Facile synthesis of pyrazoles and pyrroles via thermolysis of tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo [1,5- a]pyridines

Article abstract of DOI:10.1016/S0040-4039(00)00243-4

A simple and high yielding preparation of pyrazoles and pyrroles is described. Thermolysis of tetrazolo[1,5b]pyridazines, tetrazolo[1,5- a]pyrimidines and tetrazolo[1,5-a]pyridines allowed easy ring contraction thus providing a facile preparation of cyano

Full text of DOI:10.1016/S0040-4039(00)00243-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2699–2703
Facile synthesis of pyrazoles and pyrroles via thermolysis of
tetrazolo[1,5-b]pyridazines, tetrazolo[1,5-a]pyrimidines and
tetrazolo[1,5-a]pyridines
a,∗
a
b
b
Daniele Simoni, Riccardo Rondanin, Giancarlo Furnò, Enrico Aiello and
Francesco Paolo Invidiata b
a
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy
b
Dipartimento Farmacochimico Tossicologico e Biologico, Via Archirafi 32, Università di Palermo, 90123 Palermo, Italy
Received 1 November 1999; accepted 9 February 2000
Abstract
A simple and high yielding preparation of pyrazoles and pyrroles is described. Thermolysis of tetrazolo[1,5-
b]pyridazines, tetrazolo[1,5-a]pyrimidines and tetrazolo[1,5-a]pyridines allowed easy ring contraction thus pro-
viding a facile preparation of cyanopyrazole and cyanopyrrole heterocycles. Since the cyano group is a versatile
precursor of other functionalities, the reaction appears of particular interest for the construction of a variety of
pyrazoles and pyrroles. The simple preparation of the starting tetrazole derivatives, the relatively mild conditions
employed, and the very short reaction times make this versatile procedure of great synthetic utility and applicable
both to small and large scale preparation. © 2000 Elsevier Science Ltd. All rights reserved.
The thermal or photochemical decomposition of phenyl and heterocyclic azides 2 is a well known
1
process which gives phenyl- and heteroarylnitrenes 3. The reaction has attracted attention as a means of
constructing new heterocyclic compounds which are otherwise inaccessible by ring synthesis or by mo-
2
–5
dification of existing heterocycles. It has been also demonstrated that an azide–tetrazole tautomerism
exists (Scheme 1) in tetrazoloazines and the tetrazole compounds may be the main tautomers.6
Scheme 1.
∗
Corresponding author.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00243-4
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The work of Wentrup was particularly significant in this field.5,7–11 In fact, he demonstrated that
nitreno-azines and -diazines, generated by gas-phase pyrolysis of the corresponding tetrazolo-azines and
diazines, may produce the cyano derivatives of the corresponding five-membered heterocycles. However,
these cyano heterocycles were obtained, as the main products, only in the case of the tetrazolo[1,5-
-
7
7
c]pyrazines and tetrazolo[1,5-c]pyrimidines. In the other cases gas-phase pyrolysis produced mixtures
of compounds and the cyano components were present only in small amounts.
We were very surprised to ascertain that little is known about the ring contraction of heterocyclic
azides when the reaction is performed at the melting temperature. In this regard, we anticipated that
pyrolysis of the tetrazolo[1,5-c]pyrimidines 4 (Scheme 2) may be obtained by warming the starting
12
tetrazole derivatives at about 10–20°C over the melting temperature, and we described this reaction
as a practical means to achieve the preparation of many 1-cyanoimidazole heterocycles. In addition,
alkyl- and arylimidazoles were also obtained in high yield by pyrolysis of azidopyrazines.1
3,14
Scheme 2.
Thus, our ongoing interest in the thermolysis of azido-azines and -diazines prompted us to extend the
above cited ring contraction to other heterocyclic azides. In this letter we wish to report our preliminary
results concerning the thermolysis of the tetrazolo[1,5-a]pyrimidines 7 and tetrazolo[1,5-b]pyridazine
10 which allowed a facile preparation of 1-cyanopyrazoles. The reaction was also attempted with the
tetrazolo[1,5-a]pyridines 13a thus providing an easy preparation of 1-cyanopyrroles which is of great
synthetic utility. Therefore, unlike Wentrup, our methodology affords higher yields of the corresponding
cyano heterocycles by means of simpler operational conditions. Since the cyano group is a versatile
precursor of other functionalities, the reaction appears to be of particular interest for the construction of
a variety of pyrazoles and pyrroles.
Pyrolyses of the tetrazolo[1,5-a]pyrimidines 7 and tetrazolo[1,5-b]pyridazines 10 (Schemes 2 and 3)
were performed in a standard pyrex tube (35/5 cm) joined to a condenser and plunged (about 5 cm) in
1
5
an oil bath. About 20 mmoles of the opportune tetrazole were put on the bottom of the tube and the
system was carefully heated at about 10–20°C over the melting temperature of the sample. As soon as the
compound melted evolution of nitrogen was observed. The reaction was particularly fast (few minutes),
then the tube was allowed to cool to room temperature and the desired cyano heterocycles were in general
collected from the walls of the tube. Both the tetrazolo[1,5-a]pyrimidine and tetrazolo[1,5-b]pyridazine
heterocycles gave facile thermolysis and the ring contraction produced the pyrazole derivatives 9 and
12 as the only detectable products (Table 1: a selected list of representative results). On the contrary,
when pyrolysis of the tetrazolo[1,5-b]pyridazines was performed at 380°C/0.02–0.03 mm, as described
7
by Wentrup, a mixture of cyanoallene, tetralonitrile, propargyl cyanide and 2-cyanocyclopropene
was obtained. Surprisingly, there was no evidence of the presence of the 1-cyanopyrazole. Moreover,

2
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7
pyrolysis of the tetrazolo[1,5-a]pyrimidines, performed at 600°C/0.1 mm, gave the 1-cyanopyrazoles in
only 33% yield.
Scheme 3.
The interpretation of our results is not easy: Wentrup hypothesized that in some cases fragmentation of
the starting tetrazole derivative can occur rather than ring contraction because of an inherent instability
8
of the nitrene intermediate; it is likely that in our experiments the formation of the five-membered
heterocycles is due to the milder conditions of the reaction. Therefore, we may advance the hypothesis
that the instability of the nitrene intermediate, firstly hypothesized by Wentrup, is simply due to the higher
temperature used to generate the ring contraction.
Having demonstrated that the tetrazolo-diazines 7 and 10 can undergo facile thermolysis, we decided to
investigate the same procedure applied to the tetrazolo[1,5-a]pyridine system. Thermolysis of derivatives
1
3a gave the corresponding cyanopyrroles in 70–75% yield (see Scheme 3 and Table 1) thus offering
10,11
significant advantages when compared to the preparation described in the literature.
Surprisingly,
further attempts to affect the ring contraction of the tetrazole derivative 13b failed, resulting in a very
complex mixture of products in which only traces of the desired cyanoindole were identified.
Finally, the thermolysis of the above cited heterocyclic tetrazoles was also attempted in organic
9
solvents as described by Wentrup for the tetrazolopyrazines. In our experiments somewhat lower yields
of the pyrazole and pyrrole derivatives were obtained but appreciable amounts of the starting materials
were recovered unchanged.
In summary, as shown in Table 1, the present methodology is particularly suitable to using the
tetrazolo[1,5-a]pyridines, tetrazolo[1,5-b]pyridazines and the tetrazolo[1,5-a]pyrimidines as substrates
allowing the isolation of pyrroles and pyrazoles in good to excellent yields. In particular, when compared
with results previously described in the literature,7
,10,11
our methodology appears to be very promising
since the pyrazole and pyrrole heterocycles were obtained in a surprisingly high yield. The following
noteworthy features of the methodology should be emphasized: (a) the reaction is of general applicability
for the tetrazolo[1,5-a]pyridines, tetrazolo[1,5-b]pyridazine, and tetrazolo[1,5-a]pyrimidines; (b) the
starting materials can be easily prepared; (c) great operational simplicity: short reaction times and no
need of inert atmosphere and high vacuum conditions. We are currently investigating the feasibility of
the reaction toward the preparation of natural nucleosides.

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Table 1
Synthesis of pyrazoles and pyrroles via thermolysis of tetrazoloazines
Acknowledgements
This work was in part supported by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica (Rome).

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References
1
. Smith, P. A. S. In Azides and Nitrenes–Reactivity and Utility, Scriven, E. F. V., Ed. Aryl and heteroaryl azides and nitrenes.
Academic Press: New York, 1984; Chapter 3.
2. Dehaen, W.; Becher, J. Acta Chem. Scand. 1993, 47, 244 and references cited therein.
3. Funicello, M.; Spagnolo, P.; Zanirato, P. Ibid. 1993, 47, 231 and references cited therein.
4. Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297 and references cited therein.
5. Svenstrup, N.; Simonsen, K. B.; Thorup, N.; Brodersen, J.; Dehaen, W.; Becher, J. J. Org. Chem. 1999, 64, 2814 and
references cited therein.
6
7
8
9
. Wentrup, C. Tetrahedron 1970, 26, 4969.
. Wentrup, C.; Crow, W. D. Ibid. 1970, 26, 4915.
. Wentrup, C.; Crow, W. D. Ibid. 1971, 26, 361.
. Wentrup, C. Helv. Chim. Acta 1972, 55, 565.
1
1
1
1
1
0. Crow, W. D.; Wentrup, C. J. Chem. Soc., Chem. Commun. 1968, 1082.
1. Crow, W. D.; Wentrup, C. Ibid. 1969, 1387.
2. Giammanco, L.; Invidiata, F. P. Heterocycles 1985, 23, 1459.
3. Inoue, T.; Matsumoto, K.; Ohta, A. J. Heterocycl. Chem. 1983, 20, 1277.
4. Watanabe, T.; Ueda, I.; Hayakawa, N.; Kondo, Y.; Adachi, H.; Iwasaki, A.; Kawamata, S.; Mentori, F.; Ichikawa, M.; Yuasa,
K.; Ohta, A.; Kurihara, T.; Miyamae, H. Ibid. 1990, 27, 711.
15. The starting heterocyclic tetrazoles were prepared by standard procedures starting from readily available chloro and amino
heterocycles.