Diastereoselective synthesis of aziridines from (1R)-10-(N,N-dialkylsulfamoyl)isobornyl 2H-azirine-3-carboxylates

Article abstract of DOI:10.1039/b202321k

Reaction of the chiral azirine 1a with nucleophiles and dienes is described. Thiols, heteroaromatic nitrogen compounds and phenylmagnesium bromide add to the azirine 1a to give functionalised aziridines 2/3a-h. X-Ray crystal structures for the products 3e and 3g have been obtained. Diastereodifferentiation of the two faces of the azirine 1a is observed in most cases, but only thiophenol gives a single diastereomer (2a). Most mixtures of diastereomers were separated by dry flash chromatography. Benzylamine produced a dimer of the original azirine 1a, compound 9. Representative conjugated dienes (cyclopentadiene, furan and open chain dienes) were added to the chiral azirine 1a. Only poor selectivities were observed. The selectivity was not significantly enhanced in the cycloaddition of cyclopentadiene to the more bulky azirine 1b.

Full text of DOI:10.1039/b202321k

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Diastereoselective synthesis of aziridines from
(1R)-10-(N,N-dialkylsulfamoyl)isobornyl
2H-azirine-3-carboxylates
1
Yolanda S. P. Álvares,a M. José Alves,*a Nuno G. Azoia,a Jamie F. Bickleyb and
Thomas L. Gilchristb
a Departamento de Química, Universidade do Minho, Campus de Gualtar, 4700-320 Braga,
Portugal
b Chemistry Department, The University of Liverpool, Liverpool, UK L69 7ZD
Received (in Cambridge, UK) 5th March 2002, Accepted 25th June 2002
First published as an Advance Article on the web 12th July 2002
Reaction of the chiral azirine 1a with nucleophiles and dienes is described. Thiols, heteroaromatic nitrogen
compounds and phenylmagnesium bromide add to the azirine 1a to give functionalised aziridines 2/3a–h. X-Ray
crystal structures for the products 3e and 3g have been obtained. Diastereodifferentiation of the two faces of the
azirine 1a is observed in most cases, but only thiophenol gives a single diastereomer (2a). Most mixtures of
diastereomers were separated by dry flash chromatography. Benzylamine produced a dimer of the original azirine
1a, compound 9. Representative conjugated dienes (cyclopentadiene, furan and open chain dienes) were added to
the chiral azirine 1a. Only poor selectivities were observed. The selectivity was not significantly enhanced in the
cycloaddition of cyclopentadiene to the more bulky azirine 1b.
We have described reactions of 2H-azirine-3-carboxylic esters
Results and discussion
with nucleophiles. Sulfur nucleophiles,1,2 oxygen nucleophiles1
and aromatic nitrogen heterocycles3 formed aziridines of type
2/3. 2H-Azirine-3-carboxylates have also proved to be excellent
aza dienophiles in Diels–Alder reactions; they add to nucleo-
philic dienes giving good yields of compounds having the
aziridine fused to a six-membered ring.4 These reactions offer a
route to new aziridinecarboxylic acid derivatives, a group of
compounds that are known to have biological activity.5 The
aziridinecarboxylic acids also have the potential to act as
analogues of natural amino acids and to introduce rigidity into
a peptide chain.6 Recent work of F. A. Davis and co-workers7
has shown the usefulness of phosphonate ester azirines, the
2H-3-phosphonates act as partners in Diels–Alder reactions
to give bicyclic structures of the same type having a phos-
phonate ester group instead of a carboxylic ester group. These
compounds also are expected to exhibit a range of biological
activity.
Reaction with thiols
Freshly prepared azirine 1a in toluene was used directly in
reactions with thiols. The azirine solution was cooled in an
ice–water bath and thiols were added with magnetic stirring.
We therefore set out to synthesise a chiral 2H-azirine that
could be used to form chiral aziridines by diastereoselective
nucleophilic addition and Diels–Alder cycloaddition. The
chiral acrylate 4a was first synthesised by Oppolzer et al.8 and
was successfully used in asymmetric Diels–Alder reactions, so
this acrylate was chosen as a precursor to a chiral azirine 1a.
The azido ester 5a was prepared from the acrylate 4a via the
dibromopropionate 6a, following a general method, according
to Scheme 1.9 Finally the azirine 1a was obtained by pyrolysis of
the α-azidoacrylate 5a. The azirine 1a was characterized by
NMR. The signal for the hydrogens attached to C-2 appear as a
singlet at 1.93 ppm and that for C-3 at 157.4 ppm. Preliminary
results with this azirine showed excellent selectivity for the
addition of thiophenol but poor selectivity for Diels–Alder
cycloaddition with cyclopentadiene.2 In view of the high selec-
tivity of the nucleophilic addition reaction a more extensive
study of the addition of nucleophiles and dienes to this azirine
has been carried out.
DOI: 10.1039/b202321k
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919
This journal is © The Royal Society of Chemistry 2002
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Table 1 Isolated yields (%) of compounds 2 and 3 after dry flash
chromatography
Compound
Isomer 2
Isomer 3
Isomers 2 ϩ 3
Total yield
2/3a
2/3b
2/3c
2/3d
2/3e
2/3f
2/3g
2/3h
58 (only)
54
18
—
—
—
—
21
27
34.5
—
—
—
54
45
16
19
—
—
58
54
72
54
37
51
60.5
40
9
a
5
26
—
a The minor isomer fraction was contaminated with benzimidazole in
the ratio 1 (minor isomer) : 5 (benzimidazole).
Fig. 1 Approach of nucleophiles to the less hindered face of two
conformations of the azirine 1a.
stereochemistry of 2a would result from attack of thiophenol
on the Si face of the azirine, probably as an approach at the rear
face of conformer a (Fig. 1). Formation of the S aziridine after
nucleophilic attack could be due to an unfavourable interaction
with the ester carbonyl group or to steric hindrance by a methyl-
ene group of the norbornyl unit on the rear face (Re) of
conformation b. Nucleophilic attack would also be possible
through the less hindered face (Si) of the s-cis ester conform-
ation 8. A comparison of the NMR data for the thio aziridine
derivatives 2 and 3 shows no clear pattern of difference between
them. The S configuration was assigned to the major products 2
on the basis of an analogous mode of approach expected for
the p-substituted thiophenols compared with thiophenol itself.
Diastereoselectivity dropped to zero when methyl thioglycolate
was used as the nucleophile. Possibly the higher reactivity of the
alkyl thiol is a factor in the loss of selectivity.
Scheme 1 Reagents: i, Br2, DCM, 24 h; ii, NaN3 (3 equiv.), DMF;
iii, DBU; iv, toluene, 110 ЊC, 1.5 h.
The reaction mixture was then left to stir at room temperature
for 2–19 hours. The reactions gave mixtures of diastereomers,
generally a major and a minor isomer with the exception of
thiophenol, which produced a single compound 2a (Table 1).
4-Chlorothiophenol also showed good diastereoselectivity
giving diastereomers 2b : 3b in an 8 : 1 ratio according to the 1H
NMR spectrum of the reaction mixture. The major adduct
from 4-chlorothiophenol (2b) was obtained in a combined yield
Reactions with heteroaromatic nitrogen compounds
1
of 54% and the minor isomer could be detected by H NMR
Reaction of the 2H-azirine 1a with the heteroaromatic nitrogen
compounds benzimidazole and thymine was carried out in the
presence of sodium carbonate and in acetonitrile at room
temperature for periods between 1 hour and 6 days. Com-
pounds 2e/3e and 2f/3f were produced, in both cases as a mix-
ture in a 2 : 1 ratio of diastereomers. The major isomers were
separated by dry flash chromatography in both cases: 3e in
21% and 3f in 27% yield. Reaction of 2H-azirine 1a with
2-formylpyrrole gave diastereomers 2g/3g in a ratio of approx-
imately 1 : 1. The two were completely separated (34.5% and
26%) and were fully characterized. X-Ray crystal structures of
diastereomers 3e and 3g were obtained (Figs. 2 and 3) and in
both cases the new stereogenic centre on the aziridine had the
R-configuration. The major isomers 3e and 3g would form after
attack of the nucleophile on the Re face of the azirine, probably
as shown in conformer b (Fig. 1), but not on the less hindered
(Si) face of the s-cis conformer 8, where different stereo-
chemistry would result. When the nucleophile is a hetero-
aromatic nitrogen anion the attack of the electron pair (which is
coplanar with the aromatic ring) would be by approach to the
azirine ring in an orthogonal plane, thus avoiding the inter-
actions referred to above in the nucleophilic attack of thiols on
the Re face of conformer b.
but not isolated. 4-Nitrothiophenol did not react under neutral
conditions after 2 days at room temperature but in the presence
of sodium carbonate in acetonitrile a 4 : 1 mixture of isomers 2c
: 3c was formed after 30 hours at room temperature in a com-
bined yield of 72%. A sample of the major isomer was obtained
almost pure by flash chromatography. Methyl thioglycolate
gave a mixture of diastereomers 2d : 3d in an approximately 1 : 1
1
ratio either at room temperature or at 0 ЊC (as shown by H
NMR analysis).
Reaction of thiophenol with the azirine 1a gave compound
2a in an optically pure form (as evidenced by the NMR spec-
trum of the crude reaction mixture). After chromatography and
crystallisation 2a was obtained as a crystalline solid in 58%
yield. X-Ray crystallography established that the newly formed
stereogenic centre had the S configuration, as shown in struc-
ture 2.2 Molecular orbital calculations on the conformation of
2H-azirine-3-carboxylic acid indicate that the minimum energy
conformers 7a and 7b have similar values and that the rotation
barrier between them is only 8 kJؒmolϪ1 (Scheme 2).2 The
The first eluted products were separated from the other
isomer by simple flash chromatography in each case; there was a
considerable difference in polarity between each diastereomer
Scheme 2
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partially cleaved giving back the alcohol, N,N-diethyl-
sulfamoylisoborneol, which was isolated in 33.6% yield after
flash chromatography. The product of addition of the phenyl-
magnesium bromide to the azirine was collected as a colourless
oil in 40% yield. It was found to be a 1 : 1 mixture of two
diastereomers 2h : 3h that could not be separated by dry flash
chromatography.
Reaction with benzylamine
Several primary and secondary amines had previously been
reacted with 2H-azirine-3-carboxylates giving open chain
products of type 10.1 However 1a and benzylamine gave the
aromatised dimer 9 as the only characterizable product; this
was isolated in 17% yield. A 1,2-dihydropyrazine dimer was
previously obtained by passing a 2H-azirine-3-carboxylate
through a column of silica gel.4 The acidic properties of silica
were assumed to promote dimerisation of the azirine. It now
seems that an amine can also catalyse dimerisation. Traces of
compound 9 were also detected in the reaction of the azirine
with p-nitrothiophenol when performed in the presence of
Na2CO3.
Fig. 2 ORTEP view of the molecular structure of the aziridine 3e.
The thermal ellipsoids are drawn at the 50% probability level.
The aziridine ring was assigned on the basis of 1H, 13C NMR
spectra and X-ray structures obtained for 2a,2 3e and 3g. The
1
major features of the H NMR spectra of 2a–d are the two
broad signals for H-3 protons, one at ca. δH 2.0–2.5 ppm and
the other at ca. δH 2.5–2.9 ppm (as broad singlets 2a, 2b and 2d;
as broad doublets 2c), and the NH absorption appears at
around δH 2.4 ppm as a very broad signal, with exception of 2c
where NH is a defined triplet (J 10.2) and 2d where the NH
signal is not visible. Addition of D2O to the NMR sample tube
causes the CH signals to sharpen and the NH signal to dis-
appear. Minor isomers also show the aziridine CH as broad
signals and the NH absorption is absent. Major isomers 3e
and 3f and the first eluted isomer 3g show a doublet for each of
the CH protons and a triplet for the NH at around the same
chemical shift as for the thiol adducts. There is a splitting of ca.
10.5 Hz that is due to the vicinal NH to CH coupling. After
D2O exchange the NH triplet disappears and the CH doublets
collapse to singlets. The second isomer (2g) isolated by chrom-
atography displays a similar pattern in the 1H NMR spectra to
the first eluted isomer (3g). The spectrum of compound 2e
showed a broad signal for NH and the aziridine CH appeared
as broad singlets. These apparent differences in whether the NH
signal is present or not are presumably due to traces of acid or
moisture that cause the NH to exchange in some samples but
not in others; for example two spectra were obtained for com-
pound 2c, one clearly showing the NH signal as a well defined
triplet and the other not. Typically, no coupling is observed
between the geminal hydrogens on the aziridine ring.
Fig. 3 ORTEP view of the molecular structure of the aziridine 3g.
The thermal ellipsoids are drawn at the 50% probability level.
in the pair. Based in this observation the first eluted isomer of
reaction with thymine was assigned as the R isomer (3f ). The
minor isomer 2e was contaminated with benzimidazole, and the
major isomer 3f with a small amount of the minor isomer.
Electrophilic addition of the azirine to thymine was considered
to occur at N-1 in accordance with the general reactivity of
thymine. Moreover, an X-ray crystal structure of an adduct of
thymine with a similar azirine showed it to follow the same rule.10
Reactions with dienes
Oppolzer and coworkers have studied the selectivity of Diels–
Alder reactions in acrylates bearing the same type of chiral
auxiliary with cyclopentadiene and found excellent diastereo-
selectivities.8 The reason for this is that the acrylate function
adopts a strict antiperiplanar disposition of the carbonyl and
the carbon–carbon double bond and this causes a preferential
attack on one face. Reactions of the azirine 1a with four dienes,
namely cyclopentadiene, 1-methoxybutadiene, (E, E)-1,4-
diphenylbutadiene and furan, were investigated. The reactions
with the first three of these dienes, which are endo additions,4
showed poor diastereoselectivity and there was no diastereo-
selectivity at all in the addition to furan, a 1 : 1 mixture of two
exo adducts being obtained (the exo mode of addition is char-
acteristic of other azirine cycloadditions to furans12). Our
results with the kinetically controlled endo cycloadditions prob-
ably reflect the easy interconversion of rotamers in the azirine
(conformer a and conformer b) and the equivalent population
of both in the reaction mixture. The 2 : 1 ratio of diastereomers
When the reaction of the 2H-azirine 1a and benzimidazole
was carried out over 2 days at room temperature benzimidazole
was recovered in almost quantitative yield and pyrazine 9 was
isolated in 7% yield. The major characteristic feature of this
1
compound was its high symmetry as shown by the H and 13C
NMR spectra. The chemical shift of the hydrogens attached to
the pyrazine ring (δH 9.31 ppm) is in accord with literature
values for similar pyrazines.11
Reaction with phenylmagnesium bromide
Reaction of the azirine 1a with 1 equivalent of phenyl-
magnesium bromide was carried out at Ϫ78 ЊC. The ester was
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919
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observed with cyclopentadiene is probably due to a very small
difference in the energy of the transition states. Two possible
approaches of cyclopentadiene to the azirine are illustrated in
Fig. 4. The interaction that would lead to the major diastereo-
A preliminary X-ray investigation of the major diastereomer
15 obtained from the reaction of the azirine 1a with 1,4-
diphenylbuta-1,3-diene showed that it has the S-configuration
at the new asymmetric centre (Fig. 5). This result would be due
Fig. 4 Approach of cyclopentadiene to the less hindered face of two
conformations of the azirine 1a.
mer 12a is indicated as the preferential direction of attack on
the Re face of the azirine of conformer b. The minor isomer 11a
(the stereochemistry of the minor isomer has previously been
determined by X-ray crystallography2) would result from an
attack on the Si face of conformer a. The bulkier substituents
in azirine 1b scarcely improve the diastereodifferentiation of
the two azirine faces: the diastereomeric ratio observed with
azirine 1a bearing the diethylsulfonamido group is 2 : 1 and
with azirine 1b bearing the dicyclohexylsulfonamido group it is
3 : 1. On the other hand, the thermodynamic control generally
associated with the exo cycloadditions indicates similar energy
states for both exo isomers. The reaction of the azirine 1a with
furan was performed either at 5 ЊC and at rt. The same dia-
stereomeric mixture (17 and 18) in the same ratio (1 : 1) was
obtained in the two experiments. Also, heating of the 1 : 1
mixture of isomers for 15 hours at 75 ЊC caused no observable
change in the ratio.
Fig. 5 ORTEP view of the molecular structure of the cycloadduct 15.
The thermal ellipsoids are at the 50% probability level.
to the stereoelectronic effect of the bulky Ph groups in the diene
that cause severe interference with the isobornyl unit, especially
when the attack occurs at the rear face of conformer a. The
effect is minimized when the attack occurs at the rear face
of conformer b. The presence of water of crystallisation was
indicated from the crystal structure and also by elemental
analysis.
Conclusions
Azirine 1a reacted with thiols and nitrogen aromatic hetero-
cycles to give addition products in which the three-membered
ring is preserved. Of the reactions tested only 4-chlorothio-
phenol and thiophenol added to the chiral azirine 1a with good
to excellent diastereoselectivity. Major isomers (where formed)
have the S configuration at the stereogenic centre of the azir-
idine. Heteroaromatic nitrogen compounds gave mixtures of
both diastereomers with zero to modest diastereoselectivity.
Major isomers (where formed) have the R configuration at the
stereogenic centre of the aziridine. Phenylmagnesium bromide
added with no selectivity. Cycloaddition reactions of the
azirines 1 also showed low diastereoselectivity, whether they
resulted from kinetic control (endo additions) or thermo-
dynamic control (exo addition to furan). Nevertheless, in cases
where the diastereomers can be separated by chromatography,
these reactions represent a route to chiral aziridines of a novel
type.
Experimental
General
1H NMR spectra were recorded on a Varian Unity Plus 300
(300 MHz) spectrometer. Multiplicities are recorded as broad
peaks (br), singlets (s), doublets (d), triplets (t), quartets (q) and
multiplets (m). J values are in Hz. Infrared spectra were
recorded on a Bomem MB 104 or on a Perkin–Elmer 1600
FT-IR spectrometer. Solid samples were run as Nujol mulls
and liquids as thin films. Mass spectra were recorded on a VG
Micromass 7070E machine as electron impact (EI) spectra
1914
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919

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(70 eV) or as chemical ionisation (CI) spectra. Microanalyses
were performed in the University of Liverpool Department of
Chemistry microanalytical laboratory using a Carlo Erba
elemental analyzer or in the University of Minho using a
LECO-CHNS-932 machine. Optical rotations were measured
with an AA SERIES POLARIMETER (Optical Activity Ltd.)
using a 0.25 dm cell and are given in units of 10Ϫ1 deg cm2
(CH3), 20.4 (CH3), 25.1 (CH2), 26.4 (CH2), 27.0 (CH2), 29.9
(CH2), 32.7 (CH2), 39.3 (CH2), 44.5 (CH), 49.1 (Cq), 49.4 (Cq),
53.6 (CH2), 57.3 (CH), 78.3 (CH), 129.1 (CH), 129.8 (CH2) and
164.4 (CO).
[(1R)-10-(N,N-Dicyclohexylsulfamoyl)isobornyl] 2-azido-
acrylate 5b
g
Ϫ1.The X-ray data for compounds 3g and 3e were collected on
(i) A solution of the ester (0.8 g, 1.78 mmol) in freshly distilled
CH2Cl2 (15 ml) was stirred in an ice–water bath. Bromine
(0.28 g, 92 µl, 1.78 mmol) was added in one portion. The mix-
ture was stirred at room temperature for 19 h. The solvent was
removed on a rotary evaporator leaving a solid that was washed
with ether. The product was identified as the dibromopropion-
ate ester 6b (1.03 g, 95%) as a 1 : 1 mixture of isomers [Found:
Mϩ (EI) 609.1127. C25H41Br2NO4S requires M, 609.1123];
νmax (Nujol)/cmϪ1 1738; δH (300 MHz, CDCl3) 0.90 (3 H, sa),
a Stoe IPDS diffractometer at 213(2) K and X-ray data for
compound 15 was collected on a Bruker SMART APEX CCD
diffractometer at 150(2) K; all used Mo-Kα radiation at
0.71073 Å. Melting points (mp) were determined on a
Gallenkamp block and are uncorrected. Dry column flash
chromatography was carried out using Kieselgel 60 and a water
pump vacuum. Thin layer chromatography (TLC) was carried
out on 0.25 mm silica gel layers 60DC–Ferigplatter Durasil-25
UV254. The azirine precursor azide 5a was prepared as reported
earlier.2 The azirine 1a, although prepared before, was isolated
and characterized for the first time.
a
1.03 (3 H, s ), 1.10–1.40 (7 H, ma), 1.40–1.90 (18 H, ma),
1.90–2.10 (2 H, ma), 2.67 (1 H, d, J 13.3a), 3.22 (1 H, d,a J 13.3),
3.14–3.40 (2 H, ma), 3.62–3.78 (1 H, ma), 3.93 (0.5 H, t,b J 9.6),
4.00 (0.5 H, t,b J 9.6), 4.38–4.44 (1 H, ma) and 5.00–5.10 (1 H,
ma). [aSignals due to both isomers. bSignals due to one isomer].
(ii) The dibromo ester (1.03 g, 1.68 mmol) was dissolved in
DMF (15 ml) and NaN3 (0.33 g, 5.04 mmol) was added in one
portion. The suspension was stirred for 2.5 days at room tem-
perature then diluted in CH2Cl2 (100 ml) and washed with water
(8 × 50 ml). The organic phase was then dried over MgSO4 and
DBU (0.26 g, 250 µl, 1.68 mmol) was added. The solution was
stirred for 20 min and then washed with 10% aq. citric acid (2 ×
50 ml) and water (1 × 50 ml). The organic layer was dried over
MgSO4 and the solvent removed to give a thick transparent
oil identified as [(1R)-10-(N,N-cyclohexylsulfamoyl)isobornyl]
2-azidoacrylate 5b (0.62 g, 73%) (Found: C, 60.9; H, 8.2;
N, 11.3. C25H40N4O4S requires C, 61.0; H, 8.2; N, 11.4 %);
νmax (Nujol)/cmϪ1 2110, 1727 and 1615; δH (300 MHz, CDCl3)
0.91 (3 H, s), 1.03 (3 H, s), 1.10–1.40 (7 H, m), 1.50–1.90 (18 H,
m), 1.95–2.10 (2 H, m), 2.68 (1 H, d, J 13.3), 3.25 (1 H, d,
J 13.3), 3.10–3.25 (2 H, m), 5.16–5.19 (1 H, m), 5.30 (1 H, d,
J 1.1) and 5.73 (1 H, d, J 1.1); δC (75.5 MHz, CDCl3) 20.0
(CH3), 20.4 (CH3), 25.2 (CH2), 26.5 (CH2), 27.0 (CH2), 30.1
(CH2), 32.7 (CH2), 33.0 (CH2), 39.2 (CH2), 44.5 (CH), 49.2 (Cq),
49.8 (Cq), 53.7 (CH2), 57.6 (CH), 80.1 (CH), 109.7 (CH2), 137.1
(Cq) and 160.6 (CO).
(1R)-10-(N,N-Diethylsulfamoyl)isobornyl 2-azidoacrylate 5a
(i) Addition of bromine to the ester 4a gave the dibromoprop-
ionate ester 6a (1.46 g, 100%) as a 1 : 1 mixture of isomers
(Found: C, 40.8; H, 5.9; N, 2.7. C17H29Br2NO4S requires C,
40.6; H, 5.8; N, 2.8); νmax (Nujol)/cmϪ1 1740; δH (300 MHz,
CDCl3) 0.91 (3 H, sa), 1.03 (3 H, sa), 1.20 (6 H, t,a J 7.2),
1.40–2.20 (7 H, ma), 2.72 (1 H, d,a J 13.5), 3.20–3.35 (5 H, ma),
3.65–3.73 (1 H, ma), 3.90 (0.5 H, t,b J 10.2), 3.97 (0.5 H, t,b
J 10.2), 4.40 (0.5 H, dd,b J 4.8 and 2.1), 4.43 (0.5 H, dd,b J 4.8
and 2.1) and 5.06–5.12 (1 H, m,a CHOH). [aSignals due to both
isomers. bSignals due to one isomer].
(ii) Addition of NaN3 to the dibromopropionate ester 6a
(1.43 g, 2.84 mmol) in DMF followed by treatment with DBU
gave the azidoacrylate 5a as an oil (0.40 g, 89%) that slowly
crystallised, mp 48.5–49.5 ЊC (Found: C, 53.0; H, 7.4; N, 14.3.
C17H28N4O4S requires C, 53.1; H, 7.3; N, 14.6%); νmax (Nujol)/
cmϪ1 2111, 1726 and 1615; δH (300 MHz, CDCl3) 0.91 (3 H, s),
1.04 (3 H, s), 1.19 (6 H, t, J 7.2), 1.60–1.90 (5 H, m), 1.90–2.10
(2 H, m), 2.73 (1 H, d, J 13.6), 3.20–3.30 (5 H, m), 5.12 (1 H, dd,
J 7.7 and 2.6), 5.31 (1 H, d, J 1.4) and 5.75 (1 H, d, J 1.4);
δC (75.5 MHz, CDCl3) 14.4 (CH3), 19.9 (CH3), 20.3 (CH3), 27.0
(CH2), 30.0 (CH2), 39.2 (CH2), 41.5 (CH2), 44.6 (CH), 49.3,
49.5, 49.7 (CH2 ϩ 2 Cq), 80.1 (CH), 109.9 (CH2), 137.1 (Cq) and
160.6 (CO); m/z (CI) 402 (M ϩ NH4)ϩ.
(1R)-10-[(N,N-Dicyclohexylsulfamoyl)isobornyl]-2H-azirine 1b
A solution of the 2-azidoacrylate 5b (0.04 g, 0.08 mmol)
in dry toluene (10 ml) was heated under reflux and under N2 for
90 min. The solvent removed to leave a pale yellow oil that
contained ca. 20% of the 2-azidoacrylate according to the
NMR spectrum; the major component was identified as the
azirine 1b; νmax (Nujol)/cmϪ1 1721; δH (300 MHz, CDCl3) 0.91
(3 H, s), 1.05 (3 H, s), 1.05–1.40 (7 H, m), 1.90 (2 H, s),
1.40–2.10 (20 H, m), 2.68 (1 H, d, J 13.3), 3.10–3.31 (2 H, m),
3.31 (1 H, d, J 13.3) and 5.25–5.35 (1 H, m); δC (75.5 MHz,
CDCl3) 19.9 (CH3), 20.2 (CH3), 23.4 (CH2), 25.1 (CH2), 26.2
(CH2), 26.3 (CH2), 26.9 (CH2), 30.2 (CH2), 32.7 (CH2), 32.8
(CH2), 39.0 (CH2), 44.5 (CH), 49.1 (Cq), 49.8 (Cq), 53.4 (CH2),
57.5 (CH), 81.2 (CH), 157.3 (Cq) and 164.8 (CO).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl]-2H-azirine 1a
The α-azido acrylate 5a (0.67 g, 1.74 mmol) in dry toluene
(30 ml) was heated under reflux and under N2 for 90 min. The
solution was cooled and the toluene was removed on a rotary
evaporator to leave an oil (0.62 g, 1.74 mmol) which was identi-
fied as the 2H-azirine 1a; δH (300 MHz, CDCl3) 0.93 (3 H, s),
1.05 (3 H, s), 1.17 (6 H, t, J 6.9), 1.60–2.20 (7 H, m), 1.93 (2 H,
s), 2.66 (1 H, d, J 13.5), 3.23 (4 H, q, J 6.9), 3.27 (1 H, d, J 13.5)
and 5.27–5.32 (1H, m); δC (75.5 MHz, CDCl3) 14.5 (CH3), 19.9
(CH3), 20.3 (CH3), 23.6 (CH2), 26.9 CH2), 30.0 (CH2), 39.0
(CH2), 41.6 (CH2), 41.5 (CH2), 44.4 (CH), 49.2 (CH2), 49.3 (Cq),
49.5 (Cq), 80.1 (CH), 157.4 (Cq) and 165.0 (CO).
[(1R)-10-(N,N-Dicyclohexylsulfamoyl)isobornyl] acrylate 4b
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(phenylthio)-
aziridine-2-carboxylate 2a
The ester 4b was prepared according to the method described
by Oppolzer and co- workers.8 Mp 197.1–199.5 ЊC (from ether–
light petroleum) (Found: C 66.4; H, 9.1; N, 3.2. C25H41NO4S
requires C, 66.5; H, 9.2; N, 3.1%); νmax (Nujol)/cmϪ1 1717;
δH (300 MHz, CDCl3) 0.90 (3 H, s), 1.02 (3 H, s), 1.00–1.35
(7 H, m), 1.55–1.85 (18 H, m), 1.90–2.10 (2 H, m), 2.69 (1 H, d,
J 13.5), 3.27 (1 H, d, J 13.5), 3.15–3.30 (2 H, m), 5.05–5.15 (1 H,
m), 5.81 (1 H, dd, J 10.4 and 3.0), 6.11 (1 H, dd, J 17.4 and 10.5)
and 6.36 (1 H, dd, J 17.4 and 3.0); δC (75.5 MHz, CDCl3) 20.0
A solution of the azide 5a (1.0 g, 2.6 mmol) in dry toluene
(40 ml) was heated under reflux for 1.5 h. The solution was
cooled in an ice–water bath and thiophenol (0.29 g, 2.6 mmol)
was added. After 19 h the solvent was removed and the residue
was subjected to dry flash chromatography (hexane–ether).
This gave the ester 2a (0.71 g, 58%), mp 89–89.5 ЊC (from ether–
hexane) (Found: C, 59.3; H, 7.4; N, 6.0. C23H34N2O4S2 requires
C, 59.2; H, 7.3; N, 6.0%); [α]2D5 Ϫ48.7 (CH2Cl2, 1.6 g/100 ml);
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919
1915

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νmax (Nujol)/cmϪ1 3274 and 1719; δH (300 MHz, CDCl3) 0.65
(3 H, s), 0.81 (3 H, s), 1.24 (6 H, t, J 7.2), 1.40–1.90 (7 H, m),
2.02 (1 H, br s), 2.40 (1 H br s), 2.45 (1 H, br s), 2.66 (1 H, d,
J 13.5), 3.28 (4 H, q, J 7.2), 3.37 (1 H, d, J 13.5), 4.98–5.00 (1 H,
m) and 7.14–7.35 (5 H, m); δC (75.5 MHz, CDCl3) 14.6 (CH3),
19.4 (CH3), 20.2 (CH3), 26.9 (CH2), 30.0 (CH2), 34.2 (CH2),
38.6 (CH2), 41.7 (CH2), 43.4 (Cq), 44.5 (CH), 49.0 (CH2), 49.1
(Cq), 49.3 (Cq), 81.0 (CH), 126.4 (CH), 128.2 (CH), 128.9 (CH),
134.5 (Cq) and 170.4 (CO); m/z (EI) 466 (Mϩ).
3.3), 7.43 (2 H, d, J 9.0) and 8.14 (2 H, d, J 9.0); δC (75.5 MHz,
CDCl3) 14.6 (CH3), 19.2 (CH3), 20.1 (CH3), 26.8 (CH2), 30.1
(CH2), 34.8 (CH2), 38.6 (CH2), 41.7 (CH2), 44.3 (CH), 49.1 (Cq),
49.4 (Cq), 49.6 (CH2), 81.3 (CH), 124.1 (CH), 126.3 (CH), 145.1
(Cq), 145.7 (Cq) and 169.9 (CO).
1H NMR data of the minor isomer was taken from a
spectrum where both isomers were present; signals due to the
minor isomer were detected at δH (300 MHz, CDCl3) 0.70 (3 H,
br s), 0.83 (3H, s), 1.19 (6 H, t, J 6.9), 2.18 (1 H, br s), 2.90 (1 H,
br s), 5.05–5.15 (1 H, m), 7.63 (2 H, d, J 9.3) and 8.20 (2H, d,
J 9.3).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(4-chlorophenyl-
thio)aziridine-2-carboxylates 2b and 3b
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(methoxycarbonyl-
A solution of the azide 5a (0.30 g, 0.78 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h, then cooled in an ice–water
bath and 4-chlorothiophenol (0.11 g, 0.78 mmol) was added.
After 2 h TLC showed that none of the azirine 1a remained.
Toluene was removed and ether was added giving the ester 2b as
a solid (0.17 g). The remaining oil was subjected to dry flash
chromatography which gave (with hexane–ether 3 : 1) another
fraction of the same solid (0.038 g); total yield 0.21 g, (54%),
mp 128–130 ЊC (from CH2Cl2–hexane) (Found: C, 55.2; H, 6.6;
N, 5.6. C23H33ClN2O4S2 requires C, 55.1; H, 6.6; N, 5.6%);
[α]2D3 Ϫ44.6 (CH2Cl2, 3 g/100 ml), νmax (Nujol)/cmϪ1 3276 and
1722; δH (300 MHz, CDCl3) 0.69 (3 H, s) 0.83 (3 H, s), 1.24
(6 H, t, J 7.2), 1.40–2.00 (7 H, m), 2.11 (1 H, br s), 2.40 (1 H, br
s), 2.50 (1 H, br s), 2.66 (1 H, d, J 13.5), 3.20–3.40 (5 H, m), 5.00
(1 H, dd, J 7.8 and 3.3) and 7.20–7.35 (4 H, m); δC (75.5 MHz,
CDCl3) 14.6 (CH3), 19.5 (CH3), 20.2 (CH3), 26.9 (CH2), 30.0
(CH2), 34.3 (CH2), 38.6 (CH2), 41.7 (CH2), 43.4 (Cq), 44.4 (CH),
49.1 (Cq), 49.2 (Cq), 49.4 (CH2), 81.1 (CH), 129.0 (CH), 129.3
(CH), 132.4 (Cq), 132.9 (Cq) and 169.9 (CO).
methylthio)aziridine-2-carboxylates 2d and 3d
A solution of the azide 5a (0.27 g, 0.76 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h. The reaction solution was
cooled in an ice–water bath, and stirred under nitrogen. Methyl
thioglycolate (0.08 g, 0.77 mmol) was then added. After 18 h the
toluene was removed and the remaining oil was shown to be a
mixture (1 : 1 ratio) of the two isomers. The oil was chromato-
graphed (dry flash, hexane–ether 3 : 1) giving a small fraction
of the first eluting isomer as a transparent oil (31 mg, 9%)
[Found: Mϩ (EI) 462.185. C20H34N2O6S2 requires M, 462.186);
νmax (Nujol)/cmϪ1 3280 and 1737; δH (300 MHz, CDCl3), 0.91
(3 H, s), 1.08 (3 H, s), 1.21 (6 H, t, J 7.2), 1.50–2.05 (7 H, m),
2.07 (1 H, br s), 2.47 (1 H, br s), 2.68 (1 H, d, J 13.2), 3.20–3.57
(7 H, m), 3.70 (3 H, s) and 5.01 (1 H, dd, J 7.5 and 3.6); δC (75.5
MHz, CDCl3) 14.6 (CH3), 19.9 (CH3), 20.3 (CH3), 27.0 (CH2),
29.7 (CH2), 30.1 (CH2), 38.8 (CH2), 41.5 (CH2), 41.7 (CH2),
44.5 (CH), 49.2 (2 × Cq), 49.4 (CH2), 52.4 (CH3), 80.9 (CH),
168.0 (CO) and 169.6 (CO).
Analysis of the product by 1H NMR before chromatographic
purification showed the presence of two diastereomers in a ratio
of 8 : 1. Signals assigned to the minor isomer could be identified
at δH 0.82 (3 H, s), 0.89 (3H, s), 2.64 (1 H, d, J 13.2) and 5.07
(1 H, dd, J 7.8 and 3.0).
Another portion of a colourless oil, a mixture of isomers
(0.16 g, 45%), was obtained. 1H NMR data for the second iso-
mer was obtained from a spectrum of the isomer mixture, with
additional signals at δH (300 MHz, CDCl3) 1.05 (3 H, s), 0.91
(3H, s), 2.12 (1 H, s), 2.50 (1 H, br s), 2.70 (1 H, d, J 13.5) and
3.72 (3 H, s).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(4-nitrophenyl-
thio)aziridine-2-carboxylates 2c and 3c
[(1R)-[10-(N,N-Diethylsulfamoyl)isobornyl] 2-(benzimidazol-1-
yl)aziridine-2-carboxylates 2e and 3e
A solution of the azide 5a (0.28 g, 0.8 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h. The reaction mixture was
cooled in an ice–water bath and 4-nitrothiophenol (0.12 g,
0.8 mmol) was added. After 2 d there was no sign of reaction by
TLC. Two parts (in three) of the toluene were removed and
dry acetonitrile was added to make up the original volume of
solvent. Sodium carbonate (0.67 g, 4. 8 mmol) was added. After
30 h the solvents were removed and the remaining oil was sub-
jected to dry flash chromatography (hexane–ether) giving the
aziridine as a mixture of a major and a minor isomer, 4 : 1 ratio
(0.09 g, 28%). One of the fractions was almost pure (0.07 g,
0.14 mmol, 18%) by 1H NMR.
In a separate experiment a solution of the azide 5a (0.3 g,
0.78 mmol) in toluene (20 ml) was heated under reflux for 1.5 h.
The reaction mixture was cooled in an ice–water bath and two
thirds of the toluene were removed and dry acetonitrile was
added to make up the original volume of solvent. 4-Nitro-
thiophenol (0.12 g, 0.78 mmol) and sodium carbonate (0.5 g,
4.8 mmol) were added. The suspension was stirred for 24 h. The
solids were then filtered off and washed with acetonitrile. The
solvent was evaporated giving an oil that was chromatographed
(dry flash, light petroleum–ether) giving a mixture of the two
diastereomers in a 4 : 1 ratio, total yield (0.29 g, 72%). A small
fraction of the major isomer was obtained (0.07 g, 0.14 mmol,
18%) as an almost pure sample according to 1H NMR [Found:
Mϩ (EI) 511.181. C23H33N3O6S2 requires M, 511.181];
νmax (Nujol)/cmϪ1 3272 and 1719; δH (300 MHz, CDCl3) 0.56
(3 H, s), 0.81 (3 H, s), 1.25 (6 H, t, J 6.9), 1.50–2.00 (7 H, m),
2.20 (1 H, d, J 10.2), 2.52 (1H, t, J 10.2), 2.63 (1 H, d, J 8.4),
2.67 (1 H, d, J 13.2), 3.27–3.35 (5 H, m), 5.03 (1 H, dd, J 7.8 and
A solution of the azide 5a (0.30 g, 0.80 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h. Two thirds of the toluene
were removed and dry acetonitrile was added to make up the
original volume of solvent. Benzimidazole (0.94 g, 0.80 mmol)
was added and then sodium carbonate (0.66 g, 4.68 mol). The
mixture was stirred for 30 min at 0 ЊC and then for 30 min at
room temperature. It was filtered and the filtrate was evapor-
1
ated to leave an oil which H NMR showed to be a mixture
(2 : 1) of diastereomers. The mixture was subjected to dry flash
chromatography giving the major isomer 3e as a white solid
(0.08 g, 21%) mp 154–158 ЊC, [α]2D3 Ϫ89.7 (CH2Cl2, 1.17 g/
100 ml) (Found: C, 60.4; H, 7.2; N, 11.6. C24H34N4SO4 requires
C, 60.7; H, 7.2; N, 11.8%); νmax (Nujol)/cmϪ1 3288 and 1743;
δH (300 MHz, CDCl3) 0.06 (3 H, s), 0.62 (3 H, s), 1.17 (6 H, t,
J 7.2), 1.50–1.70 (6 H, m), 1.90 (1 H, dd, J 13.5 and 7.8),
2.29–2.35 (1 H, br, collapses to 2.31 s after D2O exchange), 2.35
(1 H, d, J 13.8), 2.39 (1 H, t, J 10.2) (signal removed by D2O
exchange), 2.52 (H, d, J 13.8), 2.93 (1H, br d, J 10.2, collapses
to s after D2O exchange), 3.16 (4 H, q, J 7.2), 5.08 (1 H, dd,
J 7.1 and 3.0), 7.22–7.34 (2 H, m), 7.40–7.48 (1 H, m), 7.74–7.82
(1 H, m) and 8.15 (1 H, s); δC (75.5 MHz, CDCl3) 14.6 (CH3),
18.6 (CH3), 19.9 (CH3), 26.7 (CH2), 29.6 (CH2), 30.2 (CH3),
30.7 (CH2), 34.1 (CH2), 38.9 (CH2), 41.6 (CH2), 44.2 (CH), 48.4
(Cq), 48.9 (Cq), 49.2 (Cq), 49.5 (CH2), 80.3 (CH), 110.1 (CH),
120.4 (CH), 122.6 (CH), 123.4 (CH), 134.0 (Cq), 143.0 (CH),
143.4 (Cq) and 168.2 (CO).
Further elution gave a mixture of the two isomers (0.06 g,
16%) then a mixture (0.09 g) of the minor isomer 2e and benz-
imidazole. Data for the minor isomer were obtained from
1916
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919

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this sample after subtracting the peaks due to benzimidazole
[Found: (M ϩ H)ϩ (FAB) 475.237. C24H35N4O4S (M ϩ H)
requires 475.238]; δH (300 MHz, CDCl3) Ϫ0.89 (3 H, s), 0.63
(3 H, s), 1.24 (6 H, t, J 7.2), 1.40–1.70 (6 H, m), 1.86 (1 H, dd,
J 13.8 and 8.1), 2.40 (1H, br s), 2.49 (1 H, d, J 13.8), 2.53 (1 H,
br s), 2.76 (1 H, d, J 13.8), 2.88 (1 H, br s), 3.22–3.30 (4 H, m),
5.03 (1 H, dd, J 7.8 and 3.0), 7.25–7.32 (2 H, m), 7.52–7.57 (1 H,
m), 7.75–7.80 (1 H, m) and 8.02 (1 H, s); δC (75.5 MHz, CDCl3)
14.6 (CH3), 18.1 (CH3), 19.8 (CH3), 26.7 (CH2), 29.6 (CH2),
30.3 (CH3), 30.6 (CH2), 33.5 (CH2), 38.9 (CH2), 41.6 (CH2),
44.1 (CH), 48.8 (Cq), 48.9 (Cq), 49.3 (Cq), 50.2 (CH2), 80.6
(CH), 110.4 (CH), 120.3 (CH), 122.9 (CH), 123.8 (CH), 134.2
(Cq), 137.7 (Cq), 142.7 (CH) and 168.2 (CO).
3289, 1723 and 1665; δH (300 MHz, CDCl3) 0.65 (3 H, s), 0.77
(3 H, s), 1.21 (6 H, t, J 7.2), 1.55–1.96 (7 H, m), 2.15 (1 H, br d,
J 11.4), 2.22 (1H, t, J 10.5), 2.48 (1 H, d, J 13.8), 2.70 (1 H, d,
J 13.8), 2.93 (1 H, d, J 11.4), 3.23 (4 H, q, J 7.2), 4.90–5.02 (1 H,
m), 6.24 (1 H, dd, J 3.9 and 2.7) 6.95 (1 H, dd, J 3.9 and 1.8),
7.31 (1 H, br s) and 9.25 (1 H, d, J 1.2); δC (75.5 MHz, CDCl3)
14.6 (CH3), 19.6 (CH3), 20.1 (CH3), 26.9 (CH2), 30.5 (CH2),
36.0 (CH2), 38.7 (CH2), 41.5 (CH2), 44.3 (CH), 49.1 (Cq), 49.2
(Cq), 49.5 (CH2), 52.0 (Cq), 80.1 (CH), 109.5 (CH), 124.4 (CH),
130.1 (CH), 133.0 (Cq), 169.0 (CO) and 179.0 (CO); m/z (EI)
451.
The second isomer was a white crystalline solid (0.1 g, 26%),
mp 124.9–129.1 ЊC [Found: (M ϩ H)ϩ (FAB) 452.221.
C22H34N3O5S (M ϩ H) requires 452.222]; [α]2D3 Ϫ85.6 (CH2Cl2,
1.35 g/100 ml); νmax (Nujol)/cmϪ1 3298, 1736 and 1665;
δH (300 MHz, CDCl3) 0.60 (3 H, s), 0.78 (3 H, s), 1.23 (6 H, t,
J 6.9), 1.60–2.00 (7 H, m), 2.35 (1 H, br s), 2.54 (1 H, d, J 13.8),
2.76 (1 H, d, J 9.6), 2.82 (1H, br d, J 13.8), 3.18–3.33 (4 H, m),
4.91–4.94 (1 H, m), 6.22 (1 H, dd, J 3.9 and 2.4), 6.93 (1 H, dd,
J 3.9 and 1.8), 7.05 (1 H, br s) and 9.56 (1 H, d, J 0.9); δC (75.5
MHz, CDCl3) 14.5 (CH3), 19.3 (CH3), 20.1 (CH3), 26.9
(CH2), 30.4 (CH2), 35.1 (CH2), 38.7 (CH2), 41.5 (CH2), 44.3
(CH), 49.1 (Cq), 49.2 (Cq), 49.8 (CH2), 52.3 (Cq), 80.4 (CH),
109.6 (CH), 124.3 (CH), 129.7 (CH), 133.1 (Cq), 168.1 (CO) and
178.9 (CO).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(5-methyl-2,4-
dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)aziridine-2-carboxylates
2f and 3f
A solution of the azide 5a (0.3 g, 0.78 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h. Two thirds of the toluene
were removed and dry acetonitrile was added to make up the
original volume of solvent. Thymine (0.10 g, 0.78 mmol) and
sodium carbonate (0.5 g, 4.68 mmol) were then added. After
6 days the reaction mixture was filtered and the filtrate was
evaporated to leave an oil showing two diastereomers (2 : 1
ratio). Dry flash chromatography (hexane–ether) gave two
diastereomers in a total yield of 51%. The major isomer 3f
was isolated as a solid (0.10 g, 27%), slightly contaminated with
the minor isomer; νmax (Nujol)/cmϪ1 3284, 1719 and 1692;
δH (300 MHz, CDCl3) 0.84 (3 H, s), 0.90 (3 H, s), 1.22 (6H, t,
J 7.2), 1.6–1.94 (7 H, m), 1.94 (3 H, d, J 1.5), 2.09 (1 H, t,
J 10.5), 2.21 (1 H, d, J 10.5), 2.69 (1 H, d, J 13.8), 2.94 (1 H, d,
J 10.5), 2.97 (1 H, d, J 13.8), 3.12–3.31 (4 H, m), 5.10–5.14 (1 H,
m), 7.38 (2 H, br d, J 1.5) and 8.05 (1 H, br s); δC (75.5 MHz,
CDCl3) 12.3 (CH3), 14.5 (CH3), 19.3 (CH3), 20.0 (CH3), 26.9
(CH2), 30.0 (CH2), 30.7 (CH2), 36.0 (CH2), 38.7 (CH2), 41.4
(CH2), 44.3 (CH), 49.3 (Cq), 49.5 (Cq), 50.5 (CH2), 51.4 (Cq),
80.1 (CH), 109.9 (Cq), 139.2 (CH), 150.4 (Cq), 163.7 (CO) and
167.6 (CO).
Further elution gave the minor isomer 2f contaminated with
the major isomer (0.07 g, 19%) and a small fraction of the pure
minor isomer (0.02 g, 5%). 1H NMR data of the minor isomer:
δH (300 MHz, CDCl3) 0.86 (3 H, s), 0.88 (3 H, s), 1.23 (6 H, t,
J 7.2), 1.60–1.94 (7 H, m), 1.91 (3 H, d, J 1.2), 2.28 (1 H,
d, J 11), 2.40 (1 H, t, J 10.8), 2.63 (1 H, d, J 13.2), 2.76 (1 H, d,
J 11), 3.18–3.38 (5 H, m), 5.10–5.15 (1 H, m), 7.18 (1 H, br d,
J 1.2) and 8.12 (1H, s); δC (75.5 MHz, CDCl3) 12.3 (CH3), 14.7
(CH3), 19.6 (CH3), 20.1 (CH3), 26.9 (CH2), 29.7 (CH2), 30.3
(CH3), 36.0 (CH2), 30.4 (CH2), 34.9 (CH2), 39.0 (CH2), 41.8
(CH2), 44.3 (CH), 49.4 (Cq), 49.7 (Cq), 49.8 (CH2), 51.8 (Cq),
80.6 (CH), 110.8 (Cq), 138.8 (CH), 150.4 (CO), 163.6 (CO) and
167.0 (CO).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-phenylaziridine-2-
carboxylates 2h and 3h
A solution of the azide 5a (0.28 g, 0.72 mmol) in toluene (15 ml)
was heated under reflux for 1.5 h. Phenylmagnesium bromide
(3M solution in ether; 1.06 ml, 0.57 mmol) was added to the
solution with stirring under nitrogen at Ϫ78 ЊC. The reaction
mixture was allowed to reach room temperature. The toluene
was then distilled off leaving a solid that was dissolved in ether,
washed with 10% aq. citric acid (2 × 50 ml) and dried. The
solution was concentrated on a rotary evaporator giving an oil
that was subjected to dry flash chromatography in hexane–
ether. The title compound was isolated as a mixture of two
diastereomers in a 1 : 1 ratio (0.10 g, 40%); δH (300 MHz,
CDCl3) 0.39 (3 H, s), 0.79 (3 H, s), 0.84 (3 H, s), 1.06 (3 H, s),
1.10 (6 H, t, J 7.2) 1.23 (6 H, t, J 6.9), 1.50–1.97 (15 H, m), 2.05
(1 H, br s), 2.39 (1 H, d, J 13.2), 2.48 (1 H, br s), 2.53 (1 H, br s),
2.54 (1 H, d, J 13.2), 2.64 (1 H, d, J 13.5), 2.80–3.00 (5 H, m),
3.28 (4 H, q, J 7.2), 4.95–5.00 (2 H, m), 7.20–7.30 (6 H, m),
7.35–7.42 (2H, m) and 7.45–7.50 (2 H, m).
Bis[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] pyrazine-2,5-
dicarboxylate 9
A solution of the azide 5a (0.26 g, 0.72 mmol) in toluene (15 ml)
was heated under reflux for 1.5 h. The solution was cooled in an
ice–water bath and benzylamine (0.08 g, 0.72 mmol) was added
under nitrogen. The reaction mixture was stirred at room
temperature for 19 h, the solvents were evaporated, and the
residual oil subjected to dry flash chromatography (hexane–
ether) to give the pyrazine 9 (90 mg, 17%), mp 238.6–241 ЊC
(from hexane–ether) (Found: C, 57.4; H, 7.7; N, 7.8.
C34H54N4O8S2 requires C, 57.4; H, 7.7; N, 7.9%); νmax (Nujol)/
cmϪ1 1746 and 1718; δH (300 MHz, CDCl3) 0.95 (6 H, s), 1.09
(12 H, t, J 7.2), 1.12 (6 H, s), 1.20–1.35 (2 H, m), 1.60–2.06
(10 H, m), 2.14 (2 H, dd, J 13.8 and 8.1), 2.75 (2 H, d, J 13.5),
3.10–3.30 (8 H, m), 3.51 (2 H, d, J 13.5), 5.31 (2 H, dd, J 8.1 and
3.6) and 9.31 (2 H, s); δC (75.5 MHz, CDCl3) 14.4 (CH3), 20.0
(CH3), 20.3 (CH3), 27.0 (CH2), 30.1 (CH2), 39.2 (CH2), 41.4
(CH2), 44.6 (CH), 49.4 (Cq), 49.5 (CH2), 49.6 (Cq), 80.3 (CH),
145.2 (CH), 145.8 (Cq) and 162.2 (CO).
[(1R)-10-(N,N-Diethylsulfamoyl)isobornyl] 2-(2-formylpyrrol-1-
yl)aziridine-2-carboxylates 2g and 3g
A solution of the azide 5a (0.34 g, 0.88 mmol) in toluene (20 ml)
was heated under reflux for 1.5 h. Two thirds of the toluene
were removed and dry acetonitrile was added to make up
the original volume of solvent. 2-Formylpyrrole (0.83 g,
0.88 mmol) and sodium carbonate (0.56 g, 5.28 mmol) were
then added. The reaction flask was kept under nitrogen with
stirring for 2 h, then filtered, and the solvent was removed from
the filtrate to leave an oil that showed the two diastereomers in a
1 : 1 ratio. Dry flash chromatography (hexane–ether) gave the
two diastereomers completely separated in a total yield of
60.5%. One isomer was isolated as white crystalline solid
(0.13 g, 34.5%), mp 160–162 ЊC (from hexane–ether) (Found:
C, 58.7; H, 7.25; N 9.1. C22H33N3O5S requires C, 58.5; H, 7.3;
N, 9.3%), [α]2D3 Ϫ62.3 (CH2Cl2, 2.4 g/100 ml); νmax (Nujol)/cmϪ1
Further elution of the column gave (R)-10-(N,N-diethyl-
sulfamoyl)isoborneol (0.07 g, 33.6%) identified by comparison
of the 1H NMR with an authentic sample.
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919
1917

View Article Online
(1R)-10-(N,N-Diethylsulfamoyl)isobornyl (4S)-2-azatricyclo-
[3.2.1.02,4]oct-6-ene-4-carboxylate 11a and
(CH2), 38.0 (Cq), 39.3 (CH2), 41.6 (CH2), 78.5 (CH), 85.6 (CH),
123.6 (CH) and 123.8 (CH).
(1R)-10-(N,N-diethylsulfamoyl)isobornyl (4R)-2-azatricyclo-
[3.2.1.02,4]oct-6-ene-4-carboxylate 12a
(1R)-10-(N,N-Diethylsulfamoyl)isobornyl 8-oxa-2-azatricyclo-
[3.2.1.02,4]oct-6-ene-4-carboxylates 17 and 18
A solution of the azide 5a (0.51 g, 1.33 mmol) in dry toluene
(30 ml) was heated under reflux for 1.5 h. The solution was
cooled to room temperature and cyclopentadiene (0.90 g,
13.3 mmol) was added. After 19 h the solvent was removed and
the residue subjected to dry flash chromatography (hexane–
ether) giving the ester 11a (0.08 g) as the first fraction, then a
mixture of esters 11a and 12a (0.20 g, 12a : 11a = 72 : 28), and a
third fraction containing the ester 12a (0.13 g); total yield from
azide 0.41 g (73%).
The ester 11a had mp 152–155 ЊC (from ether–hexane)
(Found: C, 62.2; H, 8.2; N 6.8. C22H34N2O4S requires C, 62.6;
H, 8.1; N, 6.6%); [α]2D3 ϩ19.8 (CH2Cl2, 0.8 g/100 ml);
νmax (Nujol)/cmϪ1 1726; δH (300 MHz, CDCl3) 0.89 (3 H, br s),
0.98 (3 H, s), 1.24 (6 H, t, J 7.2), 1.50–1.80 (7 H, m), 1.90–2.00
(2 H, m), 2.15 (1 H, br d, J 7.8), 2.35 (1 H, d, J 2.4), 2.63 (1 H,
J 13.2), 3.20–3.51 (5 H, m), 3.51 (1 H, s), 3.98 (1 H, s), 5.06–5.10
(1 H, m), 5.61–5.64 (1 H, m) and 6.12–6.15 (1 H, m);
δC (75.5 MHz, CDCl3) 14.7 (CH3), 20.0 (CH3), 20.4 (CH3), 27.0
(CH2), 29.9 (CH2), 39.3 (CH2), 41.7 (CH2), 42.9 (CH2), 43.5
(Cq), 44.3 (CH), 44.6 (CH), 49.1 (2 Cq), 49.3 (CH2), 60.5 (CH2),
66.3 (CH), 78.5 (CH), 127.8 (CH), 133.1 (CH) and 171.5 (CO);
m/z (EI) 422 (Mϩ).
A solution of the azide 5a (0.10 g, 0.26 mmol) in toluene (25 ml)
was heated for 1.5 h. The solution was cooled to rt and freshly
distilled furan (20 ml) was added. The solution was stirred for
3 days and the solvent removed to leave an oil that proved to be
a 1 : 1 mixture of compounds assigned as the exo diastereomers
17 and 18 by 1H NMR spectroscopy; δH (300 MHz, CDCl3) 0.88
(1.5 H, s), 0.90 (1.5 H, s), 0.98 (1.5 H, s), 0.99 (1.5 H, s), 1.21
(3 H, t, J 6.9), 1.22 (3 H, t, J 6.9), 1.54–2.02 (7 H, m), 2.41 (1 H,
s), 2.64 (0.5 H, d, J 13.5), 2.71 (0.5 H, d, J 13.2), 2.82 (0.5 H, s),
2.83 (0.5 H, s), 3.14–3.36 (5 H, m), 4.98 (0.5 H, dd, J 8.0 and
3.3), 5.03 (0.5 H, dd, J 8.0 and 3.3), 5.09 (0.5 H, d, J 1.5), 5.12
(0.5 H, d, J 1.5), 5.31 (0.5 H, d, J 1.5), 5.34 (0.5 H, d, J 1.5), 6.55
(0.5 H, dd, J 5.7 and 1.5), 6.58 (0.5 H, dd, J 5.4 and 1.5), 6.75
(0.5 H, dd, J 5.7 and 1.5) and 6.80 (0.5 H, dd, J 5.4 and 1.5).
The mixture was not characterized further.
(1R)-10-(N,N-Diethylsulfamoyl)isobornyl (6S)-2,5-diphenyl-1-
azabicyclo[4.1.0]hept-3-ene-6-carboxylate 15 and
(1R)-10-(N,N-diethylsulfamoyl)isobornyl (6R)-2,5-diphenyl-1-
azabicyclo[4.1.0]hept-3-ene-6-carboxylate 16
A solution of the azide 5a (0.30 g, 0.80 mmol) in dry toluene
(20 ml) was heated under reflux for 1.5 h. The solution was
cooled to rt. 1,4-Diphenylbuta-1,3-diene (0.16 g, 0.80 mmol)
was added to the reaction solution and the mixture was kept
stirring at rt for 2 days. As TLC showed no product the reaction
mixture was heated under reflux for 7 h. The solvent was
removed on a rotary evaporator to give an oil that was sub-
jected to dry flash chromatography (light petroleum ether–
ether) to give a 2 : 1 mixture of two isomers (0.10 g, 0.18 mmol,
23%). By crystallization it was possible to enrich the product in
the major isomer 15 to 9 : 1. The solid had mp 125–130 ЊC
(Found: C, 69.5; H, 7.7; N, 4.8. C33H42N2O4Sؒ0.5H2O requires
C, 69.4; H, 7.6; N, 4.9%); νmax (Nujol)/cmϪ1 1722; δH (300 MHz,
CDCl3) 0.76 (3 H, s), 0.82 (3 H, s), 1.00 (6 H, t, J 7.2), 1.06–1.28
(1 H, m), 1.34–1.44 (1 H, m), 1.48–1.76 (3 H, m), 1.81–2.04
(2 H, m), 2.06 (1 H, s), 2.27 (1 H, s), 2.55 (1 H, d, J 13.5), 3.02–
3.16 (2 H, m), 3.16–3.30 (3 H, m), 4.40–4.44 (1 H, m), 4.82–4.86
(1 H, m), 4.99 (1 H, dd, J 8.1 and 3.3), 5.78 (1 H, ddd, J 10.5, 3.3
and 1.8), 5.91 (1 H, br d, J 10.5) and 7.30–7.40 (10 H, m);
δC (75.5 MHz, CDCl3) 14.4 (CH3), 19.8 (CH3), 20.4 (CH3), 26.9
(CH2), 27.5 (CH2), 29.4 (CH2), 37.4 (CH), 39.3 (CH2), 41.3
(CH2), 44.3 (CH), 45.3 (Cq), 48.7 (CH2), 49.0 (Cq), 49.1 (Cq),
57.8 (CH), 57.3 (CH), 78.4 (CH), 124.8 (CH), 126.9 (CH), 127.4
(CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.9
(CH), 141.7 (Cq), 142.3 (Cq) and 170.0 (CO).
The ester 12a had mp 133–135 ЊC (from ether–hexane)
(Found: C, 62.6; H, 8.1; N, 6.7. C22H34N2O4S requires C, 62.6;
H, 8.1; N, 6.6%); [α]2D3 Ϫ150.3 (CH2Cl2, 1.55 g/100 ml);
νmax (Nujol)/cmϪ1 1711; δH (300 MHz, CDCl3) 0.89 (3 H, s), 1.04
(3 H, s), 1.18 (6 H, t, J 7.2), 1.20–1.30 (1 H, m), 1.61 (2 H, br s),
1.60–1.80 (4 H, m), 1.93–2.02 (2 H, m), 2.20 (1 H, d, J 7.5), 2.37
(1 H, d, J 2.7), 2.70 (1 H, d, J 13.5), 3.05–3.15 (5 H, m), 3.46
(1 H, br s), 4.09 (1 H, br s), 5.02 (1 H, dd, J 8.1 and 3.0), 5.61–
5.65 (1 H, m) and 6.12–6.17 (1 H, m); δC (75.5 MHz, CDCl3)
14.5 (CH3), 20.1 (CH3), 20.4 (CH3), 27.1 (CH2), 30.1 (CH2),
39.5 (CH2), 41.4 (CH2), 42.3 (CH2), 43.2 (Cq), 44.5 (CH), 44.8
(CH), 49.2 (Cq), 49.3 (Cq), 49.8 (CH2), 60.7 (CH2), 66.4 (CH),
80.0 (CH), 128.0 (CH), 133.2 (CH) and 171.5 (CO); m/z (EI)
422 (Mϩ).
(1R)-10-(N,N-Diethylsulfamoyl)isobornyl 2-methoxy-1-
azabicyclo[4.1.0]hept-3-ene-6-carboxylates 13 and 14
The azide 5a (0.40 g, 1.04 mmol) in toluene (20 ml) was heated
for 1.5 h. The solution was cooled to rt and 1-methoxy-
buta-1,3-diene (0.9 ml, 10.4 mmol) added. The solution was
stirred at rt for 5 days. The solvent was removed on a rotary
1
evaporator to leave an oil which H NMR showed a to be a
mixture of diastereomers in a 2 : 1 ratio. The crude material was
subjected to dry flash chromatography (light petroleum–ether)
to give several fractions with different ratios of isomers (0.17 g
in total, 36%). The major isomer was an oil slightly con-
taminated with the minor isomer (Found: C, 60.1; H, 8.2;
N, 6.3. C22H36N2O5S requires C, 60.0; H, 8.2; N, 6.4%);
νmax (Nujol)/cmϪ1 1718; [α]2D3 Ϫ88.5 (CH2Cl2, 2.00 g/100 ml);
δH (300 MHz, CDCl3) 0.90 (3 H, s), 1.04 (3 H, s), 1.20 (6 H,
t, J 6.9), 1.60–2.00 (7 H, m), 2.03 (2 H, s), 2.60–2.80
(2 H, m), 3.20–3.30 (6 H, m), 3.60 (3 H, s), 4.73 (1 H, br s), 4.96
(1 H, dd, J 8.1 and 3.0), 5.40–5.47 (1 H, d, J 10.2, showing
further coupling) and 5.70–5.80 (1 H, m); δC (75.5 MHz,
CDCl3) 14.5 (CH3), 19.7 (CH3), 20.4 (CH3), 22.0 (CH2),
27.0 (CH2), 27.8 (CH2), 29.9 (CH2), 37.8 (Cq), 39.4 (CH2),
41.4 (CH2), 44.4 (CH), 49.2 (Cq), 49.3 (Cq), 49.8 (CH2), 56.2
(CH3), 78.7 (CH), 85.7 (CH), 123.7 (CH), 124.0 (CH) and
170.5 (CO).
Some signals due to the minor isomer 16 could be detected in
the spectra of the major isomer at δH 0.85 (3 H, s), 0.96 (3 H, t,
J 7.2), 2.62 (1 H, d, J 13.8), 4.42–4.48 (1 H, m), 4.94–4.89 (1 H,
m), 5.70–5.84 (1 H, m) and 6.60–6.99 (1H, m).
(1R)-10-(N,N-Dicyclohexylsulfamoyl)isobornyl 2-azatricyclo-
[3.2.1.02,4]oct-6-ene-4-carboxylates 11b and 12b
A solution of the azide 5b (0.59 g, 1.2 mmol) in toluene (50 ml)
was heated under reflux for 1.5 h and then cooled. Cyclopenta-
diene (0.85 g, 12.9 mmol) was added. The solution was stirred
for 3 days at rt. Removal of the toluene gave an oil that crystal-
lised as a white solid after addition of ether. The solid (0.10 g)
was filtered and the remaining oil was subjected to dry flash
chromatography (hexane–ether) to give another crop (0.21 g)
of the same compound; (total yield 49%). 1H NMR of the
solid showed it to consist of a 1 : 3 mixture of diastereomers
of (1R)-10-(N,N-dicyclohexylsulfamoyl)isobornyl 2-azatricyclo-
[3.2.1.02,4]oct-6-ene-4-carboxylates. The major isomer showed
The minor isomer showed additional peaks at δH (300 MHz;
CDCl3) 0.90 (3 H, s), 1.02 (3 H, s), 3.62 (3 H, s) and 4.90–5.06
(1 H, dd, J 8.1 and 3.3); δC (75.5 MHz, CDCl3) 14.7 (CH3), 20.0
(CH3), 20.4 (CH3), 22.1 (CH2), 27.0 (CH2), 28.8 (CH2), 29.7
1918
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919

View Article Online
δH (300 MHz, CDCl3) 0.88 (3H, s), 1.02 (3H, s), 1.00–2.10
(32 H, m), 2.24 (1 H, dt, J 7.8 and 0.9), 2.41 (1 H, d, J 3.0), 2.65
(1 H, d, J 13.2), 3.15 (1 H, d, J 13.2), 3.10–3.40 (4 H, m), 3.48–
3.52 (1 H, m), 4.10 (1 H, br s), 5.05–5.10 (1 H, dd, J 7.2 and
2.7), 5.65–5.70 (1 H, m) and 6.10–6.18 (1 H, m).
β = 100.9090(10)Њ, γ = 90Њ, U = 1504.9(2) Å3, T = 213(2) K,
space group P21, Z = 2 µ(Mo-Kα) = 0.151 mmϪ1, 9431 reflec-
tions collected, 4817 unique (Rint = 0.0142), which were used in
all calculations. The final wR(F 2) was 0.2177 (all data). Flack
parameter13 0.18(14).
Some of the signals due to the minor isomer were detected at
δH (300 MHz, CDCl3) 0.90 (3 H, s), 1.01 (3 H, s), 2.18 (1 H, dt,
J 7.8 and 0.9), 2.46 (1 H, d, J 3.0), 2.67 (1 H, d, J 13.2) and 3.45
(1 H, br s).
Acknowledgements
We thank Fundação Ciência e Tecnologia for project funding
(POCTI 32723/Qui/2000).
Crystal structure determination for 3e†
Crystal data: C24H34N4O4S, M = 474.61, orthorhombic, a =
10.1128(13) Å, b = 8.372(4) Å, c = 18.399(2) Å, α = 90Њ, β = 90Њ,
γ = 90Њ, U = 2418.6(5) Å3, T = 213(2) K, space group P212121,
Z = 4, µ(Mo-Kα) = 0.172 mmϪ1, 15465 reflections collected,
3836 unique (Rint = 0.0770), which were used in all calculations.
The final wR(F 2) was 0.0949 (all data). Flack parameter13
Ϫ0.10(11).
References
1 M. J. Alves, T. L. Gilchrist and J. H. Sousa, J. Chem. Soc., Perkin
Trans 1, 1999, 1305.
2 M. J. Alves, J. F. Bickley and T. L. Gilchrist, J. Chem. Soc., Perkin
Trans 1, 1999, 1399.
3 M. J. Alves, P. M. T. Ferreira, H. L. S. Maia, L. S. Monteiro and
T. L. Gilchrist, Tetrahedron Lett., 2000, 41, 4991.
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299.
5 D. Tanner, Angew. Chem., Int. Ed. Engl., 1994, 33, 599; H.
M. I. Osborn and J. Sweeney, Tetrahedron: Asymmetry, 1997, 8,
1693.
6 C. Toniolo, G. Bonora, A. Bavoso, E. Beneditti, B. di Blasio,
V. Pavone and C. Pedrone, Biopolymers, 1983, 22, 205.
7 F. A. Davis, Y. Wu, H. Yan, K. R. Prasad and W. McCoull,
Org. Lett., 2002, 4, 655.
8 W. Oppolzer, C. Chapuis and G. Bernadinelli, Tetrahedron Lett.,
1984, 25, 5885.
Crystal structure determination for 3g†
Crystal data: C22H33N3O5S, M = 451.57, monoclinic, a =
10.0165(15) Å, b = 12.3521(15) Å, c = 10.5145(16) Å, α = 90Њ,
β = 115.807(16)Њ, γ = 90Њ, U = 1171.2(3) Å3, T = 213(2) K, space
group P21, Z = 2, µ(Mo-Kα) = 0.175 mmϪ1, 7463 reflections
collected, 3673 unique (Rint = 0.0603), which were used in all
calculations. The final wR(F 2) was 0.0871 (all data). Flack
parameter13 0.03(8).
9 M. Kakimoto, M. Kai and K. Kondo, Chem. Lett., 1982, 525.
10 T. L. Gilchrist and R. Mendonça, Synlett, 2000, 1843.
11 A. E. A. Porter, in Comprenhensive Heterocyclic Chemistry, Vol. 3,
ed. A. J. Boulton and A. McKillop, Pergamon Press, Oxford, 1984,
p. 159.
12 M. J. Alves, N. G. Azoia, J. F. Bickley, A. G. Fortes, T. L.
Gilchrist and R. Mendonça, J. Chem. Soc., Perkin Trans. 1, 2001,
2969.
Crystal structure determination for 15†
Crystal data: C33H44N2O5S, M = 580.76, monoclinic, a =
11.5114(9) Å, b = 10.7109(9) Å, c = 12.4297(10) Å, α = 90Њ,
† CCDC 184635–184637. See http://www.rsc.org/suppdata/p1/b2/
b202321k/ for crystallographic data in .cif or other electronic format.
13 H. D. Flack, Acta Crystallogr., Sect. A, 1983, 39, 876.
J. Chem. Soc., Perkin Trans. 1, 2002, 1911–1919
1919