Communications
DOI: 10.1002/anie.200701045
Cycloaddition
1,3-Dipolar Cycloaddition: Click Chemistry for the Synthesis of
5-Substituted Tetrazoles from Organoaluminum Azides and Nitriles**
Valentina Aureggi and Gottfried Sedelmeier*
Dedicated to Professor Horst Prinzbach
Tetrazoles are a class of heterocycles with a wide range of
applications that are receiving considerable attention.[1,2] This
functional group has a role in coordination chemistry[3] as well
as in various materials science applications, including photog-
raphy,[1] and specialty explosives.[4] Moreover, extensive work
has been carried out in the field of medicinal chemistry.[5]
Tetrazoles are frequently used as metabolically stable surro-
gates for carboxylic acids,[6] as the tetrazoles generally offer a
more favorable pharmacokinetic profile.[1,7] Driven in partic-
ular by the widespread incorporation of the tetrazole
functionality into angiotensin II antagonist structures (sar-
tans, Scheme 1), several methods have been described for the
synthesis of tetrazoles.[8c,9]
use of toxic metals, expensive reagents, and harsh reaction
conditions; water sensitivity; and the presence of dangerous
hydrazoic acid. In addition, the majority of methods use
dipolar aprotic solvents such as DMF. One of the most
common methods involves the use of sodium azide in the
presence of ammonium chloride or tertiary ammonium
chloride to form ammonium azide species in situ.[12–14] The
reaction is accompanied by the sublimation of explosive
NH4N3.[15] Trimethylsilyl and trialkyl tin azides are alternative
general reagents.[5,8d,16] In some cases, full conversion can only
be obtained with a large excess of azide and harsh reaction
conditions. The major drawback of this method is the difficult
removal of highly toxic residual organotin compounds at the
end of the reaction.[17] Organostannane catalysts are also
often used;[8d,17–19] however, it is difficult to completely
separate the desired product from the stannane compounds.
Aluminum azide was reported by Wiberg and Michaud in
1957.[20] However, during the workup, two moles of HN3 are
formed for every mole of product. Huff proposed a procedure
in 1993 using equimolar amounts of trimethylsilyl azide
activated by trimethylaluminum, but strongly hindered
nitriles resulted in poor conversion.[8b,21] Sharpless and co-
workers recently introduced the term “click chemistry” as a
chemical philosophy that uses only the most practical and
reliable chemical transformations.[22a] They have reported the
preparation of tetrazoles in water requiring stoichiometric
amounts of ZnII salts.[22] In the case of sterically hindered
aromatic or deactivated alkyl nitriles, high temperature (140–
1708C) and long reaction times are required.
During our investigation of alternative syntheses of sartan
derivatives, we became interested in finding an alternative
safe process for the preparation of tetrazoles on an industrial
scale. We report herein the discovery and development of a
novel process for the efficient transformation of a wide
variety of nitriles into the corresponding tetrazoles using
dialkyl aluminum azides. Diethylaluminum azide[23] is already
known as an activated azide donor for the conversion of esters
to acylazides,[24] ring opening of epoxyalcohols, and triazole
formation from a’-amino-a,b-unsaturated ketones[25] but has
never been employed in the synthesis of tetrazoles. We have
now found that organic aluminum azides are effective
reagents for the direct conversion of nitriles to tetrazoles
(Scheme 2).[26]
Scheme 1. Sartans.
The first reported method to synthesize tetrazoles was the
reaction of hydrazoic acid (HN3) with organic cyanides in
1932.[10] However, this procedure has not found practical
application on account of the high toxicity, explosive nature,
and low boiling point (378C) of hydrazoic acid. Currently, 5-
substituted tetrazoles are usually obtained by the addition of
azide salts to nitriles (typically at 100–1508C).[5,8,11] Unfortu-
nately, all of these protocols have disadvantages, including the
[*] V. Aureggi, Prof. Dr. G. Sedelmeier
Chemical & Analytical Development
Novartis Pharma AG
WKL.684.2.24, Klybeckstrasse 141, 4057 Basel (Switzerland)
Fax: (+41)61-696-2957
E-mail: gottfried.sedelmeier@novartis.com
[**] This work was supported by Novartis Pharma AG, Switzerland. We
would like to thank Prof. R. Neier (University of Neuchâtel) and Dr.
G. Penn (Novartis) for discussions, D. Grimler and B. BØrod for
technical support, Mr. F. Schürch for the preparation of 2, Dr. H.
Schroeder and Dr. B. Wagner for analysis, Dr. B. Martin and Dr. J.-T.
Blank for proofreading.
The differential scanning calorimetry (DSC) scans of
dialkyl aluminum azides are comparable to that of tributyltin
azide in terms of safety margins.[27] The aluminum reagents
can be prepared in a short time (Scheme 2) by addition of an
equimolecular amount of dialkyl aluminum chloride to
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Angew. Chem. Int. Ed. 2007, 46, 8440 –8444