Stereospecific synthesis of 1,5-disubstituted tetrazoles from ketoximes via a Beckmann rearrangement facilitated by diphenyl phosphorazidate

Article abstract of DOI:10.1016/j.tetlet.2019.04.014

A novel method for the stereospecific synthesis of 1,5-disubstituted tetrazoles from ketoximes via the Beckmann rearrangement was developed using diphenyl phosphorazidate (DPPA) as both the oxime activator and azide source. Various ketoximes were transformed into the corresponding 1,5-disubstituted tetrazoles with exclusive trans-group migration and no E-Z isomerization of the ketoxime. This method enables the preparation of 1,5-disubstituted tetrazoles without using toxic or explosive azidation reagents.

Full text of DOI:10.1016/j.tetlet.2019.04.014

Accepted Manuscript
Stereospecific Synthesis of 1,5-Disubstituted Tetrazoles from Ketoximes via a
Beckmann Rearrangement Facilitated by Diphenyl Phosphorazidate
Kotaro Ishihara, Takayuki Shioiri, Masato Matsugi
PII:
S0040-4039(19)30337-5
https://doi.org/10.1016/j.tetlet.2019.04.014
TETL 50729
DOI:
Reference:
Tetrahedron Letters
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Accepted Date:
23 February 2019
22 March 2019
3 April 2019
Please cite this article as: Ishihara, K., Shioiri, T., Matsugi, M., Stereospecific Synthesis of 1,5-Disubstituted
Tetrazoles from Ketoximes via a Beckmann Rearrangement Facilitated by Diphenyl Phosphorazidate, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.04.014
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Tetrahedron Letters
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Stereospecific Synthesis of 1,5-Disubstituted Tetrazoles from Ketoximes via a
Beckmann Rearrangement Facilitated by Diphenyl Phosphorazidate
Kotaro Ishihara, Takayuki Shioiri and Masato Matsugi
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +81-52-08332-01151; fax: +0-52-0835-07450; e-mail: matsugi@meijo-u.ac.jp
Article history:
Received
Received in revised form
Accepted
A novel method for the stereospecific synthesis of 1,5-disubstituted tetrazoles from ketoximes
via the Beckmann rearrangement was developed using diphenyl phosphorazidate (DPPA) as
both the oxime activator and azide source. Various ketoximes were transformed into the
corresponding 1,5-disubstituted tetrazoles with exclusive trans-group migration and no E-Z
isomerization of the ketoxime. This method enables the preparation of 1,5-disubstituted
tetrazoles without using toxic or explosive azidation reagents.
Available online
Keywords:
Ketoxime
2019 Elsevier Ltd. All rights reserved.
Beckmann Rearrangement
Diphenyl phosphorazidate
Tetrazole
Tetrazoles are a significant class of synthetic heterocyclic compounds that have been attracting increasing attention due to their wide
range of applications in various scientific fields.1 Among the tetrazole family, 1,5-disubstituted tetrazoles have been known to exhibit
biological activity.2 For example, cardiazol3 and cilostazol4 are 1,5-disubustituted tetrazoles that have been widely used medicinally for
treating schizophrenia and intermittent claudication, respectively.
Various methods have been developed for the synthesis of 1,5-disubstituted tetrazoles using a variety of substrates such as amides,
thioamides, nitriles, heterocumulenes, amines, ketones, and alkenes.5 Pioneering studies for the synthesis of 1,5-disubstituted tetrazoles from
oxime esters or ketones via the Beckmann6 or Schmidt rearrangement7 have also been reported.8 When using these methods, both the
starting materials and end products must be carefully handled because of their inherent toxicities and explosiveness.9
Diphenyl phosphorazidate (DPPA)10 is a less explosive azidation reagent than sodium azide or trifluoromethanesulfonyl azide due to the
stabilization of the azide via conjugation with the phosphorus atom. Recently, we have reported the synthesis of 5-substituted 1H-tetrazoles
from aldoximes using DPPA.11 This method improved the safety of this azidation operation and utilized DPPA as both the activator and
azide source. Therefore, 1,5-disubstituted tetrazoles could be obtained safely from ketoximes if a Beckmann-type rearrangement proceeded
by activation and azidation with DPPA.
Initially, we investigated whether the formation of a tetrazole via the Beckmann rearrangement with DPPA was viable using
acetophenone oxime 1a (E/Z=15/1) as a model substrate. We explored the reaction conditions by investigating various parameters, including
temperature, solvent, and base (Table 1).

2
Tetrahedron
The reaction performed using DPPA in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) in MeCN at room
temperature yielded the desired 1,5-disubstituted tetrazole product
2a with exclusively rearranged phenyl group. However, the yield
was low (Table 1, entry 1). To improve yields, the effect of
temperature on reactivity was examined (Table 1, entries 2 and 3).
The yield improved as the reaction temperature increased, and the
desired tetrazole 2a was obtained in high yield at reflux in MeCN.
The use of other solvents decreased the yield relative to MeCN
(Table 1, entries 4–8). The effect of base was also investigated;
however, the use of triethylamine (Et3N) or N,N-
diisopropylethylamine (DIPEA) only decreased the yield compared
with DBU (Table 1, entries 9 and 10). The use of excess reagent did
not improve the yields further (Table 1, entry 11). The tetrazole
product 2a was obtained in moderate yield at room temperature
using bis(p-nitrophenyl) phosphorazidate (p-NO2DPPA)12, which is
a more reactive phosphorazidate-type azidation reagent than DPPA.
However, the yield decreased when the reaction using p-NO2DPPA
was performed at 50 °C (Table 1, entry 13). Notably, the methyl-
rearranged 3a or hydrated products 4a were not observed as
byproducts in any of the tested conditions. Thus, the conditions of
entry 3 were the most suitable for our tetrazole formation reaction.
Since tetrazole ring formation via a Beckmann rearrangement
proceeded as anticipated, the substrate scope was investigated using
various ketoximes, as shown in Table 2. Except for entry 17 in Table 2, all reactions were performed using only the E ketoxime isomer.
Both aromatic and aliphatic substituted groups rearranged to afford the desired tetrazoles. When a single E-isomer of acetophenone oxime
1a was used, instead of the mixture of isomers used in Table 1, the desired product 2a was successfully obtained in a high yield (Table 2,
entry 1). As expected for the Beckmann rearrangement, electron-rich acetophenone oximes 1c improved the yield, whereas electron-poor
acetophenone oxime starting materials 1d-f led to lower yields (Table 2, entries 3–6). Halogenated acetophenone oximes 1g and 1h afforded
the corresponding tetrazoles in reasonable yields under these conditions (Table 2, entries 7 and 8). The substrate bearing a cyano group or a
nitro group afforded a complex mixture displaying a plurality of products, so each tetrazole could not be isolated (Table 2, entries 4 and 5).
Furthermore, heteroaromatic ketoximes 1j-l afforded lower yields compared with acetophenone oxime 1a (Table 2, entries 10–12).
Propiophenone 1m and benzophenone oximes 1n afforded the corresponding tetrazoles 2m and 2n in high yields (Table 2, entries 13 and
14) and vinylic ketoxime 1o afforded the desired product 2o in a high yield (Table 2, entry 15). Acetoxime 1p did not afford the
corresponding tetrazole; therefore, we believe the methyl
rearrangement is not favorable (Table 2, entry 16). Aliphatic
substrates afforded the corresponding tetrazoles in higher yields in
toluene than MeCN (Table 2, entries 17–24). Both acyclic and cyclic
ketoximes afforded the corresponding desired products. Although the
use of benzyl ketoxime 1q resulted in a low yield (Table 2, entry 17),

sterically hindered ketoximes 1v and 1x produced tetrazoles in moderate yields (Table 2, entries 22, and 24). Incidentally, entry 24 displays
the synthetic utility of this reaction being able to work with complex natural product-like molecules. In every reaction, only the trans-group
was exclusively rearranged.
We then applied this tetrazole formation method to bisaryl ketoxime 1y, which is prone to isomerization. As shown in Table 3, the
starting ratio of isomers resulted in the corresponding ratio of products; therefore, isomerization did not take place during our tetrazole
formation reaction. These results show that this reaction proceeds stereospecifically.
A plausible reaction mechanism for this reaction is shown in Scheme 1. Initially, the ketoxime is deprotonated by DBU and attacks
DPPA to form a phosphate intermediate. Subsequently, the phosphate intermediate undergoes a Beckmann rearrangement to generate a
nitrilium ion, followed by attack by the free azide anion and cyclization yields the desired tetrazole.
In summary, we developed a novel method for the synthesis of 1,5-tetrazole from ketoximes via a Beckmann rearrangement utilizing
DPPA as both the activator and azide source. Various ketoximes were easily converted into the corresponding tetrazoles. No ketoxime
isomerization occurred during the reaction and the rearrangement occurred stereospecifically with only the migration of trans-group. The
advantages of this method include operational simplicity and increased
safety as toxic or explosive azide reagents can be avoided.
General procedure
DPPA (52 μL, 0.24 mmol) and DBU (36 μL, 0.24 mmol) were
added to a solution of the ketoxime (0.20 mmol) in MeCN or toluene
(1 mL). After stirring for 16 h at reflux, the mixture was diluted with
AcOEt (30 mL). Then, the mixture was washed with saturated
aqueous NaHCO3 (25 mL) and brine (25 mL) and dried over Na2SO4.
Concentration of the solvent in vacuo followed by the purification of
the residue on a silica gel column (AcOEt:n-Hexane 1:3–3:1) yielded
the corresponding 1,5-disubstituted tetrazole.
Acknowledgments
This study was supported by the JSPS Grant-in-Aid for Scientific Research (C) number 26450145, and Professor Y. Uozumi’s JST-
ACCEL program (JPMJAC1401).
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Supplementary Material
Supporting information for this article is available online at XXX.
Graphical Abstract

4
Tetrahedron
Stereospecific Synthesis of 1,5-Disubstituted
Tetrazoles from Ketoximes via a Beckmann
Rearrangement Facilitated by Diphenyl
Phosphorazidate
Leave this area blank for abstract info.
Kotaro Ishihara, Takayuki Shioiri, and Masato Matsugi*
Highlights
・ Various ketoximes were easily converted into the corresponding tetrazoles.
・ No ketoxime isomerization occurred during the reaction.
・ The rearrangement occurred stereospecifically with the migration of trans group.
・ Tetrazoles can be prepared without using toxic or explosive azidation reagents.