X = Y-ZH Systems as potential 1,3-dipoles. Part 51: Halogen-induced inter- and intra-molecular formation of nitrones from oximes and alkenes

Article abstract of DOI:10.1016/S0040-4020(00)01084-X

Oximes possessing γ- and δ-alkenyl substituents are cyclised by N-bromo- or N-iodosuccinimide, iodine or ICl to the corresponding cyclic nitrones or their dimeric H-bonded hydroiodide salts in good yield; facially specific cycloaddition of these nitrones,

Full text of DOI:10.1016/S0040-4020(00)01084-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1119±1128
XvY±ZH Systems as potential 1,3-dipoles. Part 51:q
Halogen-induced inter- and intra-molecular formation
of nitrones from oximes and alkenes
H. Ali Dondas,a Ronald Grigg,a,p Maria Hadjisoteriou,a Jasothara Markandu,a Peter Kennewellb
and Mark Thornton-Petta
aSchool of Chemistry, The University of Leeds, Woodhouse Lane, Leeds LS2 9JT, UK
bRoussel Scienti®c Institute, King®sher Drive, Swindon SN3 5BZ, UK
Received 4 September 2000; revised 19 October 2000; accepted 9 November 2000
AbstractÐOximes possessing g- and d-alkenyl substituents are cyclised by N-bromo- or N-iodosuccinimide, iodine or ICl to the corre-
sponding cyclic nitrones or their dimeric H-bonded hydroiodide salts in good yield; facially speci®c cycloaddition of these nitrones, and
others derived by cyclisation of d,d-bis(alkenyl) ketoximes or by iodine induced addition of acetaldoxime to cyclohexene, furnish isoxa-
zolidines. q 2001 Elsevier Science Ltd. All rights reserved.
The electrophile induced cyclisation of hetereoatom nucleo-
philes onto an appropriately located alkene is both a versa-
tile and a powerful method for the construction of
hetereocycles.2 We have been developing an interface
between these processes3 and our oxime!nitrone!cyclo-
addition cascades.4 In the preceding paper1 we reported our
results employing phenylselenyl bromide as the electrophile
trigger for nitrone formation. In this paper we report full
details of our studies with N-bromosuccinimide (NBS),
N-iodo succinimide (NIS), I2 and ICl5 as the electrophile
trigger.
NBS or iodine in methylene chloride at room temperature
via attack of the N-atom on the intermediate halonium ion.
Interesting differences arise because the reaction liberates a
proton from the oxime hydroxy group, which is scavenged
as succinimide in the former case but, unless a base is added,
results in salt formation in the latter case. Thus, 1a,b (E/Z
2:1) react with iodine (CH2Cl2, 258C, 2 h) to produce the
cyclic nitrone salts 2a,b in essentially quantitative yield.
Thus E/Z-isomerism is faster than the 5-exo-tet ring closure
step. Work-up of 2a,b without addition of base followed by
crystallisation from methylene chloride±hexane affords the
linear H-bonded dimeric salts 3a,b (Scheme 2). A crystal
structure of 3a established the structure unequivocally (Fig.
1).5,6
Oximes are ambident nucleophiles with either the oxygen or
nitrogen atom acting as the active site depending on the
co-reagents, solvent and pH of the reaction mixture. In
situations involving intramolecular nucleophilic attack the
E/Z-stereochemistry of the oxime and the relative rates of
E/Z-isomerisation versus N- or O-nucleophilic attack on, in
this case, the halonium ion also play a role.1 In cases of
intermolecular nucleophilic attack of aldoximes the
Z-oxime is sterically favoured over the E-oxime for N-attack
due to eclipsing of the N-lone pair and R group in the latter
case (Scheme 1). Analogous situations occur in ketoximes
with sterically disparate substituents.
Cyclic (E)-ketoxime 4, prepared from ketoester 4a, under-
goes cyclisation (I2, CH2Cl2, 258C, 6 h) to a 5:1 mixture of
cis- and trans- 5 in essentially quantitative yield. After
washing with aqueous sodium thiosulphate and reduction
(2 equiv. LiAlH4, Et2O, 358C, 16 h) the major cis-isomer 6
(Me/CH2OH) was obtained in 50% overall yield from 4. The
stereochemistry of 6 was unequivocally established by a
single crystal X-ray structure determination (Fig. 2; Scheme
3). An analogous sequence on 1a afforded a 4:1 mixture of
cis-8a and trans-7a in 53% yield whilst 1b affords a 3:1
mixture of cis-8b and trans-7b in 57% yield (Scheme 4).
Oximes react readily with alkenes when treated with either
q Part 50.1
Keywords: oximes; hetereoatom nucleophiles; dimeric nitrone salts
cycloaddition.
p
Corresponding author. Tel.: 144-113-2336501; fax: 144-113-2336501;
e-mail: r.grigg@chem.leeds.ac.uk
Scheme 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01084-X

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H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
Scheme 2.
Figure 1. X-Ray crystal structure of 3a.
A range of conditions was explored for cyclisation of 1a to
9a using iodine as the electrophile. The reaction occurred in
CH3CN, CH3NO2 or CH2Cl2 in the presence of K2CO3,
Ag2CO3 or Na2S2O3 in essentially quantitative yield in all
cases. The subsequent cycloaddition of 9a with NMM was
optimised in benzene at 408C (10 h) affording 11a and 12a
as a 2:1 mixture (50%) of the endo- and exo-stereoisomers.
The stereochemistry of cycloadducts 11a/12a is based on
n.O.e data (see Experimental). Oxime 1a reacts (K2CO3,
CH2Cl2, rt, N2, 2 h) quantitatively with ICI giving corre-
sponding nitrone 9a, which was trapped in a subsequent
cycloaddition reaction (NMM, CH3CN, 808C, 5 h) yielding
a 2:1 mixture (58%) of endo-11a and exo-12a, respectively.
Slow addition of NIS to 1a (CH2Cl2, rt, N2, 2 h) over a
period of 1 h afforded not only corresponding nitrone 9a,
but trace amounts (ca 5%) of the oxazine 10a also.
The reaction of 1b with I2 (CH2Cl2, rt, 2 h) gives a mixture
of the nitrone salt 2b and unreacted Z-1b in a 2:1 ratio,
respectively. This ratio is a re¯ection of the E/Z ratio of
1b and is a further example in which the rate of the nitrone
forming cyclisation exceeds the rate of E/Z-isomerisation.
In contrast to the analogous reaction of 1a O-alkylation to
give 7-membered ring oxazine 10b was not observed. Using
anhydrous K2CO3 to liberate 1b was unfavourable as it
destroyed the nitrone. With Tl2CO3 (NMM, THF, 408C,
7 h) cycloaddition took place affording a 2:1 mixture of
endo-11b and exo-12b in a very low yield (11% overall,
16% relative to E-1b). Repeating the iodine induced cycli-
sation of 1b to 2b (CH2Cl2, rt) over 10 h gave a consistent
ratio of 2b:Z-1b of 3.6:1. After washing with aqueous
sodium thiosulphate and cycloaddition (C6H6, 408C, 7 h) a
Figure 2. X-Ray crystal structure of 6.

H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
1121
Scheme 3. (i) NH2OH´HCl, CH3COONa, CH3CN, H2O, 208C; (ii) I2, CH2Cl2, 258C, 6 h; (iii) Na2S2O3 (aq), LiAlH4, Et2O, 358C, 16 h.
Scheme 4.
2:1 mixture (50% overall) of 11b and 12b was obtained.
Stereochemical assignments of cycloadducts are based on
n.O.e data (see Experimental).
analogous manner afforded 11d and 12d (33%) as a 2.3:1
mixture of endo- and exo-stereoisomers, but no oxazine 10d
was isolated in this case. The stereochemical assignments of
cycloadducts are based on n.O.e data (see Experimental).
The conversion of 1a,b into 11/12a±d constitute examples
of Class 3 processes (intramolecular nitrone formation±
intermolecular cycloaddition) (Scheme 5).1
In contrast to the iodine induced cyclisation, the reaction of
1a with NBS (CH2Cl2, 258C, 2 h) afforded a 2:1 mixture of
nitrone 9c and oxazine 10c, which re¯ected the 2:1 ratio of
anti- and syn-oximes in the starting material. Reaction of
this product mixture (C6H6, 808C, 13 h) with NMM afforded
a 2:1 mixture (78%) of endo-11c and exo-12c cycloadducts
together with 10c (61%). The isolated yields are based on
the anti/syn ratio of the oxime 1a. Oxime 1b treated in an
An intermolecular example is provided by the addition of
acetaldehyde oxime to cyclohexene (I2, CH2Cl2, 258C, 5 h),
which affords 13 as a single stereoisomer but in low yield
(Scheme 6). In this case, the oxime is a 40:60 mixture of syn-
Scheme 5.

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H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
Scheme 6. (i) Na2S2O3 (aq); (ii) NMM, C6H6, 808C, 1 h.
and anti-isomers and only the anti-isomer undergoes
addition. This situation conforms to that illustrated in
Scheme 1.
A Class 4 process (intramolecular nitrone formation±intra-
molecular cycloaddition) is provided by the conversion (I2,
CH2Cl2, 258C) of 16 to the nitrone salt in essentially
quantitative yield followed by a sodium thiosulphate wash
to give 17, which on heating (C6H6, 808C, 5 h) afforded 18
(53%) (Scheme 7).
The free base derived from the salt 13 undergoes cyclo-
addition with NMM (C6H6, 808C, 1 h) to give 14 as a single
stereoisomer in 36% overall yield from acetaldoxime
(Scheme 6). This is an example of Class 1 process (inter-
molecular nitrone formation±intermolecular cyclo-
addition).1 The stereochemistry of 14 was established by
an X-ray crystal structure determination (Fig. 3).5,6
In summary the inter- and intra-molecular halogen induced
reactions of oximes with alkenes occur via attack of the
oxime N-atom on the intermediate halonium ions. Reactions
involving the oxime O-atom are either not observed or
Figure 3. X-Ray crystal structure of 14.
Scheme 7. (i) NH2OH´HCl, CH3COONa, MeCN, H2O, 208C. (ii) I2, CH2Cl2, 258C, 16 h. (iii) C6H6, 808C 5 h.

H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
1123
constitute a minor pathway. Thus in general E/Z-oxime
isomerisation is faster than nucleophilic attack of oximes
on the halonium ions. Examples of Class 1, 3 and 4
processes are provided.
(protonated nitrone, 100) and 113 (5). nmax (nujol):
3450(br), 1710, 1640, 1440, 1400, 1360, 1210, 990,
860 cm21. d (400 MHz) (C6D6): 4.70 (brs, 2H, NCH),
3.88 (dd, 2H, Jˆ11.1, 4.0 Hz, CHI), 3.51 (d, 2H, Jˆ
11.5 Hz, CHI), 3.28 (brs, 1H, OH), 2.93 (m, 4H), 2.65 and
2.68 (2£m, 2H), 2.33 (s, 6H, Me) and 1.90 (m, 2H).
1. Experimental
1.2.2. Compound 3b. Iodine (0.2 g, 0.78 mmol) was added
to a stirred solution of 6-hepten-2-one oxime 1b (0.1 g,
0.78 mmol) in acetonitrile and the reaction mixture stirred
at room temperature for 24 h. Hexane was added to the
mixture until the solution became cloudy. It was then cooled
in liquid nitrogen and the product (0.15 g, 30%) was
induced to crystallise, by scratching, as pale brown blocks,
mp 144.5±145.58C. Found: C, 26.4; H, 4.0; N, 4.3, I, 60.0.
C14H25N2O2I3 requires C, 26.4; H, 4.05; N, 4.4; I, 60.0%.
m/z (%) 507 (M12I, 28), 254 (protonated nitrone, 100) and
127 (5.0). d: 8.6 (brs, 1H, OH), 4.24 (brs, 2H, NCH) 3.85
(dd, 2H, Jˆ11.5, 4.0 Hz, CHI), 3.61 (dd, 2H, Jˆ11.5 Hz,
CHI), 2.91 (m, 2H), 2.64 (m, 2H), 2.4 (s, 6H, Me), 2.39 (m,
2H), 2.15 (m, 4H) and 1.86 (m, 2H).
Nuclear magnetic resonance spectra and decoupling experi-
ments were determined at 300 MHz on a Q.E 300 instru-
ment and at 400 MHz on a Bruker AM400 spectrometer as
speci®ed. Chemical shifts are given in parts per million (d)
down®eld from tetramethylsilane as internal standard.
Spectra were determined in deuteriochloroform except
where otherwise stated. The following abbreviations are
used: sˆsinglet, dˆdoublet, tˆtriplet, qˆquartet, mˆmulti-
plet, brˆbroad and brsˆbroad singlet. Infrared spectra were
recorded on a PU9706 IR Spectrophometer. Flash column
chromatography 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,b
and 4 were prepared by literature methods.7,8
1.2.3. 4a-Hydroxymethyl-2-methyl-octahydro-quinolin-
1-ol (6). Iodine (0.21 g, 0.83 mmol) was added to a stirred
solution of oxime 4 (0.2 g, 0.83 mmol) in dry dichloro-
methane (10 mL) and the mixture was stirred at rt for 6 h.
Dichloromethane (25 mL) was added and the mixture
washed with aqueous Na2S2O3 solution, dried (MgSO4),
and the solvent removed under reduced pressure. The resi-
due was taken up in dry ether, LiAlH4 (0.064 g, 1.67 mmol)
added and the mixture boiled under re¯ux for 16 h. After
cooling, 10% NaOH solution was added dropwise to the
mixture until a clear ether layer was obtained. The ether
layer was decanted and the precipitate washed further
with (20 mL) ether. The combined ether layers were dried
(MgSO4) and the solvent removed under reduced pressure to
give the product (0.08 g, 50%), which crystallised as colour-
less prisms from ether, mp 153±1548C. Found: C, 66.15; H,
10.8; N, 6.95. C11H21NO2 requires C, 66.3; H, 10.6; N,
7.05%. m/z (%) 199 (M1, 38), 184 (100), 182 (81) 168
(31) 166 (20) and 152 (28). d ( MHz): 4.18 (dd, 1H,
Jˆ11.0, 1.9 Hz, CHHOH), 3.4 (d, 1H, Jˆ11.0 Hz, CHHOH),
2.58 (m, 1H, NCHMe), 2.4 (dd, 1H, Jˆ11.5, 3.0 Hz, NCH),
2.23 (m, 1H), 1.96 (m, 1H), 1.85 (m, 1H), 1.65 (m, 2H), 1.47±
1.21 (m, 6H), 1.19 (d, 3H, Jˆ6.0 Hz, Me) and 1.07 (m, 1H).
1.1. General procedure for the oximation of aldehydes
and ketones
NH2OH´HCl (1.2 mmol) and NaOAC (1.5 mmol) were added
to a stirred solution of the aldehyde (or ketone) (1.0 mmol) in
3:1 v/v CH3CN±H2O (30 mL) at room temperature and stir-
ring continued for a further 3 h. Most of 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.
1.1.1. 1,10-Undecadien-6-one oxime 16. 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), 164 (10), 140 (13), 127 (77), 112 941), 73 (97),
55, (47) and 41 (100). d: 8.8 (brs, 1H, OH), 5.84 (m, 2H,
2£CHv), 5.0 (m, 4H, 2£CH2), 2.35 (m, 2H), 2.20 (m, 2H),
2.09 (m, 4H) and 1.61 (m, 4H).
1.2.4. trans-2,5-Dimethylpyrrolidin-1-ol (7a) and cis-2,5-
dimethyl pyrrolidin-1-ol (8a). Iodine (0.68 g, 2.7 mmol)
was added to a stirred solution of 6-hexen-2-one oxime 2a
(0.3 g, 2.7 mmol) in nitromethane (10 mL) and the reaction
mixture heated at 808C for 3 h. After cooling, nitromethane
was removed under reduced pressure, the residue taken up
in dichloromethane (20 mL) and washed with aqueous
Na2S2O3 solution (20 mL). The dichloromethane solution
was dried (MgSO4), the solvent removed under reduced
pressure, the residue taken up in dry ether (10 mL),
LiAlH4 (0.21 g, 5.39 mmol) added and the mixture stirred
at room temperature for 5 h. The mixture was then quenched
by the addition of 2N NaOH dropwise until a clear ether
layer was obtained. The ether was decanted, dried (MgSO4),
and the solvent removed under reduced pressure at room
temperature to leave a colourless oil that comprised a 4:1
mixture (1H NMR) of 7a and 8a. Puri®cation by ¯ash
1.2. Oxime!nitrone!cycloaddition cascades
1.2.1. Compound 3a. Iodine (0.23 g, 0.92 mmol) was added
to a stirred solution of 5-hexen-2-one oxime 1a (0.1 g,
0.92 mmol) in nitromethane (10 mL) and the mixture heated
at 808C for 2 h. After cooling, nitromethane was removed
under reduced pressure. The residue was taken up in a mini-
mum volume of acetonitrile and hexane was added until the
solution became cloudy. It was then cooled in liquid nitro-
gen and the product (0.08 g, 26%) was induced to crystal-
lise, as a pale brown prisms by scratching, mp 126±1278C.
Found: C, 23.7; H, 3.5; N, 4.5, I, 62.9. C12H21N2O2I3
requires C, 23.8; H, 3.7; N, 4.6; I, 62.7%). m/z (%) 240

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H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
chromatography eluting with diethyl ether afforded 7a
(0.03 g, 15%) and 8a (0.08 g, 23%).
rated under reduced pressure. The residual oil was dissolved
in benzene (10 mL), NMM (0.1 g, 0.89 mmol) added and
the resulting solution heated at 408C for 6.5 h. After cooling,
the solvent was removed under reduced pressure and the 1H
NMR spectrum of the product mixture revealed to comprise
a 2:1 mixture of 11a and 12a. Puri®cation by Kieselgel
chromatography eluting with 1:1 v/v ethyl acetate±diethyl-
ether afforded the products in 59% combined yield.
trans-7a. Obtained as a colourless liquid, found: C, 62.4; H,
11.5; N, 12.1. C6H13NO requires C, 62.7; H, 11.4; N, 12.2%.
m/z (%) (FAB): 115 (M1, 11), 114 (100), 98 (15), 85 (12), 83
(29) and 56 (5). nmax (nujol): 3250 (brs), 2950, 2860, 1590,
1370, 1120 and 860 cm21, d: 3.31 (m, 2H, 2£ NCH), 1.96
(m, 2H), 1.23 (m, 2H) and 1.15 (d, 6H, Jˆ 6.0 Hz, 2£CH3).
11a. Obtained as colourless needles from ethyl acetate±
hexane, mp 139±1418C. Found: C, 37.6; H, 4.2; I, 36.0;
N, 7.9. C11H15IN2O3 requires C, 37.7; H, 4.3; I, 36.2; N,
8.0%. m/z (%) 350 (M1, 29), 335 (11) 239 (26), 209
(100), 112 (43), 55 (46) and 41 (30). nmax (nujol): 2950,
cis-8a. Obtained as a colourless liquid, found: C, 62.6; H,
11.3; N, 12.0. C6H13NO requires C, 62.7; H, 11.4; N, 12.2%.
m/z (%) (FAB): 116 (M111, 1), 114 (100), and 98 (16), nmax
(nujol): 3300 (brs), 2960, 2860, 1450, 1370, 1320, 1200,
1140, 1020, 970 and 820 cm21, d: 6.30 (brs, 1H, OH),
2.78 (m, 2H, 2£NCH), 1.29, 1.43 (2£m, 2£2H) and 1.22
(d, 6H, Jˆ6.0 Hz, 2£CH3).
1720, 1440, 1400, 1300, 1100, 990, 840 cm21
. d
(400 MHz): 1.44 (s, 3H, Mea), 1.72 (m, 1H), 1.89 (m,
2H), 2.55 (m, 1H), 3.01 (s, 3H, NMe), 3.12 (m,1H, Hc),
3.27 (dd, 1H, Jˆ7.5, 10.0 Hz, CHI), 3.33 (d, 1H, Jˆ
8.0 Hz, Hb), 3.51 (dd, 1H, Jˆ4.4, 10.0 Hz, CHI) and 4.98
(d, 1H, Jˆ8.0 Hz, Ha).
1.2.5. trans-2,6-Dimethylpiperidin-1-ol (7b) and cis-2,6-
dimethylpiperidin-1-ol (8b). Iodine (0.6 g, 2.3 mmol) was
added to a stirred solution of 6-hepten-2-one oxime 2b
(0.3 g, 2.3 mmol) in nitromethane (10 mL) and the reaction
mixture heated at 808C for 1 h. After cooling, nitromethane
was removed under reduced pressure, the residue taken up
in dichloromethane (20 mL) and washed with aqueous
Na2S2O3 solution (20 mL). The dichloromethane solution
was dried (MgSO4), the solvent removed under reduced
pressure, the residue taken up in dry ether (10 mL),
LiAlH4 (0.18 g, 4.7 mmol) added and the mixture stirred
at room temperature for 16 h. The mixture was then
quenched by the addition of 2N NaOH dropwise until a
clear ether layer was obtained. The ether was decanted,
dried (MgSO4), and the solvent removed under reduced
pressure at room temperature to leave a colourless oil that
comprised a 3:1 mixture (1H NMR) of 7b and 8b. Puri®ca-
tion by ¯ash chromatography eluting with diethyl ether
afforded 7b (34%) and 8b (23%) as colourless solids.
cis-7b. Crystallised as colourless needles from ether±petro-
leum ether, mp 125±1268C. Found: C, 64.9; H, 11.45; N,
10.65. C7H15NO requires C, 65.05; H, 11.7; N, 10.85%. m/z
(%) 130 (M111, 100), 129 (M1, 5) and 128 (11). d: 5.0 (brs,
1H, NOH), 2.52 (m, 2H, 2£NCH), 1.75 (m, 2H), 1.6 (m,
1H), 1.24 (m, 3H) and 1.2 (d, 6H, Jˆ6.0 Hz, 2£CH3).
12a. Obtained as colourless rhombs from ethyl acetate±hex-
ane, mp 103±1048C. Found: C, 37.6; H, 4.4; I, 36.1; N, 7.9.
C11H15IN2O3 requires C, 37.7; H, 4.3; I, 36.2; N, 8.0% m/z
(%) 350 (M1, 27), 335 (12) 239 (22), 209 (100), 112 (52), 98
(58), 86 (17), 55 (51) and 41 (59). nmax (nujol): 2950, 1720,
1440, 1400, 1290 and 840 cm21. d (400 MHz): 1.24 (s, 3H,
Mea), 1.79, 1.95, 2.16 and 2.34 (4£m, 4H), 3.03 (s, 3H,
NMe), 3.19 (d, 1H, CHI), 3.82 (d, 1H, Jˆ8.0 Hz, Hb),
3.36 (m, 2H, Hc and CHI) and 4.97 (d, 1H, Jˆ8.0 Hz, Ha).
trans-8b. Crystallised as colourless needles from ether±
petroleum ether, mp 109±1108C. Found: C, 64.9; H, 11.8;
N, 10.7. C7H15NO requires C, 65.05; H, 11.7; N, 10.85%.
m/z (%) 130 (M11, 33) and 127 (90). d: 3.42 (m, 1H, NCH),
3.0 (m, 1H, NCH), 1.35±1.92 (m, 6H) and 1.15 (d, 6H,
Jˆ6.4 Hz, 2£CH3).
1.3. endo-6-Iodomethyl-2,8a-dimethylhexahydro-
dipyrrolo[1,2-b;30,40-d]isoxazole-1,3-dione (11a) and
exo-6-iodomethyl-2,8a-dimethylhexahydrodipyrrolo-
[1,2-b;30,40-d]isoxazole-1,3-dione (12a)
1.3.1. I2 as the electrophile. A solution of 5-hexen-2-one
oxime 1a (0.10 g, 0.89 mmol), and iodine (0.23 g, 0.89 mmol)
in dry dichloromethane (10 mL) were stirred at room tempera-
ture for 5 min followed by addition of anhydrous K2CO3
(0.14 g, 0.98 mmol) and stirring at room temperature for a
further 1 h. The mixture was ®ltered and the ®ltrate evapo-

H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
1125
1.3.2. ICI as the electrophile. A solution of 5-hexen-2-one
oxime 1a (0.10 g, 0.89 mmol), ICI (0.14 g, 0.89 mmol) and
anhydrous K2CO3 (0.12 g, 0.97 mmol) in dry dichloro-
methane (10 mL) was stirred at room temperature for
1.5 h, under a nitrogen atmosphere. The dichloromethane
was removed under reduced pressure and acetonitrile
(10 mL) and NMM (0.10 g, 0.89 mmol) were added and
the mixture heated at 808C for 4 h. After cooling, the solvent
was removed under reduced pressure. The residual oil was
puri®ed by Kieselgel chromatography eluting with 1:1 v/v
ethyl acetate±hexane, to give a 2:1 mixture of 11a and 12a
(0.18 g, 58%). The cycloaddition was also carried out in
benzene, which afforded a 2:1 mixture of 11a and 12a in
60% yield.
11b. Contaminated with 12b. d (400 MHz): 1.26 (s, 3H,
Mea), 1.52 and 1.62 (2£m, 2H), 1.72 (m, 2H), 2.14 and
2.33 (2£m, 2H), 2.65 (m, 1H, Hc), 2.97 (s, 3H, NMe),
3.16 (t, 1H, Jˆ7.5 Hz, CHI), 3.28 (d, 1H, Jˆ8.0 Hz, Hb),
3.52 (dd, 1H, Jˆ2.0, 9.5 Hz, CHI) and 4.88 (d, 1H, Jˆ
8.0 Hz, Ha).
1.3.3. NIS as the electrophile. NIS (1.0 g, 4.45 mmol) was
added slowly with stirring over 1 h to a solution of 5-hexen-
2-one oxime 1a (0.50 g, 4.45 mmol) in dry dichloromethane
(20 mL) and stirring was continued at rt for 2 h. The
dichloromethane was removed under reduced pressure and
benzene (10 mL) and NMM (0.10 g, 0.89 mmol) were
added to the residue and the mixture was heated at 408C
for 10 h. After cooling, the solvent was removed under
reduced pressure. The residue was puri®ed by Kieselgel
chromatography eluting with 1:1 v/v ethyl acetate±hexane,
to give a 2:1 mixture of 11a and 12a (0.65 g, 42%) together
with the oxazine 10a (0.03 g, 3%).
12b. Obtained as colourless ®ne needles from ethyl acetate±
hexane, mp 133±1348C. d (400 MHz): 1.21 (s, 3H, Mea),
1.52 and 1.62 (2£m, 2H), 1.72 (m, 2H), 2.14 and 2.33 (2£m,
2H), 2.57 (m, 1H, Hc), 3.01 (s, 3H, NMe), 3.06 (dd, 1H,
Jˆ8.5, 11.0 Hz, CHI), 3.61 (dd, 1H, Jˆ2.5, 10.0 Hz, CHI)
3.65 (d, 1H, Jˆ8.5 Hz, Hb), and 5.12 (d, 1H, Jˆ8.5 Hz, Ha).
1.3.4. 6-Iodomethyl-3-methyl-5,6-dihydro-4H-[1,2]oxazine
(10a). Obtained as colourless rhombs from ethyl acetate, mp
39±408C. Found: C, 30.0; H, 4.2; N, 6.0. C6H10INO requires
C, 30.2; H, 4.2; N, 5.9%, m/z (%) 239 (M1, 48), 170 (6), 141
(10), 127 (19), 112 (61), 98 (39), 81 (21), 68 (24), 56 (46)
and 41 (39). nmax (nujol): 2990, 2840, 1620, 1440, 1360 1320,
1300, 1250, 1210, 1090, 1040, 1000, 920, 890, 830,
690 cm21. d (400 MHz): 3.68 (m, 1H, OCH), 3.36 (dd, 1H,
Jˆ4.0, 10.0 Hz, CHI), 3.19 (dd, 1H, Jˆ7.5, 10.0 Hz, CHI),
2.22 (m, 2H) 2.16 (m, 1H) 1.93 (s, 3H, Me) and 1.72 (m, 1H).
1.3.5. endo-7-Iodomethyl-2,3b-dimethyl-8-oxa-2,7a-diaza-
cyclopenta[a]indene-1,3-dione (11b) and exo-7-iodo-
methyl-2,3b-dimethyl-8-oxa-2,7a-diazacyclopenta[a]-
indene-1,3-dione (12b). Iodine (0.68 g, 2.70 mmol) was
added to a stirred solution of 6-hepten-2-one oxime 1b
(0.20 g, 1.50 mmol) in dry dichloromethane (10 mL) and
stirring was continued at room temperature for 10 h. The
mixture was then washed with saturated aqueous Na2S2O3
(20 mL), extracted with dichloromethane (2£20 mL), the
combined organic extracts dried (MgSO4), ®ltered, and the
solvent evaporated under reduced pressure. The residual oil
was taken up in benzene (20 mL), NMM (0.18 g,
1.50 mmol) added and the mixture heated at 808C for 5 h.
After cooling the solvent was removed under reduced pres-
1.3.6. endo-6-Bromomethyl-2,8a-dimethyl-hexahydro-
dipyrrolo[1,2-b;30, 40-d]isoxazole-1,3-dione (11c) and
exo-6-Bromomethyl-2,8a-dimethyl-hexahydro-dipyrrolo-
[1,2-b;30,40-d]isoxazole-1,3-dione (12c). A solution of
5-hexen-2-one oxime 1a (0.50 g, 4.45 mmol) and NBS
(0.79 g, 4.45 mmol) in dry dichloromethane (20 mL) was
stirred at room temperature for 2 h. The dichloromethane
was removed under reduced pressure, the residue taken up
in benzene (20 mL), NMM (0.5 g, 4.45 mmol) added and
the resulting solution heated at 608C for 13 h. After cooling,
the solvent was removed under reduced pressure to leave a
yellow brown oil, which was puri®ed by ¯ash chroma-
tography eluting with 1:1 v/v ethyl acetate±hexane to give
a 2:1 mixture of 11c and 12c (0.70 g, 78% relative to E-1a)
and the oxazine 10c (0.17 g, 61% relative to Z-1a).
1
sure and the H NMR spectrum of the residue showed it to
comprise a 2:1 mixture of 11b and 12b. Kieselgel column
chromatography eluting with 1:1 v/v ethyl acetate±hexane
afforded 11b and 12b (0.29 g, 50%). Only 12b could be
isolated pure by fractional crystallisation. Found (mixed
isomers): C, 39.6; H, 4.8; I, 38.8; N, 7.6. C12H17IN2O3
requires C, 39.6; H, 4.7; I, 34.9; N, 7.7%). m/z (%) (mixed
isomers) 364 (M1, 19), 349 (11), 223 (100), 110 (6), 55 (10)
and 41 (21). nmax (nujol) (mixed isomers):1770, 1690, 1440,
10c. Obtained as colourless rhombs from diethylether±
hexane, mp 25±268C. Found: C, 37.4; H, 5.2; Br, 41.8; N,
1340, 1280, 1140 and 960 cm21
.

1126
H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
7.4. C6H10BrNO requires C, 37.5; H, 5.2; Br, 41.6; N, 7.3%.
m/z (%) 193 (M1, 16), 191 (M1, 16), 98 (100), 94 (7), 81 (9),
68 (20) and 56 (18). d: 3.87 (m, 1H, OCH), 3.54 (dd, 1H,
Jˆ5.0, 10.5 Hz, CHBr), 3.39 (dd, 1H, Jˆ6.5, 10.5 Hz,
CHBr), 2.25 (m, 2H), 2.17 (m, 1H), 1,93 (s, 3H, Me) and
1.79 (m, 1H).
exo-7-bromomethyl-2,3b-dimethyl-hexahydro-8-oxa-
2,7a-diazacyclopenta[a]indene-1,3-dione (12d). A solu-
tion of 6-hepten-2-one oxime 1b (0.20 g, 1.60 mmol), and
NBS (0.28 g, 1.60 mmol) in dry dichloromethane (20 mL)
were stirred at room temperature for 2 h. The dichloro-
methane was removed under reduced pressure. The residue
was taken up in benzene (20 mL), NMM (0.18 g, 1.60 mmol)
added and the resulting solution heated at 608C for 13 h. After
cooling the solvent was removed under reduced pressure and
the residual oil puri®ed by ¯ash chromatography eluting with
1:1 v/v ethyl acetate±hexane to give a 1:2.3 mixture (0.16 g,
33%) of 11d and 12d. Found (mixed isomers): C, 45.2; H,
5.4; Br, 25.3; N, 8.8. C12H17BrN2O3 requires C, 45.4; H, 5.7;
Br, 25.2; N, 8.8%). m/z (%) (mixed isomers) 318 (M1, 2), 316
(M1, 2), 303 (7), 301 (7), 223 (100), 112 (6), 55 (17), and 41
(21). nmax (nujol) (mixed isomers): 1780, 1700, 1440, 1370,
1340, 1280, 1140 and 960 cm21.
11c. Obtained as colourless rhombs from ethyl acetate±
hexane, mp 116±1178C. Found: C, 43.9; H, 5.1; Br, 26.6;
N, 9.4. C11H15BrN2O3 requires C, 43.6; H, 5.0; Br, 26.4; N,
9.2%. m/z (%) 304 (M1, 10), 302 (M1, 10), 289 (13), 287
(13), 209 (100), 193 (19), 191 (19), 112 (75) and 98 (65).
n
max (nujol): 2940, 1790, 1720, 1450, 1390, 1290, 1140 and
990 cm21. d: 4.99 (d, 1H, Jˆ8.0 Hz, Ha), 3.51 (dd, 1H,
Jˆ5.5, 10.5 Hz, CHBr), 3.34 (d, 1H, Jˆ8.0 Hz, Hb), 3.12
(m, 1H, Hc), 3.02 (s, 3H, NMe), 2.56 (m, 1H), 1.86 (m, 2H),
1.69 (m, 2H), and 1.44 (s, 3H, Mea).
11d. Obtained as colourless solid contaminated with 12d d:
4.88 (d, 1H, Jˆ8.1 Hz, Ha), 3.70 (dd, 1H, Jˆ2.5, 8.9 Hz,
CHBr), 3.28 (d, 1H, Jˆ8.6 Hz, Hb), 3.24 (CHBr signal
overlapping with doublet of Hb and triplet of CHBr of
12d) 2.98 (s, 3H, NMe), 2.63 (m, 1H, Hc), 2.40 (m, 1H),
1.82 (m, 2H), 1.36 (s, 3H, Mea) and 1.23 (m, 2H).
12c. Obtained as colourless rhombs from ethyl acetate±
hexane, mp 133±1348C. (Found: C, 43.9; H, 5.1; N, 9.4.
C11H15BrN2O3 requires C, 43.6; H, 5.0; N, 9.2%). m/z (%)
304 (M1, 12), 302 (M1, 13), 287 (12), 285 (12), 209 (100),
193 (27), 191 (18), 112 (85), 55 (37) and 41 (47). nmax
(nujol): 2940, 1790, 1720, 1450, 1360, 1290, 1140 and
990 cm21. d: 5.00 (d, 1H, Jˆ8.0 Hz, Ha), 3.66 (m, 2H, Hc
and CHBr), 3.47 (d, 1H, Jˆ8.0 Hz, Hb), 3.19 (m, 1H,
CHBr), 3.04 (s, 3H, NMe), 2.36, 2.18, 2.11 and 1.79
(4£m, 4£H) and 1.25 (s, 3H, Mea).
12d. Obtained as colourless needles from ethyl acetate±
hexane, mp 129±1308C. d: 5.14 (d, 1H, Jˆ8.4 Hz, Ha),
3.78 (dd, 1H, Jˆ2.5, 10.0 Hz, CHBr), 3.66 (d, 1H, Jˆ
8.5 Hz, Hb), 3.24 (dd, 1H, Jˆ9.0, 10.0 Hz, CHBr), 3.02
(s, 3H, NMe), 2.76 (m, 1H, Hc), 1.76 and 2.24 (2£m,
2£2H), 1.23 and 1.47 (2£m, 2£1H) and 1.21 (s, 3H, Mea).
1.3.7. endo-7-Bromomethyl-2,3b-dimethyl-hexahydro-8-
oxa-2,7a-diazacyclopenta[a]indene-1,3-dione (11d) and

H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
1127
1.3.8. 2-(2-Iodo-cyclohexyl)-3,5-dimethyltetrahydropyr-
rolo[3,4-d]isoxazole-4,6-dione (14). An ice cold solution
of acetaldehyde oxime (0.14 g, 2.43 mmol) in dry dichloro-
methane (5 mL) was added to a solution of cyclohexene
(0.20 g, 2.43 mmol) and iodine (0.63 g, 2.43 mmol) in dry
dichloromethane (20 mL) cooled to 08C. The reaction
mixture was stirred and allowed to reach room temperature.
The solution was then washed with saturated aqueous
Na2S2O3 (30 mL), extracted with dichloromethane
(2£20 mL), the combined organic layers dried (MgSO4),
®ltered and the ®ltrate evaporated under reduced pressure.
The residual oil was immediately taken up in benzene
(10 mL), NMM (0.27 g, 2.43 mmol) added and the solution
heated under re¯ux for 1 h. After cooling the solvent was
evaporated under reduced pressure. The residual deep
brown oil was puri®ed by Kieselgel column chroma-
tography eluting with 2:3 v/v diethylether±ethyl acetate to
afford the product (0.2 g, 25%), which crystallised from
ethyl acetate±hexane as colourless cubes, mp 128±1298C.
Found: C, 41.1; H, 5.1; I, 33.7; N, 7.5. C13H19IN2O3 requires
C, 41.3; H, 5.1; I, 33.5; N, 7.4%. m/z (%) 378 (M1, 12), 251
(11), 209 (37), 170 (6), 112 (10), 81 (100), 55 (12) and 41
(40). nmax (nujol): 2900, 1710, 1450, 1370, 1290, 1280,
1190, 1050, 940 and 860 cm21. d (400 MHz) (C6D6): 4.19
(m, 1H), 3.89 (d, 1H, Jˆ7.5 Hz), 3.42 (q, 1H, Jˆ6.5 Hz),
2.87 (m, 1H), 2.67 (s, 3H, NMe), 2.29 (d, 1H, Jˆ7.5 Hz),
1.92 (m, 2H), 1.51 (m, 4H), 1.08 (m, 4H) and 0.63 (d, 1H,
Jˆ6.5 Hz, NCMe).
1.4. Single crystal X-ray diffraction analysis of 3a, 6 and
14
Crystallographic data for all three structures were measured
on a Stoe STADI4 4-circle diffractometer using v ±u scans.
The data sets of 3a and 14 were corrected for absorption
semi-empirically using azimuthal y-scans. All three struc-
tures were solved by direct methods using shelxs-869 and
were re®ned by full-matrix least-squares (based on F2) using
shelxl-93.10 The weighting scheme used in all re®ne-
21
ments was w ˆ ‰sꢀFo2† 1 ꢀxP†2 1 yPŠ where P ˆ ꢀFo2 1
2Fc2†=3: In all cases, all non-hydrogen atoms were re®ned
with anisotropic displacement parameters whilst hydrogen
atoms were constrained to predicted positions using a riding
model a rotational parameter for methyl and hydroxyl
groups. The residuals wR2 and R1, given below, are de®ned
1.3.9. 7-Iodomethyl-octahydro-cyclopenta[3,4]isoxazolo-
[2,3-a]pyridine (18). A solution of undeca-1,10-dien-6-one
oxime 16 (0.20 g, 1.10 mmol), iodine (0.28 g, 1.10 mmol)
and the base (K2CO3 or Tl2CO3) (1.22 mmol) in dry
dichloromethane (10 mL) was stirred at room temperature
for 16 h. The solution was then washed with saturated
aqueous Na2S2O3 (30 mL), extracted with dichloromethane
(2£ 20 mL), the combined organic layers dried (MgSO4),
®ltered and the ®ltrate evaporated under reduced pressure.
The residual oil was immediately taken up in dry benzene
(10 mL) and the solution heated under re¯ux for 5 h. After
cooling the solvent was removed under reduced pressure to
leave a viscous deep brown oil, which was puri®ed by
Kieselgel column chromatography eluting with 1:1 v/v
diethyl ether±ethyl acetate to afford the product (0.11 g,
33%) as a viscous colourless oil. Found: C, 43.3; H, 6.2;
I, 41.2; N, 4.5. C11H18INO requires C, 43.0; H, 6.4; I, 41.0;
N, 4.6% m/z (%) 307 (M1, 12), 180 (9), 166 (100), 112 (8),
55 (9) and 41 (25). nmax (nujol): 2920, 2860, 1440, 1360,
1250, 1170, 1090, 1040, 940, 900 and 720 cm21. d: 1.38 (m,
3H), 1.60 and 1.76 (m, 6H), 1.98 and 2.09 (m, 3H), 2.51 (m,
1H, Hc), 2.62 (m, 1H, Hd), 3.03 (t, 1H, Jˆ9.5 Hz, Hf), 3.48
(dd, 1H, Jˆ4.0, 8.5 Hz, Hb), 3.57 (dd, 1H, Jˆ2.5, 9.5 Hz,
He) and 4.23 (t, 1H, Jˆ9.0 Hz, Ha).
P
P
P
2
1=2
as wR2 ˆ ꢀ ‰wꢀFo 2 Fc2† Š= ‰wFo4Š† and R1 ˆ uuFou 2
P
uFcuu= uFou:
1.4.1. Crystal data for 3a. [C12H12I2N2O2][I], 0.46£0.30£
0.27 mm, Mˆ606.01, monoclinic, space group I2/a, aˆ
Ê
14.9833(14), bˆ11.1692(7), cˆ10.9067(8) A, bˆ
Ê 3
23
92.700(7)8, Uˆ1823.2(2) A , Zˆ4, Dcˆ2.208 Mg m
,
mˆ5.038 mm21, F(000)ˆ1132, Tˆ160 K.
1.4.2. Data collection. Graphite monochromated MoKa
radiation, lˆ0.71069 A, scan speeds 1.5±8.08 min21, v
Ê
scan widths 1.0581a-doublet splitting, 4.0,2u,50.08.
Maximum and minimum transmission factors: 0.853,
0.576. 3323 data collected, 1603 of which were unique,
Rintˆ0.0228. There were 1536 re¯ections with
Fo.4.0s(Fo).
1.4.3. Structure re®nement. Number of parametersˆ90,
goodness of ®t, sˆ1.161; weighting parameters x,
yˆ0.0166, 2.6681; wR2ˆ0.0435, R1ˆ0.0185.
1.4.4. Crystal data for 6. C11H21NO2, 0.53£0.30£0.27 mm,
Mˆ199.29, orthorhombic, space group P212121, aˆ
Ê
8.3897(3),
bˆ11.2676(5),
cˆ11.4629(5) A,
Uˆ
,
1083.61(8) A , Zˆ4, Dcˆ1.222 Mg m23, mˆ0.658 mm21
Ê 3
F(000)ˆ440, Tˆ290 K.
1.4.5. Data collection. Graphite monochromated CuKa radia-
Ê
21
tion, lˆ1.54184 A, scan speeds 1.5±8.08 min , v scan
widths 1.0581a-doublet splitting, 4.0,2u,130.08. 2120
Data collected, 1787 of which were unique, Rintˆ0.0186.
There were 1676 re¯ections with Fo.4.0s(Fo).

1128
H. A. Dondas et al. / Tetrahedron 57 (2001) 1119±1128
1.4.6. Structure re®nement. Number of parametersˆ130,
goodness of ®t, sˆ1.061; weighting parameters x,
yˆ0.0568, 0.1128; wR2ˆ0.0903, R1ˆ0.0326.
References
1. Dondas, H. A.; Grigg, R.; Hadjisoteriou, M.; Markandu, J.;
Thomas, W. A.; Kennewell, P. Tetrahedron 2000, 56, 10087±
10096.
1.4.7. Crystal data for 14. C13H19IN2O2, 0.72£
0.38£0.2 mm, Mˆ378.2, orthorhombic, space group Pbca,
2. For recent reviews see: Frederickson, M.; Grigg, R. Org. Prep.
Procedures 1997, 29 33±62 and 63±115.
Ê
aˆ9.7403(14),
bˆ13.950(2),
cˆ21.889(2) A,
Uˆ
,
2974.2(7) A , Zˆ8, Dcˆ1.689 Mg m23, mˆ2.159 mm21
F(000)ˆ1504, Tˆ293 K.
Ê 3
3. (a) Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu, J.;
Thornton-Pett, M. J. Chem. Soc., Chem. Commun. 1992,
1388±1389. (b) Grigg, R.; Hadjisoteriou, M.; Kennewell, P.;
Markandu, J. J. Chem. Soc., Chem. Commun. 1992, 1537±
1538.
1.4.8. Data collection. Graphite monochromated MoKa
radiation, lˆ0.71069 A, scan speeds 1.5±8.08 min21, v
Ê
scan widths 1.0581a-doublet splitting, 4.0,2u,50.08.
Maximum and minimum transmission factors: 0.853,
0.576. 5228 Data collected, 2614 of which were unique,
Rintˆ0.0183. There were 2092 re¯ections with
Fo.4.0s(Fo).
4. (a) Frederickson, M.; Grigg, R.; Markandu, J.; Thornton-Pett,
M.; Redpath, J. Tetrahedron 1997, 53, 15051±15060.
(b) Dondas, H. A.; Grigg, R.; Frampton, C. S. Tetrahedron
Lett. 1997, 38, 5719±5722. (c) Dondas, H. A.; Frederickson,
M.; Grigg, R.; Markandu, J.; Thornton-Pett, M. Tetrahedron
1997, 53, 14339±14354. (d) Markandu, J.; Dondas, H. A.;
Frederickson, M.; Grigg, R.; Thornton-Pett, M. Tetrahedron
1997, 53, 13165±13176.
1.4.9. Structure re®nement. Number of parametersˆ174,
goodness of ®t, sˆ1.078; weighting parameters x,
yˆ0.0408, 2.6738; wR2ˆ0.0876, R1ˆ0.0329.
5. Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu, J.
J. Chem. Soc., Chem. Commun. 1993, 1340±1342 (prelimi-
nary communication).
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers, compound 3a CCDC 152013;
compound 6 CCDC 152014; compound 14 CCDC 152015.
6. Supplementary data for the X-ray crystallographic studies of
3a, 6 and 14, including tables of bond lengths and angles, have
been deposited with the Director of the X-ray Crystallographic
Database, Cambridge, and are available upon request.
7. House, H. O.; Lee, L. F. J. Org. Chem. 1976, 41, 863±869.
8. Belotti, D.; Cossy, J.; Pete, J. P.; Portella, C. J. Org. Chem.
1986, 51, 4196±4200.
Acknowledgements
9. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467±473.
10. Sheldrick, G. M. shelxl 93, Program for re®nement of crystal
È
structures, University of Gottingen, 1993.
We thank Mersin University (H. A. D.) for leave of absence
and Leeds University, the EPSRC and Roussel for support.