Preparation of 1,5-fused tetrazoles under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200054219

A facile and efficient procedure is developed for a one-pot synthesis of fused 1,5-disubstituted tetrazoles from cyclic ketones and sodium azide in the presence of aluminum chloride in solvent-free media. Advantages of this method are chemoselectivity, with high yields in a simple operation, and short reaction time under solvent-free conditions. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054219

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Preparation of 1,5‐Fused Tetrazoles Under
Solvent‐Free Conditions
Hossein Eshghi a & Asadollah Hassankhani b
a Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran
b Department of Chemistry, Sistan & Baluchestan University, Zahedan, Iran
Published online: 16 Aug 2006.
To cite this article: Hossein Eshghi & Asadollah Hassankhani (2005) Preparation of 1,5‐Fused Tetrazoles Under
Solvent‐Free Conditions, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:8, 1115-1120, DOI: 10.1081/SCC-200054219
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Synthetic Communicationsw, 35: 1115–1120, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054219
Preparation of 1,5-Fused Tetrazoles Under
Solvent-Free Conditions
Hossein Eshghi
Department of Chemistry, Ferdowsi University of Mashhad,
Mashhad, Iran
Asadollah Hassankhani
Department of Chemistry, Sistan & Baluchestan University,
Zahedan, Iran
Abstract: A facile and efficient procedure is developed for a one-pot synthesis of fused
1,5-disubstituted tetrazoles from cyclic ketones and sodium azide in the presence of
aluminum chloride in solvent-free media. Advantages of this method are chemoselec-
tivity, with high yields in a simple operation, and short reaction time under solvent-free
conditions.
Keywords: Aluminum chloride, ketones, tetrazoles, solvent-free
Tetrazole derivatives have attracted much attention as raw materials for
medicine, agricultural chemicals, and foaming agents, and in the automobile
inflator industry.[1,2] Especially in recent years, remarkable related develop-
ments have been made in the construction of potential anti-inflammatory,[3]
antibiotic, and antiviral agents;[1] central nervous stimulants;[4] phospho-
diesterase;[5] O-acyltransferase;[6] glycosidase inhibitors;[7] and hyperten-
sives.[8] Also, pentamethelenetetrazole has been extensively used in models
for anxiety.[9]
Received in the U.K. October 21, 2004
Address correspondence to Hossein Eshghi, Department of Chemistry, Ferdowsi
University of Mashhad, Mashhad 91775-1436, Iran. E-mail: heshghi@hamoon.
usb.ac.ir

1116
H. Eshghi and A. Hassankhani
1,5-Disubsituted tetrazoles can be synthesized by a number of methods,
for example, reaction of hydrazoic acid or its salt with imidoyl chlorides or
imino ethers, addition of alkyl (aryl) azides to nitriles, diazo coupling
of heterocyclic hydrazines, Schmidt synthesis from ketones, and also by
some other methods, which are of limited use in preparative organic
chemistry.[10–13] Among these, the Schmidt reaction of ketones with
hydrazoic acid or inorganic azides is the most widely employed method and
forms the subject of a considerable number of patents.[14] Several variants
of the procedure have been employed.[15,16] The interaction of ketoxime
esters (or the necessary reactants for their formation) and azides may be
used to obtain fused-ring tetrazoles.[17,18] In all of these procedures,
however, the use of hydrazoic acid presents considerable experimental diffi-
culties because of its toxicity and tendency to explode. Replacement of
hydrazoic acid by inorganic azides, which are poorly soluble in organic
solvents with low dielectric constants, causes an increase in reaction time
and decrease in tetrazole yield. Because of this, it was of interest to investigate
the formation of fused 1,5-disubstituted tetrazoles from cyclic ketones and
sodium azide under solvent-free conditions. To the best our knowledge, this
report describes the first examples of the synthesis of fused tetrazoles in
solvent-free media.
A mixture of cyclohexanone and sodium azide was mixed portion-wise
with aluminium chloride in an agate mortar at 508C for 10 min. Metrazole
(also known as cardiazole and 1,5-pentamethylenetetrazole) was obtained in
95% yield, which has been thoroughly studied by a number of investigators
and forms the subject of a considerable number of patents.[14]
Simple grinding of a mixture of cyclic ketones and sodium azide in the
presence of aluminum chloride at 508C usually provides pure fused tetrazoles.
The general reaction is illustrated according to Scheme 1 and the results are
reported in Table 1. All reactions were performed in 10–15 min. As shown
in Table 1, the range of the cyclic ketones that participate in these reactions
is quite broad. The tetrazoles formed can be fused to six-, seven-, eight-,
and nine-membered ring systems. Asymmetrical ketones (entries 5 and 8)
and symmetrical ketones (entries 1–4, 6) gave corresponding pure tetrazoles
Scheme 1.

Table 1. One-pot preparation of fused tetrazoles from cyclic ketones under solvent-free conditions
1H Chemical shift of
a hydrogensb
Time
(min)
Yields %
(isolated)
Mp/8C
Found (Lit.)
Entry
1
Substance
Productsa
Ha-N
Ha-C
10
90
4.4 (2)
3.0 (2)
116 (117)[16]
2
3
12
10
95
88
4.5 (2)
4.4 (2)
3.1 (2)
3.1 (2)
59 (59)[19]
69 (68)[16]
4
5
15
15
75
78
4.4 (2)
4.8 (1)
3.1 (2)
3.1 (2)
42 (42–3)[16]
33 (32)[17]
(continued)

Table 1. Continued
1H Chemical shift of
a hydrogensb
Time
(min)
Yields %
(isolated)
Mp/8C
Found (Lit.)
Entry
6
Substance
Productsa
Ha-N
Ha-C
15
15
85
51
4.7 (2)
3.3 (2)
42 (43–4)[17]
7
8
4.5 (2)
3.2 (2)
113 (115–7)[17]
15
65
—
3.1 (1)
2.9 (1)
242–3 (245–7)[20]
a IR, H-NMR, and mp confirmed structures.
b The numbers within the parentheses are the respective relative areas.
1

Preparation of 1,5-Fused Tetrazoles
1119
as the only products. In entry 7, a mixture of tetrazole was obtained by ratio of
65:35, with the major product being the one where the more bulky group has
migrated. Purification was achieved using column chromatography.
1
The H NMR (CDC13, 80 MHz) spectra of the fused tetrazoles are essen-
tially the same pattern, with two triplet bands at about d 4.3–4.8 and 2.9–3.3, cor-
1
responded to a-hydrogens of methylene groups. The H chemical shifts of
a-hydrogens are given in Table 1. The IR (KBr) spectra in all cases were
shown stretching vibrations pattern of the tetrazoles in region of about 1520,
1470, 1430, and 1250 cm21
.
In our procedure, we added a mixture of ketone and sodium azide,
portion-wise to AlCl3, and we have not observed exploding. However, in
reverse addition, explosion occurred.
In conclusion, the present procedure provides a very efficient method
for preparation of fused 1,5-disubstituted tetrazoles from cyclic ketones.
The notable advantages of this method are operational simplicity, the ready
availability of reactants, short reaction times, high yields, solvent-free con-
ditions, and good selectivity without formation of by-products[15a] such as
amides, nitriles, ureas, and o-amino tetrazoles.
EXPERIMENTAL
All melting points recorded are uncorrected open capillary measurements. IR
1
spectra were recorded on a Shimadzu-IR 470 spectrophotometer. H-NMR
spectra were recorded on a Bruker-80 and 500 MHz instrument using tetra-
methylsilane (TMS) as an internal standard. Mass spectra were determined
on a Shimadzu GCMS-QP 1000 EX instrument at 70 eV. Column chromato-
graphy was carried out on short columns of silica gel 60 (230–400 mesh) in
glass columns (2–3 cm diameter) using 15–30 g of silica gel per 1 g of crude
mixture. Silica gel 60 (230–400 mesh) was purchased from Fluka.
Preparation of Fused Tetrazoles
General Procedure
In a typical reaction, a mixture of ketone (1 mmol) and sodium azide (4 mmol)
was mixed portion-wise with aluminium chloride (3 mmol) in an agate mortar.
The mixture was grounded at 508C for 10–15 min. The completion of the
reaction was monitored by TLC (CH2C12/CH3OH-98:2) examination. After
the completion of the reaction, the mixture was cooled at room temperature,
and then water (5 ml) was added to the mixture. The resulting solution was
extracted with CH2Cl2 (2 Â 10 ml). The extracts were combined and dried
over CaCl2. Evaporation of the solvent gave tetrazoles with high purity
1
(entries 1–6, 8) (based on TLC, H-NMR, IR, and melting point). Column

1120
H. Eshghi and A. Hassankhani
chromatography of crude product of entry 7 by CH2Cl2/n-hexane eluent gave
the major product in 51% yield. Physical properties of the products thus
obtained were in good agreement with reported data.[16–20]
REFERENCES
1. Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499.
2. Butler, R. N. Comprehensive Heterocyclic Chemistry II; Storr, R. C., Ed.; Elsevier:
Oxford, UK, 1996; Vol. 4, pp. 621–678.
3. Juby, P. F.; Hudyma, T. W.; Brown, M. J. Med. Chem. 1968, 11, 111.
4. Herbst, R. M.; Roberts, C. W.; Givens, H. T.F.; Harvill, E. K. J. Org. Chem. 1952,
17, 262.
5. Segarra, V.; Crespo, M. I.; Pujol, F.; Beleta, J.; Domenech, T.; Miralpeix, M.;
Palacios, J. M.; Castro, A.; Marinez, A. Bioorg. Med. Chem. Lett. 1998, 8, 505.
6. O’Brien, P. M.; Sliskovich, D. R.; Bernabei, A.; Hurley, T.; Anderson, M. K.;
Bousley, R. F.; Krause, B. R.; Stanfield, R. L. Bioorg. Med. Chem. Lett. 1995,
5, 295.
7. Heightman, T. D.; Ermert, P.; Klein, D.; Vasella, A. Helv. Chim. Acta 1995, 78, 514.
8. (a) Duncia, J. V.; Carini, D. J.; Chiu, A. T.; Johnson, A. L.; Price, W. A.;
Wong, P. C.; Wexler, R. R.; Timmermans, P. B. M. W. M. Med. Res. Rev.
1992, 12, 149; (b) Smith, R. D.; Duncia, J. V.; Lee, R. J.; Christ, D. D.;
Chiu, A. T.; Carini, D. J.; Herblin, W. F.; Timmermans, P. B. M. W. M.;
Wexler, R. R.; Wong, P. C. Methods Neurosci. 1993, 13, 258.
9. (a) Huang, R.-Q.; Bell-Horner, C. L.; Dibas, M. I.; Covey, D. F.; Drewe, J. A.;
Dillon, G. H. J. Pharmacol. Exp. Ther. 2001, 298, 986; (b) Jung, M. E.; Lal, H.;
Gatch, M. B. Neurosci. Biobehav. Rev. 2002, 26, 429.
10. Butler, R. N. Adv. Heterocycl. Chem. 1977, 21, 323.
11. Koldobskii, G. I.; Ostrovskii, V. A.; Poplavskii, V. S. Khim. Geterotsikl. Soedin.
1981, 1299; Chem. Abstr. 1981, 95, 219973.
12. Koldobskii, G. I.; Ostrovskii, V. A. Russ. Chem. Rev. 1994, 63, 847 (Engl. transl.
1994, 63, 797).
13. (a) Klier, A. H.; Alves, R. J.; Prado, M. A. F.; Filho, J. D. S.; D’Accorso, N. B.
Synth. Commun. 2000, 30, 4361; (b) Vonhoff, S.; Vasella, A. Synth. Commun.
1999, 29, 551.
14. (a) Knoll, A. G. Chemische fabriken, German Patent 574,943, 1933, Chem. Abstr.
1933, 27, 4541; (b) Knoll, A. G. Chemische fabriken, German Patent 545,850,
Chem. Abstr. 1932, 26, 3516; (c) Knoll, A. G. Chemische fabriken, British
Patent 350,782, Chem. Abstr. 1932, 26, 5311; (d) Schmidt, K. F., U.S. Patent
1,599,493, Chem. Abstr. 1926, 20, 3460.
15. (a) Smith, P. A. S.; Antoniades, E. P. Tetrahedron 1960, 9, 210; (b) Condon, F. E.;
Waldman, R.; Kundu, N.; Trivedi, J. P. Synth. Commun. 1974, 6, 135.
16. D’Itari, F. M.; Popov, A. I. J. Am. Chem. Soc. 1968, 90, 6476.
17. Harvill, E. K.; Roberts, C. W.; Herbst, R. M. J. Org. Chem. 1950, 15, 58.
18. Burke, R. L.; Herbst, R. M. J. Org. Chem. 1955, 20, 726.
19. Schmidt, K. F. Ber. 1924, 57, 704.
20. Hunter, N. R.; Khan, M. Z.; Marat, K.; El-Kabbani, O. A. L.; Delbaere, L. T. J.
Can. J. Chem. 1987, 65, 137. .