Chemistry of diazafulvenium methides in the synthesis of functionalized pyrazoles

Article abstract of DOI:10.1021/jo070265x

(Chemical Equation Presented) The chemistry of diazafulvenium methides generated by the thermal extrusion of sulfur dioxide from 2,2-dioxo-1H,3H- pyrazolo[1,5-c] [1,3]thiazoles is described. The diazafulvenium methides unsubstituted at C-7 participate in [8π + 2π] cycloadditions giving pyrazolo-annulated heterocycles resulting from the addition across the 1,7-position. 1-Mefhyl-diazafulvenium methides and 7,7-dimethyl-diazafulvenium methides undergo intramolecular sigmatropic [1,8]H shifts giving vinyl- 1H-pyrazoles.

Full text of DOI:10.1021/jo070265x

Chemistry of Diazafulvenium Methides in the Synthesis of
Functionalized Pyrazoles
Teresa M. V. D. Pinho e Melo,*,† Cla´udio M. Nunes,† Maria I. L. Soares,† Jose´ A. Paixa˜o,‡
Ana Matos Beja,‡ and Manuela Ramos Silva‡
Department of Chemistry, UniVersity of Coimbra, 3004-535 Coimbra, Portugal, and Department of
Physics, UniVersity of Coimbra, 3004-516 Coimbra, Portugal
tmelo@ci.uc.pt
ReceiVed February 7, 2007
The chemistry of diazafulvenium methides generated by the thermal extrusion of sulfur dioxide from
2,2-dioxo-1H,3H-pyrazolo[1,5-c] [1,3]thiazoles is described. The diazafulvenium methides unsubstituted
at C-7 participate in [8π + 2π] cycloadditions giving pyrazolo-annulated heterocycles resulting from the
addition across the 1,7-position. 1-Methyl-diazafulvenium methides and 7,7-dimethyl-diazafulvenium
methides undergo intramolecular sigmatropic [1,8]H shifts giving vinyl-1H-pyrazoles.
Introduction
“higher-order” azomethine ylides and azomethine imines,
respectively. In fact, the authors described the thermal extrusion
of sulfur dioxide from 2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]-
thiazoles under flash vacuum pyrolysis (FVP) to give transient
1-azafulvenium methide systems (1) that can be trapped in
pericyclic reactions. The dipolar systems 1a-1c undergo
sigmatropic [1,8]H shifts giving vinylpyrroles, and the acyl
derivatives 1d electrocyclize to give pyrrolo[1,2-c][1,3]oxazines.5
On the other hand, the SO2 extrusion of the studied 2,2-dioxo-
1H,3H-pyrazolo[1,5-c][1,3]thiazole led to 1,2-diazafulvenium
methide 2, which could be intercepted in [8π + 2π] cycload-
dition with silylated acetylenes giving adducts resulting from
the addition across the 1,7-position (Scheme 1).5
The study of pericyclic reactions of extended dipoles (with
more than 4π electrons) is one of our current research
interests.1-4 Storr and co-workers have shown that 2,2-dioxo-
1H,3H-pyrrolo[1,2-c][1,3]thiazoles and 2,2-dioxo-1H,3H-pyra-
zolo[1,5-c][1,3]thiazoles are masked aza- and diazafulvenium
methides (1 and 2). These 8π 1,7-dipoles can be considered
† Department of Chemistry.
‡ Department of Physics.
(1) (a) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Rocha Gonsalves,
A. M. d’A.; McNab, H. Tetrahedron Lett. 2004, 45, 3889-3893. (b) Pinho
e Melo, T. M. V. D.; Soares, Maria I. L.; Rocha Gonsalves, A. M. d’A.;
Paixa˜o, J. A.; Matos Beja, A.; Ramos Silva, M. J. Org. Chem. 2005, 70,
6629-6638.
(2) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Nunes, C. M.
Tetrahedron 2007, 63, 1833-1841.
(5) (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.
(3) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; Rocha Gonsalves, A.
M. d’A. Tetrahedron Lett. 2006, 47, 791-794.
(4) Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2873-2888.
10.1021/jo070265x CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/10/2007
4406
J. Org. Chem. 2007, 72, 4406-4415

Chemistry of DiazafulVenium Methides
SCHEME 1
SCHEME 2
Our own contribution allowed for the definition of a reactivity
pattern of azafulvenium methides (Scheme 2).1,2 The intramo-
lecular trapping of the transient 8π 1,7-dipoles derived from
1-unsubstitued-2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]thiazoles in
pericyclic reactions, namely, sigmatropic [1,8]H shifts and 1,7-
electrocyclization, affords N-vinylpyrroles and C-vinylpyrroles,
which under flash vacuum pyrolysis conditions are converted
into 5-oxo-5H-pyrrolizines or 4-oxo-1,4-dihydro-1-aza-benzo-
[f]azulenes. 7-Methyl- and 7,7-dimethyl-azafulvenium methides
undergo sigmatropic [1,8]H shifts to give C-vinylpyrroles even
in cases where an alternative pericyclic reaction could in
principle occur. Azafulvenium methides generated from C-3
unsubstituted 1-methyl-2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]-
thiazole can only undergo the same type of [1,8]H shift to the
corresponding C-vinylpyrrole. However, from the reaction of
the 1,3-dimethyl-2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]thiazole
derivative the corresponding azafulvenium methide undergoes
the two possible sigmatropic [1,8]H shifts. Rearrangements of
these C-vinylpyrroles afford 5-oxo-5H-pyrrolizines or function-
alized C-allyl-1H-pyrroles.
Results and Discussion
We prepared the 2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole
35,6 and observed that it undergoes SO2 extrusion in refluxing
1,2,4-trichlorobenzene to give 1,2-diazafulvenium methide 4,
which could be trapped by reacting with bis(trimethylsilyl)-
acetylene, confirming the result reported by Storr et al.5 In our
hands, the dimethyl 5,6-bis(trimethylsilyl)-4,7-dihydropyrazolo-
[1,5-a]pyridine-2,3-dicarboxylate 5 was obtained in 54% yield
together with the formation of the aromatized derivative 6 in
7% yield (Table 1). However, the dipolar system 4 also
participates in the cycloaddition with electron-deficient dipo-
larophiles. Diazafulvenium methide 4 reacts with DMAD to give
a mixture of dihydropyrazolo[1,5-a]pyridines (8 and 9) in 45%
yield and pyrazolo[1,5-a]pyridine 7 in 10% yield. The mixture
of 8 and 9 can be converted into 7 in 44% yield by treatment
with DDQ. The [8π + 2π] cycloaddition of diazafulvenium
methide 4 with methyl propiolate affords regioisomers 10 (28%)
and 11 (33%). The thermolysis of 2,2-dioxo-1H,3H-pyrazolo-
[1,5-c][1,3]thiazole 3 in refluxing 1,2,4-trichlorobenzene for 7
h in the presence of N-phenylmaleimide gave hexahydro-5H-
pyrrolo[3′,4′:5,6]pyrazolo[1,5-a]pyridine 12 in 87% yield. This
cycloadduct could be obtained in 98% yield by increasing the
reaction time to 11 h. The dipole 4 can also be trapped by
The chemistry of 1,2-diazafulvenium methides has also
attracted our attention, and our preliminary results have been
described.3 In this paper, we describe full details of an extensive
study on the generation and reactivity of 1,2-diazafulvenium
methides.
(6) Sutcliffe, O. B.; Storr, R. C.; Gilchrist, T. L.; Rafferty, P. Tetrahedron
2000, 56, 10011-10021.
J. Org. Chem, Vol. 72, No. 12, 2007 4407

Pinho e Melo et al.
TABLE 1. Solution Pyrolysis of 2,2-Dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole 3 in the Presence of Dipolarophiles
[8π + 2π] cycloaddition with heterodipolarophiles. In fact, the
reaction with N-benzylidenebenzenesulfonamide7 gives the
corresponding cycloadduct 13 in 45% yield as the only
regioisomer. On the other hand, pyrazolo[1,5-d][1,2,4]triazine
14 could be obtained in 65% yield from the cycloaddition of
1,2-diazafulvenium methide 4 with diethyl diazene-1,2-dicar-
boxylate (Table 1). These results contradict the previously
described experimental observation where cycloaddition of 1,2-
diazafulvenium methide 4 could only be observed with silylated
acetylenes and attempts to carry out the reaction with electron-
deficient dipolarophiles were not successful.5 However, the
reactivity of 1,7-dipole 4 toward [8π + 2π] cycloaddition hereby
described, characterized by the participation in the reaction with
both electron-rich and electron-deficient dipolarophiles, is in
agreement with the reported MO calculations.5
The work was extended to diazafulvenium methide systems
generated from 3-methyl-, 1,1-dimethyl-, and 1,1,3-trimethyl-
2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazoles 19. The 3-
methyl-2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole 19a3 was
prepared from thiazolidine 15a as outlined in Scheme 3. The
sydnone 17a is a stable mesoionic species, which can be isolated
and undergoes 1,3-dipolar cycloaddition with DMAD to give
3-methyl-1H,3H-pyrazolo[1,5-c][1,3]thiazole 18a in 60% yield.
1H,3H-Pyrazolo[1,5-c][1,3]thiazoles 18b and 18c were obtained
using a similar synthetic strategy. Thiazolidines 15b and 15c
were prepared from the condensation of DL-penicillamine with
(7) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Organic Syntheses;
Wiley: New York, 1993; Collect. Vol. VIII, pp 546-550.
4408 J. Org. Chem., Vol. 72, No. 12, 2007

Chemistry of DiazafulVenium Methides
SCHEME 3
mixture of (2R,4R), (2S,4R), (2S,4S), and (2R,4S) stereoisomers.
However, after the nitrosation reaction N-nitrosothiazolidine-
4-carboxylic acid 16c can be obtained as an enantiomeric
mixture. Therefore, again in this case two rotamers would be
observed in the 1H NMR spectrum of 16c. Evidence of restricted
rotation of N-nitroso compounds is well documented, and
equilibrium between rotational isomers at room temperature has
been encountered for several N-nitrosoamines, including five-
membered cyclic derivatives such as pyrrolidine, thiazolidine,
and oxazoline.10
The 3-methyl-2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole
19a also undergoes SO2 extrusion in solution to give 20, which
can be intercepted in [8π + 2π] cycloadditions with electron-
deficient dipolarophiles giving the corresponding adducts result-
ing from the addition across the 1,7-positions in high yields
(Table 2). The reaction with DMAD gives a mixture of dihydro-
pyrazolo[1,5-a]pyridines (21 and 22) in 85% yield. This mixture
can be oxidized with DDQ to give tetramethyl 7-methylpyra-
zolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate (23) in 40% yield.
The thermolysis of 19a in the presence of methyl propiolate
afforded a mixture of regioisomers 4,7-dihydropyrazolo[1,5-a]-
pyridine-2,3,6-tricarboxylate 24 (30%) and 4,7-dihydropyrazolo-
[1,5-a]pyridine-2,3,5-tricarboxylate 25 (38%).
The 1,7-dipolar cycloaddition of 1,2-diazafulvenium methide
20 with N-phenylmaleimide gave two racemic diastereoisomeric
products, cycloadducts 26 (81%) and 27 (13%). The structure
of the major product (26) was determined by X-ray crystal-
lography (see Supporting Information). The crystal structure
showed that the unit cell contains four molecules that are two
pairs of enantiomers. The stereochemistry of the enantiomers
was established as beeing (4aS,7aS,8S) and (4aR,7aR,8R). The
formation of cycloadducts 26 and 27 can be explained consider-
ing a cycloaddition with endo selectivity but with the involve-
ment of the two possible configurations of diazafulvenium
methide 20 (see Scheme 7). The lower stability of the config-
uration having the inward methyl group explains the formation
of heterocycle 27 in a lower yield.
formaldehyde and acetaldehyde, respectively, and converted into
the corresponding sydnone via nitrosation followed by treatment
with TFAA. Sydnones 17b and 17c are also stable and could
be isolated and fully characterized. The reaction of 17b with
DMAD gave the expected 1H,3H-pyrazolo[1,5-c][1,3]thiazole
in 80% yield. However, carrying out the 1,3-dipolar cycload-
dition of 17c under the same reaction conditions affords 1H,3H-
pyrazolo[1,5-c][1,3]thiazole 18c in only 10% yield. The yield
could be improved to 20% by reducing the reaction time from
3 h to 1 h. The oxidation of 1H,3H-pyrazolo[1,5-c][1,3]thiazoles
18 with MCPBA afforded sulfones 19 in good yield.
1
The H NMR spectra of N-nitrosothiazolidine-4-carboxylic
acids 16a-16c showed two sets of signals indicating the
existence of isomers. Thiazolidine 15a is obtained from L-
cysteine as a (2S,4R) and (2R,4R) diastereoisomeric mixture,
but the corresponding N-nitroso derivative (16a) can be obtained
as a single stereoisomer. In fact, it is known that the acylation
of a mixture of (2S,4R)- and (2R,4R)-2-substituted-1,3-thiazo-
lidine-4-carboxylates can lead to the selective synthesis of
N-acyl-2-substituted-1,3-thiazolidine-4-carboxylates as pure ste-
reoisomers with (2R,4R) or (2S,4R) stereochemistry depending
on the reaction conditions. 2-Substituted-1,3-thiazolidine-4-
carboxylates can undergo selective inversion at C-2 through a
mechanism involving the opening of the ring, but the protection
with the acyl group prevents this epimerization and allows the
isolation of pure diastereoisomers.8 A similar chemical behavior
was observed in the one-pot synthesis of the chiral hexahydro-
pyrrolo[1′,2′,5′:3,4,5]thiazolo[3,4-c]oxazol-1-one ring system
from R-amino acids (L-cysteine and D-penicillamine).9 There-
fore, the 1H NMR spectrum of 16a could be explained
considering the existence of two rotamers. This interpretation
is reinforced by the fact that N-nitrosothiazolidine-4-carboxylic
acid 16b, which has only one chiral center, also shows two sets
of signals corresponding to two rotamers. Thiazolidine 15c was
prepared from DL-penicillamine. Thus, 15c was obtained as a
An efficient cycloaddition was observed when sulfone 19a
was heated in the presence of N-benzylidenebenzenesulfonamide
(Table 2). A single cycloadduct 28 was obtained in 81% yield.
The structure of compound 28 was unambiguously established
on the basis of its 1H NMR spectrum. It shows an ABX system
corresponding to H-4 and H-5 protons and a quartet assigned
to proton H-7. The cycloaddition of 1,2-diazafulvenium methide
20 with diethyl diazene-1,2-dicarboxylate gave 7-methyl-4H,7H-
pyrazolo[1,5-d][1,2,4]triazine-2,3,5,6-tetracarboxylate 29 in 79%
1
yield. In the H NMR spectrum of 29 the presence of two
conformational isomers could be clearly identified, whereas in
the case of derivative 14, unsubstituted at C-7, the six-membered
ring protons are observed as broad signals.
It is noteworthy that the thermolysis of 3-methyl-2,2-dioxo-
1H,3H-pyrazolo[1,5-c][1,3]thiazole 19a in the presence of
electron-deficient dipolarophiles requires shorter reaction time
than the thermolysis of 2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]-
thiazole 3 (Tables 1 and 2). However, an attempt to react 19a
(8) (a) Szila´gyi, L.; Gyo¨rgydea´k, Z. J. Am. Chem. Soc. 1979, 101, 427-
432. (b) Gyo¨rgydea´k, Z.; Kajta´r-Peredy, M.; Kajta´r, J.; Kajta´r, M. Liebigs
Ann. Chem. 1987, 927-934. (c) Benedini, F.; Ferrario, F.; Sala, A.; Sala,
L.; Soresinetti, P. A. J. Heterocycl. Chem. 1994, 31, 1343-1347. (d) Fu¨lo¨p,
F.; Mattinen, J.; Pihlaja, K. Tetrahedron 1990, 46, 6545-6552. (e) La´za´r,
L.; Fu¨lo¨p, F. Eur. J. Org. Chem. 2003, 3025-3042. (f) Pinho e Melo, T.
M. V. D. 1,3-Thiazolidine-4-carboxylic Acids as Building Blocks in Organic
Synthesis. In Targets in Heterocyclic Systems-Chemistry and Properties;
Attanasi, O. A., Spinelli, D., Eds.; Italian Society of Chemistry: Rome,
2004; Vol. 8, pp 288-329.
(10) (a) Anet, F. A. L.; Muchowski, J. M. Chem. Ind. 1963, 81-82. (b)
Jeyaraman, R.; Senthilkumar, U. P. J. Org. Chem. 1995, 60, 7461-7470.
(c) Polonski, T.; Milewska, M. J.; Katrusiak, A. J. Am. Chem. Soc. 1993,
115, 11410-11417. (d) Roohi, H.; Deyhimi, F.; Ebrahimi, A. J. Mol. Struct.
(Theochem) 2001, 543, 299-308. (e) Wu, H.; Loeppky, N.; Glaser, R. J.
Org. Chem. 2005, 70, 6790-6801. (f) Haky, J. E.; Saavedra, J. E.; Hilton,
B. D. Org. Magn. Reson. 1983, 21, 79-82. (g) Luinsky, W.; Keefer, L.;
Loo, J. Tetrahedron 1970, 26, 5137-5153.
(9) Pinho e Melo, T. M. V. D.; Lopes, S. M. M.; Rocha, Gonsalves, A.
M. d’A.; Kaczor, A. Fausto, R.; Paixa˜o, J. A.; Matos Beja, A.; Ramos Silva,
M. Lett. Org. Chem. 2006, 3, 820-826.
J. Org. Chem, Vol. 72, No. 12, 2007 4409

Pinho e Melo et al.
TABLE 2. Solution Pyrolysis of 3-Methyl-2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole 19a in the Presence of Dipolarophiles
with bis(trimethylsilyl)acetylene led only to the synthesis of the
corresponding 1-vinyl-1H-pyrazole 30 in 16% yield (see Scheme
4).
larophiles. This was confirmed experimentally, and in fact dipole
20 does not even react with electron-rich dipolarophiles.
Calculations predict a larger atomic orbital coefficient on C-1
than on C-7 in the HOMO of 1,2-diazafulvenium methide 4.5
On the other hand, MNDO and CNDO/2 calculations show a
larger atomic orbital coefficient on C-3 than on C-2 in the
LUMO of methyl propiolate.11 One would therefore expect the
selective synthesis of trimethyl 4,7-dihydropyrazolo[1,5-a]-
pyridine-2,3,5-tricarboxylate 11 from the reaction of dipole 4
with methyl propiolate (Table 1). The experimental result
confirmed that regioisomer 11 is the major product, although it
is obtained with low selectivity. The same regioselectivity was
observed in the reaction of diazafulvenium methide 20 with
methyl propiolate (Table 2). In contrast with this result, only
one regioisomer was obtained from the [8π + 2π] cycloaddition
of dipoles 4 and 20 with N-benzylidenebenzenesulfonamide
As previously mentioned the experimentally observed reactiv-
ity of 1,7-dipole 4 toward [8π + 2π] cycloaddition is character-
ized by the participation in the reaction with both electron-rich
and electron-deficient dipolarophiles. This is in agreement with
the reported semiempirical molecular orbital calculations.5 The
HOMO and LUMO energies were calculated for 1,2-diazaful-
venium methide 4 (HO ) -8.5 eV and LU ) -1.9 eV),
allowing prediction that the addition to electron-deficient
dipolarophiles should be dipole-HOMO controlled while the
addition to electron-rich dipolarophiles should be dipole-LUMO
controlled. The 1,2-diazafulvenium methide 20 has an extra
methyl group at C-1 leading to an increase of the HOMO and
LUMO energies. Therefore, cycloaddition of 20 with electron-
deficient dipolarophiles should be easier than with dipole 4 but
the process should be less favorable with electron-rich dipo-
(11) Dieter, R. K.; Balke, W. H.; Fishpaugh, J. R. Tetrahedron 1988,
44, 1915-1924.
4410 J. Org. Chem., Vol. 72, No. 12, 2007

Chemistry of DiazafulVenium Methides
SCHEME 4
SCHEME 5
SCHEME 6
(Tables 1 and 2). A similar regioselectivity pattern is observed
in the 1,3-dipolar cycloaddition of mesoionic N-methyl-1,3-
oxazolium-5-olates, dipoles that give only one regioisomer from
the reaction with N-benzylidenebenzenesulfonamide but lead
to a ca. 1:1 mixture of regioisomers on reacting with ethyl
propiolate.12
The generation and reactivity of diazafulvenium methide
systems in the absence of dipolarophiles were studied. By
carrying out flash vacuum pyrolysis (FVP) of sulfone 19a at
500 °C, 1-vinyl-1H-pyrazole 30 was obtained selectively via
the diazafulvenium methide 20, which was trapped in an
intramolecular sigmatropic [1,8]H shift. When the FVP was
carried out at 700 °C, the same 1-vinyl-1H-pyrazole 30 was
obtained, together with 2-vinyl-2H-pyrazole 31. Pyrazole 31 is
formed by thermal rearrangement of 1-vinyl-1H-pyrazole 30
since the FVP of this compound leads to a mixture of 30 and
31 (Scheme 4).
heterocycle 33 in 90% yield (Scheme 5). Attempts to promote
a rearrangement of 33 under FVP led only to sublimation of
the pyrazole. On the other hand, the solution pyrolysis of sulfone
19b in the presence of electron-deficient dipolarophiles (N-
phenylmaleimide or DMAD) or bis(trimethylsilyl)acetylene also
gave C-vinylpyrazole 33 in yields ranging from 40% to 50%,
and no [8π + 2π] cycloadducts were detected. This result can
be explained considering the ease with which diazafulvenium
methide 32 undergoes sigmatropic [1,8]H shift, although steric
effects can also play an important role making the cycloaddition
less favorable. In the absence of dipolorophiles, the optimized
solution pyrolysis of sulfone 19b (reflux in 1,2,4-trichloroben-
zene for 13 h) gave C-vinylpyrazole 33 in 65% yield.
Flash vacuum pyrolysis 1,1,3-trimethyl-2,2-dioxo-1H,3H-
pyrazolo[1,5-c][1,3]thiazole 19c also leads to the corresponding
C-vinylpyrazole 35 in high yield (Scheme 6). In this particular
case, the SO2 extrusion leads to diazafulvenium methide 34
where two potential [1,8]H sigmatropic shifts could in principle
occur. However, the FVP of 19c did not afford N-vinylpyrazole,
giving instead C-vinylpyrazole 35 exclusively. The same type
of selectivity was previously observed for sigmatropic [1,8]H
shifts of azafulvenium methides generated from 1,1,3-trimethyl-
2,2-dioxo-1H,3H-pyrrolo[1,2-c][1,3]thiazoles.2 The solution py-
rolysis of 19c in the presence of N-phenylmaleimide gave
The thermolysis of pyrazole 19b bearing two methyl groups
at C-1 was also studied. Under FVP reaction conditions
compound 19b affords C-vinylpyrazole 33. The optimized
conditions (600 °C, 2.0 × 10-2 mbar) allowed the synthesis of
(12) Bonati, L.; Ferraccioli, R.; Moro, G. J. Phys. Org. Chem. 1995, 8,
452-462.
J. Org. Chem, Vol. 72, No. 12, 2007 4411

Pinho e Melo et al.
SCHEME 7
SCHEME 8
C-vinylpyrazole 35 as the only product. By heating at reflux a
solution of sulfone 19c in 1,2,4-trichlorobenzene for 14 h,
C-vinylpyrazole 35 could be obtained in high yield (86%).
[1,5-c]pyrimidines, and tetrahydropyrazolo[1,5-d][1,2,4]triazines,
some of which have potential biological activity.13
In the absence of dipolarophiles, 1-methyl-diazafulvenium
methide and 7,7-dimethyl-diazafulvenium methides undergo
intramolecular sigmatropic [1,8]H shifts giving N-vinyl-1H-
pyrazoles and C-vinyl-1H-pyrazoles, respectively.
Therefore, it has been demonstrated that diazafulvenium
methides are valuable intermediates for the synthesis of func-
tionalized pyrazoles.
The difference in reactivity observed between diazafulvenium
methide 20 and diazafulvenium methides 32 and 34 may reflect
the different ease with which the dipoles can attain the
configuration required for the sigmatropic shift. In fact, the 7,7-
dimethyl-diazafulvenium methides (32 and 34) always have a
methyl group in the correct position, whereas in the case of
diazafulvenium methide 20 only the configuration having the
inward methyl group undergoes the pericyclic reaction (Scheme
7).
Experimental Section
General Procedure for [8 + 2] Cycloadditions. A suspension
of the appropriate 2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole-
6,7-dicarboxylate (0.87 mmol) and dipolarophile (1.74 mmol) in
1,2,4-trichlorobenzene (2.5 mL) was heated at reflux under dry
nitrogen (for 6-7 h, starting from 3; for 3-4 h starting from 19a)
for 6-11 h. After cooling to room temperature, the mixture was
purified by flash chromatography [hexane] to remove 1,2,4-
trichlorobenzene followed by elution with ethyl acetate-hexane.
Dimethyl 5,6-Bis(trimethylsilyl)-4,7-dihydro-pyrazolo[1,5-a]-
pyridine-2,3-dicarboxylate3,5 5 and Dimethyl 5,6-Bis(trimeth-
ylsilyl)-pyrazolo[1,5-a]pyridine-2,3-dicarboxylate3,5 6. The re-
action of 3 with bis(trimethylsilyl)acetylene gave a mixture, which
was purified by flash chromatography [hexane, ethyl acetate-
hexane (1:4), then ethyl acetate-hexane (1:2)] to give 5 as a solid
(54%) and 6 as an oil (7%). Data for 5: mp 86.1-87.9 °C (from
ethyl ether-hexane) (compound previously described as a yellowish
oil5b). 1H NMR 0.28 (9H, s), 0.30 (9H, s), 3.78 (2H, approximately
The reactivity pattern of the studied diazafulvenium methides
is shown in Scheme 8. Thus, diazafulvenium methides unsub-
stituted at C-7 generated from the solution pyrolysis of 2,2-
dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazoles participate in [8π +
2π] cycloadditions, giving pyrazolo[1,5-a]pyridine derivatives.
The diazafulvenium methide derivatives bearing methyl groups
at C-1 or C-7 undergo intramolecular sigmatropic [1,8]H shifts,
giving vinyl-1H-pyrazoles.
Conclusions
We described new chemistry of diazafulvenium methides,
generated by the thermal extrusion of sulfur dioxide from 2,2-
dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazoles.
(13) (a) Allen, S. H.; Johns, B. A.; Gudmundsson, K. S.; Freeman, G.
A.; Boyd, F. L., Jr.; Sexton, C. J.; Selleseth, D. W.; Creech, K. L.; Moniri,
K. R. Biorg. Med. Chem. 2006, 14, 944-954. (b) Elgemeie, G. H.; Zaghary,
W. A.; Amin, K. M.; Nasr, T. M. Nucleosodes, Nucleotides, Nucleic Acids
2005, 24, 1227-1247. (c) Jones, P.; Atack, J. R.; Braun, M. P.; Cato, B.
P.; Chambers, M. S.; O’Connor, D.; Cook. S. M.; Hobbs, S. C.; Maxey,
R.; Szekeres, H. J.; Szeto, N.; Wafford, K. A.; MacLeod, A. M. Bioorg.
Med. Chem. Lett. 2006, 16, 872-875.
The diazafulvenium methides unsubstituted at C-7 can be
intercepted in [8π + 2π] cycloadditions giving pyrazolo[1,5-
a]pyridine derivatives resulting from the addition across the 1,7-
position. A range of pyrazolo-annulated heterocycles was
obtained, namely, pyrazolo[1,5-a]pyridines, hexahydro-5H-
pyrrolo[3′,4′:5,6]pyrazolo[1,5-a]pyridines, tetrahydropyrazolo-
4412 J. Org. Chem., Vol. 72, No. 12, 2007

Chemistry of DiazafulVenium Methides
t, J ) 4.7 Hz), 3.86 (3H, s), 3.95 (3H, s), 4.76 (2H, approximately
t, J ) 4.7 Hz); MS (EI) m/z 380 (M+, 11%), 365 (30), 348 (48),
275 (100), 73 (36). Data for 6: 1H NMR 0.42 (9H, s), 0.44 (9H,
s), 3.94 (3H, s), 4.03 (3H, s), 8.45 (1H, d, J ) 0.8 Hz), 8.58 (1H,
d, J ) 0.8 Hz); MS (EI) m/z 378 (M+, 100%), 363 (18), 347 (43),
331 (75), 259 (34), 73 (24).
(1:4), then ethyl acetate-hexane (1:2)] to give 13 as a solid (45%).
mp 165-170 °C (from diethyl ether); 1H NMR 3.02 (1H, dd, J )
7.3 and 18.6 Hz), 3.6 (1H, d, J ) 18.6 Hz), 3.81 (3H, s), 3.95 (3H,
s), 4.74 (1H, d, J ) 14.3 Hz) 5.54 (1H, d, J ) 7.3 Hz), 5.96 (1H,
d, J ) 14.3 Hz), 7.16-7.96 (10H, m); MS (EI) m/z 455 (M+, 8%),
424 (13), 286 (100), 253 (30), 223 (15), 210 (94), 151 (90), 77
(17). HRMS (EI) m/z 445.1159 (C22H21N3O6S [M+], 445.1151).
5,6-Diethyl 2,3-Dimethyl 4,5,6,7-Tetrahydropyrazolo[1,5-d]-
[1,2,4]triazine-2,3,5,6-tetracarboxylate 14. The reaction of 3 with
diethyl diazene-1,2-dicarboxylate gave a product, which was
purified by flash chromatography [hexane, ethyl acetate-hexane
(1:4), then ethyl acetate-hexane (1:2)] to give a colorless oil
(65%): IR (KBr) 1733, 1402, 1211, 1090; 1H NMR 1.30-1.34 (6H,
m), 3.87 (3H, s), 3.97 (3H, s) 4.27-4.29 (4H, m), 4.7 (1H, bs),
5.40 (2H, bs), 6.2 (1H, bs); 13C NMR 14.3, 14.5, 42.5 (bs), 52.0,
52.7, 61.4 (bs), 63.4, 64.2, 110.8, 139.3, 143.9, 154.0, 161.8; MS
(EI) m/z 384 (M+, 11%), 352 (83), 284 (45), 235 (46), 207 (83),
179 (100), 151 (44). HRMS (EI) m/z 384.1274 (C15H20N4O8 [M+],
384.1281).
Tetramethyl Pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate
7, Tetramethyl 4,7-Dihydro-pyrazolo[1,5-a]pyridine-2,3,5,6-tet-
racarboxylate 8, and Tetramethyl 6,7-Dihydro-pyrazolo[1,5-a]-
pyridine-2,3,5,6-tetracarboxylate 9. The reaction of 3 with DMAD
gave a mixture, which was purified by flash chromatography
[hexane, ethyl acetate-hexane (1:2), then ethyl acetate-hexane (1:
1)] to give in order of elution 7 as a yellow solid (10%) and a
mixture of 8 and 9 as a white solid (ratio 28:72) (45%). Data for
7: mp 94.7-96.8 °C (from diethyl ether-hexane). IR (KBr) 1730,
1578, 1428, 1328, 1245 cm-1; 1H NMR 3.96 (3H, s), 3.97 (3H, s),
3.98 (3H, s), 4.05 (3H, s), 8.40 (1H, s), 9.01 (1H, s); 13C NMR
52.1, 53.2, 53.3, 105.4, 118.5, 120.2, 131.7, 132.0, 140.7, 149.6,
161.6, 162.3, 163.9, 166.1; MS (EI) m/z 350 (M+, 63%), 319 (100),
229 (7), 201 (7); HRMS (EI) m/z 350.0757 (C15H14N2O8 [M+],
350.0750). Data for 8 and 9: mp 71.9-73.3 °C (from diethyl
Tetramethyl 7-Methyl-4,7-dihydro-pyrazolo[1,5-a]pyridine-
2,3,5,6-tetracarboxylate 21 and Tetramethyl 7-Methyl-6,7-
dihydro-pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate 22. The
reaction of 19a with DMAD (reaction time 3 h) gave a mixture,
which was purified by flash chromatography [hexane, ethyl
acetate-hexane (1:2), then ethyl acetate-hexane (1:1)] to give a
mixture of 21 and 22 (ratio 40:60) as a yellowish oil (85%). IR
1
ether). IR (KBr) 1738, 1721, 1486, 1433, 1256, 1215 cm-1; H
NMR (minor isomer 8) 3.88 (3H, s), 3.90 (3H, s), 3.91 (3H, s),
3.99 (3H, s), 4.71 (2H, s), 5.26 (2H, s); (major isomer 9) 3.69 (3H,
s), 3.90 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 4.19 (1H, dd, J ) 1.3
and 6.7 Hz), 4.30 (1H, dd, J ) 6.7 and 13.8 Hz), 5.04 (1H, dd,
J ) 1.3 and 13.8 Hz), 7.93 (1H, s); MS (EI) m/z 352 (M+, 11%),
321 (15), 307 (12), 293 (30), 261 (100), 203 (8). Anal. Calcd for
C15H16N2O8: C, 51.14; H, 4.58; N, 7.95. Found: C, 51.12; H, 4.99;
N, 7.63.
1
(KBr) 1730, 1433, 1217, 1090 cm-1; H NMR (minor isomer 21)
1.40 (3H, d, J ) 6.9 Hz), 3.68 (3H, s), 3.86 (3H, s), 3.90 (3H, s),
3.96 (3H, s), 4.05-4.07 (1H, m), 4.52-4.56 (1H, m), 5.22-5.32
(1H, m); (major isomer 22) 1.78 (3H, d, J ) 6.8 Hz), 3.66 (3H, s),
3.86-3.98 (2H, m), 3.88 (3H, s), 3.91 (3H, s), 3.96 (3H, s), 7.96
(1H, s); MS (EI) m/z 366 (M+, 9%), 335 (14), 307 (48), 275 (100),
261 (19), 59 (9). HRMS (EI) m/z 366.1062 (C16H18N2O8 [M+],
366.1064).
Trimethyl 4,7-Dihydropyrazolo[1,5-a]pyridine-2,3,6-tricar-
boxylate 10 and Trimethyl 4,7-Dihydropyrazolo[1,5-a]pyridine-
2,3,5-tricarboxylate 11. The reaction of 3 with methyl propiolate
gave a mixture, which was purified by flash chromatography
[hexane, then ethyl acetate-hexane (1:2)] to give 10 (28%) and
11 (33%) as white solids. Data for10: mp 119.5-121.0 °C (from
ethyl acetate-hexane). IR (KBr) 1744, 1697, 1431, 1293, 1251,
Trimethyl 7-Methyl-4,7-dihydropyrazolo[1,5-a]pyridine-2,3,6-
tricarboxylate 24 and Trimethyl 7-Methyl-4,7-dihydropyrazolo-
[1,5-a]pyridine-2,3,5-tricarboxylate 25. The reaction of 19a with
methyl propiolate gave a mixture, which was purified by flash
chromatography [hexane, then ethyl acetate-hexane (1:2)] to give
24 (30%) and 25 (38%). Data for 24: obtained as a colorless oil;
1H NMR 1.63 (3H, d, J ) 6.5 Hz), 3.78-4.04 (2H, m), 3.86 (3H,
s), 3.87 (3H, s), 3.97 (3H, s), 5.31-5.38 (1H, m), 7.18-7.21 (1H,
m); 13C NMR 22.7, 25.2, 51.7, 52.3, 52.6, 53.6, 109.9, 130.6, 132.4,
139.8, 144.1, 162.6, 162.7, 164.4; MS (EI) m/z 308 (M+, 2%), 277
(14), 261 (100), 217 (11). HRMS (CI+) m/z 309.1087 (C12H16N2O4
[MH+], 309.1087). Data for 25: obtained as a white solid; mp
99-100 °C (from ethyl acetate-hexane). IR (KBr) 1745, 1721,
1
1220, 1087 cm-1; H NMR 3.86 (3H, s), 3.86 (3H, s), 3.90 (1H,
dd, J ) 5.5 and 3.9 Hz), 3.92 (1H, dd, J ) 5.5 and 3.8 Hz), 3.97
(3H, s), 4.95 (1H, dd, J ) 5.6 and 2.1 Hz), 4.97 (1H, dd, J ) 5.6
and 2.0 Hz), 7.22-7.24 (1H, m); 13C NMR 25.6, 46.8, 51.7, 52.4,
52.6, 110.1, 124.5, 132.5, 140.2, 144.2, 162.3, 162.5, 164.3. HRMS
(CI) m/z 295.0930 (C13H15N2O6 [M - H+], 295.0930). Data for
1
11: mp 141.1-142.5 °C (from ethyl acetate-hexane). H NMR
3.86 (3H, s), 3.88 (3H, s), 3.94 (1H, dd, J ) 5.6 and 1.8 Hz), 3.96
(1H, m), 3.96 (3H, s), 4.95 (1H, dd, J ) 5.6 and 3.4 Hz), 4.97
(1H, dd, J ) 5.6 and 3.4 Hz), 7.13-7.16 (1H, m); 13C NMR 24.5,
47.8, 51.8, 52.4, 52.6, 110.6, 125.5, 129.9, 141.3, 144.3, 162.3,
162.5, 165.2. HRMS (CI) m/z 295.0929 (C13H15N2O6 [M - H+],
295.0930).
1
1710, 1313, 1270, 1091, 1064 cm-1; H NMR 1.69 (3H, d, J )
6.9 Hz), 3.84 (3H, s), 3.87 (3H, s), 3.91 (1H, dd, J ) 5.0 and 2.1
Hz), 3.94 (1H, dd, J ) 5.0 and 1.6 Hz), 3.97 (3H, s), 5.07-5.08
Dimethyl 6-Phenyl-5,7-dioxo-4a,5,6,7,7a,8-hexahydro-5H-pyr-
rolo[3′,4′:5,6]pyrazolo[1,5-a]pyridine-2,3-dicarboxylate 12. The
reaction of 3 with N-phenylmaleimide required longer reaction time
(11 h), giving a product that was purified by flash chromatography
[hexane, ethyl acetate-hexane (2:1), then ethyl acetate-hexane (4:
1)] to give 12 as a white solid (98%): mp 144.8-146.7 °C (from
(1H, m), 7.05 (1H, approximately dt, J ≈ 2.1, 1.6 and 3.6 Hz); 13
C
NMR 21.6, 24.4, 51.7, 52.4, 52.6, 53.8, 110.2, 124.3, 135.6, 140.8,
144.3, 162.6, 162.7, 165.4; MS (EI) m/z 308 (M+, 4%),277 (20),
261 (100), 217 (15). HRMS (CI+) m/z 309.1083 (C12H16N2O4
[MH+], 309.1087).
(4aS,7aS,8S)-Dimethyl 8-Methyl-5,7-dioxo-6-phenyl-4a,5,6,7,-
7a,8-hexahydro-1H,3H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyridine-
2,3-dicarboxylate 26 and (4aS,7aS,8R)-8-Methyl-5,7-dioxo-6-
phenyl-4a,5,6,7,7a,8-hexahydro-1H,3H-pyrazolo[1,5-a]pyrrolo[3,4-
d]pyridine-2,3-dicarboxylate 27. The reaction of 19a with
N-phenylmaleimide (reaction time 3 h) gave a mixture, which was
purified by flash chromatography [hexane, ethyl acetate-hexane
(2:1), then ethyl acetate] to give in order of elution 27 as an oil
(13%) and 26 as a white solid (81%). Data for 26: mp 155.6-
157.7 °C (from ethyl acetate-hexane); IR (KBr) 1735, 1716, 1562,
1473, 1447, 1383, 1222 cm-1; 1H NMR 1.69 (3H, d, J ) 7.0 Hz),
3.53-3.72 (4H, m), 3.87 (3H, s), 3.95 (3H, s), 4.85-4.94 (1H,
m), 7.15-7.18 (2H, m), 7.41-7.47 (3H, m); 13C NMR 15.4, 21.2,
37.3, 44.7, 51.9, 52.7, 53.3, 111.9, 126.2, 129.1, 129.3, 131.0, 141.0,
1
diethyl ether). IR (KBr) 1715, 1497, 1385, 1221, 1150 cm-1; H
NMR 3.20 (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), 7.37-7.44 (3H, m); 13C NMR 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; MS (EI) m/z 383 (M+, 28%), 351 (100), 204 (61), 176 (12),
147 (7), 119 (8), 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.
Dimethyl 5-Phenyl-6-(phenylsulfonyl)-4,5,6,7-tetrahydropy-
razolo[1,5-c]pyrimidine-2,3-dicarboxylate 13. The reaction of 3
with N-benzylidenebenzenesulfonamide7 gave a product, which was
purified by flash chromatography [hexane, ethyl acetate-hexane
J. Org. Chem, Vol. 72, No. 12, 2007 4413

Pinho e Melo et al.
143.4, 162.3, 162.4, 173.3, 176.2; MS (EI) m/z 397 (M+, 15%),
365 (100), 218 (13), 203 (54), 77 (8). Anal. Calcd for
C20H19N3O6: C, 60.45; H, 4.82; N, 10.57. Found: C, 60.63; H,
4.99; N, 10.43. Data for 27: IR (KBr) 1740, 1715, 1670, 1541,
(3H, s), 3.96 (3H, s), 5.03 (1H, dd, J ) 0.7 and 8.8 Hz), 5.87 (1H,
dd, J ) 0.7 and 15.2 Hz), 7.19 (1H, dd, J ) 8.8 and 15.2 Hz); 13
C
NMR 13.4, 51.8, 53.2, 105.0, 114.1, 129.7, 145.0, 151.0, 160.7,
163.1; MS (EI) m/z 224 (M+, 40%), 192 (100), 167 (7), 135 (11),
79 (6).
1
1491, 1393, 1229 cm-1; H NMR 1.69 (3H, d, J ) 7.0 Hz), 3.37
Dimethyl 5-Methyl-1-vinyl-1H-pyrazole-3,4-dicarboxylate 30.
Pyrolysis of 19a at 500 °C/2 × 10-2 mbar gave a product, which
was purified by flash chromatography [ethyl acetate-hexane (1:
2), then ethyl acetate-hexane (1:1)] to give 30 as a white solid
(51%). Compound 30 was identified by comparison with the
specimen previously prepared (see above).
(1H, dd, J ) 8.2 and 16.8 Hz), 3.42 (1H, dd, J ) 2.9 and 9.6 Hz),
3.61 (1H, ddd, J ) 3.1, 8.2 and 9.6 Hz), 3.86 (3H, s), 3.92 (1H,
dd, J ) 3.1 and 16.8 Hz), 3.94 (3H, s), 5.12 (1H, dq, J ) 2.9 and
7.0 Hz), 7.12-7.27 (2H, m), 7.38-7.46 (3H, m); 13C NMR 20.5,
22.0, 36.4, 46.2, 52.0, 52.6, 53.9, 112.2, 126.1, 129.0, 129.2, 131.0,
140.2, 143.4, 162.1, 162.2, 174.8, 176.2; MS (EI) m/z 397 (M+,
24%), 365 (100), 217 (10), 203 (59), 183 (8). HRMS (EI) m/z
397.1279 (C20H19N3O6 [M+], 397.1274).
Dimethyl 1-Methyl-5-(prop-1-en-2-yl)-1H-pyrazole-3,4-dicar-
boxylate 33. Pyrolysis of 19b at 600 °C/2 × 10-2 gave a product,
which was purified by flash chromatography [ethyl acetate-hexane
(1:1)] to give 33 as a white foam (90%): IR (KBr) 1745, 1736,
Dimethyl 7-Methyl-5-phenyl-6-(phenylsulfonyl)-4,5,6,7-tet-
rahydropyrazolo[1,5-c]pyrimidine-2,3-dicarboxylate 28. The
reaction of 19a with N-benzylidenebenzenesulfonamide7 (reaction
time 3 h) gave a product, which was purified by flash chromatog-
raphy [hexane, then ethyl acetate-hexane (2:1)] to give 28 as a
white foam (81%): IR (KBr) 1745, 1736, 1336, 1216, 1173, 1082
1
1475, 1317, 1221, 1074 cm-1; H NMR 2.07 (3H, bs), 3.83 (3H,
s), 3.85 (3H, s), 3.91 (3H, s), 5.13 (1H, bs), 5.54 (1H, m); 13C
NMR 22.6, 37.3, 51.9, 52.5, 112.8, 121.2, 133.6, 142.1, 147.4,
162.2, 163.0; MS (EI) m/z 238 (M+, 17%), 206 (100), 195 (25),
248 (24), 120 (12). HRMS (EI) m/z 238.0963 (C11H14N2O4 [M+],
238.0954).
cm-1 1H NMR 1.18 (3H, d, J ) 6.6 Hz), 2.91 (1H, dd, J )
;
17.8 and J ) 7.4 Hz), 3.75 (1H, dd, J ) 17.8 and J ) 2.4 Hz),
3.86 (3H, s), 3.94 (3H, s) 5.57 (1H, dd, J ) 7.4 and J ) 2.4 Hz),
6.31 (1H, q, J ) 6.6 Hz), 7.27-7.33 (4H, m), 7.49-7.52 (4H, m),
7.80-7.83 (2H, m); 13C NMR 23.1, 24.1, 51.2, 51.8, 52.7, 68.1,
110.2, 126.8, 127.4, 128.4, 128.9, 129.7, 133.6, 138.3, 139.0, 140.4,
143.8, 162.5. HRMS (EI) m/z 469.1297 (C23H23N3O6S [M+],
469.1308).
Dimethyl 1-Ethyl-5-(prop-1-en-2-yl)-1H-pyrazole-3,4-dicar-
boxylate 35. Pyrolysis of 19c at 650 °C/2 × 10-2 gave a product,
which was purified by flash chromatography [ethyl acetate-hexane
(1:1)] to give as a colorless oil (92%): IR (film) 1746, 1730, 1480,
1
1320, 1216, 1083 cm-1; H NMR 1.44 (3H, t, J ) 7.2 Hz), 2.08
(3H, m), 3.83 (3H, s), 3.94 (3H, s), 4.16 (2H, q, J ) 7.2 Hz), 5.13
(1H, m), 5.53 (1H, m); 13C NMR 15.8, 23.0, 45.1, 51.8, 52.4, 112.5,
120.9, 133.7, 142.4, 146.9, 162.5, 163.0; MS (EI) m/z 252 (M+,
21%), 220 (100), 205 (73), 193 (12), 161 (12). HRMS (EI+) m/z
252.1111 (C12H16N2O4 [M+], 252.1110).
General Procedure for Solution Thermolysis. A solution of
the appropriate 1,1-dimethyl-2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]-
thiazole-6,7-dicarboxylate (0.30 mmol) in 1,2,4-trichlorobenzene
(1.8 mL) was heated at reflux under dry nitrogen for 13-14 h.
After cooling to room temperature, the mixture was purified by
flash chromatography [hexane] to remove 1,2,4-trichlorobenzene
followed by elution with ethyl acetate-hexane to give the products.
Dimethyl 1-Methyl-5-(prop-1-en-2-yl)-1H-pyrazole-3,4-dicar-
boxylate 33. Compound 33 was obtained from 19b in 65% yield.
Pyrazole 33 was purified by flash chromatography [hexane, then
ethyl acetate-hexane (1:1)] and was identified by comparison with
the specimen previously prepared (see above).
5,6-Diethyl 2,3-Dimethyl 7-methyl-4,5,6,7-tetrahydropyra-
zolo[1,5-d][1,2,4]triazine-2,3,5,6-tetracarboxylate 29. The reaction
of 19a with diethyl diazene-1,2-dicarboxylate gave 29 as a white
solid (79%): mp 119-119.5 °C (from diethyl ether); IR (KBr)
1753, 1741, 1721 1376, 1338, 1314, 1289, 1210; 1H NMR (DMSO-
d6) (the 1H NMR spectrum showed the existence of two rotamers)
(major rotamer) 1.16-1.21 (6H, m), 1.60 (3H, d, J ) 6.4 Hz), 3.77
(3H, s), 3.84 (3H, s), 4.10-4.21 (4H, m), 4.58 (1H, d, J )
17.2 Hz), 5.27 (1H, d, J ) 17.2 Hz), 6.39 (1H, q, J ) 6.4 Hz); 13
C
NMR (DMSO-d6) 14.1, 14.3, 19.6, 41.8, 51.8, 52.5, 60.6, 62.7,
63.5, 108.8, 138.6, 143.6, 154.3, 161.3, 162.3; MS (EI) m/z 398
(M+, 4%), 367 (16), 284 (100), 253 (19), 221 (19), 193 (50), 180
(144), 116 (42). HRMS (EI) m/z 398.1426 (C16H22N4O8 [M+],
398.1438).
General Procedure for Flash Vacuum Pyrolysis. Pyrolysis of
the appropriate 2,2-dioxo-1H,3H-pyrazolo[1,5-c][1,3]thiazole-6,7-
dicarboxylate (1.0 mmol) at 500-800 °C and 2 × 10-2 to 4 ×
10-2 mbar onto a surface cooled at -196 °C over a period of 1.5-
2 h gave a colorless pyrolysate. [The rate of volatilization of the
starting material was controlled by the use of a Kugelrohr oven,
which heated the sample at 80-180 °C]. After cooling to room
temperature the pyrolysate was removed from the cold finger with
dichloromethane, and the solvent was removed in vacuo.
Dimethyl 1-Ethyl-5-(prop-1-en-2-yl)-1H-pyrazole-3,4-dicar-
boxylate 35. Compound 35 was obtained from 19c in 86% yield.
Pyrazole 35 was purified by flash chromatography [hexane, then
ethyl acetate-hexane (1:3)] and was identified by comparison with
the specimen previously prepared (see above).
Tetramethyl Pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate
7 from 8 and 9. A suspension of the mixture of 4,7-dihydro-
pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate 8 and 6,7-dihydro-
pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate
9
(0.09 g,
0.26 mmol) and DDQ (0.07 g, 1.2 equiv, 0.31 mmol) in 1,2,4-
trichlorobenzene (5.0 mL) was heated in sealed tube at 260 °C
for 3 h. After cooling to room temperature, the tube was opened,
and the mixture filtered through celite. The crude product was
purified by flash chromatography [hexane] to remove 1,2,4-
trichlorobenzene followed by elution with ethyl acetate-hexane
(1:1), then ethyl acetate-hexane (2:1) to give 7 as a yellow solid
(44%). Compound 7 was identified by comparison with the
specimen previously prepared.
Tetramethyl 7-Methylpyrazolo[1,5-a]pyridine-2,3,5,6-tetra-
carboxylate 23. A suspension of the mixture 7-methyl-4,7-dihydro-
pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate 21 and 7-methyl-
6,7-dihydro-pyrazolo[1,5-a]pyridine-2,3,5,6-tetracarboxylate 22
(0.04 g, 0.12 mmol) and DDQ (0.03 g, 1.2 equiv., 0.14 mmol) in
1,2,4-trichlorobenzene (2.0 mL) was heated in sealed tube at
260 °C for 3 h. After cooling to room temperature, the tube was
Dimethyl 5-Methyl-1-vinyl-1H-pyrazole-3,4-dicarboxylate 30
and Dimethyl 5-Methyl-2-vinyl-2H-pyrazole-3,4-dicarboxylate
31. Pyrolysis of 19a at 700 °C/4 × 10-2 mbar gave a mixture,
which was purified by flash chromatography [ethyl acetate-hexane
(1:2), then ethyl acetate-hexane (1:1)] to give in order of elution
31 as a colorless oil (4%) and 30 as a white solid (59%). Data for
30: mp 46.3-48.0 °C (from diethyl ether-hexane); IR (KBr) 1740,
1
1719, 1648, 1320, 1269, 1088 cm-1; H NMR 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); 13
C
NMR 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),
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. Data for 31: IR (KBr) 1719,
1
1646, 1545, 1442, 1260, 1109 cm-1; H NMR 2.46 (3H, s), 3.84
4414 J. Org. Chem., Vol. 72, No. 12, 2007

Chemistry of DiazafulVenium Methides
opened and the mixture was filtered through celite. The crude
product was purified by flash chromatography [hexane] to remove
1,2,4-trichlorobenzene followed by elution with ethyl acetate-
hexane (1:2), then ethyl acetate-hexane (1:1) to give 23 (40%) as
a yellow solid: mp 110.5-111.3 °C (from ethyl ether-hexane);
IR (KBr) 1744, 1714, 1304, 1272, 1210, 1120 cm-1; 1H NMR 2.85
(3H, s), 3.97 (6H, s), 3.99 (3H, s), 4.05 (3H, s), 8.68 (1H, s); 13C
NMR 15.3, 52.1, 53.1, 53.2, 53.3, 105.5, 119.7, 120.1, 130.0, 138.9,
139.8, 148.5, 162.0, 163.1, 164.6, 166.6; MS (EI) m/z 364 (M+,
70%), 333 (100), 301 (14), 274 (29), 246 (16), 59 (11). Anal. Calcd
for C16H16N2O8: C, 52.75; H, 4.43; N, 7.69. Found: C, 52.79; H,
4.66; N, 7.68.
Acknowledgment. We thank Chymiotechnon, Fundac¸a˜o
para a Cieˆncia e a Tecnologia (POCI/QUI/55584/2004 and
SFRH/BD/9123/2002) and FEDER for financial support.
Supporting Information Available: Experimental procedures
and characterization data for compounds 16a-16c, 17a-17c, 18a-
18c, and 19a-19c. NMR spectra for all new compounds. Crystal-
lographic data for dimethyl 8-methyl-5,7-dioxo-6-phenyl-4a,5,6,7,-
7a,8-hexahydro-1H,3H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyridine-2,3-
dicarboxylate 26 in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO070265X
J. Org. Chem, Vol. 72, No. 12, 2007 4415