Reactivity of 2-halo-2H-azirines. Part II. Thermal ring expansion reactions: Synthesis of 4-haloisoxazoles

Article abstract of DOI:10.1055/s-2002-23542

The thermolysis of haloazidoalkenes and 2-halo-2H-azirines is described. 2-Benzoyl-2-halo-2H-azirine-3-carboxylates (2a and 2b) underwent ring expansion leading to the synthesis of new 4-haloisoxazoles in high yield. The same isoxazoles were also obtained in high yield directly from haloazidoalkenes (1a and 1b). The thermolysis of the β-azido-α,β-unsaturated ketone 1e led to complete conversion to form the corresponding isoxazole 4e. An isoxazole derivative 4c could also be obtained, in moderate yield, from 2-bromo-3-phenyl-2H-azirine-2-carboxylate (1c). From the thermolysis of azidoalkene 1d the only product that could be isolated was pyrazine-2,3,5,6-tetracarboxylate (5).

Full text of DOI:10.1055/s-2002-23542

PAPER
605
1
Reactivity of 2-Halo-2H-azirines. Part II. Thermal Ring Expansion
Reactions: Synthesis of 4-Haloisoxazoles
a
a
a
b
R
T
eactivity of 2-
e
Halo-2
H
-a
z
r
irines. esa M. V. D. Pinho e Melo,* Cláudia S. J. Lopes, António M. d’A. Rocha Gonsalves, Richard C. Storr
a
Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade de Coimbra, 3004-535 Coimbra, Portugal
Fax +351(239)826068; E-mail: tmelo@ci.uc.pt
b
Chemistry Department, The University of Liverpool, Liverpool L697 ZD, UK
Received 29 November 2001; revised 14 February 2002
N
O
Abstract: The thermolysis of haloazidoalkenes and 2-halo-2H-
azirines is described. 2-Benzoyl-2-halo-2H-azirine-3-carboxylates
∆
N
Ph
CHO
(
2a and 2b) underwent ring expansion leading to the synthesis of
Ph
new 4-haloisoxazoles in high yield. The same isoxazoles were also
obtained in high yield directly from haloazidoalkenes (1a and 1b).
The thermolysis of the -azido- , -unsaturated ketone 1e led to
complete conversion to form the corresponding isoxazole 4e. An
isoxazole derivative 4c could also be obtained, in moderate yield,
from 2-bromo-3-phenyl-2H-azirine-2-carboxylate (1c). From the
thermolysis of azidoalkene 1d the only product that could be isolat-
ed was pyrazine-2,3,5,6-tetracarboxylate (5).
Scheme 2 Thermolysis of 2H-azirines to form isoxazoles.
nitrenes), used to prepare 2H-azirines. Evidence for the
existence of this intermediate comes from the thermal ring
opening of 2,3-diaryl-2-cyano-2H-azirine (where the vi-
nylnitrene was trapped with phosphanes) (Scheme 3).8
Key words: ring expansion, phosphorus ylides, haloazidoalkenes,
2
-halo-2H-azirines, 4-haloisoxazoles
N
N
Ar
CN
N
Ar
CN
Ar
Ph3P
∆
Ar
Ph3P
It is known that isoxazole derivatives can be obtained by
CN
Ar
Ar
thermolysis of (Z)- -azido- , -unsaturated ketones and
2
–6
esters (Scheme 1). A concerted mechanism has been
Scheme 3 Trapping of the thermal ring opening products of 2,3-di-
postulated for this reaction, supported by the fact that the aryl-2-cyano-2H-azirine with phosphanes.
thermal reactions of the corresponding (E)- -azido deriv-
2
atives do not lead to isoxazoles. The mechanistic propos-
al is also in line with the fact that azidofumarates
decompose when heated giving a mixture of the corre-
sponding 2H-azirines and isoxazoles whereas the azi-
In this paper we describe the thermolysis of 2-halo-2H-
azirines (2a–e) and of -azido- , -unsaturated ketones
and esters (1a–e), which allowed the synthesis of ha-
loisoxazoles. They represent interesting heterocyclic
compounds since several isoxazole derivatives show me-
dicinal or agricultural activity or have some industrial ap-
plications (Scheme 4).9
6
domaleates give exclusively the 2H-azirines.
O
O
R1
N
N
N
R1
N
∆
We have previously described a route to 2-halo-2H-azir-
-
N2
10,11
R2
R3
R2
ines.
The process involves the reaction of phosphorus
R3
ylides with N-halosuccinimides in the presence of azidot-
rimethylsilane, which gives the corresponding haloazi-
doalkenes with elimination of triphenylphosphine oxide.
These haloazidoalkenes bearing a conjugative carbonyl
substituent were completely converted into the corre-
sponding 2H-azirines on heating in n-heptane for 2 hours.
In this study we could not detect the formation of isox-
azoles even in the case in which we had a mixture of the
E and Z haloazidoalkenes.
R1 = Ar, OEt or OMe
Scheme 1 Synthesis of isoxazole derivatives by thermolysis of (Z)-
azido- , -unsaturated ketones and esters.
-
Alternatively or competing with this concerted process
the synthesis of isoxazoles could involve the formation of
H-azirines. In fact, by heating a solution of 3-phenyl-2H-
azirine-2-carboxaldehyde at 200 °C, 3-phenylisoxazole is
obtained in high yield (Scheme 2).
2
7
Using this strategy, bromo and chloro azidoalkenes 1a–e
were prepared and converted to the haloazirines 2a–e by
heating in n-heptane for 2 hours.11 Although the config-
uration of the azidoalkenes was not established in every
case they were obtained selectively as single isomers ex-
cept in the case of 1d which was obtained as a mixture of
E and Z isomers.
The thermolysis of 2H-azirines usually results in cleavage
of the N-C2 single bond giving a transient vinylnitrene (a
process which is the reverse of the cyclization of vinyl-
Synthesis 2002, No. 5, 08 04 2002. Article Identifier:
1
437-210X,E;2002,0,05,0605,0608,ftx,en;T11201SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
©

6
06
T. M. V. D. Pinho e Melo et al.
PAPER
N
X
Table 1 Selected Bond Distances (Å), Bond Angles (°) and Torsion
Angles (°) for Compound 1a
N3
X
R2
R2
O
O
C3-C4
1.347(9)
1.492(9)
1.398(8)
1.878(7)
1.502(10)
1.475(9)
119.1(6)
116.9(6)
C3-C4-Br1
120.2(5)
127.4(6)
124.0(6)
112.3(4)
5.6(8)
R1
R1
1
2
C3-C2
C3-C4-C5
C3-N1
N1-C3-C2
O
O
R1
R1
N
N
C4-Br1
C4-C5
C5-C4-Br1
R2
R2
N1-C3-C4-Br1
C2-C3-C4-C5
O2-C2-C3-C4
C3-C4-C5-O3
X
X
C5-C6
5.8(9)
3
4
C4-C3-N1
C4-C3-C2
14.4(10)
81.9(9)
R1
R2
X
a
Ph
CO2Me
CO2Me
Ph
Br
b
c
d
e
Ph
Cl
Br
Br
Br
1
12.7 ppm (Table 2). On the other hand there was no sig-
OEt
OMe
Ph
nal in the region expected for the carbonyl carbon of the
benzoyl group (178.8 ppm for 2H-azirine 2a). These data
are in agreement with the structure of 4-bromoisoxazole
CO2Me
Ph
4
a, which had been formed by ring expansion (Scheme 4).
O
O
MeO2C
MeO2C
N
CO2Me
CO2Me
Using the same reaction conditions, 2-chloro-2-benzoyl-
2H-azirine 2b was converted into the corresponding 4-
chloroisoxazole 4b in 96% yield. In both cases, the prod-
ucts were isolated simply by removal of the solvent with-
out the need for further purification. These thermal
reactions can be rationalized by cleavage of the azirine N–
C2 single bond giving transient vinyl nitrenes 3, which
subsequently cyclise to the isoxazoles 4.
Ph
Ph
N
PPh3
5
6
Scheme 4 Thermolysis of 2-halo-2H-azirines (2a–e) and of -azi-
do- , -unsaturated ketones and esters (1a–e).
Since the azirines were obtained by thermolysis of the azi-
doalkenes, as expected, prolonged heating of the azi-
Meanwhile, in the case of alkene 1a a single crystal was doalkenes gave the isoxazoles directly. In the case of 1a
obtained and its configuration was confirmed as Z by X- and 1b monitoring of the thermolysis in refluxing toluene
ray crystallography (Figure and Table 1).
by TLC showed that the alkene was completely converted
into the 2H-azirine within 2 hours and that on further heat-
ing the isoxazoles were formed and became the sole prod-
ucts after 7 hours. Thus, azidoalkenes 1a and 1b are
converted into isoxazoles 4a and 4b via intermediate 2-
benzoyl-2-halo-2H-azirines 2a and 2b and not directly.
Indeed, the configuration of 1a and 1b precludes their di-
rect conversion by a concerted process.
Heating a solution of 2-bromo-2-benzoyl-2H-azirine 2a
in toluene at reflux for 5 hours gave one compound in high
1
3
yield (97%). The C NMR spectrum showed no signals in
3
the region expected for the sp carbon of the 2-halo-2H-
azirines (42.8 ppm for 2a) but instead showed a signal at
Ring expansion of azirine to isoxazole occurs readily if a
benzoyl group at C-2 is involved and if there is an electron
withdrawing group at C-3. Thus 2a and 2b both have an
ester group at C-3. The reaction also proceeds well when
2
R is aryl as indicated by the thermolysis of azidoalkene
1
e, which gave isoxazole 4e in high yield. Cyclisation in-
Table 2 Selected Chemical Shifts from 13C NMR Spectra
Azirine 2a
C-3 C-2
65.9 42.8
Isoxazoles
C-3
COPh
178.8
C-4
C-5
1
4a
150.0
148.7
112.7
126.6
149.9
147.8
4
b
Figure X-ray structure of compound 1a.
Synthesis 2002, No. 5, 605–608 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Reactivity of 2-Halo-2H-azirines
607
volving an ester group is less satisfactory. Azirine 2c was Methyl 4-Bromo-5-phenylisoxazole-3-carboxylate (4a)
Yield: 97%; mp 66–68 °C.
recovered from heating under reflux in toluene for 24
–
1
hours and only gave the isoxazole 4c in moderate yield IR (KBr): 1737, 2958 cm .
(
25%) after heating in sulfolane at 210 °C for 30 minutes.
1H NMR: = 4.04 (3 H, s), 7.48–7.51 (3 H, m, Ar-H), 8.03–8.06 (2
Attempts to obtain a haloisoxazole from azidoalkene 1d H, m, Ar-H).
and azirine 2d failed. The only product isolated from pro-
longed heating of azirine 2d in n-heptane was pyrazine
13C NMR:
= 53.5, 112.7 (C-Br), 125.8, 126.3, 129.0, 130.3, 149.9,
1
50.0, 155.3.
MS (EI, 70 eV): m/z (%) = 283 [M( Br) ] (100), 281 [M( Br) ]
100), 223 (18), 221 (18), 105 (55), 77 (89).
Anal. Calcd for C H NO Br: C, 46.84; H, 2.86; N, 4.97. Found: C,
2
2
,3,5,6-tetracarboxylate (5) (2%) and thermolysis at
10 °C in sulfolane led to a complex mixture.
81
+
79
+
(
In conclusion, we have described a new and efficient ap-
1
1
8
3
proach to 4-haloisoxazoles. The nature of the azirine car- 47.24; H, 3.12; N, 5.29.
bonyl substituent at C-2 has a marked influence on the
Methyl 4-Chloro-5-phenylisoxazole-3-carboxylate (4b)
Yield: 96%; mp 71–72 °C.
reaction: 2H-azirines with a benzoyl group at C-2 undergo
thermal ring expansion more efficiently than 2H-azirines
with an ester group at C-2. Thus, 2-benzoyl-2H-azirines
with phenyl or an ester group at C-3 can be easily convert-
13C NMR:
48.7, 155.3.
= 53.5, 125.6, 125.9, 126.6 (C-Cl), 129.0, 130.2, 147.8,
1
3
7
+
35
+
ed into the corresponding isoxazoles whereas in the case MS (EI, 70 eV): m/z (%) = 239 [M( Cl) ] (34), 237 [M( Cl) ]
(
100), 177 (17), 128 (8), 105 (55), 77 (59).
of 2H-azirine-2-carboxylate derivatives, which require
more drastic thermolysis conditions, only the more stable Anal. Calcd for C H NO Cl: C, 55.60; H, 3.39; N, 5.89. Found: C,
1
1
8
3
1
1
5
5.66; H, 3.32; N, 5.92.
3
-arylazirines lead to isoxazoles.
4
-Bromo-5-ethoxy-3-phenylisoxazole (4c)
Unless otherwise indicated all common commercial reagents were
used as obtained from their suppliers without further purification.
The 2H-azirine 2c (2.81 mmol) was dissolved in sulfolane (5 g), and
the reaction mixture was heated at reflux for 0.5 h. The residue ob-
tained upon removal of the solvent was purified by preparative TLC
1
H NMR spectra were recorded on a Bruker AMX 300 MHz or on
1
3
a Bruker DPX 300 MHz instrument operating at 300 MHz.
C
[with hexanes–EtOAc (9:1)]. Isoxazole 4c was isolated as a solid in
spectra were recorded on a Bruker AMX 300 MHz or on a Bruker
DPX 300 MHz instrument operating at 75.5 MHz. The solvent was
25% yield.; mp 37.8–40 °C.
1H NMR: = 1.43 (3 H, t, J = 7.1 Hz), 4.46 (2 H, q, J = 7.1 Hz),
7
13C NMR: = 14.3, 61.5, 126.9 (C-Br), 128.4, 128.6, 128.7, 128.8,
130.3, 131.1.
CDCl . NMR data are reported in parts per million downfield from
3
.48–7.52 (3 H, m, Ar-H), 8.10–8.19 (2 H, m, Ar-H).
tetramethylsilane as an internal standard ( = 0.0) and coupling con-
stants are given in Hertz. IR spectra were recorded on a Perkin El-
mer 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 (CI) with ammonia. Melting
points were recorded on a Reichert hot stage and are uncorrected.
Flash column chromatography was performed with Merck 9385 sil-
ica gel as the stationary phase. Compounds 1a–d and 2a–2d were
Isoxazole 4c underwent auto condensation to give diethyl 3,6-
diphenylpyrazine-2,4-dicarboxylate when subjected to conditions
required to obtain the mass spectrum.
+
MS (EI, 70 eV): m/z (%) = 376 [M ] (62), 347 (2), 304 (100), 231
(42), 105 (44), 77 (25).
1
1
prepared as described in the literature.
Isoxazoles from Haloazidoalkenes; General Procedure
3
-Azido-2-bromo-1,3-diphenylpropenone (1e)
1
2
The azidoalkene (1 mmol) was dissolved in PhCH (10 mL) and the
Ylide 6 (2.18 g, 4.5 mmol) was dissolved in CH Cl (50 mL) and
a soln of azidotrimethylsilane (0.71 g, 6.5 mmol) and NBS (6.5
mmol) in CH Cl (100 mL) was added. The reaction was complete
after 5 min. The residue obtained upon removal of the solvent was
purified by flash chromatography [with hexanes–EtOAc (6:1)]. Vi-
nyl azide 1e was isolated as an oil in 49% yield.
3
2
2
reaction mixture was heated under reflux for 7 h. The solvent was
evaporated and the residue was washed with cooled Et O giving the
2
2
2
isoxazole as a solid.
Methyl 4-Bromo-5-phenylisoxazole-3-carboxylate (4a)
Identified by comparison with the specimen isolated earlier.
–
1
IR (KBr): 1679, 1733, 2129 cm .
1H NMR: = 7.44–7.51 (4 H, m, Ar-H), 7.59–7.63 (2 H, m, Ar-H),
Yield: 95%.
7
.87–7.89 (2 H, m, Ar-H), 8.02–8.04 (2 H, m, Ar-H).
13C NMR:
= 118.0 (C-Br), 129.0, 129.1, 129.3, 129.7, 129.8,
31.1, 134.5, 134.6, 160.3 (C-N ), 188.4.
Methyl 4-Chloro-5-phenylisoxazole-3-carboxylate (4b)
Identified by comparison with the specimen isolated earlier.
1
3
Yield: 98%.
8
1
+
81
+
MS (EI, 70 eV): m/z (%) = 330 [M( Br)H ] (1), 329 [M( Br) ] (5),
3
79
+
79
+
28 [M( Br)H ] (1), 327 [M( Br) ] (5), 301 (21), 299 (21), 206
4-Bromo-3,5-diphenylisoxazole (4e)
(
100).
Isolated as a solid.
Yield: 95%
Isoxazoles 4a and 4b from 2-Halo-2H-azirines; General Proce-
Mp 133.9–136.3 °C (Lit.13 mp 133–135 °C).
1H NMR: = 7.26–7.53 (6 H, m, Ar-H), 7.98–8.00 (4 H, m, Ar-H).
dure
The 2H-azirine11 (2.81 mmol) was dissolved in PhCH (10 mL) and
3
the reaction mixture was heated at reflux for 5 h. The solvent was
evaporated giving the isoxazole as a solid.
Tetramethyl Pyrazine-2,3,5,6-tetracarboxylate (5)10
A soln of the dimethyl 2-azido-3-bromobut-2-enedioate (1d) (2.0
mmol) in n-heptane (10 mL) was heated under reflux for 17 h. The
residue obtained upon removal of the solvent was purified by col-
Synthesis 2002, No. 5, 605–608 ISSN 0039-7881 © Thieme Stuttgart · New York

6
08
T. M. V. D. Pinho e Melo et al.
PAPER
umn chromatography [hexanes–EtOAc (1:1)] giving the pyrazine in References
% yield; mp 180–182 °C.
2
(
1) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Rocha Gonsalves,
A. M. d’A.; Beja, A. M.; Paixão, J. A.; Silva, M. R.; Alte da
Veiga, L. J. Org. Chem. 2002, 67, 66.
–
1
IR (KBr): 1664, 1745 cm .
1H NMR: = 4.04 (12 H, s).
13C NMR:
(2) L’abbé, G. Angew. Chem., Int. Ed. Engl. 1975, 14, 775.
3) Türck, U.; Behringer, H. Chem. Ber. 1965, 98, 3020.
(4) Friedrich, K.; Thieme, H. K. Chem. Ber. 1970, 103, 1982.
= 53.8, 145.1, 163.4.
(
HRMS (CI): m/z calcd for C H N O , 313.067; found, 313.066.
1
2
13
2
8
(
5) Hassner, A.; L’abbé, G.; Miller, M. J. J. Am. Chem. Soc.
971, 93, 981.
6) L’abbé, G.; Dekerk, J.-P.; Van Stappen, P. Bull. Soc. Chim.
Belg. 1981, 90, 1073.
X-ray Structure Determination of Methyl (Z)-2-Azido-3-bro-
1
1
5
mo-3-benzoylpropenoate (1a)
Crystal Data: C H BrN O , M = 310.11; monoclinic; space group
(
11
8
3
3
r
P2 /c, a = 7.6498(9) Å, b = 5.6174(7) Å, c = 28.456(4) Å, = 90°,
1
(7) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc.
1975, 97, 4682.
(
3
=
90.534(16)°, = 90°, V = 1222.8(3) Å , Z = 4,
= 1.685
cal
mgm , = 3.365 mm–1.
–3
8) Nishiwaki, T. J. Chem. Soc., Chem. Commun. 1972, 565.
9) Lang, S. A. Jr.; Lin, Y.-i. In Comprehensive Heterocyclic
Chemistry, Vol. 6; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: New York, 1984, 127.
(
Data Collection: Measurements were made on a Rigaku AFC6S
diffractometer with graphite monochromated MoK radiation and a
1
2KW rotating anode generator. The measurements were made in
(
10) Pinho e Melo, T. M. V. D.; Rocha Gonsalves, A. M. d’A.;
the range 2.66 < 2 < 24.26°. 7358 reflections were collected of
which 1940 were unique (Rint = 0.2073).
Lopes, C. S. J.; Gilchrist, T. L. Tetrahedron Lett. 1999, 40,
789.
Structure Solution and Refinement: The structure was solved using
(
11) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Cardoso, A. L.;
Rocha Gonsalves, A. M. d’A. Tetrahedron 2001, 57, 6203.
12) Phosphorus ylide 6 was prepared using the general
procedure described in: Aitken, R. A.; Hérion, H.; Janosi,
A.; Karodia, N.; Raut, S. V.; Seth, S.; Shannon, I. J.; Smith,
F. C. J. Chem. Soc., Perkin Trans. 1 1994, 2467.
1
4
direct methods (MITHRIL ). The final cycle of full-matrix least-
squares refinement was based on 1940 observed reflections [(I > 2
(
(
I)] and 163 variable parameters with weighted and unweighted
agreement factors of R = 0.0605, R = 0.0944.
w
(
13) Hansen, J. F.; Easter, J. A.; Eckert, D. A.; Hunt, K. J.; Little,
D. A. J. Heterocycl. Chem. 1994, 31, 281.
Acknowledgement
We thank Dr R. A. Aitken (University of St. Andrews, U.K.) for
helpful discussions on the preparation of the phosphorus ylides. We
also thank Dr. Thomas McGrath (Baylor University, USA) for run-
ning some of the NMR spectra and Mr. J. F. Bickley (University of
Liverpool, UK) for determining the X-ray crystal structure of com-
pound 1a. Financial support from Chymiotechnon and Fundação
para a Ciência e a Tecnologia (POCTI 36137/99) is gratefully ack-
nowledged.
(14) Gilmore, C. J. J. Appl. Crystallogr. 1984, 17, 42.
(15) Chrystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with
Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC 181125. Copies of the data can be
obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 IEZ, UK (fax:
+44(1223)336033, email: deposit@ccdc.com.ac.uk).
Synthesis 2002, No. 5, 605–608 ISSN 0039-7881 © Thieme Stuttgart · New York