2H-Azirines as dipolarophiles

Article abstract of DOI:10.1016/S0040-4039(03)01534-X

2H-Azirine-3-carboxylates unsubstituted at C-2 act as dipolarophiles in the reaction with diazomethane giving new 4,5-dihydro-3H-pyrazole derivatives. The synthesis of a pyrimidine was also achieved via 1,3-dipolar cycloaddition of methyl 2-bromo-3-phenyl

Full text of DOI:10.1016/S0040-4039(03)01534-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6313–6315
2
H-Azirines as dipolarophiles
Teresa M. V. D. Pinho e Melo,* Ana L. Cardoso, Clara S. B. Gomes and
Ant o´ nio M. d’A. Rocha Gonsalves
Departamento de Qu ´ı mica, Faculdade de Ci eˆ ncias e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
Received 20 May 2003; accepted 13 June 2003
Abstract—2H-Azirine-3-carboxylates unsubstituted at C-2 act as dipolarophiles in the reaction with diazomethane giving new
4
2
,5-dihydro-3H-pyrazole derivatives. The synthesis of a pyrimidine was also achieved via 1,3-dipolar cycloaddition of methyl
-bromo-3-phenyl-2H-azirine-2-carboxylate with an azomethine ylide.
©
2003 Elsevier Ltd. All rights reserved.
2
H-Azirines represent a particular type of imine-based
exploiting the use of these 2-halo-2H-azirines as
dipolarophiles.
dipolarophiles. The strain inherent in the 2H-azirine
ring system allows to overcome the low reactivity nor-
mally associated to N-alkylimines. The reaction of
1
Methyl 2-bromo-3-phenyl-2H-azirine-2-carboxylate 1
3a
diazomethane with 2-aryl-3-methyl-2H-azirines to give
allyl azides was the first example reported of 1,3-dipolar
cycloaddition of 2H-azirines acting as a 2p-compo-
was prepared and attempts were made to carry out its
reaction with diazomethane. However, complex mix-
tures were obtained, indicating that the cycloadduct
generated from diazomethane and the 2-halo-2H-aziri-
nes can undergo ring opening by various competitive
pathways in agreement with the work described by
2
nent. Subsequently, it has been demonstrated that
2
H-azirines participate also in 1,3-dipolar cycloaddition
1
with nitrile oxides and with azomethine ylides. In this
communication we report our studies aiming at extend-
ing the use of 2H-azirines as dipolarophiles.
4
Storr et al.
The synthesis of 2-halo-2H-azirines starting from a-
oxophosphorus ylides and the study of their reactivity
3
is one of our current interests. We became interested in
Scheme 1.
Keywords: 2H-azirines; 1,3-dipolar cycloaddition; 3H-pyrazole; pyrimidine.
*
Corresponding author. Fax: +351 239 826068; e-mail: tmelo@ci.uc.pt
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01534-X

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T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 44 (2003) 6313–6315
This result led us to study the reaction of diazomethane
with a simpler C-2 unsubstituted 2H-azirine-3-carboxy-
late 3a (Scheme 1). This 2H-azirine was generated from
benzyl a-azidoacrylate 2a by thermolysis, following a
The synthesis of 4,5-dihydro-3H-pyrazole-3-carboxy-
lates (6a and 6b) constitutes a new example of 1,3-dipo-
lar cycloaddition of C-2 unsubstituted 2H-azirine-
3
-carboxylates.
5
known synthetic procedure.
Aziridines undergo thermal ring opening in a conrota-
tory manner to generate azomethine ylides which par-
ticipate in cycloadditions with 2H-azirines giving
Benzyl 2H-azirine-3-carboxylate 3a was not isolated
but instead freshly prepared 2H-azirine in toluene was6
1a,d
bicyclic heterocycles.
We decided to explore similar
used directly to react with diazomethane (Scheme 1).
reactions using methyl 2-bromo-3-phenyl-2H-azirine-2-
carboxylate 1 as dipolarophile.
The azirine solution was cooled at 0°C and diazo-
methane was added in excess. The reaction mixture
was then left at room temperature for 12 h. One
product (6a) was obtained in 49% yield. The process
involves the reaction of 2H-azirine 3a with diazo-
methane, leading to the cycloadduct 4a which under-
goes a rearrangement generating the allyl azide 5a. This
compound participates in a second 1,3-dipolar cycload-
dition with diazomethane to give benzyl 3-azidomethyl-
Ethyl (3S,2R)-3-phenylaziridine-2-carboxylate 7 was
9
prepared as described in the literature. After heating a
solution of this aziridine and 2H-azirine 1 in toluene
for two hours the pyrimidine 11 was isolated in 12%
yield. Thus, we could conclude that 2-bromo-2H-
azirine 1 participated in the 1,3-dipolar cycloaddition
with the azomethine ylide generated from 7 by thermal
ring opening. The cycloadduct 9 underwent a ring
opening reaction with elimination of HBr, leading to
dihydropyrimidine 10 followed by the aromatisation to
4,5-dihydro-3H-pyrazole-3-carboxylate 6a.
Encouraged by this result we went on to study the
reactivity of methyl 2H-azirine-3-carboxylate 3b
towards diazomethane. Methyl 2-azidoacrylate 2b was
prepared from the reaction of methyl 2,3-dibromopro-
pionate with sodium azide using the procedure
10
2,5-diphenylpyrimidine-4,6-dicarboxylate 11 (Scheme
2).
In conclusion, we have proved that C-2 unsubstituted
2H-azirine-3-carboxylates participate in 1,3-dipolar
cycloadditions with diazomethane, leading to new 4,5-
dihydro-3H-pyrazole derivatives. Methyl 2-bromo-3-
phenyl-2H-azirine-2-carboxylate can also act as a
dipolarophile and its reaction with an azomethine ylide
gave 2,5-diphenylpyrimidine-4,6-dicarboxylate. This
study has shown that 2H-azirines are an attractive
system to be explored for the synthesis of new com-
pounds via 1,3-dipolar cycloaddition.
7
described for the ethyl ester. The thermolysis of methyl
2
-azidoacrylate 2b, was carried out as described above
for acrylate 2a although it was found that the conver-
sion into methyl 2H-azirine-3-carboxylate 2b was com-
plete after 2 hours. A solution of the 2H-azirine in
toluene was treated with diazomethane, allowing the
synthesis of methyl 3-azidomethyl-4,5-dihydro-3H-pyr-
azole-3-carboxylate 6b in 38% yield (Scheme 1).
Gilchrist et al. reported the generation of methyl 2H-
azirine-3-carboxylate 2b although the reactivity of this
heterocycle, described as highly unstable and volatile,
Acknowledgements
8
was not studied. The reaction of tert-butyl 2H-azirine-
3
-carboxylate, generated in situ from the corresponding
The authors wish to thank Dr. R. Storr (University of
Liverpool, U.K.) for very useful discussions concerning
this project. They also thank Chymiotechnon and Fun-
da c¸ a˜ o para a Ci eˆ ncia e a Tecnologia (POCTI/36137/
QUI/2000) for financial support.
a-azidoacrylate, with an azomethine ylide giving func-
1
e
tionalized b-lactams has also been reported. The same
authors indicate that a similar reaction can be pro-
moted with methyl 2H-azirine-3-carboxylate 2b.
Scheme 2.

T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 44 (2003) 6313–6315
6315
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9
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0
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2
4
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2
5
6
[hexane–ethyl acetate (3:1), hexane–ethyl acetate (2:1),
5
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(
(
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(
3
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3
−
1
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+
1
7
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