pubs.acs.org/joc
It was agreed by most that the tetrazole ring resists
The Tetrazole 3-N-Oxide Synthesis
oxidation even when very strong oxidizing agents were
employed because of its low HOMO.6 Indeed, we found no
reports for the preparation of tetrazole N-oxides. The only
formation of nitrogen-oxygen bond in this family of com-
pounds led to 1- and 2-hydroxytetrazoles with a limited
scope of possible starting materials.7,8
Tal Harel and Shlomo Rozen*
School of Chemistry, Tel-Aviv University, Tel-Aviv,
Israel 69978
We report here that the N-selective oxidation of this ring,
leading to the N-oxide moiety, is possible when using the
acetonitrile complex of the hypofluorous acid: HOF CH3CN.
Received February 18, 2010
3
This readily made reagent9 has established itself as one of
the best oxygen transfer agents chemistry has in its arsenal.
HOF CH3CN is a unique source of a strong electrophilic
3
oxygen since it is bonded to fluorine, the only atom more
electronegative than itself. Its unusual properties constituted
the base of some theoretical studies concerning its geometry
and the general mechanism of the oxygen transfer pro-
cesses.10 Earlier processes developed with the aid of this
reagent are summarized in two reviews describing many first
or difficult to achieve transformations.11,12 Other unique
reactions involve synthesis of episulfones,13 oligothiophenes
S,S0-dioxides,14,15 quinoxaline N,N0-dioxides,16 R-alkylation
of natural amino acids,17 and more. Exploring the new
possibilities offered by this reagent in transforming tetrazole
rings into their corresponding N-oxide derivatives was there-
fore very attractive.
An efficient procedure for transferring an oxygen atom to
the 1- or 2-substituted 5-alkyl or aryl tetrazole ring, result-
ing, for the first time, in the corresponding N-oxides, was
developed using HOF CH3CN. This novel route features
3
mild conditions and high yields. X-ray structure analysis
and 15N NMR experiments indicate that the preferred
position for the incorporation of the oxygen is on the N-3
atom.
Treating 1,5-pentamethylenetetrazole (1a) with a stochio-
metric amount or small excess of HOF CH3CN did not
3
affect the starting material. However, using a large excess
(10 mol equiv) of the reagent at 0 °C changed the outcome and
the previously unknown 1,5-pentamethylenetetrazole-3N-
oxide (2a) was formed in 95% yield (50% conversion)18 in a
few minutes (Scheme 1). Electron-withdrawing groups located
at the carbon atom of the terazole as in 5-chloro-1-phenylte-
trazole (1b) did not inhibit the quantitative formation (50%
conversion, in minutes) of the new 5-chloro-1-phenyltetrazole-
3N-oxide (2b) (Scheme 1). The sterically hindered 1-cyclohex-
yl-5-(4-chlorobutyl)tetrazole (1c) was also successfully oxi-
Although not found in nature, the tetrazole ring appears in
a wide range of important products such as propellants,1
explosives,2 and many drugs.3 In the past decade, due to their
extraordinary stability under metabolic conditions, many
tetrazole derivatives showed enhanced biological activities
when used as antiviral, antibacterial, and antifungal agents,4
as well as when used as a promoter in the synthesis of
oligonucleotides.5
dized by the HOF CH3CN complex to give the previously
3
unknown 1-cyclohexyl-5-(4-chlorobutyl)tetrazole-3N-oxide
(6) Eicher, T.; Hauptmann, S. The chemistry of heterocycles; Thieme:
New York, 1995; p 212.
(7) Begtrup, M.; Vedsoe, P. J. Chem. Soc., Perkin Trans. 1 1995, 243–247.
(8) Giles, R. G.; Lewis, N. J.; Oxley, P. X.; Quick, J. K. Tetrahedron Lett.
1999, 40, 6093–6094.
(9) Dayan, S.; Bareket, Y.; Rozen, S. Tetrahedron 1995, 55, 3657–3664.
(10) (a) Srnec, M.; Oncak, M.; Zahradnik, R. J. Phys. Chem. A 2008, 112,
3631–3637. (b) Sertchook, R.; Boese, A. D.; Martin, J. J. Phys. Chem. A 2006,
110, 8275–8281. (c) Berski, S.; Lundell, J.; Latajka, Z.; Leszczynski, J.
J. Phys. Chem. A 1998, 102, 10768–10776.
*To whom correspondence should be addressed. Fax: þ972 3 640 9293.
Phone: þ972 3 640 8378.
(1) Brown, M. U.S. Patent 3,338,915, 1967; Chem. Abstr., 1968, 87299.
(2) (a) Tarver, C. M.; Goodale, T. C.; Shaw, R.; Cowperthwaite, M. Office of
Naval Research (Technical Report), ACR (U.S.), ACR-221, Proc. Symp. Int.
Detonation, 6th, 1967, pp 231-249; Chem. Abstr., 1980, 92, 8480. (b) Henry,
R. A. U.S. Patent 3,096,312, 1963.
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(5) (a) Hayakawa, Y.; Kataoka, M. J. Am. Chem. Soc. 1997, 119, 11758–
11762. (b) Beaucage, S. L.; Caruthers, M. H. Tetrahedron Lett. 1981, 22,
1859–1862. (c) Froehler, B. C.; Matteucci, M. D. Tetrahedron Lett. 1983, 24,
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(13) Harel, T.; Amir, E.; Rozen, S. Org. Lett. 2006, 8, 1213–1216.
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(15) Shefer, N.; Harel, T.; Rozen, S. J. Org. Chem. 2009, 74, 6993–6998.
(16) Carmeli, M.; Rozen, S. J. Org. Chem. 2006, 71, 5761–5765.
(17) Harel, T.; Rozen, S. J. Org. Chem. 2007, 72, 6500–6503.
(18) For example, “95% yield (50% conversion)” means that based on the
consumed SM the reaction is almost quantitative, while from the mole
equivalents perspective the product obtained is only about 50% of the mole
equivalents of the SM. The other unchanged 50% of the starting material
could be recycled.
DOI: 10.1021/jo100278z
r
Published on Web 03/26/2010
J. Org. Chem. 2010, 75, 3141–3143 3141
2010 American Chemical Society