
cooling the solvent was removed under reduced pressure
and the residue was puri®ed by ¯ash chromatography
eluting with 1:1 v/v petroleum ether±diethyl ether to
give to give the product (0.23 g, 70% overall from oxime)
as a 3:2 mixture of endo- and exo- isomers. The isomers
were separated by fractional crystallisation from ethyl
acetate±ether.
Experimental
Nuclear magnetic resonance spectra and decoupling experi-
ments were determined at 300 MHz on a QE 300 instrument
and at 400 MHz on a Bruker AM400 spectrometer. Data
refer to 300 MHz unless otherwise speci®ed. Chemical
shifts are given in parts per million (d) down®eld from
tetramethylsilane as internal standard. Spectra were deter-
mined in deuteriochloroform except where otherwise stated.
The following abbreviations are used; sˆsinglet, dˆ
doublet, tˆtriplet, qˆquartet, mˆmultiplet, brˆbroad and
brsˆbroad singlet. Infra-red spectra were recorded on a
PU9706 IR Spectrophometer. Flash column chroma-
tography was performed using silica gel 60 (230±
400 mesh). Kieselgel columns were packed with silica gel
GF254 (Merck 7730). Petroleum ether refers the fraction
with bp 40±608C unless otherwise speci®ed. Melting points
were determined on a Ko¯er hot stage apparatus and are
uncorrected. Microanalyses were obtained using a Carlo±
Erba Model 1106 instrument. Mass spectra were recorded at
70 ev on a VG Autospec mass spectrometer. Oximes
(1a±d),10 8,11 1512 and 2412 were prepared by literature
methods.
4a. Obtained as colourless rods, mp 138.5±139.58C.
(Found: C, 53.5; H, 5.34; N, 7.1. C17H20N2O3Se requires
C, 53.8; H, 5.27; N, 7.38%). m/z (%) 379 (M1, 34), 209
(100), 98 (28) and 55 (56). d (400 MHz): 7.4 (m, 2H, ArH),
7.2 (m, 3H, ArH), 4.9 (d, 1H, Jˆ7.8 Hz, Hd), 3.3 (m, 2H, Hb
and He), 2.9 (m, 1H, Ha), 2.8 (dd, 1H, Jˆ12.2 and 8.8 Hz,
Hc), 2.7 (s, 3H, NMe), 2.56 (m, 1H), 1.96 (m, 1H), 1.8 (m,
1H), 1.61 (m, 1H) and 1.4 (s, 3H, Me).
NOEDS (%) (400 MHz) irradiation of the proton signal for
Hd caused enhancements of the proton signal for He (9.5).
Irradiation of the proton signal for Mea caused an enhance-
ment of proton signal for He (4.7).
General procedure for the oximation of aldehydes and
ketones
NH2OH´HCl (1.20 mmol) and NaOAC (1.50 mmol) were
added to a stirred solution of the aldehyde or ketone
(1.00 mmol) in 3:1 v/v CH3CN±H2O (30 mL) at room
temperature and stirring continued for a further 3 h. Most
of the CH3CN was removed under reduced pressure and the
remaining aqueous solution was extracted with CH2Cl2
(2£30 mL). The combined organic extracts were washed
with water (30 mL), dried (MgSO4), ®ltered, the solvent
removed under reduced pressure and the residue subjected
to column chromatography on silica, eluting with petroleum
ether±diethyl ether.
5a. Obtained as colourless rods, mp 128±1298C. (Found: C,
53.65; H, 5.2; N, 7.45. C17H20N2O3Se requires C, 53.8; H,
5.27; N, 7.38%). m/z (%) 380 (M1, 8), 209 (100), 95 (45)
and 55 (28). d (400 MHz): 7.5 (m, 2H, ArH), 7.3 (m, 3H,
ArH), 4.86 (d, 1H, Jˆ7.8 Hz, Hd), 3.5 (m, 1H, Ha), 3.4 (d,
1H, Jˆ7.8 Hz, He), 3.3 (dd, 1H, Jˆ12.1 and 5.0 Hz, Hb),
3.0 (s, 3H, NMe), 2.8 (dd, 1H, Jˆ12.1 and 9.8 Hz, Hc), 2.3
(m, 1H), 2.1 (m, 1H), 1.9 (m, 1H), 1.7 (m, 1H) and 1.2 (s,
3H, Me).
1, 10-Undecadien-6-one oxime 19. Obtained (76%) as a
colourless oil. (Found: C, 73.0; H, 10.8; N, 7.8. C11H19NO
requires C, 72.9; H, 10.55; N, 7.75%.); m/z (%) 181 (M1, 1),

H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
10093
endo-2,3b-Dimethyl-7-phenylselanylmethyl-hexahydro-
8-oxa-2,7a-diaza-cyclopenta[a]indene-1,3-dione (4c) and
exo-2,3b-dimethyl-7-phenylselanylmethyl-hexahydro-8-
oxa-2,7a-diaza cyclopenta[a]indene-1,3-dione (5c)
PhSeBr (0.18 g, 0.78 mmol) was added to a stirred solution
of oxime 1c (0.1 g, 0.78 mmol) in dry dichloromethane
(10 mL) and the mixture was stirred at rt for 0.5 h during
which time quantitative conversion of oxime into the corre-
sponding nitrone salt 2c occurred. Anhydrous K2CO3
(0.108 g, 0.78 mmol) was added and the reaction mixture
was stirred overnight to liberate the nitrone. The mixture
was ®ltered and to remove inorganic salts, dichloromethane
was removed under reduced pressure and the residue was
taken up in dry CH3CN (10 mL), NMM (0.1 g, 0.88 mmol)
added and the mixture heated at 808C for 9 h. After cooling
the solvent was removed under reduced pressure. The
residue was puri®ed by ¯ash chromatography eluting
with 1:1 v/v petroleum ether±diethyl ether to give to
give the product (0.22 g, 72% overall yield) as a 3:2
mixture of endo- and exo-isomers. The isomers were sepa-
rated by fractional crystallisation from ethyl acetate±
petroleum ether.
endo-2-Methyl-7-phenylselenylmethyl-hexahydro-8-oxa-
2,7a-diaza-cyclopenta[a]indene-1,3-dione (4b). A solu-
tion of 5-hexanal oxime 1b (0.10 g, 0.88 mmol) and PhSeBr
(0.21 g, 0.88 mmol) in dry CH3CN (10 mL) was stirred at
room temperature for 0.5 h. Anhydrous K2CO3 (0.12 g,
0.88 mmol) and NMM (0.20 g, 1.77 mmol) were then
added sequentially and the reaction mixture heated at
808C for 5 h. After cooling the solvent was removed
under reduced pressure and the residue puri®ed by Kieselgel
column chromatography, eluting with 1:1 v/v diethyl ether±
petroleum ether afforded the product (0.23 g, 61%) as a
single stereoisomer which crystallised from ethyl acetate±
petroleum ether as colourless ®ne needles, mp 104±1058C.
[Found (HRMS) 380.0632, C17H21N2O3Se requires
380.0639]. m/z (%) 380(M11, 3), 253 (4), 209 (100), 158
(19), 111 (7), 82(23) and 41 (35). nmax (nujol): 1780, 1710,
1580, 1420, 1310, 1290, 1130, 1070, 960, 730, 690, 630 and
610 cm21: d: 7.52 (m, 2H, ArH), 7.26 (m, 3H, ArH), 4.71 (d,
1H, Jˆ7.7 Hz, Ha), 3.6 (m, 1H, Hd), 3.40 (m, 2H, Hb and
CHSe), 3.00 (s, 3H, NMe), 2.79 (m, 2H, Hc and CHSe), 2.09
(m, 3H), 1.63 (m, 1H) and1.38 (m, 2H).
4c. Obtained as colourless rods, mp 111.5±112.58C.
(Found: C, 54.85; H, 5.55; N, 7.1. C18H22N2O3Se requires
C, 54.9; H, 5.6; N, 7.1%). m/z (%) 393 (M1, 20), 223 (100),
91 (45) and 41 (67). d. 7.45 (m, 2H, ArH), 7.25 (m, 3H,
ArH), 4.8 (d, 1H, Jˆ7.98 Hz, Hd), 3.4 (dd, 1H, Jˆ12.3 and
2.9 Hz, Hb), 3.24 (d, 1H, Jˆ7.98 Hz, He), 2.89 (dd, 1H, Jˆ
12.3 and 8.75 Hz, Hc), 2.78 (s, 3H, NMe), 2.62 (m, 1H, Ha),
2.42 (m, 1H), 1.97 (m, 1H), 1.79 (m, 1H), 1.49 (m, 1H), 1.34
(s, 3H, Me) and 1.14 (m, 2H).
5c. Obtained as colourless needles, mp 131.5±132.58C.
(Found: C, 54.95; H, 5.65; N, 7.15. C18H22N2O3Se requires
C, 54.9; H, 5.6; N, 7.1%). m/z (%) 393 (M1, 56), 223
(93), 98 (20) and 41 (43). d (400 MHz) (C6D6): 7.46
(m, 2H, ArH), 7.0 (m, 3H, ArH), 4.26 (d, 1H, Jˆ
8.36 Hz, Hd), 3.55(dd, 1H, Jˆ12.6 and 8.9 Hz, Hb),
2.7 (d, 1H, Jˆ 8.3 Hz, He), 2.66 (dd, 1H, Jˆ12.6 and
8.9 Hz, Hc), 2.54 (s, 3H, NMe), 2.35 (m, 1H, Ha), 1.86
(m, 2H), 1.26 (m, 1H), 1.1 (s, 3H, Me), 1.08 (m, 1H)
and 0.9 (m, 2H).

10094
H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
endo-2,3b-Dimethyl-8-phenylselenylmethyl-octahydro-
9-oxa-2,8a-diaza-cyclopenta[a]azulene-1,3 dione (4d)
and exo-2,3b-dimethyl-8-phenylselanylmethyl-octahydro-
9-oxa-2,8a-diaza-cyclopenta[a]azulene-1,3-dione (5d)
A solution of 7-octen-2-one oxime 1d (0.30 g, 2.12 mmol)
and PhSeBr (0.5 g, 2.12 mmol) in dry CH3CN (15 mL) was
stirred at room temperature for 48 h. Triethylamine (0.23 g,
0.31 mmol) and NMM (0.24 g, 2.12 mmol) were then added
sequentially and the reaction mixture heated at 808C for
16 h. After cooling the solvent was removed under reduced
pressure and the residue puri®ed by Kieselgel column
chromatography, eluting with 1:1 v/v diethyl ether±hexane
to afford the product (0.45 g, 55%) as a 3:1 mixture of endo-
4d and exo-5d.
4d. Obtained as colourless ®ne needles from ethyl acetate±
hexane, mp 101±1028C. (found: C, 56.2; H, 6.1; N, 6.8.
C19H24N2O3Se requires C, 55.9; H, 5.9; N, 6.9%). m/z (%)
408(M11, ,1), 237(100), 140(74), 111 (21), 77(20) and 41
(47). nmax (nujol): 2990, 1850, 1680, 1420, 1340, 1260,
1120, 1000, 960, 840, 720 and 670 cm21. d (400 MHz)
(C6D6): 7.57(m, 2H, ArH), 6.94 and 6.99 (2£m, 3H, ArH),
4.05 (d, 1H, Jˆ7.7 Hz, Ha), 3.43 (dd, 1H, Jˆ2.1 and
11.2 Hz, CHSe), 3.15 (dd, 1H, Jˆ9.0 and 11.2 Hz, CHSe),
3.08 (m, 1H, NCH), 2.51 (s, 3H, NMe), 2.43 (d, 1H,
Jˆ7.7 Hz, Hb), 1.81 (m, 3H), 1.27 and 1.48 (2£m, 4H),
1.06 (s, 3H, Mea) and 0.99(m, 1H).
Reaction of oxime 1a with PhSeCl±AgOTf
A suspension of PhSeCl (0.34 g, 1.76 mmol) and AgOTf
(0.45 g,1.76 mmol) in dry dichloromethane (10 mL) was
stirred at 08C in the dark. After 10 min. 1a (0.2 g,
1.76 mmol) was added and the reaction mixture stirred at
rt for 3 h. K2CO3 (1.24 g, 1.76 mmol) was then added and
stirring continued at rt for a further 16 h The mixture was
then ®ltered and the ®ltrate evaporated under reduced
pressure to give a thick oil which was chromatographed
on a short column of kieselgel to give nitrone 6a (0.24 g,
51%) and oxazine 3a (0.12 g, 25%).
Oxazine 3a. Identical to that reported previously.8 (Found:
C, 54.0; H, 5.4; N, 4.9. C12H15NOSe requires C, 53.74; H,
5.59; N, 5.22%). m/z (%) 269 (M111, 37), 252 (5),
112(100), 91 (75) and 43 (85). d: 7.52 (m, 2H, ArH), 7.25
(m, 3H, ArH), 3.76 (m, 1H, OCH), 3.25 (dd, 1H, Jˆ12.6 and
4.8 Hz, CHHSePh), 2.91 (dd, 1H, Jˆ12.6 and 8.1 Hz,
CHHSePh), 2.16 (m, 3H), 1.89 (s, 3H, Me and 1.48 (m, 1H).
Nitrone 6a. Identical to that reported previously.8 (Found:
C, 53.4; H, 5.4; N, 4.95. C12H15NOSe requires C, 53.74; H,
5.59; N, 5.22%). m/z (%) (FAB) 269 (M111, 100) and
112(20). d: 7.58 (m, 2H, ArH), 7.26 (m, 3H, ArH), 4.28
(m, 1H, NCH), 3.6 (dd, 1H, Jˆ12.7 and 3.3 Hz, CHHSePh),
3.24 (dd, 1H, Jˆ12.7 and 8.1 Hz, CHHSePh), 2.6 (m, 2H),
2.29 (m, 1H), 1.98 (s, 3H, Me), and 1.9 (m, 1H).
3-(1-Phenylselenyl-methyl)-hexahydro-cyclopenta[c]-
pyrrolo[1,2-b]isoxazole (11). A solution of deca-1,9-dien-
5-one oxime 8 (0.2 g, 1.20 mmol) and PhSeBr (0.28 g,
1.20 mmol) in dry CH3CN (10 mL) was stirred at room
temperature for 2 h. Anhydrous K2CO3 (0.2 g, 1.43 mmol)
was then added and stirring continued for a further 10 min
before the reaction mixture was boiled under re¯ux for 6 h.
After cooling the solvent was removed under reduced
pressure to leave a viscous yellow brown oil. The residue
was puri®ed by Kieselgel column chromatography, eluting
with 1:1 v/v diethyl ether±hexane to afford the product 11
(0.14 g, 35%) as a colourless viscous oil. (Found: C, 59.9;
H, 6.7; N, 4.3. C16H21NOSe requires C, 59.6; H, 6.5; N,
4.4%). m/z (%) 323 (M111, 100), 269 (6), 224(7), 210
(6), 152 (55) and 134 (6). nmax (nujol): 3060, 2940, 2860,
1580, 1470, 1435, 1320, 1290, 1020, 920, 730 and
5d. Obtained as colourless ®ne needles from ethyl acetate±
hexane, mp 124±1258C. (found: C, 56.1; H, 6.0; N, 6.8
C19H24N2O3Se requires C, 55.9; H, 5.9; N, 6.9%). m/z (%)
408(M11, 2), 237(100), 200 (5), 157 (18), 140(68), 111 (7),
77(19) and 41 (39). nmax (nujol): 2990, 1850, 1680, 1420,
1340, 1260, 1120, 1000, 960, 840, 720 and 670 cm21. d
(400 MHz) (C6D6): 7.55 (m, 2H, ArH), 7.03 (m, 3H,
ArH), 4.09 (d, 1H, Jˆ7.9 Hz, Ha), 3.37 (dd, 1H, Jˆ3.3
and 12.2 Hz, CHSe), 3.06 (m, 1H, NCH), 2.89 (dd, 1H,
Jˆ8.4 and 11.9 Hz, CHSe), 2.64 (s, 3H, NMe), 2.50 (d,
1H, Jˆ7.9 Hz, Hb), 1.76 (m, 1H), 1.48 (m, 3H), 1.33 (m,
1H), 1.24 (s, 3H, Mea), and 1.09 (m, 1H).

H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
10095
685 cm21. d (400 MHz): 7.48 (m, 2H, ArH), 7.22 (m, 3H,
ArH), 4.05 (dd, 1H, Jˆ6.6 and 8.9 Hz, Ha), 3.61(dd, 1H,
Jˆ2.6 and 8.9 Hz, Hb), 3.28(m, 2H, Hd and CHSe), 2.91
(m, 1H, CHSe), 2.47 (m, 1H, Hc), 1.98 (m, 4H), 1.77 (m,
2H) and 1.58 (m, 4H).
pressure and the residue was taken up in dry CH3CN
(10 mL) and the solution heated at 808C for 5 h. After cool-
ing the solvent was removed under reduced pressure and the
residue was puri®ed by Kieselgel column chromatography
eluting with 1:1 v/v petroleum ether±diethyl ether to give to
give the product (0.065 g, 65% yield) as a colourless thick
oil (Found: C, 60.85; H, 6.95; N, 3.95. C17H23NOSe requires
C, 60.7; H, 6.84; N, 4.16%). m/z (%) 336 (M1, 45), 192 (23),
91 (56) and 41 (40). d: (C6D6): 7.5 (d, 2H, Jˆ6.8 Hz, ArH),
6,97 (m, 3H, ArH), 3.8 (t, 1H, Jˆ8.7 Hz, He), 3.66 (dd, 1H,
Jˆ12.3 and 2.76 Hz, Ha), 3.15 (dd, 1H, Jˆ8,7 and 4.07 Hz,
Hd), 2.90 (dd, 1H, Jˆ12.3 and 8.7 Hz, Hb), 2.55 (m, 1H,
Hc), 2.17 (m, 1H), 2.05 (m, 1H, Hf), 1.9 (m, 1H) and 1.68±
0.84 (m, 10H).
3-(1-Phenylselenyl-propyl)-hexahydro-cyclopenta[c]pyr-
rolo[1,2-b]isoxazole (17). A solution of dodeca-1,9-dien-6-
one oxime 15 (0.1 g, 0.43 mmol) and PhSeBr (0.1 g,
0.43 mmol) in dry CH3CN (10 mL) was stirred at room
temperature for 2 h. Anhydrous K2CO3 (0.06 g,
0.45 mmol) was then added and stirring continued for a
further 1 h before the reaction mixture was boiled under
re¯ux for 5 h. After cooling the solvent was removed
under reduced pressure to leave a viscous yellow brown
oil. The residue was puri®ed by Kieselgel column chroma-
tography, eluting with 6:1 v/v petroleum ether±diethyl
ether, to afford the product (0.09 g, 61%) as a colourless
viscous oil which comprised a single stereoisomer. (Found:
C, 61.9; H, 7.2; N, 4.0. C18H25NOSe requires C, 61.6; H,
7.1; N, 4.0%). m/z (%) 351 (M111, 14), 194(27), 152(100),
134 (6), 93 (12)77 (14), 55 (16) and 41 (29). nmax (nujol):
3080, 2960, 2880, 1590, 1490, 1440, 1380, 1340, 1130, 920,
840, 740 and 700 cm21. d: 7.54 and 7.26 (2£m, 5H, ArH),
4.00 (t, 1H, Jˆ7.2 Hz, Ha), 3.59 (d, 1H, Jˆ7.9 Hz, Hb),
3.34 (m, 1H, Hd), 3.26 (m, 1H, He), 2.45 (m, 1H, Hc),
1.58, 1.78, 2.04 and 2.06 (4£m, 12H) and 1.05 (t, 3H,
Jˆ7.3 Hz, Me).
7-Phenylselenylmethyl-octahydro-cyclopenta[3,4]isoxa-
zolo[2,3-a]pyridine (29) and 7-(1-phenylselenylethyl-
octahydro-cyclopenta[3,4]isoxazolo[2,3-a]pyridine (30)
A solution of dodeca-1,10-dien-6-one oxime 24 (0.2 g,
1.02 mmol) and PhSeBr (0.24 g, 1.02 mmol) in dry
CH3CN (10 mL) was stirred at room temperature for 2 h.
Anhydrous K2CO3 (0.15 g, 1.02 mmol) was then added and
stirring continued for a further 1 h before the reaction mixture
was boiled under re¯ux for 4 h. After cooling the solvent was
removed under reduced pressure to leave a viscous yellow
brown oil. The residue was puri®ed by Kieselgel column
chromatography, eluting with 6:1 v/v petroleum ether±
diethyl ether to afford the products 29 (0.18 g, 47%) and
30 (0.09 g, 25%) as colourless viscous oils.
29. (Found: C, 61.6; H, 7.3; N, 4.1. C18H25NOSe requires C,
61.6; H, 7.1; N, 4.0%). m/z (%) 351(M21, 6), 180 (100),
157 (6), 91 (15), 77 (10), 55 (13) and 41 (19). d (400 MHz):
7.51 (m, 2H, ArH), 7.21 (m, 3H, ArH), 3.69(m, 1H, Ha),
3.46 (m, 1H, Hd), 2.88 (m, 2H, Hc and He), 2.14 (t, 1H,
Jˆ6.7, Hz, Hb), 2.01 (m, 4H), 1.52, 1.56 and 1.66 (3£m,
7H), 1.44 (m, 1H) and 1.20 (d, 3H, Jˆ6.7 Hz, Me).
4-Methyl-7-phenylselenylmethyl-octahydro-cyclopenta-
[3,4] isoxazolo[2,3-a]pyridine (22). PhSeBr (0.13 g,
0.55 mmol) was added to a stirred solution of oxime 19
(0.1 g, 0.55 mmol) in dry dichloromethane (10 mL) and
the mixture stirred at rt for 0.5 h to give the nitrone salt
quantitatively. Anhydrous K2CO3 (0.73 g, 0.55 mmol) was
added and the reaction mixture was stirred at room tempera-
ture for 16 h to generate the nitrone. The inorganic salt were
®ltered and the dichloromethane removed under reduced

10096
H. A. Dondas et al. / Tetrahedron 56 (2000) 10087±10096
30. (Found: C, 61.8; H, 7.4; N, 4.2. C18H25NOSe requires C,
61.6; H, 7.1; N, 4.0%). m/z (%) 351(M21, ,1), 194 (1), 166
(100), 55 (5) and 41 (5). nmax (nujol): 3020, 2920, 2860,
1570, 1470, 1430, 1370, 1200, 1030, 930, 900, 730 and
690 cm21. d: 7.81 (m, 2H, ArH), 7.06 (m, 3H, ArH), 4.10
(t, 1H, Jˆ8.7 Hz, Ha), 3.87 (m, 1H, He), 3.28 (dd, 1H,
Jˆ4.2 and 8.6 Hz, Hb), 2.62 (m, 1H, Hd), 2.24 (m, 1H,
Hc), 1.70 (m, 1H), 1.52 (m, 3H), 1.51 (d, 3H, Jˆ7.2 Hz,
Me), 1.42 (m, 4H) and 1.01 and 1.31 (2£m, 2£2H).
References
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Acknowledgements
We thank Mersin University (Turkey) (H. A. D.), Leeds
University and the EPSRC for support.
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