Reactivity of 2-halo-2H-azirines. Part 3: Dehalogenation of 2-halo-2H-azirine-2-carboxylates

Article abstract of DOI:10.1016/S0040-4020(03)00248-5

The dehalogenation of 2-halo-3-phenyl-2H-azirine-2-carboxylates is described. Using sodium borohydride and tributyltin hydride 3-phenyl-2H-azirine-2-carboxylates were obtained in moderate yields. The synthesis of a new 2-bromo-2H-azirines with a chiral au

Full text of DOI:10.1016/S0040-4020(03)00248-5

Tetrahedron 59 (2003) 2345–2351
Reactivity of 2-halo-2H-azirines. Part 3:q Dehalogenation of
2-halo-2H-azirine-2-carboxylates
*
Teresa M. V. D. Pinho e Melo, Ana L. Cardoso and Antonio M. d’A. Rocha Gonsalves
´
´ ˆ
Departamento de Quımica, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
Received 2 September 2002; revised 24 December 2002; accepted 5 February 2003
Abstract—The dehalogenation of 2-halo-3-phenyl-2H-azirine-2-carboxylates is described. Using sodium borohydride and tributyltin
hydride 3-phenyl-2H-azirine-2-carboxylates were obtained in moderate yields. The synthesis of a new 2-bromo-2H-azirines with a chiral
auxiliary, 10-phenylsulfonylisobornyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate, is reported. Its dehalogenation led to 10-phenyl-
sulfonylisobornyl 2H-azirine-2-carboxylate as single stereoisomer together with the formation of 10-phenylsulfonylisobornyl acetate. q 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
2H-Azirines are very important class of compounds not only
due to their theoretical interest but also because they are
versatile building blocks for organic synthesis.2 Chiral
derivatives bearing a carboxylic acid group or an ester group
at C-2 are of particular interest since some of these
substituted 2H-azirines are naturally occurring antibiotics.
In fact azirinomycin (1), isolated from Streptomyces auras
cultures, and its methyl ester exhibit antibiotic activity.
Moreover, both enantiomers of (R)-(þ)- and (S)-(2)-
dysidazirine 2 and (S)-(þ)-antazirine 3 were isolated from
the marine sponge Dysidea fragilis. Therefore, the develop-
ment of new asymmetric synthesis of 2H-azirine-2-
carboxylates has recently attracted great attention.3
Chiral 2H-azirines have been prepared by elimination
We have developed a very general route to 2-halo-2H-
azirines starting from a-oxophosphorus ylides which allows
the synthesis of a range of 2-iodo-, 2-bromo and 2-chloro-
2H-azirines. The 2H-azirines, including 2-halo-2H-azirine-
2-carboxylate derivatives, are obtained by our synthetic
procedure as racemic mixtures.4
reaction of N-substituted aziridines namely dehydro-
chlorination of N-chloroaziridines,3a Swern oxidation of
aziridines3b and elimination from N-sulphynilaziridines.3d
The latest procedure has been used in the asymmetric
synthesis of (R)-(þ)- and (S)-(2)-disydazirine. These
interesting methods involve nevertheless the use of high
enantiopure aziridine esters as starting materials. A different
approach has also been described consisting in an alkaloid-
mediated Neber reaction (Scheme 1).3c
Our aim was to achieve the synthesis of chiral 2H-azirine-2-
carboxylates by dehalogenation of these 2-halo-2H-azirine-
2-carboxylates. The synthetic strategy should be a process
involving an intermediate (carbocation or radical) with a
chiral auxiliary to control the configuration of the new chiral
center. Two reducing agents, which allow the formation of
the referred intermediates are sodium borohydride and
tributyltin hydride. The approach could be the synthesis of
the chiral esters of 2-halo-2H-azirine-2-carboxylic acids
followed by the dehalogenation reaction.
q See Ref. 1.
Keywords: dehalogenation; 2-halo-2H-azirine-2-carboxylates; chiral 2H-
azirine-2-carboxylates.
*
Corresponding author. Fax: þ351-239-826-068;
e-mail: tmelo@ci.uc.pt
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00248-5

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T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
Scheme 1.
2. Results and discussion
sodium borohydride at room temperature giving 2H-azirine
5a (37%), 2H-azirine 6 (5%) and aziridine 7a (8%). 2H-
azirine 5a was obtained as the sole product in 30% yield
when the reaction was performed at 08C for 24 h.
The first objective was to determine, if tin hydrides and
sodium borohydride could be used as reducing agents to
promote dehalogenation of 2-halo-2H-azirine-2-carboxyl-
ates.
The conversion of 2-iodo-2H-azirine 4c into 2H-azirine 5b
(17% yield) was also carried out at 08C. The low yield can
be explained by lower stability of the iodo-2H-azirine. The
reaction of methyl 2-bromo-3-phenyl-2H-azirine-2-car-
boxylate 4d with NaBH4 at room temperature gave 2H-
azirine 5b in 22% yield and aziridine 7b in 34% yield.
The reaction of 2-chloro-, 2-bromo- and 2-iodo-3-phenyl-
2H-azirine-2-carboxylates4 with sodium borohydride was
studied (Table 1). It was known3c that 2H-azirine can be
converted into the corresponding aziridine on reacting with
NaBH4/EtOH. For this reason, reaction conditions should be
found to allow the selective formation of 3-phenyl-2H-
azirine-2-carboxylates.
The dehalogenation of 2-bromo-2H-azirine 4b with tri-
butyltin hydride was also performed (Table 2). Different
reaction conditions were studied and these include the use of
radical initiators and also the use of triethylborane reported
to act as catalyst in the reduction of alkyl bromides with
tributyltin hydride.6 These attempted improvements did not
allow significant differences of yields. However, the
reaction of 2-bromo-2H-azirine 4b with tributyltin hydride
and ACN performed at 808C for 30 min led to 2H-azirine 5a
in an acceptable yield of 31%.
The dehalogenation of ethyl 2-chloro-2H-azirine-2-car-
boxylate 4a was carried out at room temperature and after
2 h two products were obtained: 2H-azirine 5a in 5% yield
and aziridine 7a in 27% yield. When the reaction of
2-chloro-2H-azirine 4a with sodium borohydride was
carried out at 508C for 15 min a mixture of two isomeric
2H-azirines was obtained: 3-phenyl-2H-azirine-2-carboxyl-
ate 5a in 28% yield and 2-phenyl-2H-azirine-3-carboxylate
6 in 20% yield. The formation of 2H-azirine 6 can be
rationalized considering a process involving an SN20
mechanism. Alternatively, if an azacyclopropenyl cation
was formed it could lead to the synthesis of the isomeric 2H-
azirines 5a and 6. In fact azacyclopropenyl cation has been
suggested as an intermediate in the thermal isomerization of
2-chloro-2,3-dimethyl-2H-azirine.5
The results described above prove that 3-phenyl-2H-
azirines can be obtained from dehalogenation of 2-halo-
2H-azirine-2-carboxylates with tributyltin hydride and
sodium borohydride. Low moderate yields obtained for
these reactions are certainly a consequence of the
competitive side reactions namely the reduction of the
iminic bond or azirine isomerization when sodium boro-
hydride was used or radical coupling reactions when
tributyltin hydride was the reducing agent.
The 2-bromo-2H-azirine-2-carboxylate 4b reacted with
Table 1.
2H-Azirine
Reagents
Temperature
Reaction time
Products (yield)
4a
4a
4b
4b
4c
4d
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
rt
508C
rt
08C
–5/08C
rt
2 h
15 min
2 h
24 h
0.5 h
2 h
5a (5%)
–
6 (20%)
6 (5%)
–
–
–
7a (27%)
–
7a (8%)
5a (28%)
5a (37%)
5a (30%)
5b (17%)
5b (22%)
–
–
7b (34%)

T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
2347
Table 2.
The 10-phenylsulfonylisoborneol 10 was prepared from
camphorsulfonic acid following a procedure described in
the literature.7 This alcohol reacted with bromoacetyl
bromide to give ester 11 in 94% yield which on reacting
with triphenylphosphine gave the new chiral phosphorus
ylide 12 (87%). Esters 13 and 14 were also prepared and
used as precursors of ylide 12. However, the best result was
obtained when compound 11 was used as the starting
material (Scheme 2).
Reagents
Temperature
Reaction time (h)
5a (Yield) (%)
a
–
–
rt
08C
rt
08C
rt
rt
24
24
1
24
2
15
–
b
AIBNa
AIBNa
ACNa
ACNb
ACNb
ACNc
ACNc
Et3Bd
Et3Bd
12
13
27
18
19
31
18
15
13
The reaction of compound 12 with benzoyl chloride allowed
the synthesis of chiral ylide 15 in 81% yield. Using our
synthetic methodology8 ylide 15 reacted with N-bromo-
succinimide in the presence of azidotrimethylsilane giving
the corresponding haloazidoalkene 16 in 58% yield. Alkene
was easily converted into the diastereoisomeric mixture of
10-phenylsulfonylisobornyl 2-bromo-3-phenyl-2H-azirine-
2-carboxylate 17 on heating in heptane for 2–3 h. The
reaction was followed by TLC and by IR by monitoring
the disappearance of the band corresponding to the azido
group (n¼2114 cm21) of the starting azidoalkene
(Scheme 3).
2
rt
24
1/2
1
1/2
1
808C
808C
08C
08C
a
In pentane.
In ether.
In DMF.
In toluene.
b
c
d
Having selected the reducing agents we went on to
investigate the possibility of preparing 2-halo-2H-azirines
with a chiral auxiliary. The synthetic strategy is outlined in
Schemes 2 and 3.
The 10-phenylsulfonylisobornyl 2-bromo-3-phenyl-2H-
azirine-2-carboxylate 17 was obtained as a diastereo-
isomeric mixture as shown by the complexity observed in
Scheme 2.
Scheme 3.

2348
T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
Scheme 4.
Scheme 5.
the 1H NMR spectrum. However, the diastereoisomers
could be separated by preparative TLC.
suggested that the product was obtained as a single
stereoisomer. A diastereoisomeric mixture should be easily
detected. The assignment of the most relevant proton and
1
In order to confirm the structure of 2H-azirine 17 we
promoted its reaction with 1,2-phenylenediamine. The
reaction was carried out in an ultrasound bath leading to
the synthesis of the chiral quinoxaline 19 which was
completely characterized. In agreement with the reactivity
previously observed for other 2-halo-2H-azirines8 the
process involved the halide displacement and addition to
the iminic double bond of the 2H-azirine giving 18. The
opening of the aziridine ring followed by the elimination of
ammonia led to quinoxaline 19 (Scheme 4).
carbon signals in the H and 13C spectra of 2H-azirine 20
was made on the basis of an HETCOR spectrum. The
structural assignment was also achieved using a two-
dimensional technique: the NOESY spectrum showed cross
peaksbetweenH-2oftheazirineringwiththeortho-protonsof
the C-3 phenyl group. This points to the proposed stereo-
chemistry, S configuration at C-2, for 10-phenylsulfonyl-
isobornyl 3-phenyl-2H-azirine-2-carboxylate 20.
The diastereoselectivity observed in synthesis of (2S)-2H-
azirine-2-carboxylate 20, starting from a 2-bromo-2H-
azirine 17 as a diastereoisomeric mixture, can only be
explained considering that a SN1 type mechanism is
involved. In fact the already mentioned formation of 2H-
azirine 6 in the dehalogenation of 2-chloro- and 2-bromo-
2H-azirines 4a and 4b is in agreement with such
mechanism. Although typical SN2 reaction conditions
were used, a SN1 process may occur since it would lead to
the formation of an aromatic 2p-electron system, an
azacyclopropenyl cation. The presence of a chiral auxiliary
in the intermediate allows asymmetric induction.
The dehalogenation reactions of 2H-azirine 17 using
sodium borohydride and tributyltin hydride as reducing
agents were studied (Scheme 5). From the reaction with
tributyltin hydride a complex mixture was obtained and the
dehalogenated 2H-azirine 20 could only be obtained in very
low yield. The dehalogenation of 2H-azirine 17 with sodium
borohydride led to the synthesis of two products, the
expected 10-phenylsulfonylisobornyl 3-phenyl-2H-azirine-
2-carboxylate 20 in 24% yield and 10-phenylsulfonyl-
isobornyl acetate 21 in 27% yield.
1
The H NMR spectrum of dehalogenated 2H-azirine 20
The unexpected formation of compound 21 can be
Scheme 6.

T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
2349
rationalized as resulting from ring opening of 10-phenyl-
4.1. General procedures for the dehalogenation of
2-halo-3-phenyl-2H-azirine-2-carboxylates
sulfonylisobornyl 3-phenylaziridine-2-carboxylate 22
followed by reduction reactions (Scheme 6). In fact, the
reaction conditions used to promote the dehalogenation of
2H-azirine 17 should lead to a mixture of the corresponding
dehalogenated 2H-azirine and aziridine as observed with
2H-azirines 4a and 4d (Table 1). However, from the
reaction of 2H-azirine 17 with sodium borohydride the
aziridine was not isolated and instead 10-phenylsulfonyl-
isobornyl acetate 21 was obtained. The aziridine 22 leads to
azomethine ylide 23, which can be converted to the imine 24
through a 1,3-prototropic rearrangement. This compound
undergoes a reduction reaction to give 25 which on
reacting with sodium borohydride gives 10-phenylsulfonyl-
isobornyl acetate 21. Studies are underway to further clarify
the mechanism for the synthesis of this chiral compound
(21).
(a) Dehalogenation with sodium borohydride. To a stirred
solution of the 2-halo-2H-azirine (6.42 mmol) in DMF
(90 mL), cooled to 08C, sodium borohydride (0.53 g,
14.12 mmol) was cautiously added. The mixture was stirred
using the reaction conditions indicated in Table 1
(temperature and reaction time). After addition of dichloro-
methane the solution was washed with water, dried
(MgSO4) and evaporated off. The product was purified by
flash chromatography (ethyl acetate/hexane (1:2)).
(b) Dehalogenation with tributyltin hydride. To a stirred
solution (10 mL) of 2-bromo-3-phenyl-2H-azirine-2-car-
boxylate 4b (0.25 g, 0.93 mmol) cooled to 08C and under N2
atmosphere, tributyltin hydride (0.31 mL, 1.13 mmol) was
slowly added. The mixture was stirred using the reaction
conditions indicated in Table 2 (solvent, presence or
absence of radical initiators, temperature, reaction time,
etc.). After addition of dichloromethane the solution was
washed with water, dried (MgSO4) and evaporated off. The
product was purified by flash chromatography (ethyl
acetate/hexane (1:2)).
3. Conclusion
The work described proved that 3-phenyl-2H-azirine-2-
carboxylates can be obtained in moderate yield from
dehalogenation of 2-halo-3-phenyl-2H-azirine-2-carboxyl-
ates using sodium borohydride and tributyltin hydride as
reducing agents.
4.1.1. Ethyl 3-phenyl-2H-azirine-2-carboxylate 5a.9 dH
1.31 (3H, t), 2.66 (1H, s), 4.23 (2H, q), 7.10–7.15 (1H, m,
Ar-H), 7.31–7.38 (2H, m, Ar-H) and 7.50–7.57 (2H, m,
Ar-H); m/z (EI) 190 (MHþ, 5), 176 (31), 161 (100) and 145
(43).
The synthesis of a 2-bromo-2H-azirine with a chiral
auxiliary was achieved and its dehalogenation reaction
with sodium borohydride was promoted allowing the
development of a diastereoselective synthesis of (2S)-2H-
azirine-2-carboxylate 20. In this reaction 10-phenyl-
sulfonylisobornyl acetate was also formed.
4.1.2. Methyl 3-phenyl-2H-azirine-2-carboxylate 5b.3 dH
2.50 (1H, s), 3.51 (3H, s) and 7.06–7.53 (5H, m, Ar-H); m/z
(CI) 178 [(MH3)þ, 100], 177 [(MH2)þ, 3], 139 (12) and 78
(1).
10
4.1.3. Ethyl 2-phenyl-2H-azirine-3-carboxylate 6. dH
4. Experimental
1.31 (3H, t), 3.46 (1H, s), 4.26 (2H, q), 7.12–7.14 (1H, m,
Ar-H), 7.27–7.35 (2H, m, Ar-H) and 7.54–7.57 (2H, m,
Ar-H); dC 14.0, 41.6, 61.8, 120.0, 124.5, 128.9, 137.4, 163.0
and 169.8; m/z (CI) 208 [(MHþNH4)þ, 100], 207
[(MþNH4)þ, 25] and 93 (22).
4.1.4. Ethyl 2-phenylaziridine-3-carboxylate 7a.11 dH
0.85–1.03 (3H, m), 2.99–3.03 (1H, m), 3.46–3.48 (1H,
m), 3.94–4.02 (2H, m) and 7.24–7.39 (5H, m, Ar-H); dC
14.3, 37.6, 61.5, 128.1, 128.3, 129.4, 130.1 and 162.8; m/z
(CI) 209 [(MNH4)þ, 1], 192 (MHþ, 100), 191 (Mþ, 3), 139
(15) and 122 (17).
1H NMR spectra were recorded on a Bruker AMX300
instrument operating at 300 MHz or on a Varian (400 MHz)
instrument. 13C spectra were recorded on a Bruker AMX300
instrument operating at 75.5 MHz or on a Varian (400 MHz)
instrument operating at 100.6 MHz. The solvent is deuterio-
chloroform except where indicated otherwise. IR spectra
were recorded on a Perkin–Elmer 1720X FTIR spec-
trometer. Mass spectra were recorded on a HP GC
6890/MSD5973 instrument or in a Trio 1000 GC mass
spectrometer either under electron impact (EI) or under
chemical ionization (CI) with ammonia by GC inlet or
direct inlet for the thermally labile products Mass
spectra were also recorded in a LCQ Advantage,
Thermo Finnigan mass spectrometer under APCIþ
where indicated. Optical rotations were measured on
an Optical Activity AA-5 electrical polarimeter. Micro-
analyses were performed in the University of Coimbra
using a EA 1108-CHNS-O Fisons instrument or in the
University of Liverpool using a Carlo-Erba elemental
analyser. Mp were recorded on a Reichert hot stage and
are uncorrected. Flash column chromatography was
performed with Merck 9385 silica as the stationary phase.
2-Halo-2H-azirines 4a–4d were prepared as described in
the literature.4
4.1.5. Methyl 2-phenylaziridine-3-carboxylate 7b. dH
3.27–3.33 (1H, m), 3.69 (3H, s), 3.79–3.82 (1H. m),
7.22–7.26 (2H, m, Ar-H) and 7.36–7.40 (3H, m, Ar-H); dC
44.6, 49.1, 53.5, 126.9, 129.0, 129.4, 129.5 and 165.6; m/z
(CI) 195 [(MNH4)þ, 2], 178 (MHþ, 100), 146 (3), 118 (5),
89 (30) and 60 (9); m/z (APCIþ) 178 [ms/ms of 178:146 and
118].
4.1.6. 10-Isobornylsultone 9. This was prepared from d-10-
camphorsulfonic acid 8 by a procedure described in the
literature (65%).7a Mp 120.8–122.58C (lit.,7a 114–1168C).
(Found: C, 55.17; H, 7.51; S, 14.40. C10H15O3S requires C,
55.53; H, 7.46; S, 14.82). dH 0.94 (3H, s), 1.12 (3H, s),

2350
T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
1.22–1.33 (1H, m), 1.34–1.42 (1H, m), 1.88–1.98 (4H, m),
2.24–2.31 (1H, m), 3.18 (1H, d, J¼13.7 Hz), 3.28 (1H, d,
J¼13.7 Hz), 4.38 (1H, dd, J¼3.4, 7.8 Hz); dC 19.8, 19.9,
26.7, 29.0, 35.8, 44.3, 47.4, 49.0, 55.5, 87.9; m/z (EI) 216
(Mþ, 100), 215 (65), 168 (15) and 152 (10).
15.65 mmol) in toluene triphenylphosphine (4.35 g,
14.43 mmol) was added. The mixture was heated under
reflux for 12 h. Filtration of the solution gave the
corresponding phosphonium salt which was dissolved in
water (170 mL). The solution was neutralized by the
addition of aqueous sodium hydroxide (10.9 g, 330 mL of
water). The solid which resulted was collected by filtration
and dried giving 8.16 g of 12 (13.7 mmol, 87%). Mp 201–
2028C (from ethyl acetate–hexane). (Found: C, 71.9; H, 6.4.
C36H37O4SP requires C, 74.5; H, 6.3%). dH 0.84 (3H, s),
0.94 (3H, s), 1.45–1.50 (1H, m), 1.65–1.93 (6H, m), 2.94
(1H, d, J¼13.9 Hz), 3.79 (1H, d, J¼13.9 Hz), 4.46 (1H, m),
7.25–7.30 (2H, m, Ar-H), 7.36–7.38 (1H, m, Ar-H), 7.44–
7.51 (6H, m, Ar-H), 7.53–7.59 (3H, m, Ar-H), 7.64–7.72
(6H, m, Ar-H) and 7.93–7.96 (2H, m, Ar-H); m/z (CI) 597
(MHþ, 20%), 294 (19), 277 (100), 281 (61), 207 (97) and 73
(33). Accurate mass (ESþ): 597.2228. C36H38O4SP [MH]þ
requires 597.2217. [a]2D5¼þ48.7 (c¼0.1, CH2Cl2).
4.1.7. 10-Phenylsulfonylisoborneol 10. This was prepared
from 10-Isobornylsultone 9 by a procedure described in the
literature (64%).7b Mp 135.2–136.38C (lit.7b 141.5–
143.58C). (Found: C, 65.29; H, 7.58. C16H22O3S requires
C, 65.27; H, 7.53). dH 0.78 (3H, s), 1.05 (3H, s), 1.10–1.25
(1H, m), 1.54–1.86 (6H, m), 2.92 (1H, d, J¼13.6 Hz), 3.49
(1H, d, J¼13.6 Hz), 4.22–4.27 (1H, m), 7.57–7.63 (2H, m,
Ar-H), 7.66–7.72 (1H, m, Ar-H), 7.95–7.99 (2H, m, Ar-H);
dC 19.8, 20.4, 27.4, 30.4, 38.9, 44.1, 49.1, 51.1, 56.1, 76.3,
127.6, 129.3, 133.8, 140.5; m/z (CI) 312 [(MþNH4)þ, 33],
294 (MHþ, 4) and 277 (100).
4.1.8. 10-Phenylsulfonylisobornyl bromoacetate 11. To a
stirred solution of the alcohol 10 (8.01 g, 27.2 mmol) in
4.1.12. 10-Phenylsulfonylisobornyl 3-oxo-3-phenyl-2-tri-
phenylphosphoranylidenepropanoate 15 (81%). A sol-
ution of ylide 11 (4.8 g, 8.04 mmol) and triethylamine
(1.9 mL) in dry tetrahydrofuran (1.0 mL) was stirred at
room temperature while a solution of benzoylchloride
(8.04 mmol, 1.0 mL) in dry tetrahydrofuran was added
dropwise to it. The mixture was stirred under nitrogen at
room temperature for 12 h, filtered and the filtrate was
washed with water, dried (MgSO4) and concentrated under
vacuum. The product was purified by flash chromatography
[ethyl acetate/hexane (1:1)] giving 15 in 81% yield (4.58 g,
6.53 mmol). Mp 196.4–198.08C. (Found: C, 73.62; H, 6.05.
C43H41O5SP requires C, 73.69; H, 5.9%). dH 0.13 (3H, s),
0.63 (3H, s), 0.94–1.02 (1H, m), 1.25–1.72 (6H, m), 2.61
(1H, d, J¼13.9 Hz), 3.04 (1H, d, J¼13.9 Hz), 4.77 (1H, t,
J¼3.6 Hz), 7.18–7.22 (2H, m, Ar-H), 7.28–7.33 (1H, m,
Ar-H), 7.44–7.59 (12H, m, Ar-H), 7.67–7.71 (2H, m, Ar-
H) and 7.83–7.91 (8H, m, Ar-H); dC 19.45, 20.06, 26.92,
29.85, 36.94, 43.96, 49.07, 49.13, 54.50, 69.10 (d,
dichloromethane
bromoacetyl
bromide
(4.8 mL,
54.4 mmol) was added dropwise. The mixture was stirred
under nitrogen at room temperature for 12 h. The solution
was washed with water, dried (MgSO4) and evaporated off
giving 11 as an oil (10.6 g, 25.6 mmol, 94%). dH 0.87 (3H,
s), 0.99 (3H, s), 1.20–1.25 (1H, m), 1.65–2.05 (6H, m),
2.99 (1H, d, J¼13.9 Hz), 3.58 (1H, d, J¼13.9 Hz), 3.79 (1H,
d, J¼12.8 Hz), 3.84 (1H, d, J¼12.8 Hz), 4.97–4.99 (1H,
m), 7.55–7.60 (2H, m, Ar-H), 7.64–7.69 (1H, m, Ar-H),
7.93–7.96 (2H, m, Ar-H); dC 19.8, 20.2, 26.2, 27.0, 29.7,
39.0, 43.9, 49.6, 49.9, 54.9, 79.5, 127.7, 129.2, 133.6, 141.0,
165.4; m/z (CI) 434 [(MþNH4)þ, 54], 432 (40), 278 (18))
and 277 (88).
4.1.9. 10-Phenylsulfonylisobornyl chloroacetate 13. To a
stirred solution of the alcohol 10 (2.5 g, 8.49 mmol) in
dichloromethane chloroacetyl chloride (1.9 mL, 17 mmol)
was added dropwise. The mixture was heated under reflux
for 24 h. The solution was washed with water, dried
(MgSO4) and evaporated off. The product was purified by
flash chromatography (ethyl acetate/hexane (3:1)) giving 13
as an oil in 53% yield (1.67 g, 4.5 mmol). dH 0.98 (3H, s),
1.29 (3H, s), 1.17–1.29 (1H, m), 1.64–2.04 (6H, m), 2.97
(1H, d, J¼13.9 Hz), 3.57 (1H, d, J¼13.9 Hz), 4.00 (1H, d,
J¼14.9 Hz), 4.06 (1H, d, J¼14.9 Hz), 4.97–5.01 (1H, m),
7.25–7.59 (2H, m, Ar-H), 7.63–7.66 (1H, m, Ar-H), 7.91–
7.94 (2H, m, Ar-H).
3
1JCP¼114 Hz), 125.40, 128.57 (d, JCP¼12.5 Hz), 131.65
(d, 4JCP¼2.7 Hz), 133.32 (d, 2JCP¼9.82 Hz), 141.56, 143.63
3
2
(d, JCP¼9.66 Hz), 167.07 (d, JCP¼15.4 Hz), 192.60 (d,
2JCP¼6.0 Hz); m/z (FAB) 701 (Mþ, 66%), 551 (Mþ, 6%),
460 (9%) and 407 (100). Accurate mass (ESþ): 701.2491.
C43H42O5SP, [MþH]þ requires 701.2506. [a]2D5¼þ47.6
(c¼0.1, CH2Cl2).
4.1.13. 10-Phenylsulfonylisobornyl 3-phenylquinoxaline-
2-carboxylate 19. The ylide 15 (3.15 g, 4.5 mmol) was
dissolved in dichloromethane (50 mL) and a solution of
azidotrimethylsilane (0.71 g, 6.5 mmol) and N-bromo-
succinimide (1.15 g, 6.5 mmol) in dichloromethane
(100 mL) was added. The reaction was complete after
5 min. The residue obtained upon removal of the solvent
was purified by flash chromatography (ethyl acetate/hexane
(3:1)) and gave 10-phenylsulfonylisobornyl 3-azido-2-
chloro-3-phenylpropenoate 16 (58%). nmax (film) 1738
and 2114 cm21; Accurate mass (ESþ): 538.0675. C25H26-
NO4NaS79Br, [MNa2N2]þ requires 538.0664.
4.1.10. 10-Phenylsulfonylisobornyl iodoacetate 14. To a
stirred solution of the ester 13 (0.3 g, 0.81 mmol) in acetone
KI (0.135, 0.81 mmol) was added. The mixture was stirred
under nitrogen at room temperature for 12 h. After addition
of dichloromethane the solution was washed with water,
dried (MgSO4) and evaporated off giving 14 (0.302 g, 89%)
as an oil. dH 0.85 (3H, s), 0.95 (3H, s), 1.14–1.24 (1H, m),
1.56–1.94 (6H, m), 1.97 (2H, s), 2.99 (2H, d, J¼14.1 Hz),
3.56 (2H, d, J¼14.1 Hz), 4.76 (2H, dd, J¼3.2, 7.9 Hz),
7.53–7.59 (2H, m, Ar-H), 7.62–7.68 (1H, m, Ar-H), 7.89–
7.93 (2H, m, Ar-H); dC 19.9, 20.3, 21.2, 27.1, 29.8, 39.6, 44.0,
49.2, 49.9, 55.2, 77.7, 127.7, 129.2, 133.6, 141.3, 196.5.
A solution of the vinyl azide 16 (1.0 g, 2.0 mmol) in heptane
(10 mL) was heated under reflux for 2–3 h (the reaction was
monitored by TLC). The reaction mixture was cooled and
the solvent evaporated giving 10-phenylsulfonylisobornyl
4.1.11. 10-Phenylsulfonylisobornyl triphenylphosphor-
anylideneacetate 12. To a stirred solution of 11 (6.5 g,

T. M. V. D. Pinho e Melo et al. / Tetrahedron 59 (2003) 2345–2351
2351
2-bromo-3-phenyl-2H-azirine-2-carboxylate 17 as a dia-
stereoisomeric mixture. nmax (film) 1752 and 2956 cm21
10-Phenylsulfonylisobornyl acetate 21. dH 0.86 (3H, s), 0.96
(3H, s), 1.18–1.28 (1H, m), 1.60–1.99 (9H, m), 3.00 (1H, d,
J¼14.1 Hz), 3.57 (1H, d, J¼14.1 Hz), 4.78 (1H, dd, J¼3.2,
7.9 Hz), 7.54–7.68 (3H, m, Ar-H) and 7.90–7.94 (2H, m,
Ar-H); dC 19.7, 20.0, 21.0, 26.9, 29.6, 39.4, 43.8, 49.1, 49.7,
55.0, 77.5, 127.5, 129.1, 133.5, 141.1 and 169.4; m/z (CI)
354 [(MþNH4)þ, 78], 337 (MHþ, 1), 294 (8) and 277 (100).
Accurate mass (ESþ): 359.1291. C18H24O4NaS, [MþNa]þ
requires 359.1293.
.
Accurate mass (ESþ): 538.0641 C25H26NO4NaS79Br,
[MNa]þ requires 538.0664. The diastereoisomers were
separated by preparative TLC (ethyl acetate/hexane (1:3))
giving in order of elution: (i) dH 0.84 (3H, s), 0.88 (3H, s),
1.24–1.26 (1H, m), 1.61–2.05 (6H, m), 2.91 (1H, d,
J¼13.7 Hz), 3.64 (1H, d, J¼13.7 Hz), 5.03 (1H, dd, J¼3.1,
7.9 Hz), 7.56–7.63 (4H, m, Ar-H), 7.66–7.73 (2H, m, Ar-
H) and 8.02–8.09 (4H, m, Ar-H); dC 19.7, 20.2, 27.1, 29.7,
39.1, 44.0, 44.5, 49.9, 50.0, 54.9, 80.8, 119.7, 127.9, 129.3,
129.6, 131.1, 133.6, 135.0, 141.1, 164.5, 165.4; (ii) dH 0.83
(3H, s), 0.95 (3H, s), 1.24–1.28 (1H, m), 1.77–2.04 (6H,
m), 2.88 (1H, d, J¼13.9 Hz), 3.40 (1H, d, J¼13.9 Hz), 4.97
(1H, dd, J¼2.9, 7.7 Hz), 7.50–7.56 (2H, m, Ar-H), 7.59–
7.67 (3H, m, Ar-H), 7.72–7.78 (1H, m, Ar-H), 7.81–7.85
(1H, m, Ar-H) and 7.97–8.00 (2H. m, Ar-H); dC 19.9, 20.2,
27.0, 29.6, 39.3, 43.9, 44.6, 49.6, 50.0, 54.7, 80.5, 119.8,
127.8, 129.3, 129.7, 131.1, 133.6, 135.1, 140.9, 164.6,
165.0.
Acknowledgements
The authors wish to thank Dr Rui M. Brito (University of
Coimbra) for the HETCOR and NOESY spectra. We also
ˆ
thank Chymiotechnon and Fundac¸a˜o para a Ciencia e a
Tecnologia (POCTI/36137/QUI/2000) for financial support.
The diastereoisomeric mixture 2H-azirine 17 (0.143,
0.28 mmol) was dissolved in DMF (10 mL) and 1,2-
phenylenediamine (32 mg, 0.28 mmol) was added. The
reaction mixture was agitated in an ultrasound bath for 2 h.
The solvent was evaporated and the residue was subjected to
flash chromatography (with hexane/ethyl acetate (1:2))
giving the quinoxaline 19 as an oil (66 mg, 45%). dH 0.59
(3H, s), 0.81 (3H, s), 1.24–1.29 (1H, m), 1.61–2.05 (6H,
m), 2.86 (1H, d, J¼13.8 Hz), 3.44 (1H, d, J¼13.8 Hz), 5.29
(1H, dd, J¼3.3, 7.9 Hz), 7.29–7.40 (3H, m, Ar-H), 7.46–
7.60 (4H, m, Ar-H), 7.81–7.95 (6H, m, Ar-H) and 8.20–
8.27 (1H, m, Ar-H); dC 19.4, 20.3, 27.2, 29.4, 38.4, 44.1,
49.7, 49.8, 54.5, 79.8, 127.7, 128.8, 128.9, 129.2, 129.4,
129.5, 129.9, 130.5, 131.6, 133.4, 137.3, 137.4, 140.0,
141.2, 142.2, 146.1, 151.9 and 165.3; m/z (APCIþ) 529
(Mþ2, 10%), 528 (Mþ1, 34), 527 (M, 100) and 277 (5).
Accurate mass (ESþ): 527.2019. C31H31N2O4S, [MþH]þ
requires 527.2005.
References
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4.1.14. 10-Phenylsulfonylisobornyl (2S)-3-phenyl-2H-
azirine-2-carboxylate 20 and 10-phenylsulfonylisobornyl
acetate 21. To a stirred solution of azirine 17 (0.68 g,
1.32 mmol) in DMF (30 mL), cooled to 08C, sodium
borohydride (0.1 g, 2.64 mmol) was cautiously added. The
mixture was stirred under nitrogen at room temperature for
2 h. After addition of dichloromethane the solution was
washed with water, dried (MgSO4) and evaporated off. The
product was purified by flash chromatography (ethyl
acetate/hexane (1:2)) giving the dehalogenated azirine 20
(0.14 g, 24%) and 21 (0.12 g, 27%).
5. Ciabattoni, J.; Cabell, Jr. M. J. Am. Chem. Soc. 1971, 93,
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10. .1H NMR chemical shifts are in agreement with the values
described for methyl 2-phenyl-2H-azirine-3-carboxylate Knit-
tel, D. Synthesis 1985, 186–188.
10-Phenylsulfonylisobornyl 3-phenyl-2H-azirine-2-car-
boxylate 20 (24%). dH 0.84 (3H, s), 0.89 (3H, s), 1.21–
1.29 (1H, m), 1.65 (1H, s), 1.66–2.02 (6H, m), 2.91 (1H, d,
J¼13.7 Hz), 3.65 (1H, d, J¼13.7 Hz), 5.03 (1H, dd, m),
7.59–7.63 (4H, m, Ar-H), 7.67–7.69 (2H, m, Ar-H) and
8.03–8.09 (4H, m, Ar-H); dC 19.7, 20.2, 27.1, 29.7, 39.1,
44.0, 44.5, 49.9, 50.0, 54.8, 80.8, 119.7, 127.9, 129.3, 129.6,
131.1, 133.6, 135.0, 141.1, 164.5 and 165.4. [a]2D5¼þ48.1
(c¼0.1, CH2Cl2).
11. Ethyl (3R,2R)- and (3S,2R)-3-phenylaziridine-2-carboxylate
were prepared as described in Gelas-Mialhe, Y.; Touraud, E.;
Vessiere, R. Can. J. Chem. 1982, 60, 2830–2851, by
comparison of the characterization data of these compounds
and the one of 7a we confirmed that we had obtained a mixture
of aziridines.