Reactivity of azafulvenium methides derived from pyrrolo[1,2-c]thiazole-2, 2-dioxides: Synthesis of functionalised pyrroles

Article abstract of DOI:10.1016/j.tetlet.2004.03.111

Extrusion of sulfur dioxide from pyrrolo[1,2-c]thiazole-2,2-dioxides led to the synthesis of functionalised pyrroles via the generation of 1-azafulvenium methides. Sealed tube reaction conditions allowed the synthesis of N- and C-vinylpyrroles whereas fro

Full text of DOI:10.1016/j.tetlet.2004.03.111

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3889–3893
Reactivity of azafulvenium methides derived from pyrrolo-
[1,2-c]thiazole-2,2-dioxides: synthesis of functionalised pyrroles
a
a
Teresa M. V. D. Pinho e Melo,a, Maria I. L. Soares, Antonio M. d’A. Rocha Gonsalves
*
ꢀ
and Hamish McNabb
a
ꢀ
Departamento de Quımica, Universidade de Coimbra, 3004-535 Coimbra, Portugal
bSchool ofChemistry, The University ofEdinburgh, West Mains Road, Edinburgh, Scotland EH9 3JJ, UK
Received 19 February 2004; revised 19 March 2004; accepted 19 March 2004
Abstract—Extrusion of sulfur dioxide from pyrrolo[1,2-c]thiazole-2,2-dioxides led to the synthesis of functionalised pyrroles via the
generation of 1-azafulvenium methides. Sealed tube reaction conditions allowed the synthesis of N- and C-vinylpyrroles whereas
from FVP methyl 1,3-dimethyl-5-oxo-5H-pyrrolizine-2-carboxylate and 4-oxo-1,4-dihydro-1-aza-benzo[f]azulene-3-carboxylates
were obtained. These last compounds could also be obtained from the FVP of the N- and C-vinylpyrroles.
ꢀ 2004 Elsevier Ltd. All rights reserved.
It has been reported the generation of 1-azafulvenium
methides (1–4) by the thermal extrusion of sulfur diox-
ide from pyrrolo[1,2-c]thiazole-2,2-dioxides.1 These
extended dipolar systems 1–3 undergo sigmatropic
[1,8]H shifts giving vinylpyrroles and the acyl derivatives
4 electrocyclise to give pyrrolo[1,2-c]-[1,3]oxazines.
Having access to a broad range of pyrrolo[1,2-c]thiaz-
oles2 we decided to explore the generation of new aza-
fulvenium methides in order to get further knowledge on
the reactivity of these transient 8p 1,7-dipoles.
As a first objective we decided to prepare 3,5-diphenyl-
1H-pyrrolo[1,2-c]thiazole-2,2-dioxide 6a from 5a2d by
oxidation with MCPBA and promote its thermolysis
(Scheme 1). We found that the extrusion of SO2 from
pyrrolo[1,2-c]thiazole-2,2-dioxide 6a could be carried out
in a sealed tube leading to styryl-1H-pyrrole 9a. The best
result was obtained by heating at 220 ꢁC for 1.5 h a
solution of 6a in sulfolane giving 9a in 80% yield (Table 1).
A similar result was obtained starting from 5-methyl-3-
phenyl-1H-pyrrolo[1,2-c]thiazole-2,2-dioxide 6b and the
corresponding styryl-1H-pyrrole 9b3 could be obtained
in 54% yield (Scheme 1 and Table 1). Storr and
co-workers1b have described attempts of thermal extru-
sion of SO2 from 6b although no products of this reac-
tion were reported.
CO Me
2
1
R
CO Me
2
2
R
N
Me
3
R
1
2
3
The formation of styryl-1H-pyrroles 9 can be explained
considering the generation of azafulvenium methides 7
followed by an 1,7-electrocyclic reaction giving 8, which
rearrange to the final products. Attempts were made to
trap 7a by promoting the sealed tube thermolysis in the
presence of DMAD and also in the presence of
bis(trimethylsilyl)acetylene although no evidence was
obtained for the formation of adducts and the only
product was styryl-1H-pyrrole 9a. Nevertheless, the
synthesis of pyrroles 9 is a strong evidence of the gen-
eration of the new azafulvenium methides 7.
1 R = R = H; R = CH
3
1
2
3
2 R = H; R = CH ; R = H
3
1
2
3
3 R = R = CH ; R = H
3
1
2
3
4 R = H; R = COR; R = H
Keywords: 1-Azafulvenium methides; N- and C-Vinylpyrroles; 1,3-Di-
methyl-5-oxo-5H-pyrrolizine-2-carboxylate; 1-Aza-benzo[f]azulene-3-
carboxylate.
Encouraged by the preceding results we decided to look
more carefully into the generation of azafulvenium
* Corresponding author. Tel.: +351-239-852080; fax: +351-239-8260-
68; e-mail: tmelo@ci.uc.pt
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.111

3890
T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 45 (2004) 3889–3893
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Sealed Tube
S
N
N
O2S
N
MCPBA
∆
R
R
R
- SO
Ph
2
Ph
Ph
R = Ph
R = Me
R = Ph
R = Me
5a
5b
6a
6b
R = Ph
R = Me
7a
7b
CO2Me
MeO2C
CO2Me
R
H
CO2Me
N
N
H
Ph
R
Ph
80%
54%
R = Ph
R = Me
8a
8b
9a
9b
R = Ph
R = Me
Scheme 1.
46% yield, which was identified as being methyl 1,3-di-
methyl-5-oxo-5H-pyrrolizine-2-carboxylate 124 (Scheme
2).
Table 1. Sealed tube reactions using sulfolane as solvent
Starting compound
Reaction conditions
Product
6a
6a
6a
6b
6b
6b
11
11
11
215 ꢁC, 3 h
9a, 5%
190–195 ꢁC, 3 h
220 ꢁC, 1.5 h
185–195 ꢁC, 3 h
240 ꢁC, 3 h
220 ꢁC, 1.5 h
260 ꢁC, 3 h
9a, 20%
9a, 80%
9b, 8%
1H and 13C NMR data of pyrrolizinone 12 is collected in
Table 2.5 The 13C NMR spectra with broad band proton
decoupling and with proton off-resonance decoupling
(1JCH) of compound 12 allowed the assignment of sig-
nals corresponding to the carbons double bond with
chemical shifts of 119.0 (C-6) and 135.9 (C-7) ppm. This
assignment was also supported by a two-dimensional
HMQC spectrum (750 MHz). The fully coupled 13C
NMR spectrum of compound 12 was also recorded
leading to the assignment of signals corresponding to
the carbonyl carbons: at 164.3 ppm one quartet is
observed (C-9, 3J ¼ 3:8 Hz) and the carbonyl carbon C-
5 is observed at 165.6 ppm as a double doublet
9b, 31%
9b, 54%
11, 17%
11, 8%
215 ꢁC, 3 h
260 ꢁC, 2 h
11, 61%
methide 1. It has been reported that on FVP (700 ꢁC/
1.3 · 10ꢀ3 mbar) sulfone 10 leads to vinylpyrrole 11 via
an allowed, suprafacial [1,8]H shift in the 8p 1,7-dipolar
system 1.1 We found that the same vinylpyrrole (11)
could be obtained in 61% yield carrying out the reaction
in a sealed tube allowing us to conclude that sulfone 10
extrudes SO2 without the need of FVP conditions
(Scheme 2 and Table 1).
3
(2J ¼ 7:7 Hz and J ¼ 12:1 Hz). The fully coupled 13C
NMR spectrum with selective proton irradiation at
d ¼ 7:12 ppm (the chemical shift of H-7) was recorded.
This converted the signal at 165.6 (C-5) into a doublet
2
with coupling constant of J ¼ 7:7 Hz thus proving that
The flash vacuum pyrolysis of sulfone 10 was also
studied. Interestingly our FVP conditions (700 ꢁC/
8 · 10ꢀ2 mbar) led to a different outcome than the pre-
viously reported result.1 One product was obtained in
H-7 was coupled with C-5. On the other hand, the signal
at 135.9 ppm shown as a double doublet (2J ¼ 3:3 Hz
and 1J ¼ 175:3 Hz) in the fully coupled 13C NMR
spectrum becomes a doublet (2J ¼ 3:3 Hz) on irradia-
CO2Me
CO2Me
MeO2C
Me
CO2Me
Me
∆, Sealed Tube
61%
H
N
N
- SO
2
H
Me
H
CO2Me
CO2Me
11
1
700 C
4x10 mbar
˚
O2S
N
79%
-2
Me
Me
10
Me
MeO2C
Me
CO2Me
Me
700 C
8x10 mbar
˚
-2
46%
MeO C
2
N
N
- SO
2
O
Me
12
11
Scheme 2.

T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 45 (2004) 3889–3893
3891
Table 2. 1H NMR and 13C NMR (with proton off-resonance decou-
pling) data for methyl 1,3-dimethyl-5-oxo-5H-pyrrolizine-2-carboxyl-
ate 12
When the FVP of 10 was carried out at 700 ꢁC/
4 · 10ꢀ2 mbar a mixture of 12 (44%) and 11 (27%) was
obtained. This suggested that the lower pressure reduces
the period of time that the substance to be pyrolysed
remains in the hot zone not allowing the complete
conversion of 10 into compound 12. The result of the
sulfone 10 FVP (700 ꢁC/1.3 · 10ꢀ3 mbar) described by
Storr and co-workers1 is also in agreement with this
observation. Thus, vinylpyrrole 11 must in fact be an
intermediate in the formation of methyl 1,3-dimethyl-5-
oxo-5H-pyrrolizine-2-carboxylate 12 from sulfone 10.
8
Me
1
7
7a
9
10
2
6
MeO C
2
N
5
3
4
11
O
Me
C
1H NMR
13C NMR
C-8
C-11
C-10
C-2
C-6
C-1
C-7a
C-7
C-3
C-9
C-5
2.11 (3H, s)
2.57 (3H, s)
3.73 (3H, s)
––
10.9 (q, J ¼ 129:2 Hz)
11.2 (q, J ¼ 130:7 Hz)
49.9 (q, J ¼ 147:4 Hz)
117.1 (s)
In order to corroborate this mechanistic interpretation
we performed the FVP of dimethyl 2,5-dimethyl-1-vinyl-
1H-pyrrole-3,4-dicarboxylate 11 (Scheme 2). In fact, the
flash vacuum pyrolysis carried out at 700 ꢁC/
4 · 10ꢀ2 mbar led to the efficient synthesis of compound
12 (79%).
5.58 (1H, d, J ¼ 6:0 Hz)
119.0 (d, J ¼ 181:9 Hz)
123.7 (s)
131.4 (s)
––
––
7.12 (1H, J ¼ 6:0 Hz)
135.9 (d, J ¼ 174:7 Hz)
141.3 (s)
164.3 (s)
––
––
––
165.6 (s)
The formation of methyl 1,3-dimethyl-5-oxo-5H-pyr-
rolizine-2-carboxylate 12 from N-vinylpyrroles 11 can be
rationalised as outlined in Scheme 3. It is known that
2-substituted 3-(pyrrol-2-yl)propionate methyl esters
undergo concerted elimination of methanol on FVP
to give pyrrol-2-ylideneketene intermediates, which
give pyrrolizinones by electrocyclisation.5b;6 Thus methyl
3-(4-methoxycarbonyl-3,5-dimethylpyrrol-2-yl)propionate
methyl 16 must be an intermediate in the synthesis of 12.
In our case we envisage that pyrrole 16 is formed from
11 through a sequence of sigmatropic shifts.
tion at d ¼ 7:12 ppm, which confirms the assignment of
the carbon C-7. In the HMBC spectrum of compound
12, H-7 show connectivity with C-6, C-5, C-7a and H-6
show connectivity with C-7, C-5, C-7a (Fig. 1). The
signals for H-11 show connectivity with C-2, C-1, C-7a,
C-3, C-9 whereas H-8 correlates with C-2, C-1, C-7a,
C-7, C-3, C-9. On the other hand, the protons of the
methyl ester group show connectivity with C-2. This
NMR study allowed us to establish unambiguously the
structure of methyl 1,3-dimethyl-5-oxo-5H-pyrrolizine-
2-carboxylate 12. It is noteworthy that this compound
has an intense orange colour typical of pyrrolizinone
derivatives.5b
The FVP of compound 11 was also performed using
milder reaction conditions (400 ꢁC and 550 ꢁC/
4 · 10ꢀ2 mbar) in attempting to intercept intermediates
of the synthesis of 12. However, only sublimation of
N-vinylpyrroles 11 occurred.
5-Methyl-3-phenyl-1H-pyrrolo[1,2-c]thiazole-2,2-diox-
ide 6b is converted into methyl 2-methyl-4-oxo-1,4-di-
hydro-1-aza-benzo[f]azulene-3-carboxylate 187 on flash
vacuum pyrolysis (Scheme 4). Under these reaction
conditions styryl-1H-pyrrole 9b is formed and converted
into a pyrrole fused to a benzocyclohepten-5-one ring
system. This was confirmed by promoting the FVP of
styryl-1H-pyrrole 9b, which also gave compound 18
(31%).
H
O
Me
Me
Me
Me
H
MeO C
MeO C
2
2
N
N
O
Figure 1. Main connectivity observed in the HMBC spectrum
(750 MHz) of compound 12.
Me
Me
MeO2C
Me
CO2Me
Me
MeO2C
Me
CO2Me
Me
MeO2C
Me
CO Me
CO2Me
2
MeO C
2
N
N
N
N
15
Me
Me
13
14
11
Me
Me
Me
CO Me
2
- MeOH
MeO C
2
MeO C
2
MeO C
NH
N
O
2
N
Me
O
Me
12
16
17
Scheme 3.

3892
T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 45 (2004) 3889–3893
CO2Me
CO2Me
O
MeO2C
Ph
CO2Me
Me
CO2Me
Me
700 C
700 C
˚
˚
O2S
N
-2
-2
N
H
4x10 mbar
4x10 mbar
Me
N
Ph
6b
H
18, 22% (from 8b)
18, 31% (from 9b)
9b
O
H
O
O
CO2Me
Me
CO2Me
Me
CO2Me
[1,5]H
Me
FVP
- MeOH
9b
N
N
N
H
19
20
21
[1,5]H
18
Scheme 4.
The most likely mechanism for the formation of 18 is
shown in Scheme 4. It has been reported that methyl
pyrrole-2-carboxylate undergoes elimination of metha-
nol to produce pyrrol-2-ylketene under FVP condi-
tions.8 In a similar manner styryl-1H-pyrrole 9b
generates pyrrol-3-ylketene 19 on eliminating methanol.
Electrocyclisation of 19 followed by two sigmatropic H-
shifts gives compound 18.
References and notes
1. (a) Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty,
P.; Crew, A. P. A. Chem. Commun. 2000, 675–676; (b)
Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty, P.
J. Chem. Soc., Perkin Trans. 1 2001, 1795–1806.
2. (a) Pinho e Melo, T. M. V. D.; Barbosa, D. M.; Ramos,
P. J. R. S.; Rocha Gonsalves, A. M. d’A.; Gilchrist, T. L.;
~
Beja, A. M.; Paixao, J. A.; Silva, M. R.; Alte da Veiga, L.
J. Chem. Soc., Perkin Trans. 1 1999, 1219–1223; (b) Pinho
Compound 6a and 9a showed similar chemical behav-
iour when compared with 6b and 9b, respectively,
and the corresponding 4-oxo-1,4-dihydro-1-aza-
benzo[f]azulene-3-carboxylate could be obtained on
FVP although in low yield.
e Melo, T. M. V. D.; Soares, M. I. L.; Barbosa, D. M.;
~
Rocha Gonsalves, A. M. d’A.; Paixao, J. A.; Beja, A. M.;
Silva, M. R.; Alte da Veiga, L. Tetrahedron 2000, 56,
3419–3424; (c) Pinho e Melo, T. M. V. D.; Soares, M. I.
~
L.; Rocha Gonsalves, A. M. d’A.; Paixao, J. A.; Beja,
A. M.; Silva, M. R.; Alte da Veiga, L.; Costa Pessoa, J.
J. Org. Chem. 2002, 67, 4045–4054; (d) Pinho e Melo, T.
M. V. D.; Gomes, C. S. B.; Rocha Gonsalves, A. M. d’A.;
~
Paixao, J. A.; Beja, A. M.; Ramos Silva, M.; Alte da
Veiga, L. Tetrahedron 2002, 58, 5093–5102.
In conclusion, we have shown that 1-azafulvenium
methides, generated by the thermal extrusion of sulfur
dioxide from pyrrolo[1,2-c]thiazole-2,2-dioxides, are
valuable intermediates for the synthesis of heterocylic
compounds. Sealed tube reaction conditions allow the
synthesis of N-(11) and C-vinylpyrroles (9) whereas FVP
conditions lead to heterocycles where another ring
system is annulated to pyrrole namely 1,3-dimethyl-5-
oxo-5H-pyrrolizine-2-carboxylate (12) and 2-methyl-4-
oxo-1,4-dihydro-1-aza-benzo[f ]azulene-3-carboxylate
(13). The efficient synthesis of 1,3-dimethyl-5-oxo-5H-
pyrrolizine-2-carboxylate (12) was also achieved via
FVP of N-vinylpyrrole 11 and the styryl-1H-pyrroles 9
FVP gave 4-oxo-1,4-dihydro-1-aza-benzo[f]azulene-3-
carboxylates.
3. Dimethyl 2-methyl-5-styryl-1H-pyrrole-3,4-dicarboxylate
9b. 3-Methyl-5-phenyl-1H-pyrrolo[1,2-c]thiazole-2,2-diox-
ide 6b (0.34 g, 0.93 mmol) was dissolved in sulfolane
(2 mL) in a glass pyrolysis tube, which was cooled in liquid
nitrogen, evacuated, sealed and heated at 220 ꢁC for 1.5 h.
After cooling to room temperature the tube was opened,
the reaction mixture diluted with dichloromethane and
washed with water. Purification by flash chromatography
[SiO2, ethyl-acetate–hexane (1:2) then ethyl-acetate–hex-
ane (1:1)] gave 9b as a solid (54%). Mp 151.9–153.6.0 ꢁC
(from ethyl ether). dH (CDCl3, 300 MHz) 2.40 (3H, s, Me),
3.80 (3H, s, CO2Me), 3.85 (3H, s, CO2Me), 6.77 (1H, d,
J ¼ 16:8 Hz), 7.32 (1H, d, J ¼ 16:8 Hz), 7.19–7.38 (5H, m,
Ar–H); dC (CDCl3, 75.5 MHz) 12.6, 51.5, 51.8, 113.0,
114.2, 116.3, 126.4, 127.8, 127.9, 128.6, 132.3, 135.7, 136.5,
165.7, 165.9; m=z (EI) 299 (Mþ, 100%), 267 (53), 236 (39),
209 (25), 180 (51). Anal. Calcd for C17H17NO3: C, 68.22;
H, 5.72; N, 4.68. Found: C, 68.60; H, 6.07; N, 4.79%.
4. Methyl 1,3-dimethyl-5-oxo-5H-pyrrolizine-2-carboxylate
12. Pyrolysis of 3,5-dimethyl-1H-pyrrolo[1,2-c]thiazole-
2,2-dioxide 10 (0.20 g, 0.67 mmol) at 700 ꢁC/8 · 10ꢀ2 mbar
onto a surface cooled at ꢀ196 ꢁC over a period of 2 h
20 min gave a yellowish pyrolysate. (The rate of volatil-
isation of the starting material was controlled by the use of
a Kugelrohr oven, which heated the sample at 200 ꢁC.)
After cooling to room temperature the pyrolysate was
Acknowledgements
~
We thank Prof. A. Mourino and Dr. M. M. Pastor
(University of Santiago de Compostela) and Dr. Rui M.
Brito and J. Rui Rodrigues (University of Coimbra) for
the NMR studies. We also thank Chymiotechnon and
Fundaßc~ao para a Ci^encia e a Tecnologia (POCTI/36137/
QUI/2000 and SFRH/BD/9123/2002) for financial sup-
port.

T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 45 (2004) 3889–3893
3893
removed from the cold finger with dichloromethane. The
solvent was removed in vacuo and the residue purified by
flash chromatography [SiO2, ethyl-acetate–hexane (1:1)] to
give 12 as an orange solid (46%). Mp 116.0–118.0 ꢁC (from
ethyl ether–hexane). m (KBr) 1614, 1695 and 1729 cmꢀ1; dH
(CDCl3, 500 MHz) 2.11 (3H, s, H-8), 2.57 (3H, s, H-11),
3.73 (3H, s, H-10), 5.58 (1H, d, J ¼ 6:0 Hz, H-6), 7.12 (1H,
d, J ¼ 6 Hz, H-7); dC (CDCl3, 125.7 MHz, off-resonance
decoupling) 10.9 (q, J ¼ 129:2 Hz, C-8), 11.2 (q,
J ¼ 130:7 Hz, C-11), 49.9 (q, J ¼ 147:4 Hz, C-10), 117.1
(s, C-2), 119.0 (d, J ¼ 181:9 Hz, C-6), 123.7 (s, C-1), 131.4
(s, C-7a), 135.9 (d, J ¼ 174:7 Hz, C-7), 141.3 (s, C-3),
164.3 (s, C-9), 165.6 (s, C-5); m=z (EI) 205 (Mþ, 100%), 190
(24), 174 (69), 162 (16), 145 (45) and 117 (16).
Comer, M. C.; Derbyshire, P. A.; Despinoy, X. L. M.;
McNab, H.; Morrison, R.; Sommerville, C. C.; Thornley,
C. J. Chem. Soc., Perkin Trans. 1 1997, 2195–2202.
6. McNab, H.; Parson, S.; Stevenson, E. J. Chem. Soc.,
Perkin Trans. 1 1999, 2047–2048.
7. Methyl
2-methyl-4-oxo-1,4-dihydro-1-aza-benzo[f]azul-
ene-3-carboxylate 18 obtained as a yellow solid. Mp
261.0–263.0 ꢁC (from ethyl ether–hexane). dH 2.77 (3H, s,
Me), 3.95 (3H, s, CO2Me), 7.36 (1H, d, J ¼ 12:0 Hz), 7.75–
7.76 (1H, m, Ar–H), 7.77–7.80 (1H, m, Ar–H), 7.84 (1H,
dd, J ¼ 1:4 and 7.8 Hz, Ar–H), 8.27 (1H, d, J ¼ 12:0 Hz),
9.96 (1H, dd, J ¼ 1:5 and 8.0 Hz, Ar–H); m=z (EI) 267
(Mþ, 100%), 252 (11), 236 (64), 178 (12), 152 (37) and 76
(16). Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N,
5.24. Found: C, 72.27; H, 5.52; N, 5.28.
5. NMR data in agreement with the NMR spectra reported
for other pyrrolizinones in: (a) McNab, H. J. Chem. Soc.,
Perkin Trans. 1 1987, 657–659; (b) Campbell, S. E.;
8. Gross, G.; Wentrup, C. J. Chem. Soc., Perkin Trans. 1
1982, 360–361.