New chemistry of diazafulvenium methides: One way to pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2005.11.094

Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in [8π+2π] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl- diazafulvenium, generated under flash vacuum pyrolysis r

Full text of DOI:10.1016/j.tetlet.2005.11.094

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 791–794
New chemistry of diazafulvenium methides: one way to pyrazoles
*
´
Teresa M. V. D. Pinho e Melo, Maria I. L. Soares and Antonio M. dÕA. Rocha Gonsalves
Departamento de Quı´mica, Universidade de Coimbra, 3004-535 Coimbra, Portugal
Received 23 September 2005; revised 15 November 2005; accepted 18 November 2005
Available online 5 December 2005
Abstract—Diazafulvenium methides generated from the solution pyrolysis of pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides participate in
[8p+2p] cycloadditions giving pyrazolo[1,5-a]pyridine derivatives. 1-Methyl-diazafulvenium, generated under flash vacuum pyroly-
sis reaction conditions, undergoes an intramolecular sigmatropic [1,8]H shift giving 1-vinyl-1H-pyrazoles.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The study of pericyclic reactions of extended dipoles
(with more than 4p electrons) is an almost unexplored
research area. However, Storr and co-workers explored
the reactivity of pyrrolo[1,2-c]thiazole-2,2-dioxides
(1) and pyrazolo[1,5-c][1,3]thiazole-2,2-dioxides (3) and
proved that they can be considered masked aza- and di-
azafulvenium methides (2 and 4).1 Earlier, Padwa and co-
workers described unsuccessful attempts to extrude SO2
from pyrrolo[1,2-c]thiazole-2,2-dioxides for the genera-
tion of an azafulvenium methide, both thermally
(300 ꢁC) and photochemically.2 Azafulvenium methides
can be considered as Ôhigher-orderÕ azomethine ylides
and, in principle, can act as 4p 1,3-dipoles or as 8p
1,7-dipoles.
Storr and co-workers found that the generation of 1-
azafulvenium methides (2a–d) by the thermal extrusion
of sulfur dioxide from pyrrolo[1,2-c]thiazole-2,2-diox-
ides 1 could be achieved under flash vacuum pyrolysis
(FVP) reaction conditions. They described the first evi-
dence for trapping of transient 1-azafulvenium methide
systems in pericyclic reactions. These extended dipolar
systems 2a–c undergo sigmatropic [1,8]H shifts giving
vinylpyrroles and the acyl derivatives 2d electrocyclise
to give pyrrolo[1,2-c][1,3]oxazines.1
It was also reported that the SO2 extrusion of the pyra-
zole derivative 33 occurs more easily than from the anal-
ogous pyrrolo sulfone. The authors reported that the
CO Me
2
CO Me
CO Me
2
2
1
1
R
R
CO Me
2
CO Me
2
2
CO Me
R
2
2
R
N
N
O S
N
2
2
R
Me
Me
1
3
3
R
R
R
1
2
3
1
2
1
2a R = R = H; R = CH
2e R = Ph; R = CH
3
3
1
2
3
1
2
2b R = H; R = CH ; R = H
2f R = CH Ph; R = CH
3
2 3
1
2
3
1
2
2c R = R = CH ; R = H
2g R = CH CH ; R = CH
3
3
2
3
1
2
3
1
2
2d R = H; R = COR; R = H
2h R = CH(CH ) ; R = CH
3 2
3
1
2
2i R = C(CH ) ; R = CH
3 3
3
1
2
2k R = CH ; R = Ph
3
CO Me
2
1
2
CO Me
2
2l R = R = Ph
1
2
2m R = CH ; R = H
CO Me
2
CO Me
3
2
1
2
2n R = Ph; R = H
N N
O S
2
N N
H C
2
4
3
Keywords: Diazafulvenium methides; Vinyl-1H-pyrazoles; Pyrazolo[1,5-a]pyridines; Pyrazolo[1,5-a]pyrrolo[3,4-c]pyridine; [8p+2p] Cycloaddition;
Sigmatropic shift.
*
Corresponding author. Tel.: +351 239 854475; fax: +351 239 826068; e-mail: tmelo@ci.uc.pt
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.094

792
T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 47 (2006) 791–794
1,2-diazafulvenium methide 4 did not react with N-
phenylmaleimide or dimethyl acetylenedicarboxylate
but could be intercepted in 8p+2p cycloaddition with
silylated acetylenes giving adducts resulting from the
addition across the 1,7-position.1
pyrazolo[1,5-a]pyridine-2,3-dicarboxylate 6 was obtained
in 54% yield together with the formation of the aroma-
tised derivative 7 in 7% yield. However, the dipolar
system 4 also participates in the cycloaddition with N-
phenylmaleimide giving the corresponding cycloadduct
55 in 87% yield (Scheme 1). This result contradicts the
reported experimental observation although the reactiv-
ity of this 1,7-dipole 4 towards [8p+2p] cycloaddition,
characterised by the participation in the reaction with
both electron-rich and electron-deficient dipolarophiles,
is in agreement with the reported MO calculations for
the unsubstituted diazafulvenium methide.1
We have further studied the reactivity of azafulvenium
methides including the reactivity of a range of new
derivatives 2e–n and showed that these transient 8p
1,7-dipole systems are interesting intermediates for the
synthesis of functionalised heterocyclic compounds.
The intramolecular trapping of the 1,7-dipoles in pericy-
clic reactions, namely sigmatropic [1,8]H shifts and 1,7-
electrocyclisations, allowed the synthesis of N-vinyl- and
C-vinylpyrroles, which, under flash vacuum pyrolysis
conditions, are converted into heterocycles where
another ring system is annulated to pyrrole.4
We decided to explore the possibility of generating new
diazafulvenium methides systems and study their reac-
tivity in the absence of dipolarophiles. 3-Methyl-pyra-
zolo[1,5-c][1,3]thiazole-2,2-dioxide 12 was prepared as
outlined in Scheme 2. Sydnone 10 is a stable mesoionic
species, which can be isolated and undergoes 1,3-dipolar
cycloaddition with DMAD to give pyrazolo[1,5-c]-
[1,3]thiazole 11. The oxidation of 11 with MCPBA gives
sulfone 12 (Scheme 2).
1,2-Diazafulvenium methidesÕ chemistry has also
attracted our attention and our preliminary results are
described in this letter. We prepared the 4H-pyrazolo-
[1,5-c][1,3]thiazole-5,5-dioxide 31,3 and observed that it
undergoes SO2 extrusion in the solution to give 1,2-di-
azafulvenium methide 4, which could be trapped by
reacting with bis(trimethylsilyl)acetylene, confirming
the result reported by Storr and co-workers.1 In our
hands, dimethyl 5,6-bis(trimethylsilyl)-4,7-dihydro-
Carrying out flash vacuum pyrolysis of sulfone 12 at
500 ꢁC, we obtained 1-vinyl-1H-pyrazole 146 selectively.
When the FVP was carried out at 700 ꢁC the same 5-
methyl-1-vinyl-1H-pyrazole 14 was obtained, together
MeO C
CO Me
2
MeO C
2
CO Me
2
MeO C
CO Me
2
2
1,2,4-trichlorobenzene
2
∆, 7 h
∆
N
N
N
N
N
N
O
O S
2
CH
2
O
O
N
PhN
Ph
4
3
5 87%
O
1,2,4-trichlorobenzene
∆, 3 h
MeO C
2
CO Me
2
MeO C
2
CO Me
2
Me Si
3
SiMe
3
N
N
N
N
Me Si
Me Si
3
3
Me Si
Me Si
3
3
6 54%
7 7%
Scheme 1.
O
CO H
CO H
2
2
O
N N
58%
43%
S
S
NH
Me
S
N
NO
NaNO
TFAA
Et O
2
2
HCl
Me
10
Me
9
8
CO Me
2
MeO C
CO Me
2
2
CO Me
2
60%
DMAD
60%
N
S
N N
N
MCPBA
O S
2
Me
Me
11
12
Scheme 2.

T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 47 (2006) 791–794
793
MeO C
2
CO Me
2
CO Me
2
MeO C
2
CO Me
2
CO Me
2
Sigmatropic [1,8]H
(500 oC)
N
H
H
N
N
Me
N N
FVP
N
O S
2
H
Me
(700 oC)
12
13
14 51%
MeO C
CO Me
2
2
MeO C
2
CO Me
2
N
N
Me
Me
N
N
14 59%
15 4%
Scheme 3.
with 1-vinyl-1H-pyrazole 15. The FVP of 5-methyl-1-
vinyl-1H-pyrazole 14 led only to sublimation of this
compound and to the formation of a small percen-
tage of 3-methyl-1-vinyl-1H-pyrazole derivative 15
(Scheme 3).
oxylate giving the corresponding adducts resulting from
the addition across the 1,7-positions in high yields
(Scheme 4). An attempt to react 13 with bis(trimethyl-
silyl)acetylene led only to the synthesis of 1-vinyl-1H-
pyrazole 14 in 16% yield.
The mechanism of conversion of pyrazolo[1,5-c][1,3]thi-
azole-2,2-dioxides into 1-vinyl-1H-pyrazole involves the
generation of diazafulvenium methide 13 which is
trapped in an allowed, suprafacial [1,8]H sigmatropic
shift. This reactivity, observed for the first time for the
diazafulvenium methide derivatives, is similar to the
one shown by azafulvenium methides 2a,f–k and 2m.4
However, 5-methyl-1-vinyl-1H-pyrazole 14 proved to
be more stable under FVP reaction conditions than
the N-vinylpyrroles obtained previously from azafulve-
nium methides. In fact, 5-methyl-1-vinyl-1H-pyrazole
14 was recovered almost unchanged on FVP whereas
the N-vinylpyrroles are converted into 5-oxo-5H-
pyrrolizines.
In conclusion, in this letter, we describe new diazafulve-
nium methidesÕ chemistry. These intermediates can be
generated via thermal sulfur dioxide extrusion of pyr-
azolo[1,5-c][1,3]thiazole-2,2-dioxides.
The SO2 extrusion of pyrazolo[1,5-c][1,3]thiazole-2,2-
dioxides occurs more easily than from the analogous
pyrrolo sulfones and can be carried out in refluxing
1,2,4-trichlorobenzene. The diazafulvenium methides,
generated this way, can be intercepted in 8p+2p cyclo-
additions giving adducts resulting from the addition
across the 1,7-position. This type of reactions is an inter-
esting approach to the synthesis of pyrazolo[1,5-a]pyri-
dine derivatives, a class of compounds with potential
interest as antiherpetics.7 In the absence of dipolaro-
philes, the 1-methyl-diazafulvenium methide, generated
under FVP reaction conditions, undergoes an intra-
molecular sigmatropic [1,8]H shift giving 1-vinyl-1H-
pyrazoles.
3-Methyl-pyrazolo[1,5-c][1,3]thiazole-2,2-dioxide 12 also
undergoes SO2 extrusion in the solution to give 13,
which can be intercepted in 8p+2p cycloadditions
with N-phenylmaleimide and dimethyl acetylenedicarb-
CO Me
2
MeO C
CO Me
2
2
CO Me
2
N
N
1,2,4-trichlorobenzene
∆, 3 h
N
N
O S
2
Me
Me
13
12
Ph
N
O
O
MeO C
CO Me
2
2
MeO C
CO Me
2
2
MeO C
CO Me
2
2
MeO C
CO Me
2
2
N
N
N
N
N
N
O
Me
MeO C
2
MeO C
2
Me
PhN
Me
MeO C
2
MeO C
O
2
16a
17 94%
16b
16a,16b 85% (40:60)
Scheme 4.

794
T. M. V. D. Pinho e Melo et al. / Tetrahedron Letters 47 (2006) 791–794
1385, 1497 and 1715 cmÀ1; dH (CDCl3, 300 MHz): 3.20
Acknowledgements
(1H, dd, J = 7.2 and 16.4 Hz), 3.58–3.70 (2H, m), 3.85 (3H,
s), 3.93 (3H, s), 3.93–4.00 (1H, m), 4.31 (1H, dd, J = 5.7
and 13.9 Hz), 4.90 (1H, dd, J = 2.5 and 13.9 Hz), 7.07–7.10
(2H, m, Ar–H), 7.37–7.44 (3H, m, Ar–H); dC (CDCl3,
75.5 MHz): 22.5, 37.1, 40.4, 46.1, 51.9, 52.6, 112.0, 126.1,
129.0, 129.2, 131.0, 141.5, 143.3, 162.0, 174.9, 176.0; m/z
(EI) 383 (M+, 28%), 351 (100), 204 (61), 176 (12), 147 (7),
119 (8) and 77 (7). Anal. Calcd for C19H17N3O6: C, 59.53;
H, 4.47; N, 10.96. Found: C, 59.49; H, 4.64; N, 10.84.
We thank Chymiotechnon and Fundac¸ao para a Cieˆncia
˜
e a Tecnologia (POCI/QUI/55584/2004 and SFRH/BD/
9123/2002), for financial support.
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)
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nan, M. K.; Wong, G. S. K. J. Org. Chem. 1989, 54, 644–
652.
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6. Dimethyl
5-methyl-1-vinyl-1H-pyrazole-3,4-dicarboxylate
14. Pyrolysis of dimethyl 3-methyl-1H,3H-pyrazolo[1,5-c]-
[1,3]thiazole-6,7-dicarboxylate-2,2-dioxide 12 (0.21 g, 0.73
mmol) at 500 ꢁC/2 · 10À2 mbar onto a surface cooled at
À196 ꢁC over a period of 1 h gave a colourless pyro-
lysate. [The rate of volatilisation of the starting material
was controlled by the use of a Kugelrohr oven which heated
the sample at 100–250 ꢁC.] After cooling to room temper-
ature the pyrolysate was removed from the cold finger with
dichloromethane and the solvent was removed in vacuo.
The crude product was purified by flash chromatography
[ethyl acetate–hexane (1:2), then ethyl acetate–hexane (1:1)]
to give 14 as a white solid (51%). Mp 46.3–48.0 ꢁC (from
diethyl ether–hexane). m (KBr) 1088, 1269, 1320, 1648, 1719
and 1740 cmÀ1; dH (CDCl3, 300 MHz): 2.56 (3H, s), 3.85
(3H, s), 3.95 (3H, s), 5.14 (1H, dd, J = 0.9 and 8.8 Hz), 5.95
(1H, dd, J = 0.9 and 15.2 Hz), 6.99 (1H, dd, J = 8.8 and
15.2 Hz); dC (CDCl3, 75.5 MHz): 10.3, 51.7, 52.5, 106.4,
112.6, 128.2, 142.9, 144.4, 162.8, 163.0; MS (EI) m/z 224
(M+, 28%), 193 (100), 163 (27), 133 (12) and 68 (9). Anal.
Calcd for C10H12N2O4: C, 53.57; H, 5.39; N, 12.49. Found:
C, 53.75; H, 5.28; N, 12.39.
L.; Rocha Gonsalves, A. M. dÕA.; Paixao, J. A.; Matos
˜
Beja, A.; Ramos Silva, M. J. Org. Chem. 2005, 70, 6629–
6638.
5. Dimethyl 5,7-dioxo-6-phenyl-4a,5,6,7,7a,8-hexahydro-4H-
pyrazolo[1,5-a]pyrrolo[3,4-d]pyridine-2,3-dicarboxylate 5.
A suspension of dimethyl 5,5-dioxo-4H-pyrazolo[1,5-c]-
[1,3]thiazole-2,3-dicarboxylate-2,2-dioxide 3 (0.16 g, 0.58
mmol) and N-phenylmaleimide (2 equiv, 0.20 g, 1.16 mmol)
in 1,2,4-trichlorobenzene (1.8 mL) was heated at reflux
under dry nitrogen for 7 h. After cooling to room temper-
ature, the mixture was purified by flash chromatography
[hexane] to remove 1,2,4-trichlorobenzene followed by
elution with ethyl acetate–hexane (2:1), then ethyl ace-
tate–hexane (4:1) to give 5 as a white solid (87%). Mp
144.8–146.7 ꢁC (from diethyl ether). m (KBr) 1150, 1221,
7. Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S.
H.; Samano, V. A.; Ray, J. A.; Freeman, G. A.; Boyd, F.
L., Jr.; Sexton, C. J.; Selleseth, D. W.; Creech, K. L.;
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