X=Y-ZH Systems as potential 1,3-dipoles. Part 53: Sequential nucleophilic ring opening-1,3-dipolar cycloaddition reactions of Z-oxime anions with aziridines and dipolarophiles

Article abstract of DOI:10.1016/S0040-4020(01)00767-0

Nucleophilic ring opening of aziridines involving attack of the nitrogen atom of Z-oxime anions generates nitrones which are then trapped in 1,3-dipolar cycloaddition reactions with N-methylmaleimide to afford 1:1 mixture of endo- and exo-cycloadducts.

Full text of DOI:10.1016/S0040-4020(01)00767-0

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 7951±7964
XˆY±ZH Systems as potential 1,3-dipoles. Part 53:
Sequential nucleophilic ringopening-1,3-dipolar cycloaddition
reactions of Z-oxime anions with aziridines and dipolarophilesq
H. Ali Dondas, Jonathan E. Cummins, Ronald Griggp and Mark Thornton-Pett
Molecular Innovation, Diversity and Automated Synthesis ꢀMIDAS) Centre, School of Chemistry, The University of Leeds,
Woodhouse Lane, Leeds LS2 9JT, UK
Received 27 April 2001; revised 21 June 2001; accepted 19 July 2001
AbstractÐNucleophilic ring opening of aziridines involving attack of the nitrogen atom of Z-oxime anions generates nitrones which are
then trapped in 1,3-dipolar cycloaddition reactions with N-methylmaleimide to afford 1:1 mixture of endo- and exo-cycloadducts. q 2001
Elsevier Science Ltd. All rights reserved.
Ring opening of aziridines and aziridinium ions by various
nucleophiles 3e.g. alkoxides, nitrogen, sulfur, etc.) has been
extensively studied2±6 and aziridinium ion intermediates
have been characterised.7 Various catalysts have been
reported to promote aziridine ring-opening and to improve
the regioselectivity2,7±9 of the process. Methods for the
synthesis of enantiopure aziridines and their stereoselective
ring-opening have considerably increased their synthetic
utility.10±12 It has also been reported that the enantio-
selectivity of the ring-opening reactions can be controlled
by chiral copper catalysts.13 We have shown regiospeci®c
nucleophilic ring-opening reactions of epoxide by Z-oximes
generates nitrones in good yield. The nitrones when trapped
by dipolarophiles gave isoxazolidine also in good yield.14,15
Z-Benzaldoxime 31) reacts with sodium hydride and the
aziridine 32) in THF 3rt, 18 h) to afford nitrone 33) in 61%
yield. The nitrone upon heating in xylene 31208C, 20 h) with
phenyl vinyl sulphone gave cycloadduct 34) as a single
endo-isomer in 64% yield.
The stereochemistry of 34) was assigned on the basis of
n.O.e data and 2D-COSY studies. In contrast, nitrone 33)
when heated in xylene 31208C, 20 h) with N-methyl-
maleimide 3NMM) gave a 1:1 mixture of exo-36)- and
endo-37)-cycloadducts in 79% yield. The stereochemistry
of 36) and 37) was determined from n.O.e. data and
2D-COSY studies. The formation of a single cycloadduct
from 33) and phenyl vinyl sulphone re¯ects the greater steric
demand of phenylsulphonyl group which disfavours the
transition state leading to 38) 3Scheme 2).
To date oximes have not been used as nucleophiles in the
ring opening reactions of aziridines. We now report that
nucleophilic ring opening of aziridines by Z-oxime anions
occurs under mild conditions to generate nitrones in good
to excellent yield. The nitrones can then be reacted with
dipolarophiles to give isoxazolidines in good to excellent
yield 3Scheme 1).
The E-benzaldoxime did not give the ring-opening reaction.
This is ascribed to the steric hindrance of the nitrogen lone
pair, by the phenyl ring, in the ring-opening transition state
3Scheme 3). Z,E-Isomerisation must be effectively pro-
hibited under the ring-opening reactions i.e. ambient
Scheme 1.
q See Ref. 1 for Part 52.
Keywords: aziridine ring-opening; aziridinium ion; Z-oximes; nitrones; 1,3-dipolar cycloaddition.
Corresponding author. Tel./fax: 144-113-2336501; e-mail: r.grigg@chem.leeds.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00767-0

7952
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
Scheme 4.
temperatures. This was also observed in the analogous
epoxide-ring opening reactions.14
Nitrone formation also occurred when Z-benzaldoxime was
reacted with 2-chloroethyl-N,N-dibenzylamine hydro-
chloride 312) in the presence of NaH and LiI at 08C for
6 h. The nitrone 314) was heated in xylene with NMM at
608C for 20 h to give a 1:2 mixture of endo-315) and exo-
316) cycloadducts in 53% yield. The stereochemistry of
the products was assigned on the basis of n.O.e. difference
spectroscopy and 2D-COSY studies 3Scheme 4).
A series of 4-substituted Z-aryl oxime sodium salts 317)
were evaluated in the ring opening reaction 3Scheme 5)
and the results are collected in Table 1.
The isolated yield of nitrones increases from 45% with the
most strongly electron-withdrawing group 3Table 1, entry 6,
RˆCN) to 76% with 4-methoxy benzaldoxime 3Table 1,
entry 2). The substituent effect is not clear cut due to the
reaction species being the oxime anion, the negative charge
of which cannot be localised on the nitrogen atom but which
clearly potentiates the nucleophilicity of the nitrogen-lone
pair. The dimethylamino group is a strongly electron-
donating moiety 3Table 1, entry 1) and might be expected
to give the highest yield of nitrone. The lower yield of
nitrone 359%) in this case may be due to the nucleophilic
lone pair on the amino nitrogen attacking the aziridine ring
causing side reactions. The stereochemistry of the cyclo-
adducts was determined from n.O.e. data and 2D-COSY
studies and con®rmed in the case of 319) by an X-ray crystal
structure 3Table 1, entry 2, RˆOMe) 3Fig. 1).
Scheme 2.
Scheme 3.

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7953
Scheme 5.
Table 1.
Entry
effect aziridine ring opening 3Scheme 7). The yield of
nitrone 328) obtained from the standard reaction of the
oxime anion with N-3-4-chlorophenylsulphonyl)aziridine
increased from 56% in the case of furan, oxygen being the
least electron-donating heteroatom, to 70% in the case of
thiophene. However, the yield dropped to 53%, in the case
of pyrrole, which is the most strongly electron-donating
heterocycle 3Table 2). This is may be due to deprotonation
of the weakly acidic proton on the pyrrole nitrogen
3pKa,16), by sodium hydride, generating a second ambi-
dent nucleophile. It was again noted that the yields of
nitrones increased with the insertion of a double bond
between the heteroaryl and oxime moieties 3Table 2).
173a±g)
R
183a±g)
Nitrone 3%)a,b
193a±g)
Isoxazolidine 3%)a,c
1
2Ome
NMe2
59
81
76
91
3
4
5
6
7
Br
H
CF3
69
65
58
45
75
87
79
92
80
57
CN
Cinnamaldoxime
a
Isolated yield.
Reactions carried out in THF, rt for 16 h.
Reactions carried out in xylene at 1408C for 16 h. In each case a 1:1
mixture of endo- and exo-isomers was obtained.
b
c
1,3-Dipolar cycloaddition of the nitrones, with NMM
occurred smoothly to give the corresponding isoxazolidines
329) and 330) 3Scheme 7) as mixtures of endo-and exo-
isomers in good yields. Pyrrole nitrone 328, XˆNH, nˆ1)
did not undergo 1,3-dipolar cycloaddition with NMM even
after prolonged reaction times. This is probably due to the
formation of a stable 6,6-hydrogen bonded system 331) as
can be seen in the crystal structure determined by X-ray
diffraction studies 3Fig. 2).
Oxime 320) reacts with aziridine 32) in the presence of NaH
3THF, rt, 18 h) to give nitrone 321) 375%). Heating nitrone
321) in xylene 31208C, 12h) afforded a 1:1 mixture of endo-
322) and exo-323) cycloadducts in 57% yield. Nitrone 321)
when heated in xylene with phenyl vinyl sulphone 31208C,
18 h) resulted in 5:1:1 ratio of the endo-4-substituted
isoxazolidine 324) and the exo-325)- and endo-326)-5-substi-
tuted isomers in 67% combined yield. The stereochemistry
of 322)±326) were determined from n.O.e. data and
2D-COSY studies 3Scheme 6).
This new sequential process allows access to a range of
novel isoxazolidines, in good yield, under mild conditions,
from readily available starting materials.
A series of Z-heteroaryl oxime anions 327) was utilised to
Figure 1. X-Ray crystal structure of 319).

7954
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
Bruker WP 400 instrument. Deuterochloroform was used as
solvent unless stated otherwise, and chemical shifts 3d) are
1
given in parts per million. H Spectra are referenced to
tetramethylsilane or residual protonated solvent. Assign-
1
ments of H signals were made with the aid of 2D-COSY
spectra where necessary. Microanalyses were obtained
using a Carlo Erba Elemental Analyser MOD 1106
instrument. Mass spectra were recorded on a VG-AutoSpec
spectrometer using electron impact 3EI) operating at 70 eV
or by fast atom bombardment 3FAB), as speci®ed. IR
spectra were performed on a Nicolet FT IR. A ®lm of the
analyte was depositied on a germanium crystal by evapo-
ration of a dichloromethane solution. The following abbre-
viation are used: wˆweak, mˆmedium, sˆstrong, brˆ
broad. Flash column chromatography employed silica gel
60 3Merk 230±400 mesh) or Kieselgel 60 HF254. Ether
refers to diethyl ether and petroleum ether refers to the
fraction with boiling point 40±608C.
1.1. Synthesis of startingmaterials
The aryl oximes 317),16a±f 327b),16g and 327d)16h were
prepared by standard procedures from aryl or heteroaryl
aldehydes, hydroxylamine hydrochloride and sodium
acetate, to give E-aldoximes. Conversion to the Z-isomers
was effected by bubling dry hydrogen chloride gas through
an etheral solution of the oxime, to precipitate the hydro-
chloride salt, followed by neutralisation of the salt by
addition to a warm aqueous sodum bicarbonate solution.16b
Z-Heteroaryl oximes 327a),17a 327c)17b and 327e)17c were
synthesised by heating the appropriate heteroaryl-2-carbox-
aldehyde in pyridine, with hydroxylamine hydrochloride,
under re¯ux for 1.5 h. The solvent was then removed
under reduced pressure and the residue shaken vigorously
with water to precipitate the Z-oxime. N-34-Chlorophenyl-
sulphonyl) aziridine and. N-32-bromophenylsulphonyl)aziri-
dine were prepared from the NH aziridine18 and the
appropriate arylsulphonyl chloride under basic conditions.19
1.2. General procedure for the preparation of nitrones
A solution of Z-oxime 32.5 mmol) and NaH 3100 mg, 60%
dispersion in mineral oil, 2.5 mmol) in dry THF 330 ml),
were stirred for 20 min at room temperature under nitrogen.
Then aziridine 30.65 g, 3 mmol) was added to the reaction
mixture and the resulting solution stirred at room tempera-
ture for a further 14 h. THF was removed under reduced
pressure, water 325 ml) added and the mixture extracted
with DCM 35£20 ml). The combined organic layer was
dried 3MgSO4), the solvent removed under reduced
pressure, the residue washed with ether and the solid residue
crystallised from ethyl acetate.
1.2.1. C-24-Dimethylaminophenyl)-N-[2-240-chlorophenyl-
sulphonamido)ethyl]nitrone 218a). Obtained as colourless
needles from ethyl acetate 3556 mg, 59%), mp 176±1788C.
3Found: C, 53.4; H, 5.0; N, 11.25; S, 8.3. C17H20ClN3O3S
requires: C, 53.45; H, 5.3; N, 11.0; S, 8.4%); d: 3.03 3s, 6H,
Me2N), 3.40 3m, 2H, CH2NH), 3.95 3m, 2H, CH2N1), 6.65
3m, 3H, 2ArH1NH), 7.23 3s, 1H, CHvN1), 740, 7.80 and
8.05 33£d, Jˆ8.1 Hz, 3£2ArH). nmax 3®lm): 3000 3br, CH,
NH), 1604 3CvN), 1523, 1366, 1328, 1160, 1094, 821 and
Scheme 6.
1. Experimental
Melting points were determined on a Ko¯er hot-stage
apparatus and are uncorrected. H Nuclear magnetic reso-
nance spectra were recorded at 300 MHz on a Bruker QE
300 instrument unless otherwise stated or at 400 MHz on a
1

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7955
Scheme 7.
Table 2.
1898C. 3Found: C, 52.4; H, 4.7; N, 7.55; S, 8.6.
C16H17ClN2O4S requires: C, 52.1; H, 4.65; N, 7.6; S,
8.7%); d: 3.45 3t, 2H, Jˆ5.0 Hz, CH2NH), 3.80 3s, 3H,
OMe), 4.0 3t, 2H, Jˆ5.0 Hz, CH2N1), 6.20 3br, 1H, NH),
6.90 3d, Jˆ8.0 Hz, 2H, ArH), 7.25 3s, 1H, CHvN1), 7.46,
7.80 and 8.14 33£d, Jˆ8.0 Hz, 3£2ArH). nmax 3®lm): 3000
3br, CH, NH), 1600 3CvN), 1507, 1331, 1251, 1149, 1094,
824 and 759 cm21. m/z3%) 3683M1, 13), 193 342), 175324),
148 3100), 135 351), 121 366) and 111 339).
Entry
X/n
283a±e) 3%)a,b
329a±e):330a±e)
329)/330) 3%)a,c
1
2S/3
NH/1
53
±
±
86
1:1
82
3
4
5
S/1
O/3
O/1
70
70
56
1:1
1:1
2:1
68
78
74
a
Isolated yield.
Reactions carried out in THF, at rt for 16 h.
Reactions carried out in xylene at 1408C for 16 h.
b
c
1.2.3. C-24-Bromophenyl)-N-[2-240-chlorophenylsulphona-
mido)ethyl]nitrone 218c). Obtained as colourless needles
from ethyl acetate 3720 mg, 69%), mp 203±2048C. 3Found:
C, 43.1; H, 3.35; N, 6.45; S, 7.6. C15H14BrClN2O3S requires:
C, 43.15; H, 3.4; N, 6.7; S, 7.7%); d: 3.50 3m, 2H, CH2NH)
4.05 3t, Jˆ5.1 Hz, 2H, CH2N1), 5.87 3t, Jˆ5.9 Hz, 1H, NH),
7.24 3s, 1H, CHvN1) and 7.40±8.05 34£d, Jˆ8.0 Hz,
4£2ArH). nmax 3®lm): 3100 3br, CH, NH), 1586 3CvN),
725 cm21. m/z3%) 381 3M1, 7), 365 37), 161 3100), 148 340)
and 134 322).
1.2.2. C-24-Methoxyphenyl)-N-[2-240-chlorophenylsul-
phonamido)ethyl]nitrone 218b). Obtained as colourless
needles from ethyl acetate 3710 mg, 76%), mp 187±
Figure 2. X-Ray crystal structure of 331).

7956
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
1477, 1424, 1396, 1329, 1157, 1095, 825 and 755 cm21
.
1328, 1158, 1094, 825 and 753 cm21. m/z3%)327 3M1, 6),
244 36), 175 317), and 107 3100).
m/z3%) 418 3M1, 3), 241 319), 198 3100), 175 354) and
111383).
1.2.9. C-[2-220-Thienyl)ethenyl]-N-[22-40-chlorophenyl-
sulphonamido)ethyl]nitrone 228b). Obtained as colourless
needles from ethyl acetate 3797 mg, 86%), mp 172±1738C.
3Found: C, 48.5; H, 4.3; N, 7.5. C15H15ClN2O3S2 requires:
C, 48.6; H, 4.1; N, 7.6%); d: 3.423t, Jˆ5.1 Hz, 2H,
CH2NH), 3.94 3t, Jˆ5.0 Hz, 2H, CH2N1), 6.61 3m, 1H,
NH), 7.1±7.38 3m, 6H, 3£thiophene H, CHvCHvCH),
7.50 and 7.83 32£d, Jˆ8.5 Hz, ArH); nmax 3®lm): 3080 br,
CH), 16023C vN), 1569, 1473, 1324, 1161, 1132, 1093,
967 and 752cm 21. m/z3%)370 3M1, 16), 353 312), 260
343), 195 319), 175 357), 166 343), 150 391), 136 338), 121
334) and 111 3100).
1.2.4. C-2Phenyl)-N-[2-240-chlorophenylsulphonamido)-
ethyl]nitrone 218d). Obtained as colourless amorphous
solid, mp 149±1518C. 3Found: C, 52.2, H, 4.45; N, 8.1, S,
9.7. C15H15 N2O3ClS requires: C, 53.2, H, 4.45; N, 8.25, S,
9.45 %). HRMS: 338.0493. C15H15N2O3 requires: 338.0492;
d: 8.13d, 2H, Jˆ8.1 Hz, Ar±H), 7.73d, 2H, Jˆ8.1 Hz, Ar±
H), 7.353m, 5H, Ar±H), 6.48 3br, 1H, HCvN), 4.1 3m, 2H,
NCH2N), 3.65 3br, 1H, NH) and 3.413m, 2H, NCH2N).
m/z3%) 339 3M11, 100), 323 37), 218 311), 149 321), 91
325), 69 347), 57 356) and 43 340).
1.2.5.
C-24-Tri¯uoromethylphenyl)-N-[2-240-chloro-
1.2.10.
C-22-Thienyl)-N-[2-240-chlorophenylsulphona-
phenylsulphonamido)ethyl]nitrone 218e). Obtained as
colourless needles from ethyl acetate 3590 mg, 58%), mp
171±1728C. 3Found: C, 47.1; H, 3.6; N, 6.85; S, 7.8.
C16H14ClF3N2O3S requires: C, 47.25; H, 3.45; N, 6.9; S,
7.95%); d: 3.50 3q, Jˆ5.4 Hz, 2H, CH2NH), 4.10 3t,
Jˆ5.1 Hz, 2H, CH2N1), 5.923t, Jˆ5.4 Hz,1H, NH), 7.45
3m, 3H, CHvN112ArH) and 7.70±8.20 33£d, Jˆ8.0 Hz,
3£2H, ArH). nmax 3®lm): 31003br, CH), 15883CvN), 1475,
mido)ethyl]nitrone 228c). Obtained as colourless needles
from ethyl acetate 3604 mg, 70%)], mp 174±175.58C.
3Found: C, 45.15; H, 3.95; N, 7.85, S 18.5. C13H13ClN2O3S2
requires: C, 45.3; H, 3.8; N, 8.1, S 18.6 %); d: 3.47 3q,
Jˆ5.1 Hz, 2H, CH2NH), 4.08 3t, Jˆ5.1 Hz, 2H, CH2N1),
6.173m, 1H, NH), 7.15 3m, 1H, CHvNO) and 7.7±7.8 3m,
7H, thiophene H and ArH). nmax 3®lm): 3050 3br,CH), 1586
3CvN), 1476, 1335, 1161, 1093, 828 and 758 cm21. m/z3%)
344 3M1, 10), 174 329), 169 342), 152 323), 124 398) and 111
3100).
1422, 1325, 1174, 1160, 1133, 1095, 861 and 765 cm21
.
m/zꢀ%) 406 3M1, ,1), 186 3100), 175 343), 159 354) and
111 368).
1.2.11. C-[2-220-Furyl)ethenyl]-N-[2-240-chlorophenylsul-
phonamido)ethyl]nitrone 228d). Obtained as colourless
amorphous solid from ethyl acetate). [5 mmol scale
31.28 g, 72%)], mp 167±1688C. 3Found: C, 51.10; H, 4.5;
N, 7.7. C15H15ClN2O4S requires: C, 50.8; H, 4.3; N, 7.9%);
d: 340 3t, Jˆ5.0 Hz, 2H, CH2NH), 3.94 3t, Jˆ5.0 Hz, 2H,
CH2N1), 6.46 3m, 1H, CHvCHvCH),6.59 3m, 1H, furyl
H) and 7.45±7.9 3m, 8H, ArH, furyl H, and CHvN1); nmax
3®lm): 3080 3br, CH), 2800 3br), 1619 3CvN), 1578, 1475,
1324, 1203, 1160, 1131, 1091, 931 and 738 cm21. m/z3%)
356 3M1, 4), 354 3M1, 11), 175 333), 161 314), 150 314), 134
3100), 121 337) and 111 363).
1.2.6. C-24-Cyanophenyl)-N-[2-240-chlorophenylsulphona-
mido)ethyl]nitrone 218f). Obtained as colourless needles
from ethyl acetate 3309 mg, 34%), mp 149±1518C.
3Found: C, 52.55; H, 4.05; N, 11.4; S, 8.95. C16H14ClN3O3S
requires: C, 52.8; H, 3.9; N, 11.55; S, 8.8%); d: 3.49 3t,
Jˆ5.3 Hz, 2H, CH2NH), 4.13 3t, Jˆ5.0 Hz, 2H, CH2N1),
5.80 3t, Jˆ 5.8 Hz,1H, NH), 7.45 3m, 3H, CHvN112ArH)
and 7.70±8.25 33£d, Jˆ8.0 Hz, 3£2H, ArH). nmax 3®lm):
3250 3br, NH), 3084 3br, CH), 22283CvN), 1587 3CvN),
1475, 1426, 1324, 1157, 1096, 1085, 830 and 754cm21
.
m/z3%) 363 3M1, ,1), 217 311), 188 327), 175 355), 143
3100), 130 327) and 111 376).
1.2.12. C-22-Furyl)ethenyl]-N-[2-40-chlorophenylsulphona-
mido)ethyl]nitrone 228e). Obtained as colourless amor-
phous solid from ethyl acetate 3460 mg, 56%)], mp
143.5±1468C. 3Found: C, 47.3; H, 3.9; N, 8.45, S, 9.75.
C13H13ClN2O4S requires: C, 47.5; H, 4.0; N, 8.5, S,
9.75%); d: 3.47 3q, Jˆ5.4 Hz, 2H, CH2NH), 4.023t, Jˆ
5.1 Hz, 2H, CH2N1), 6.07 3t, Jˆ5.7 Hz, 1H, NH), 6.57
3m, 1H, furyl H) and 7.45±7.9 3m, 8H, ArH, furyl H, and
CHvN1); nmax 3®lm): 3080 3br, CH), 28003br), 1586
3CvN), 1478, 1332, 1225, 1158, 1085, 824 and
775 cm21. m/z3%) 330 3M1, 2), 328 3M1, 6), 175 324),
153 320), 125 320) and 108 3100).
1.2.7.
C-22-Phenylethenyl)-N-[2-240-chlorophenylsul-
phonamido)ethyl]nitrone 218g). Obtained as colourless
needles from ethyl acetate [1.5 mmol scale 3409 mg,
75%)], mp 186±1888C. 3Found: C, 56.1; H, 4.9; N, 7.95.
C17H17ClN2O3S requires: C, 56.0; H, 4.7; N, 7.7%); d
3DMSO-d6): 3.26 3t, Jˆ5.3 Hz, 2H, CH2NH), 3.48 3q, Jˆ
5.5 Hz, 2H, CH2N1) and 7.30±8.40 3m, 12H, ArH). nmax
3®lm): 3000 3br, NH, CH), 1569 3CvN), 1473, 1410,
1326, 1162, 1132, 1094, 983,826 and 749 cm21. m/z3%)
364 3M1, 2), 345 38), 260 325), 175 360), 160 320), 144
375), 130 342), and 111 3100).
1.2.8. C-22-Pyrrolo)-N-[2-240-chlorophenylsulphonamido)-
ethyl]nitrone 231). Obtained as colourless needles from
ethyl acetate 3433 mg, 53%), mp 164.5±1668C. 3Found: C,
47.7; H, 4.35; N, 13.0, S, 9.65. C13H13ClN3O3S requires: C,
47.8; H, 4.05; N, 12.9, S, 9.8%); d: 3.37 3q, Jˆ5.2Hz, 2H,
CH2NH), 3.90 3t, Jˆ4.9 Hz, 2H, CH2N1), 6.30, 6.46 and
6.97 3d, t, Jˆ3.0 Hz, 3H, pyrrole H), 6.90 3t, Jˆ6.0 Hz,
1H, NH), 7.45 and 7.85 32£d, Jˆ8.0 Hz, 2£2H, ArH), and
11.70 3br, 1H, pyrrole NH). nmax 3®lm): 3375 3br, NH), 3030
3br, CH), 2800 3br, NH), 1621 3CvN), 1585, 1476, 1423,
1.3. General procedure for the 1,3-dipolar cycloaddition
of nitrones
The nitrone 30.3 mmol) was taken up in dry xylene 320 ml)
and the dipolarophile 30.33 mmol) added. The mixture was
heated to 1208C for 16 h, cooled and xylene removed under
reduced pressure. The residue was puri®ed by column
chromatography on kieselgel, eluting with 1:1 v/v petro-
leum ether±ethyl acetate, followed by crystallisation from

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7957
petroleum ether±ethyl acetate. Products usually comprised
a 1:1 mixture of endo- and exo-isomers.
1.3.1. Cycloadduct 24). Obtained as a single endo-stereo-
isomer [0.3 mmol scale 397 mg, 64%)] as colourless needles
from ether, mp 163±1658C. 3Found: C, 54.4, H, 4.65; N,
5.45. C23H24ClN2O5S2 requires: Found: C, 54.5, H, 4.55; N,
5.55%); d: 2.6 and 2.8 32£m, 2H, CH2-isoxazolidine) 3,05±
3.232 £m, 2H, CH2NHSO2PhCl), 3.97 3d, Jˆ8.0 Hz, 1H,
H2), 4.013m, 1H, H1), 4.15 3t, Jˆ9.0 Hz, 1H, H4), 4.45
3dd, Jˆ3.0 and 10.0 Hz, 1H, H3), 5.1 3t, Jˆ5.5 Hz, 1H,
NH) and 7.0±7.8 3m, 9H, ArH), nmax 3®lm): 3250 3br,
NH), 2900 3br, CH), 1787 3w, imide), 1707 3s, CvO,
imide), 1611, 151 3, 1436, 1330, 12 52, 1163, 1086, 829
and 736 cm21. m/z3%) 5073M1, ,1), 365 35), 3023100),
245 351), 175 323), 160 319), 141 314), 118 371) and 91355).
endo-Isomer: Colourless needles from ethyl acetate±
hexane, mp 189±1918C. 3Found: C, 53.45; H, 4.95; N,
11.6, S, 6.4. C20H19ClN3O5S requires: C, 53.6; H, 5.1; N,
11.35, S, 6.5%); d: 3300 MHz, 508C), 2.55 3m, 2H, CH2NO)
2.95 3s, 6H, NMe2), 3,03 3s, 3H, NMe), 3.08 3m, 2H,
CH2NH), 3.63 3dd, Jˆ2.8 and 7.1 Hz, 1H, H2), 4.05
[broad peak at 208C 3508C, d, Jˆ2.8 Hz, 1H, H3)], 4.86
3d, Jˆ7.1 Hz, 1H, H1), 4.90 3t, Jˆ5.3 Hz, 1H, NH) and
6.60±7.80 34£d, Jˆ8.6 Hz, 4£2H, ArH),. m/z3%) 3FAB)
495 3M11, 33), 493 3M11, 100), 381 318) and 288 344).
1.3.2. Cycloadduct 219a). Obtained as a 1:1 mixture
[1.40 mmol scale 3560 mg, 81% combined yield)] of sepa-
rable endo- and exo-isomers.
1.3.3. Cycloadduct 219b). Obtained as a 1:1 mixture
[1.28 mmol scale 3560 mg, 91% combined yield)] of sepa-
rable endo- and exo-isomers.
exo-Isomer: Colourless amorphous solid from ethyl acetate±
hexane, mp 202±2048C. 3Found: C, 53.7; H, 5.1; N, 11.5, S,
6.4. C22H25ClN4O5S requires: C, 53.65; H, 5.1; N, 11.35, S,
6.5%); d: 2.65 and 2.9 32£m, 2H, CH2NO), 2.95, 3s, 6H,
NMe2), 3,03 3s, 3H, NMe), 3.02±3.2 3m, 2H, CH 2NH), 3.6
3dd, Jˆ8.5 and 7.5 Hz, 1H, H2), 3.88 3d, Jˆ8.5 Hz, 1H, H3),
4.87 3d, Jˆ7.5 Hz, 1H, H1), 5.16 3t, Jˆ5.8 Hz, 1H, NH) and
6.55±7.80 34£d, Jˆ8.6 Hz, 4£2H, ArH), nmax 3®lm): 3250
3br, NH), 2900 3br, CH), 1786 3w, imide), 1706 3s, CvO),
1612, 1525, 1425, 1435, 1329, 1285, 1164, 1086, 820 and
752cm 21. m/z3%) 3FAB) 495 3M11, 33), 493 3M11, 100),
381 321) and 288 351).
exo-Isomer: Colourless prisms from ethyl acetate±hexane,
mp 185±1868C. 3Found: C, 52.5, H, 4.7; N, 8.65, S, 6.85.
C21H22ClN3O6S requires: C, 52.55; H, 4.6; N, 8.75, S,
6.7%); d: 2.68 and 2.88 32£m, 2H, CH2NO) 3.02, 3s, 3H,
NMe), 3,05±3.3 3m, 2H, CH2NH), 3.65 3t, Jˆ8.0 Hz, 1H,
H2), 3.80 3s. 3H, OMe), 3.91 3d, Jˆ8.8Hz, 1H, H3), 4.89 3d,
Jˆ7.3 Hz, 1H, H1), 5.15 3t, Jˆ6.0 Hz, 1H, NH) and 6.80±
7.85 34£d, Jˆ8.7 Hz, 4£2H, ArH), nmax 3®lm): 3250 3br,
NH), 2900 3br, CH), 1787 3w, imide), 1707 3s, CvO,
imide), 1611, 151 3, 1436, 1330, 12 52, 1163, 1086, 829
and 736 cm21. m/z3%) 481/479 3M1, ,1), 275 310), 175
322), 148 3100), 121 381) and 111 349).

7958
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
endo-Isomer: colourless amorphous solid from ethyl
acetate±hexane, mp 186±1878C. 3Found: C, 45.7, H, 3.6;
N, 7.7, S, 6.25. C20H19BrClN3O5S requires: C, 45.45, H, 3.6;
N, 7.95, S, 6.05%); d: 3508C): 2.5 and 2.63 32£m, 2H,
CH2NO), 3.5 3s, 3H, NMe), 3.123m, 2H, CH 2NH), [broad
peak at 208C, 3.63 3508C dd, Jˆ3.1 and 7.6 Hz, 1H, H2)],
4.123d, Jˆ3.1 Hz, 1H, H3), 5.01 3d, Jˆ7.5 Hz, 1H, H1), 5.1
3br, 1H, NH) and 6.80±7.80 34£d, Jˆ8.7 Hz, 4£2H, ArH),
m/z3%) 3FAB) 529 3M1, 100), 527 3M1, 75), and 323 353).
endo-Isomer: Colourless amorphous solid from ethyl
acetate±hexane, mp 153±1548C. 3Found: C, 52.65, H,
4.85; N, 8.45, S, 6.75. C21H22ClN3O6S requires: C, 52.55;
H, 4.6; N, 8.75, S, 6.7%); d: 2.4 and 2.58 32£m, 2H,
CH2NO), 3.08 3m, 5H, NMe1CH2NH), 3.63 3dd, Jˆ3.0
and 7.3 Hz, 1H, H2), 3.823s. 3H, OMe), 4.1 3d, Jˆ3.0 Hz,
1H, H3), 4.91 3d, Jˆ7.3 Hz, 1H, H1), 5.17 3t, Jˆ6.0 Hz, 1H,
NH) and 6.80±7.80 34£d, Jˆ8.7 Hz, 4£2H, ArH). m/z3%)
481/479 3M1, ,1), 275 310), 175 322), 148 3100), 121 377)
and 111 366).
1.3.5. Cycloadduct 219d). A solution of nitrone 318d)
30.17 g, 0.5 mmol) and NMM 30.08 g, 1.2equiv.) in
degassed xylene was boiled under re¯ux under a nitrogen
atmosphere for 18 h. After cooling the solvent was removed
in vacuo and the residue, which comprised a 1:1 mixture of
endo- and exo-isomers, was subjected to column chroma-
tography on silica eluting with 1:9 v/v ethyl acetate±hexane
to afford the endo- and exo-isomers 30.18 g, 79 % combined
yield).
exo-Isomer: Colourless prisms from petroleum ether±ether,
mp 196±1988C.3Found: C, 53.05, H, 4.5, N, 9.6. C20H20
N3O5ClS requires: C, 53.5, H, 4.5, N, 9.35 %.); d
3400 MHz): 7.82 3d, 2H, Ar±H), 7.51 3d, 2H, Ar±H), 7.35
3m, 3H, Ar±H), 7.11 3m, 2H, Ar±H), 5.11 3br, 1H, NH),
4.90 3d, 1H, Jˆ7.24 Hz, H1), 3.97 3d, 1H, Jˆ8.7 Hz, H3),
3.70 3t, 1H, Jˆ8.0 Hz, H2), 3.22 and 3.11 32£m 2 H,
SNCH2), 3.0 3s, 3H, NMe), 2.91 and 2.70 32£m, 2H,
ONCH2). m/z3%) 3FAB) 450 3M11, 100), 245 351), 176
311), 71 313), 57 315) and 43 310).
1.3.4. Cycloadduct 219c). Obtained as a 1:1 mixture
[1.44 mmol scale 3592mg, 69% overall)] of separable
endo- and exo-isomers.
exo-Isomer: Colourless needles from ethyl acetate±hexane,
mp 178±1818C. 3Found: C, 46.65, H, 3.65; N, 8.05, S, 6.15.
C20H19BrClN3O5S requires: C, 45.45, H, 3.6; N, 7.95, S,
6.05%); d: 3400 MHz), 2.7 and 2.87 32£m, 2H, CH2NO),
3.01 3s, 3H, NMe), 3.1 and 3.232£m, 2H, CH2NH), 3.71 3t,
Jˆ8.0 Hz, 1H, H2), 3.93 3d, Jˆ8.7 Hz, 1H, H3), 4.91 3d,
Jˆ7.3 Hz, 1H, H1), 5.15 3br, 1H, NH) and 7.0±7.85 34£d,
Jˆ8.6 Hz, 4£2H, ArH), nmax 3®lm): 3278 3br, NH), 2900
3br, CH), 1790 3w, imide), 1705 3s, CvO, imide), 1331,
1280 11671095, 827 and 751 cm21. m/z3%) 3FAB) 529
3M1, 100), 527 3M1, 75), and 323 359).
endo-Isomer: Colourless plates from petroleum ether±ether
mp. 177±1798C. 3Found: C, 53.95, H, 4.5; N, 9.35, Cl, 7.9.
C20H20 N3O5ClS requires: C, 53.5, H, 4.5; N, 9.35, Cl,
7.9%); d 3400 MHz): 7.813d, 2H, Ar±H), 7.5 3d, 2H,
Ar±H), 7.4 3m, 3H, Ar±H), 7.3 3m, 2H, Ar±H), 5.13 3t,
1H, Jˆ6.0 Hz, NH), 4.91 3d, 1H, Jˆ7.3 Hz, H1), 3.68 3dd,
1H, Jˆ7.4 and 3.1 Hz, H2), 3.1 3s, 3H, NMe), 3.2±3.1 3m,
3H, H3 and NCH2) and 2.6±2.5 32m, 2H, NCH2). m/z3%)

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7959
3FAB) 450 3M11, 63), 413 325), 391 350), 245 360), 149
3100) and 43 352).
1.3.7. Cycloadduct 219f). Obtained as a 1:1 mixture
[0.5 mmol scale 3198 mg, 80% combined yield)] of separ-
able endo- and exo-isomers.
exo-Isomer: Colourless amorphous solid from ethyl
acetate±hexane, mp 138±1408C. 3Found: C, 53.15, H, 4.3;
N, 11.6, S, 6.7.4. C21H19ClN4O5S requires: C, 53.1, H, 4.05;
N, 11.8, S, 6.75 %), d: 2.75 and 2.93 32£m, br, 2H,
CH2NO), 2.98 3s, 3H, NMe), 3.16 3m, 2H, CH2NH), 3.77
3t, Jˆ8.0 Hz, 1H, H2), 4.03 3d, Jˆ8.7 Hz, 1H, H3), 4.93 3d,
Jˆ7.3 Hz, 1H, H1), 5.25 3t, Jˆ6.0 Hz, 1H, NH) and 7.3±7.8
34£d, Jˆ8.3 Hz, 4£2H, ArH), nmax 3®lm): 3250 3br, NH),
2900 3br, CH), 2230 3CN), 1788 3imide), 1707 3CvO,
imide), 1587, 1435, 1331, 1283, 1163, 1086, 831 and
735 cm21. m/z3%) 3FAB): 477 3M11, 33), 475 3M11,
100) and 270 359).
1.3.6. Cycloadduct 219e). Obtained as a 1:1 mixture
[1.40 mmol scale 3667 mg, 92% combined yield)] of sepa-
rable endo- and exo-isomers.
exo-Isomer: Colourless prisms from ethyl acetate±hexane,
mp 187±1898C. 3Found: C, 48.8, H, 3.9; N, 7.85, S, 6.4.
C21H19Cl F3N3O5S requires: C, 48.7, H, 3.7; N, 8.1, S,
6.2%); d: 3400 MHz), 2.7 and 2.9 32£m, 2H, CH2NO), 3.1
3s, 3H, NMe), 3.23m, 2H, CH 2NH), 3.75 3t, Jˆ8.0 Hz, 1H,
H2), 4.03 3d, Jˆ8.6 Hz, 1H, H3), 4.9 3d, Jˆ7.3 Hz, 1H, H1),
5.15 3t, Jˆ5.1 Hz, 1H, NH) and 7.2±7.8 34£d, Jˆ8.6 Hz,
4£2H, ArH), nmax 3®lm): 3280 3br, NH), 2900 3br, CH),
1788 3imide), 1708 3CvO, imide), 1620, 1586, 1436,
1324, 1288, 1164, 1068, 830 and 738 cm21. m/z3%)
3FAB) 519 3M1, 32), 517 3M1, 97) and 313 3100).
endo-Isomer: Colourless amorphous solid from ethyl
acetate±hexane, mp 182±1848C. 3Found: C, 53.15, H, 4.0;
N, 11.65, S, 6.75. C21H19ClN4O5S requires: C, 53.1, H, 4.05;
N, 11.8, S, 6.75 %). d 3300 MHz) 2.5 and 2.65 32£m, br, 2H,
CH2NO), 3.07 3m, 5H, NMe1CH2NH), 3.65 3dd, Jˆ3.2and
7.2Hz, 1H, H 2), 4.2[broad peak at 20 8C, 3508C, d, Jˆ
3.2Hz, 1H, H 3), 4.95 3d, Jˆ7.3 Hz, 1H, H1), 5.09 3t, Jˆ
6.0 Hz 1H, NH) and 7.4±7.8 34£d, Jˆ8.6 Hz, 4£2H,
ArH), m/z3%) 3FAB) 477 3M11, 33), 475 3M11, 100)
and 270 395).
endo-Isomer: Colourless prisms from ethyl acetate±hexane,
mp 157±1588C. 3Found: C, 48.7, H, 3.85; N, 8.0, S, 6.25.
C21H19Cl F3N3O5S requires: C, 48.7, H, 3.7; N, 8.1, S, 6.2
%). d 3300 MHz, 508C) 2.57 and 2.7 32£m, 2H, CH2NO),
3.073s, 3H, NMe), 3.123m, 2H, CH 2NH), [broad peak at
208C, 3.65 3508C, dd, Jˆ3.5 and 7.4 Hz, 1H, H2), 4.22 3d,
Jˆ3.2Hz, 1H, H 3), 4.88 3d, Jˆ7.3 Hz, 1H, H1), 5.05 3br,
1H, NH) and 7.2±7.80 34£d, Jˆ8.6 Hz, 4£2H, ArH).
m/z3%) 3FAB): 519 3M1, 22), 517 3M1, 67) and 313 3100).
1.3.8. Cycloadduct 219g). Obtained as a 1:1 mixture
[0.3 mmol scale 373 mg, 57% combined yield)] of separable
endo- and exo-isomers.
exo-Isomer: Colourless amorphous solid from ethyl ace-
tate±hexane, mp 96±988C. 3Found: C, 55.4, H, 4.8; N,
8.6,. C22H22ClN3O5S requires: C, 55.5, H, 4.7; N, 8.8%),
d: 2.7 3m, br, 1H, CHHNO), 3.09 3s, 3H, Nme), 3.0±3.2
3m, 3H, CH2NH, CHHNO), 3.47 3t, Jˆ8.5 Hz, 1H, H3), 3.61
3t, Jˆ7.7 Hz, 1H, H2), 4.84 3d, Jˆ7.4 Hz, 1H, H1), 5.13 3t,
Jˆ5.1 Hz, 1H, NH), 5.79 3dd, Jˆ15.8 and 9.2Hz, 1H, H 2),

7960
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
6.66 3d, Jˆ15.8 Hz, 1H, H5) and 7.35±7.8 3m, 9H, ArH),
N 9.15. C28H29N3O3 required: C, 73.8; H, 6.4; N, 9.2%); d
3400 MHz): 7.4±7.1 3m, 15H, Ar±H), 4.87 3d, 1H, Jˆ
7.3 Hz, H1), 3.93 3d, 1H, Jˆ8.6 Hz, H3), 3.68 3t, 1H, Jˆ
8.0 Hz, H2), 3.75 3m, 4H, CH2), 2.92 3s, 3H, NMe) and
2.81±2.62 3m, 4H, CH2); m/z3%) 3FAB) 456 3M11, 26),
364 312), 226 349), 210 370), 91 3100) and 55 323).
n
max 3®lm): 3300 3br, NH), 2900 3br, CH), 1786 3w, imide),
1705 3s, CvO, imide), 1586, 1432, 1332, 1284, 1165, 1095
and 752cm 21. m/z3%) 175 325), 144 373), 130 320) and 111
3100).
1.4.2. Cycloadduct 216). Obtained 325%) as a pale yellow
thick oil. 3HRMS: 455.2203. C28H29N3O3 requires:
455.2208). d 3400 MHz) 3C6D6): 7.6±7.0 3m, 15H, Ar±H),
4.18 3d, 1H, Jˆ7.4 Hz, H1), 3.523s, 2H, CH 2), 3.423d, 1H,
Jˆ5.6 Hz, H3), 3.4±3.23m, 2H, CH 2), 3.35 3s, 3H, NMe),
endo-Isomer: Colourless amorphous solid from ethyl
acetate±hexane, mp 174.5±1768C. 3Found: C, 55.45, H,
4.85; N, 8.85 C22H22ClN3O5S requires C, 55.5, H, 47; N,
8.8%); d: 2.8 and 2.9 3m, br, 2H, CH2NO), 3.05 3s, 3H,
NMe), 3.1 3m, 2H, CH2NH), 3.47 3d, Jˆ7.1 Hz, 1H, H2), 3.9
3m, br, 1H, H3), [note: becomes a doublet at 508C, 4.83 3d,
Jˆ7.3 Hz, 1H, H1), 5.13 3t, Jˆ6.0 Hz, 1H, NH), 6.15 3dd,
Jˆ15.8 and 7.1 Hz, 1H, H4), 6.63 3d, Jˆ15.8 Hz, 1H, H5)
and 7.16±7.9 3m, 9H, ArH), m/z3%) 175 340), 160 335), 144
383), 130 325) and 111 3100).
2.9 and 2.89 3dd, 1H, Jˆ3.2and 7.3 Hz, H ), 2.59 3s, 2H,
2
CH2) and 2.37 3m, 2H, CH2); m/z 3FAB) 456 3M11, 18),
364 39), 240 327), 210 391) and 91 3100).
1.5. Cycloadducts 224)±226)
Obtained as a 5:1:1 mixture of isomers which were sepa-
rated by column chromatography eluting with 10:1 v/v
toluene±EtOAc. [2mmol scale 3710 mg, 64% combined
yield)]
1.4. Compounds 214)±216)
anti-Benzaldoxime 30.13 g, 1 mmol) was added to a stirred,
ice-cold suspension of NaH 360% oil dispersion; 90 mg,
2.2 mmol) in DMF 35 ml), followed immediately by
addition of 2-chloro-N,N-dibenzylaminoethane hydro-
chloride 30.33 g, 1.1 mmol). After 1 h, LiI 330 mg) was
added and stirring continued for 4 h at 208C, Heating at
908C for a further 1 h was required to complete the reaction
based on TLC evidence. Water 320 ml) was then added and
the mixture extracted with DCM 35£25 ml). The combined
organic layer was dried 3MgSO4), the solvent removed
under reduced pressure, the residue taken up in degassed
xylene and NMM 30.11 g, 0.99 mmol) added. The mixture
was boiled under re¯ux under a nitrogen atmosphere for
18 h. Removal of xylene under reduced pressure gave a
pale yellow solid which consisted of a 2:1 mixture of 315)
and 316). Flash chromatography 3SiO2) of the this solid
eluting with 9:1 v/v ether±petroleum ether afforded
cycloadducts 315) and 316) in 53% combined yield.
1.5.1. Cycloadduct 224). Obtained as a colourless amor-
phous solid from toluene±ethyl acetate 3497 mg, 47%),
mp 54.5±55.58C. 3Found: C, 56.4, H, 5.0; N, 5.0.
C25H225ClN2O5S2 requires: Found: C, 56.3, H, 4.7; N,
5.2%); d: 2.75 and 2.85 32£m, 2H, CH2NO), 3.10 3m, 2H,
CH2NH), 3. 5 3t, Jˆ7.5 Hz, 1H, H4), 3.85 3m, 1H, H3). 3.85
3m, 1H, H3), 4.0 3dd, Jˆ8 and 10 Hz, 1H, H1), 4.4 3dd,
Jˆ3.5 and 10 Hz, 1H, H2) 5.7 3dd, Jˆ8.5 and 16 Hz, 1H,
H5), 6.1 3d, Jˆ16 Hz, 1H, H6) and 7.0±8.0 3m, 14H, ArH),
m/z3%) 411 31), 347 36), 284 33), 213 33), 175 327), 144
3100), and 115 370).
1.4.1. Cycloadduct 215). Obtained 328%) as a colourless
amorphous solid, mp 149±1518C. 3Found: C, 73.5, H, 6.7,

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7961
1.5.4. Cycloadducts 229b) and 230b). Obtained as a 1:1
mixture [2.24 mmol scale 3881 mg, 82% combined yield)]
of separable endo- and exo-isomers.
exo-Isomer 329b): Colourless cubes from ethyl acetate±hex-
ane, mp 179±1818C. 3Found: C, 50.0, H, 4.25; N, 8.55.
C20H20ClN3O6S requires: C, 49.85, H, 4.2; N, 8.7%); d:
2.65 3m, br, 1H, CHHNO), 3.09 3s, 3H, Nme), 3.0±3.25
3m, 3H, CH2NH and CHHNO), 3.43 3t, Jˆ8.6 Hz, 1H,
H3), 3.6 3t, Jˆ7.6 Hz, 1H, H2), 4.83 3d, Jˆ7.3 Hz, 1H,
H1), 5.15 3t, Jˆ5.9 Hz, 1H, NH), 5.6 3dd, Jˆ15.6 and
9.3 Hz, 1H, H4), 6.6 3d, Jˆ15.5 Hz, 1H, H5), 7.0 and 7.25
32£m, 3H, thienyl H) and 7.45 and 7.8 32£d, 4H, Jˆ8.8 Hz,
ArH), nmax 3®lm): 3300 3NH), 2900 3CH), 1786 3imide),
1705 3CvO imide), 1586, 1435, 1332, 1286, 1163, 1094,
961, 829 and 735 cm21. m/z3%) 370 36), 262 312), 195 311),
175 332), 150 381), 136 324), 121 326) and 111 3100).
1.5.2. Cycloadduct 225). Obtained as colourless amorphous
solid from toluene±ethyl acetate 3102mg, 10%); d: 2.65 3m,
2
1H, CHHNO), 2.86 3t, Jˆ9.2Hz, 2H, H and H3) 2.93 3m,
1H, CHHNO), 3.16 3m, 2H, CH2NH), 3.34 3m, 1H, H4), 4.9
3t, Jˆ7.1 Hz, 1H, H1), 5.44 3t, Jˆ5.1 Hz, 1H, NH), 5.88 3dd,
Jˆ16.0 and 8.6 Hz, 1H, H5), 6.53 3d, Jˆ16.0 Hz, 1H, H6)
and 7.1±7.95 3m, 9H, ArH), m/z3%) 361 315), 175 315), 144
345), 125 325), 115 340) and 77 354).
endo-Isomer 330b): Colourless amorphous solid from ethyl
acetate±hexane, mp 165.5±167.58C. 3Found: C, 49.85, H,
4.35; N, 8.4. C20H20ClN3O6S requires: C, 49.85, H, 4.20; N,
8.7%); d: 2.76 and 2.9 32£m, 2H, CH2NO), 3.04 3s, 3H,
NMe), 3.13m, 2H, CH2NH), 3.48 3d, Jˆ6.7 Hz, 1H, H2),
3.9 3m, 1H, H3) [at 508C becomes a doublet Jˆ8.0 Hz],
4.823d, Jˆ7.2Hz, 1H, H 1), 5.1 3br, 1H, NH), 5.93 3dd,
Jˆ15.4 and 9.8 Hz, 1H, H4), 6.74 3d, Jˆ15.7 Hz, 1H, H5),
7.0 and 7.232 £m, 2H, thiophene H), 7.45 and 7.8 32£d, 4H,
Jˆ8.5 Hz, ArH), m/z3%) 353 37), 260 316), 175 333), 166
321), 150 376), 136 326), 121 322) and 111 3100).
1.5.3. Cycloadduct 226). Obtained as colourless amorphous
solid from toluene±ethyl acetate 3111 mg, 10%), d: 2.63 3m,
1H, H2), 3.05 3m, 5H, ONCH2CH2NH and H3), 3.8 3m, 1H,
H4), 4.89 3m, 1H, H1), 5.17 3s, br, 1H, NH), 5.9 3dd, Jˆ16.0
and 9.3 Hz, 1H, H5), 6.56 3d, Jˆ16.0 Hz, 1H, H6) and 7.2±
7.95 3m, 9H, ArH), m/z3%) 361 315), 175 325), 144 348), 125
344), 115 349) and 77 3100).
1.5.5. Cycloadduct 229c) and 230c). Obtained as a 1:1

7962
H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
mixture [1.16 mmol scale 3460 mg, 68% combined yield)]
of separable endo- and exo-isomers.
1436, 1331, 1287, 1163, 1094, 963, 829, and 736 cm21
.
m/z3%) 175 333), 161 329), 134 391) and 111 3100).
exo-Isomer 329c): Colourless prisms from ethyl acetate±
hexane, mp 177±1788C. 3Found: C, 47.2, H, 4.1, N, 9.15,
S, 13.95. C18H18ClN3O5S2 requires: C, 47.4, H, 4.0; N, 9.2,
S, 14.05%), d: 2.77 and 2.98 32£m, 2H, CH2NO), 3.023s,
3H, NMe), 3.23m, 2H, C H2NH), 3.71 3t, Jˆ8.3 Hz, 1H, H2),
4.33 3d, Jˆ9.2Hz, 1H, H 3), 4.93 3d, Jˆ7.2Hz, 1H, H 1), 5.1
3br, 1H, NH), and 7.01±7.83 3m, 7H, ArH1thiophene H),
nmax 3®lm): 3300 3NH), 2900 3CH), 1788 3imide), 1707
3CvO imide), 1586, 1436, 1331, 1286, 1163, 1086, 831
and 735 cm21., m/z3%) 344 312), 251 333), 175 327), 124
386) and 111 3100).
endo-Isomer 330d): Colourless cubes from ethyl acetate±
hexane, mp 156±1588C. 3Found: C, 51.7, H, 4.4; N, 9.0.
C20H20ClN3O6S requires: C, 51.6, H, 4.3; N, 9.0%); d:
2.75 and 2.9 32£m, 2H, CH2NO), 3.05 3s, 3H, NMe) 3.10
3m, 2H, CH2NH), 3.47 3d, Jˆ7.7 Hz, 1H, H2), 3.9 3m, 1H,
H3), [at 508C becomes a doublet Jˆ8.0 Hz], 4.823d,
Jˆ7.3 Hz, 1H, H1), 5.01 3t, Jˆ5.8 Hz, 1H, NH), 6.06 3dd,
Jˆ15.8 and 8.5 Hz, 1H, H4), 6.35 3m, 3H, H5 and furyl H),
7.38 3s, 1H, furyl H) and 7.48±7.78 32£d, 2£2H, Jˆ8.4 Hz,
ArH), m/z3%) 354 34), 338 36), 175 330), 161 322), 134 3100)
and 111 392).
endo-Isomer 330c): Colourless amorphous solid from
ethyl acetate±hexane, mp 160±1638C. 3Found: C, 47.2, H,
4.2; N, 8.95, S, 13.85. C18H18ClN3O5S2 requires: C, 47.4, H,
4.0; N, 9.2, S, 14.05%), d: 2.5 and 2.65 32£m, 2H, CH2NO),
3.08 3m, 5H, NMe1CH2NH), 3.65 3d, Jˆ7.6 Hz, 1H, H2),
4.70 [broad peak at 208C, 3508C, s, 1H, H3)], 4.9 3d,
Jˆ7.7 Hz, 2H, H11NH) and 6.9±7.8 3m, 7H, ArH1
thiophene H), m/z3%) 251 314), 175 328), 124 384) and
111 3100).
1.5.6. Cycloadducts 229d) and 230d). Obtained as a 1:1
mixture [2.8 mmol scale 31.02 g, 78% combined yield)] of
separable endo- and exo-isomers.
1.5.7. Cycloadducts 229e) and 230e). Obtained as a 2:1
mixture [0.95 mmol scale 3309 mg, 74% combined yield)]
of separable endo- and exo-isomers.
exo-Isomer 329d): Colourless cubes from ethyl acetate±
hexane, mp 142±1448C. 3Found: C, 51.6, H, 4.25, N,
8.95. C20H20ClN3O6S requires:: C, 51.6, H, 4.3; N, 9.0%),
d: 3400 MHz), 2.62 3m, 1H, CHHNO), 3.06 3s, 3H, NMe),
2.9±3.2 3m, 3H, CH2NH, CHHNO), 3.39 3t, Jˆ8.7 Hz, 1H,
H3), 3.57 3t, Jˆ7.7 Hz, 1H, H2), 4.823d, Jˆ7.3 Hz, 1H, H1),
5.21 3t, Jˆ5.3 Hz, 1H, NH), 5.68 3dd, Jˆ15.7 and 9.5 Hz,
1H, H4), [6.3 3d, Jˆ3.3 Hz, 1H), 6.37 3dd, Jˆ3.3 and 1.8 Hz,
1H), 7.37 3d, Jˆ1.6 Hz, 1H, furyl H), 6.4 3d, Jˆ15.7 Hz, 1H,
H5) and 7.45 and 7.8 32£d, Jˆ8.8 Hz, 4H, ArH), nmax 3®lm):
3300 3NH), 2900 3CH), 1786 3imide), 1705 3CvO imide),
exo-Isomer 329e): Colourless needles from ethyl acetate±
hexane, mp 170±1718C. 3Found: C, 49.15, H, 4.05, N, 9.45,
S, 7.35. C18H18ClN3O6S requires: C, 49.15, H, 4.1; N, 9.55,
S, 7.3%); d: 3400 MHz), 2.75 and 2.9 32£m, 2H, CH2NO),
3.04 3s, 3H, NMe) 3.15 3m, 2H, CH2NH), 3.68 3t, Jˆ8.0 Hz,
1H, H2), 4.06 3d, Jˆ8.7 Hz, 1H, H3), 4.8 3d, Jˆ7.3 Hz, 1H,
H1), 5.1 3br, 1H, NH), [6.25 3d, Jˆ3.3 Hz, 1H), 6.45 3dd,
Jˆ3.0 and 1.8 Hz, 1H), 7.45 3d, Jˆ1.7 Hz, 1H furyl H, 7.5
and 7.8 32£d, Jˆ8.6 Hz, 2£2H, ArH), nmax 3®lm): 3300
3NH), 2900 3CH), 1788 3imide), 1706 3CvO imide),

H. A. Dondas et al. / Tetrahedron 57 ꢀ2001) 7951±7964
7963
1586, 1436, 1331, 1289, 1163, 1094, 829, and 736 cm21. m/
z3%) 235 3100) and 108 387).
collected of which 3808 with Fo . 4:0sꢀFo† were con-
sidered `observed'.
Structure re®nement. Number of parametersˆ296, good-
ness of ®t, sˆ1.071; wR2 3all data)ˆ0.0904, R1 3'observed'
data)ˆ0.0335.
1.6.2. Crystal data for 31. C13H14ClN3O3S, 0.45£0.20£
0.20 mm, Mˆ327.78, monoclinic, space group P21/n,
Ê
aˆ7.261831),
bˆ21.692637),
cˆ9.854733) A,
bˆ
23
Ê 3
108.35232)8, Vˆ1473.4337) A , Zˆ4, Dcˆ1.48 mg m
mˆ0.41 mm21, F3000)ˆ680, Tˆ190 K.
,
Data collection. 2.18,2u,26.08; 2888 unique data
collected of which 2552 with Fo . 4:0sꢀFo† were con-
sidered `observed'.
endo-Isomer 330e): Colourless needles from ethyl acetate±
hexane, mp 164±1668C. 3Found: C, 49.25, H, 4.25; N, 9.5,
S, 7.2. C18H18ClN3O6S requires: C, 49.15, H, 4.1; N,
9.55%); d: 2.4 and 2.8 32£m, 2H, CH2NO), 3.08 3m, 5H,
NMe and CH2NH), 3.8 3d, Jˆ8.0 Hz, 1H, H2), 4.5 [broad
peak at 208C, 3508C. d, Jˆ8.0 Hz, 1H, H3], 4.9 3d, Jˆ8.4 Hz,
1H, H1), 5.0 3t, Jˆ5.6 Hz, 1H, NH), [6.25 3d, Jˆ3.3 Hz,
1H), 6.4 3dd, Jˆ3.0 and 1.8 Hz, 1H), 7.4 3d, Jˆ1.8 Hz,
1H, furyl H and 7.5±7.8 32£d, 2£2H, Jˆ8.6 Hz, ArH),
m/z3%) 235 393), 108 3100).
Structure re®nement. Number of parametersˆ195, good-
ness of ®t, sˆ1.024; wR2 3all data)ˆ0.0859, R1 3`observed'
data)ˆ0.0319.
Supplementary data-sets for both structures, which include
hydrogen co-ordinates, all thermal parameters and complete
sets of bond lengths and angles, have been deposited at the
Cambridge Crystallographic Data Centre and are available
on request.
Acknowledgements
We thank Mersin University 3Turkey) 3H. A. D.) for leave of
absence, Leeds University for support and P®zer Pharma-
ceutical Company for a generous gift of compounds 32) and
312).
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