Synthesis of 2-halo-2H-azirines

Article abstract of DOI:10.1016/S0040-4020(01)00598-1

α-Oxophosphonium ylides react with N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide in the presence of azidotrimethylsilane giving the corresponding haloazidoalkenes which were completely converted to the 2-halo-2H-azirines on heating in heptane.

Full text of DOI:10.1016/S0040-4020(01)00598-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6203±6208
Synthesis of 2-halo-2H-azirines
p
Teresa M. V. D. Pinho e Melo, Claudia S. J. Lopes, Ana L. Cardoso and
Â
Antonio M. d'A. Rocha Gonsalves
Â
 Ã
Departamento de Quõmica, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
Received 13 April 2001; revised 18 May 2001; accepted 30 May 2001
AbstractÐa-Oxophosphonium ylides react with N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide in the presence of
azidotrimethylsilane giving the corresponding haloazidoalkenes which were completely converted to the 2-halo-2H-azirines on heating in
heptane. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have previously described a non-classical Wittig
reaction which offers a route to some simple tetrasubstituted
alkenes of a type that was poorly represented in the litera-
ture.1 Diethyl 2-oxo-3-triphenylphosphoranylidene-butane-
Scheme 1.
dioate 1a reacts with chlorine and bromine in the presence
The formation of an halophosphonium salt as an intermedi-
ate is in agreement with the known halogenation of a-
oxophosphonium ylides which gives the corresponding
halophosphonium salt 23 (Scheme 3).
of a range of nucleophiles giving 2,3-disubstituted diethyl
butenedioates with elimination of triphenylphosphine oxide
(Scheme 1). The reaction of N-bromosuccinimide and
N-chlorosuccinimide in methanol or in the presence of
azidotrimethylsilane also gave 2,3-disubstituted diethyl-
butenedioates. Several of the reactions were highly stereo-
selective whereas others gave both (E) and (Z) isomers.
On the other hand, one example is known of an intramole-
cular non-classical Wittig reaction of the type described
above. In fact the reaction of a-oxophosphonium ylides,
bearing a terminal carboxylic acid group acting as the
nucleophile, with halogenating agents leads to the formation
of E- and Z-halo enol lactones.4,5 The cyclization is also
thought to proceeds via a halophosphonium salt followed
The study of the reactivity of ylides 1b±d towards reagent
systems XY (electrophile/nucleophile), where X±Y, clearly
indicates that the electrophile binds exclusively to the
carbon of the phosphoranylidene group of the starting
ylide and the oxygen which is eliminated in the process is
always from the keto carbonyl group.2
We postulated that isomeric halonium ions were intermedi-
ates in the formation of the observed products. These halo-
nium ions could interconvert by way of an acyclic cation.
The opening of the two halonium ions by a nucleophile
would lead to the isomeric alkenes after the elimination of
triphenylphosphine oxide (Scheme 2).
Scheme 2.
Keywords: 2-halo-2H-azirines; haloazidoalkenes; phosphorus ylides;
pyrazine-2,3,5,6-tetracarboxylate.
p
Corresponding author. Tel: 1351-239-852-080; fax: 1351-239-826-068;
e-mail: tmelo@lyra.ci.uc.pt
Scheme 3.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00598-1

6204
T. M. V. D. Pinho e Melo et al. / Tetrahedron 57 (2001) 6203±6208
Scheme 4.
by loss of triphenylphosphine oxide. Scheme 4 illustrates
one case where it is possible to isolate the bromophospho-
nium salt 4 if the reaction of ylide 3 with bromine is
promoted at 08C. Treatment of 4 with triethylamine gives
the corresponding bromo enol lactones.5
In the course of our work we have found that haloazido-
alkenes prepared from phosphorus ylides can be easily
converted into the corresponding 2-halo-2H-azirines.10,11
In this paper, we describe this general route to 2-halo-2H-
azirines starting from phosphorus ylides which allowed the
synthesis of the ®rst examples of 2-bromo- and 2-iodo-2H-
azirine derivatives.
One aspect of particular interest in this methodology for the
synthesis of tetrasubstituted alkenes is the possibility of
preparing haloazidoalkenes from the reaction of phosphorus
ylides with N-halosuccinimide in the presence of azido-
trimethylsilane since these compounds were potential
precursors of 2-halo-2H-azirines.
2. Results and discussion
Aiming the synthesis of a variety of 2-halo-2H-azirines in
order to evaluate the scope of the synthetic methodology, a
variety of stabilised ylides were selected. a-Oxoalkylidene-
tri-phenylphosphoranes bearing two carboxylate substitu-
ents (1a and 1f), derivatives with a phenyl and a
carboxylate group (1d and 1e), ylide 1g with a carboxylate
group and a benzoyl group and ylide 1h with a methyl and a
carboxylate group as substituents were prepared using
synthetic procedures described in the literature.12±14
2H-Azirines are unsaturated three-membered heterocycles
which are used for various synthetic purposes due to their
high reactivity.6 The most general method of synthesis of
2H-azirines is the thermal or photochemical decomposition
of vinyl azides involving vinyl nitrenes as intermediates.6±9
There are very few literature reports of halo substituted
azirines.8,9 The reaction of iodine azide8a,b or chlorine
azide8c with chloroalkenes followed by elimination of
hydrogen iodide or hydrogen chloride gives the correspond-
ing chlorovinyl azides which can be converted into chlor-
oazirines (6a±c). There are also a few examples of
¯uorinated 2H-azirines, such as 7a and 7b, prepared from
¯uorovinyl azides.9a,b
These ylides reacted with N-halosuccinimide in the
presence of azidotrimethylsilane giving the corresponding
haloazidoalkenes 8a±f and 8h±n (Scheme 5). The alkene 8g
could not be isolated since the reaction of ylide 1e with
N-bromosuccinimide and azidotrimethylsilane led directly
to the synthesis of 2-bromo-2H-azirine 9g in 89% yield.
Alkenes 8d±f could be characterised by IR spectroscopy
but attempts to purify these alkenes in order to get the
complete characterisation data led to the isolation of
the corresponding 2H-azirines. These results indicate that
the conversion of 3-azido-2-halo-3-phenylpropenoates to
Scheme 5.

T. M. V. D. Pinho e Melo et al. / Tetrahedron 57 (2001) 6203±6208
6205
Table 1. 13C NMR in CDCl3 of the haloazidoalkenes (d in ppm)
Table 2. 13C NMR in CDCl3 of the 2H-azirines 9a±e, 9g±j, 9m and 9n (d
in ppm)
Alkene
C±X
C±N3
2H-Azirine
C-2
C-3
8a
8ba
8c
8h
8i
8j
8m
8n
114.8
114.3
105.4
73.5
129.6
117.6
99.9
136.8
137.6
138.9
153.9
134.3
133.9
143.9
146.1
9a
9b
9c
9d
9e
9g
9i
9j
9m
9n
63.3
54.6
42.9
54.0
44.2
43.7
54.4
42.8
43.4
13.7
154.7
155.0
155.0
163.5
164.5
164.4
166.4
165.9
166.9
166.6
72.9
a
Major component
2-halo-3-phenyl-2H-azirine-2-carboxylate is extremely
favourable.
and 2-bromo-2H-azirines were obtained in high yield (89±
99%) whereas the yields obtained in the synthesis of the
2-iodo-2H-azirine derivatives ranged from 36 to 85%.
The reactions with N-chlorosuccinimide and N-bromo-
succinimide were completed after 5 min. However, the reac-
tion with N-iodosuccinimide required the use of excess of
this halogenating agent and was only completed after 4.5 h.
The 13C NMR spectra of the 2-chloro- and 2-bromo-2H-
azirines show the sp2 carbon between 155.0 and
166.9 ppm and the sp3 carbon between 43 and 63 ppm
depending on the substitution pattern. Compounds 9b and
9i show the signal for the sp3 carbon coincident with the
signal for the methyl group. Methyl 2-iodo-3-methyl-2H-
azirine-3-carboxylate 9n shows the sp2 carbon at
166.6 ppm and the sp3 carbon at 13.7 ppm (Table 2).
The majority of these reactions showed high stereoselectiv-
ity leading to the synthesis of the alkenes as single isomers
(8d±n). However, the 2-azido-3-halobut-2-enedioates (8a±
c) were obtained as mixtures of E/Z isomers.
The 13C NMR spectra of the haloazidoalkenes show the
C±X carbon between 72.9 and 129.6 and the C±N3 between
133.9 and 146.1 ppm (Table 1). In the case of the 2-azido-3-
chlorobut-2-enedioates (8a±c) the assignment was made on
the basis of a comparison of its 13C NMR spectra with those
of dimethyl azidofumarate and dimethyl azidomaleate.7 The
completed assignment of the 13C NMR spectrum of methyl
2-azido-3-bromo-3-benzoylprop-2-enoate 8j was supported
On attempting to obtain mass spectra of 2-halo-2H-azirines
9a±c, using chemical ionisation with ammonia, we could
only observe the spectra of the corresponding pyrazine-
2,3,5,6-tetracarboxylate (10a and 10b).
1
1
by H±1H COSY and H±13C COSY spectra.
Alkenes 8a±f and 8h±n are easily converted into the corre-
sponding 2-halo-2H-azirines (9a±f, 9h±n) on heating in
heptane for 2±3 h (Scheme 6). The reaction can be followed
by TLC and by IR by monitoring the disappearance of the
band corresponding to the azido group of the starting
azidoalkenes (n,2110±2120 cm21). 2-Chloro-2H-azirines
To con®rm this observation tetramethyl pyrazine-2,3,5,6-
tetracarboxylate 10b was prepared by heating a solution
of dimethyl 2-bromo-2H-azirine-2,3-dicarboxylate 9c in
heptane for 17 h (Scheme 7). Using this procedure pyrazine
10b was obtained in low yield (2%).
The comparison of the mass spectrum of pyrazine 10b with
the mass spectra obtained from azirines 9b and 9c con®rmed
that they were identical. This result allowed us to conclude
that 2-halo-2H-azirines 9a±c undergo auto-condensation to
give pyrazine-2,3,5,6-tetracarboxylates when subjected to
the conditions required to obtain the mass spectra.
Chloro- and bromo-2H-azirines with electron withdrawing
groups at C-3 decomposed in the condensed phase within
2±3 days at room temperature whereas azirines with a
phenyl or methyl group at C-3 showed more stability.
Scheme 6.
Scheme 7.

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T. M. V. D. Pinho e Melo et al. / Tetrahedron 57 (2001) 6203±6208
The iodo-2H-azirines showed lower stability than the
corresponding chloro and bromo derivatives.
s) and 3.91 (3H, s); dC 63.5, 63.7, 114.3 (C±Cl), 137.6
(C±N3), 161.2 and 162.3. Accurate mass (CI): 220.012
[MH]1. C6H7ClN3O4 requires 220.012.
3. Conclusion
4.1.3. Dimethyl 2-azido-3-bromobut-2-enedioate 8c. The
title compound was puri®ed by column chromatography
[dichloromethane] and was isolated directly as an oil
This work has provided a very general and ef®cient route to
2-halo-2H-azirines starting from phosphorus ylides. A range
of 2-chloro-, 2-bromo- and 2-iodo-2H-azirines bearing a
variety of substituents were obtained including derivatives
having electron withdrawing groups at C-2 and C-3
(9a±c, 9i, 9j and 9l), 2-halo-2H-azirines bearing elec-
tron withdrawing groups at C-2 and a phenyl at C-3
(9d±h) and 2-halo-2H-azirine derivatives having an
electron withdrawing group at C-2 and a methyl group
at C-3 (9m and 9n).
1
(89%). H NMR [both isomers (24:76)] 3.83 and 3.84 (s,
together 3H), 3.92 and 3.93 (s, together 3H). Major isomer
(isolated from the mixture by crystallization): mp 49±508C
(from ethyl ether/pentane); nmax (KBr) 1599, 1737 and
2120 cm21; dH 3.83 (3H, s) and 3.92 (3H, s); dC 53.9,
54.0, 105.4 (C±Br), 138.9 (C±N3), 161.4 and 163.4. Accu-
rate mass (CI): 263.961 [MH]1. C6H7BrN3O4 requires
263.961.
4.1.4. Ethyl 3-azido-2-chloro-3-phenylpropenoate 8d.
The title compound was puri®ed by column chromato-
graphy [ethyl acetate/hexane (3:1)] and was isolated directly
as an oil (98%). It can be characterized by IR spectroscopy
[nmax (®lm) 1697, 1734, 2120 and 2986 cm21] and 1H NMR
[dH 1.26 (3H, t) and 4.12 (2H, q)]. Attempts to purify this
alkene in order to get more characterization data led to the
isolation of the corresponding 2H-azirine.
4. Experimental
1H NMR spectra were recorded on a Bruker AMX300
instrument operating at 300 MHz. 13C spectrum were
recorded on a Brucker AMX300 instrument operating at
75.5 MHz. The solvent is deuteriochloroform except
where indicated otherwise. IR spectra were recorded on a
Perkin±Elmer 1720X FTIR spectrometer. Mass spectra
were recorded under electron impact at 70 eV on a VG
Micromass 7070E instrument or where indicated, by
chemical ionisation with ammonia (CI). Mp's were
recorded on a Reichert hot stage and are uncorrected.
Flash column chromatography was performed with Merck
9385 silica as the stationary phase. Phosphorus ylides were
prepared using general procedures described in the literature
(1a,12 1f,12 1d,13 1e,13 1g13 and 1h14).
4.1.5. Ethyl 3-azido-2-bromo-3-phenylpropenoate 8e.
The title compound was puri®ed by column chromato-
graphy [ethyl acetate/hexane (3:1)] and was isolated directly
as an oil (60%). It can be characterized by IR spectroscopy
[nmax (®lm) 1695 and 2135 cm21]. Attempts to purify this
alkene in order to get more characterization data led to the
isolation of the corresponding 2H-azirine.
4.1.6. Methyl 2-azido-3-chloro-3-benzoylpropenoate 8i.
The title compound was puri®ed by column chromato-
graphy [ethyl acetate/hexane (6:1)] and was isolated directly
as a solid (40%). Mp 62±648C. (Found: C, 49.0; H, 2.7; N,
15.8. C11H8ClN3O3 requires C, 49.7; H, 3.0; N, 15.8%), nmax
(KBr) 1674, 1732 and 2137 cm21; dH 3.58 (3H, s), 7.48
(2H, t, Jˆ16 Hz, Ar±H), 7.60±7.64 (1H, m, Ar±H) and
7.87±7.89 (2H, m, Ar±H); dC 53.1, 129.0, 129.4, 129.6
(C±Cl), 134.1, 134.3 (C±N3), 160.4 and 187.5. Accurate
mass (CI): 283.059 [M1NH4]1. C11H12ClN4O3 requires
283.059.
4.1. General procedure for the synthesis of chloro- and
bromoazidoalkenes
The ylide (4.5 mmol) was dissolved in dichloromethane
(50 mL) and
a
solution of azidotrimethyilsilane
(0.71 g, 6.5 mmol) and N-chloro- or N-bromosuccini-
mide (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
puri®ed by column chromatography and gave the vinyl
azide.
4.1.7. Methyl 2-azido-3-bromo-3-benzoylpropenoate 8j.
The title compound was puri®ed by column chromato-
graphy [ethyl acetate/hexane (6:1)] and was isolated directly
as a solid (44%). Mp 73±748C. (Found: C, 42.6; H, 2.6; N,
13.4. C11H8BrN3O3 requires C, 42.6; H, 2.6; N, 13.6%). nmax
(®lm) 1601, 1663, 1732 and 2124 cm21; dH 3.57 (3H, s),
7.48±7.53 (2H, m, Ar±H, H±C-m), 7.60±7.63 (1H, m, Ar±
H, H±C-p) and 7.87±7.91 (2H, m, Ar±H, H±C-o); dC 53.2
(CH3), 117.6 (C±Br), 128.8 (Ar, C-m), 129.4 (Ar, C-o),
131.2 (Ar, C-ipso), 133.9 (C±N3), 134.1 (Ar, C-p), 159.9
(CO2CH3) and 188.1 (COPh). Accurate mass (CI): 327.009
[M1NH4]1. C11H12BrN4O3 requires 327.009.
4.1.1. Diethyl 2-azido-3-chlorobut-2-enedioate 8a. The
title compound was puri®ed by column chromatography
[ethyl acetate/hexane (3:1)] and isolated directly as an oil
as a mixture of isomers (90%). nmax (®lm) 1601, 1734 and
2125 cm21; dH 1.25±1.39 (m, 6H), 4.28 and 4.38 (q,
together 4H); dC 13.8, 13.9, 62.7, 63.2, 114.8 (C±Cl),
136.8 (C±N3), 160.6 and 161.8. Accurate mass (CI):
247.036. C8H10ClN3O4 requires 247.036.
4.1.2. Dimethyl 2-azido-3-chlorobut-2-enedioate 8b. The
title compound was puri®ed by column chromatography
[dichloromethane] (75%). dH [both isomers (32:68)] 3.83
and 3.86 (s, together 3H), 3.91 and 3.95 (s, together 3H).
Major isomer (isolated from the mixture by crystallization):
mp 48±508C (from pentane) (Found: C, 33.07; H, 2.79; N,
18.60. C6H6ClN3O4 requires C, 32.88; H, 2.74; N, 19.18%);
4.1.8. Methyl 3-azido-2-bromobut-2-enoate 8m. The title
compound was puri®ed by column chromatography
[dichloromethane] and was isolated directly as an oil
(93%). nmax (®lm) 1673, 1745 and 2131 cm21; dH 2.30
(3H, s), 3.74 (3H, s); dC 20.1, 52.8, 99.9 (C±Br), 143.9
n
max (KBr) 1678, 1709, 1721 and 2137 cm21; dH 3.83 (3H,

T. M. V. D. Pinho e Melo et al. / Tetrahedron 57 (2001) 6203±6208
6207
(C±N3) and 162.6. Accurate mass (CI): 219.972 [MH]1.
C5H7BrN3O2 requires 219.972.
carboxylate] 330 [M1NH4]1 (100%), 313 [MH]1 (28),
194 (27), 175 (35) and 160 (26).
4.3.4. Ethyl 2-chloro-3-phenyl-2H-azirine-2-carboxylate
9d. The title compound was isolated directly as an oil
(97%). nmax (®lm) 1745 and 2984 cm21; dH 1.27 (3H, t),
4.27 (2H, q), 7.60±7.66 (2H, m, Ar±H), 7.70±7.76 (1H, m,
Ar±H) and 7.93±7.97 (2H, m, Ar±H); dC 13.9, 54.0 (C-2),
63.2, 119.6, 129.6, 130.7, 134.9, 163.5 (C-3) and 167.3.
Accurate mass (CI): 241.074 [M1NH4]1. C11H14ClN2O2
requires 241.074.
4.2. General procedure for the synthesis of the
iodoazidoalkenes
The ylide (4.5 mmol) was dissolved in dichloromethane
(50 mL) and a solution of azidotrimethyilsilane (0.71 g,
6.5 mmol) and N-iodosuccinimide (13 mmol) in dichloro-
methane (100 mL) was added. The reaction was complete
after 4.5 h. The residue obtained upon removal of the
solvent was puri®ed by column chromatography [ethyl
acetate/hexane (1:2)] giving the vinyl azide.
4.3.5. Ethyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate
9e. The title compound was isolated directly as an oil (97%).
(Found: C, 49.24; H, 5.76; N, 5.22. C11H10BrNO2 requires
C, 49.24; H, 5.75; N, 5.67%). nmax (®lm) 1742 and
2984 cm21; dH 1.28 (3H, t), 4.27 (2H, q), 7.61±7.66
(2H, m, Ar±H), 7.71±7.77 (1H, m, Ar±H) and 7.95±
7.99 (2H, m, Ar±H); dC 14.1, 44.2 (C-2), 63.6, 119.8,
129.7, 130.9, 135.1, 164.5 (C-3) and 166.7; m/z (EI) M1
268 (35%), 241 (20), 222 (10), 196 (18), 188 (86) and
89 (100).
4.2.1. Ethyl 3-azido-2-iodo-3-phenylpropenoate 8f. 65%.
n
max (®lm) 1691, 2114 and 2983 cm21; dH 0.92 (3H, t), 3.95
(2H, q), 7.27±7.31 (2H, m, Ar±H), 7.46±7.51 (1H, m, Ar±
H) and 7.61±7.69 (2H, m, Ar±H).
4.2.2. Methyl 3-azido-2-iodo-3-phenylpropenoate 8h.
37%. nmax (®lm) 1693, 1716, 2135 and 2999 cm21; dH
3.51 (3H, s), 7.26±7.29 (2H, m, Ar±H), 7.43±7.49 (1H,
m, Ar±H) and 7.59±7.65 (2H, m, Ar±H); dC 52.9, 73.5
(C±I), 153.9 (C±N3) and 172.5.
4.3.6. Ethyl 2-iodo-3-phenyl-2H-azirine-2-carboxylate
9f. The title compound was isolated directly as an oil
(36%). dH 1.28 (3H, t), 4.22 (2H, q), 7.60±7.65 (2H, m,
Ar±H), 7.71±7.74 (1H, m, Ar±H) and 7.91±7.94 (2H, m,
Ar±H). Accurate mass (CI): 333.009 [M1NH4]1.
C11H14IN2O2 requires 333.010.
4.2.3. Methyl 2-azido-3-iodo-3-benzoylpropenoate 8l.
43%. nmax (®lm) 1660, 1724 and 2125 cm21; dH 3.57 (3H,
s) and 7.47±7.90 (5H, m, Ar±H).
4.2.4. Methyl 3-azido-2-iodo-but-2-enoate 8n. The titled
compound was isolated directly as an oil (73%). nmax (®lm)
1709 and 2110 cm21; dH 2.43 (3H, s) and 3.81 (3H, s); dC
23.7, 63.1, 72.9 (C±I), 146.1 (C±N3) and 164.6.
4.3.7. Methyl 2-bromo-3-phenyl-2H-azirine-2-carboxy-
late 9g. 89%, directly from ylide 1c and after puri®cation
by column chromatography with ethyl acetate/hexane (1:2).
(Found: C, 47.46; H, 3.11; N, 5.48. C10H8BrNO2 requires C,
47.27; H, 3.17; N, 5.51%). nmax (®lm) 1670, 1759 and
2954 cm21; dH 3.82 (3H, s), 7.62±7.67 (2H, m, Ar±
H), 7.72±7.78 (1H, m, Ar±H) and 7.95±7.99 (2H, m,
Ar±H); dC 43.7 (C-2), 54.2, 119.7, 129.7, 131.0, 135.2,
164.4 (C-3) and 167.2.
4.3. General procedure for the synthesis of 2H-azirines
A solution of the vinyl azide (2.0 mmol) in heptane (10 mL)
was heated under re¯ux for 2±3 h (the reaction was moni-
tored by TLC). The reaction mixture was cooled and the
solvent evaporated giving the azirine.
4.3.8. Methyl 2-iodo-3-phenyl-2H-azirine-2-carboxylate
9h. 77%. nmax (®lm) 1756 cm21; dH 3.82 (3H, s), 7.63±
7.68 (2H, m, Ar±H), 7.73±7.79 (1H, m, Ar±H) and 7.94±
7.98 (2H, m, Ar±H). Accurate mass (EI): 301.9666.
C10H9INO2 requires 301.9678.
4.3.1. Diethyl 2-chloro-2H-azirine-2,3-dicarboxylate 9a.
The title compound was isolated directly as an oil (98%).
n
t), 4.26 (2H, q) and 4.50 (2H, q); dC 13.9, 14.0, 63.3 (C-2),
63.9, 64.6, 154.67 (C-3), 162.7 and 165.4; m/z (CI)
max (®lm) 1628 and 1733 cm21. dH 1.29 (3H, t), 1.43 (3H,
4.3.9. Methyl 2-benzoyl-2-chloro-2H-azirine-3-carboxy-
late 9i. The title compound was isolated directly as an oil
(97%). nmax (®lm) 1680, 1748 and 2961 cm21. dH 3.85
(3H, s), 7.56±7.64 (2H, m, Ar±H), 7.73±7.81 (1H, m,
Ar±H) and 8.17±8.22 (2H, m, Ar±H); dC 54.4 (C-2 and
CH3), 129.6, 129.9, 133.8, 136.5, 164.3, 166.4 (C-3) and
179.1. Accurate mass (EI): 237.019. C11H8ClNO3
requires 237.019.
[Tetraethyl
pyrazine-2,3,5,6-tetracarboxylate]
386
[M1NH4]1 (12%), 369 [MH]1 (5), 302 (10), 285
(100) and 203 (16).
4.3.2. Dimethyl 2-chloro-2H-azirine-2,3-dicarboxylate
9b. The title compound was isolated directly as an oil
(99%). nmax (®lm) 1652 and 1755 cm21. dH 3.85 (3H, s)
and 3.90 (3H, s); dC 54.39, 54.57 (C-2 and CH3), 155.0
(C-3), 162.6 and 165.7; m/z (CI) [Tetramethyl pyrazine-
2,3,5,6-tetracarboxylate] 330 [M1NH4]1 (16%), 313
[MH]1 (6), 194 (62), 175 (52) and 160 (100).
4.3.10. Methyl 2-benzoyl-2-bromo-2H-azirine-3-carbox-
ylate 9j. The title compound was isolated directly as an oil
(98%). (Found: C, 47.29; H, 2.81; N, 4.58. C11H8BrNO3
requires C, 46.84; H, 2.86; N, 4.97. nmax (®lm) 1674, 1748
and 2834 cm21; dH 3.87 (3H, s), 7.60±7.65 (2H, m, Ar±H),
7.70±7.82 (1H, m, Ar±H) and 8.21±8.25 (2H, m, Ar±
H); dC 42.8 (C-2), 54.6, 129.5, 129.9, 133.8, 136.5,
164.6, 165.9 (C-3) and 178.8; m/z (EI) [M(81Br)1],
4.3.3. Dimethyl 2-bromo-2H-azirine-2,3-dicarboxylate
9c. The title compound was isolated directly as an oil
(98%). nmax (®lm) 1653 and 1749 cm21. dH 3.85 (3H, s)
and 4.09 (3H, s); dC 42.9 (C-2), 54.5, 155.0 (C-3), 163.1
and 165.3; m/z (CI) [Tetramethyl pyrazine-2,3,5,6-tetra-

6208
T. M. V. D. Pinho e Melo et al. / Tetrahedron 57 (2001) 6203±6208
283 (36%), [M(79Br)1], 281 (36%), 128 (8), 105 (100)
and 77 (91).
References
1. Rocha Gonsalves, A. M. d'A; Cabral, A. M. T. D. P. V.; Pinho
e Melo, T. M. V. D.; Gilchrist, T. L. Synthesis 1997, 673±676.
2. Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d'A.;
Carrapato, S. M. S.; Taborda, A. M. O. M. P. Molecules 1999,
4, 219±231.
4.3.11. Methyl 2-benzoyl-2-iodo-2H-azirine-3-carboxy-
late 9l. 36%. dH 4.10 (3H, s), 7.47±7.56 (3H, m, Ar±H)
and 8.00±8.07 (2H, m, Ar±H). Accurate mass (EI):
328.9549. C11H8NO3I requires 328.9547.
3. Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27, 998±1000.
4. Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999,
3049±3066.
4.3.12. Methyl 2-bromo-3-methyl-2H-azirine-2-carboxy-
late 9m. The title compound was isolated directly as an oil
(99%). nmax (®lm) 1693 and 1747 cm21. dH 2.58 (3H, s) and
3.77 (3H, s); dC 10.74, 43.44 (C-2), 53.95, 166.91 (C-3) and
167.49. Accurate mass (CI): 208.992 [M1NH4]1.
C5H10BrN2O2 requires 208.992.
5. Abell, A. D.; Hoult, D. A.; Morris, K. M.; Taylor, J. M.; Trent,
J. O. J. Org. Chem. 1995, 58, 1531±1537.
6. (a) Backes, J. Methoden der Organischen Chemie (Houben-
Weyl), Vol. E16; Georg Thieme Verlag: Stuttgart, 1992; pp
316±369. (b) Padwa, A.; Woolhouse, A. D. Comprehensive
Heterocyclic Chemistry, Vol. 7; Pergamon: Oxford, 1984; pp
47±93.
4.3.13. Methyl 2-iodo-3-methyl-2H-azirine-3-carboxy-
late 9n. 85%, nmax (®lm) 1734 cm21. dH 2.56 (3H, s) and
3.80 (3H, s); dC 11.4, 13.7 (C-2), 54.3, 166.6 (C-3) and
167.7; m/z (CI) 257 [M1NH4]1 (1%), 239 (2), 224 (10),
130 (4) and 86 (26). The 2-iodo-2H-azirine 9n was
converted into its halide displacement product on reacting
with potassium phthalimide as described previously:11
methyl 2-phthalimido-3-methyl-2H-azirine-2-carboxylate
dH 2.81 (3H, s), 3.77 (3H, s), 7.76±7.79 (2H, m) and
7.87±7.90 (2H, m); dC 13.0, 41.2 (C-2), 53.3, 123.8,
131.7, 134.5, 159.9 (C-3), 167.2 and 168.1. Accurate mass
(CI): 276.098 [M1NH4]1. C13H14N3O4 requires 276.098.
Â
7. L'abbe, G.; Dekerk, J.-P.; Van Stappen, P. Bull. Soc. Chim.
Belg. 1981, 90, 1073±1074.
8. (a) Ciabattoni, J.; Cabell, Jr., M. J. Am. Chem. Soc. 1971, 93,
1482±1483. (b) Padwa, A.; Blacklock, T. J.; Carlsen, P. H. J.;
Pulwer, M. J. Org. Chem. 1979, 44, 3281±3287. (c) Galla-
gher, T. C.; Sasse, M. J.; Storr, R. C. Chem. Commun. 1979,
419±420. (d) Gallagher, T. C.; Storr, R. C. Tetrahedron Lett.
1981, 27, 2905±2908. (e) Hamana, H.; Sugasawa, T. Chem.
Lett. 1985, 571±574.
9. (a) Banks, R. E.; McGlinchey, M. J. J. Chem. Soc. (C) 1970,
2172±2175. (b) Banks, R. E.; Moore, G. J. J. Chem. Soc. (C)
1966, 2304±2307. (c) Morawietz, J.; Sander, W. J. Org.
Chem. 1996, 61, 4351±4354.
4.3.14. Tetramethyl pyrazine-2,3,5,6-tetracarboxylate
10b. 2%. A solution of the dimethyl 2-bromo-2H-azirine-
2,3-dicarboxylate 9c (2.0 mmol) in heptane (10 mL) was
heated under re¯ux for 17 h. The residue obtained upon
removal of the solvent was puri®ed by column chromato-
graphy [ethyl acetate/hexane (1:1)] giving the pyrazine. Mp
180±1828C (lit.15 mp 181±1828C). nmax (®lm) 1664 and
1745 cm21. dH 4.04 (12H, s); dC 53.8, 145.1 and 163.4.
Accurate mass (CI): 313.066 [M1NH4]1. C12H13N2O8
requires 313.067.
10. Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d'A.;
Lopes, C. S. J.; Gilchrist, T. L. Tetrahedron Lett. 1999, 40,
789±792.
11. Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Rocha Gonsalves,
A. M. d'A. Tetrahedron Lett. 2000, 41, 7217±7220.
Â
12. Aitken, R. A.; Herion, H.; Janosi, A.; Raut, S. V.; Seth, S.;
Shannon, I. J.; Smith, F. C. Tetrahedron Lett. 1993, 34, 5621±
5622.
Â
13. Aitken, R. A.; Herion, H.; Janosi, A.; Karodia, N.; Raut, S. V.;
Seth, S.; Shannon, I. J.; Smith, F. C. J. Chem. Soc., Perkin
Trans. 1 1994, 2467±2471.
Acknowledgements
The authors wish to thank Drs T. L. Gilchrist and R. Storr
(University of Liverpool) for very useful discussions
concerning this project. We also thank Chymiotechnon
Ã
and FundacËaÄo para a Ciencia e a Tecnologia (POCTI
36137/99) for ®nancial support.
14. Wasserman, H. H.; Ennis, D. S.; Blum, C. A.; Rotello, V. M.
Tetrahedron Lett. 1992, 33, 6003±6006.
15. (a) Williams, J. R.; Cossey, J. J.; Adler, M. J. Org. Chem.
1972, 37, 2963±2965. (b) Mager, H. I. X.; Berends, W.
Recl. Trav. Chim. Pays-Bas 1960, 79, 282±284.