Synthesis of 5-Substituted 1 H -Tetrazoles from Aldoximes Using Diphenyl Phosphorazidate

Article abstract of DOI:10.1055/s-0035-1561668

A novel method for the synthesis of 5-substituted 1H-tetrazoles using diphenyl phosphorazidate (DPPA) has been developed. Aromatic and aliphatic aldoximes underwent cycloaddition to afford the corresponding 5-substituted 1H-tetrazoles with ease and efficiency.

Full text of DOI:10.1055/s-0035-1561668

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
K. Ishihara et al.
Letter
Synlett
Synthesis of 5-Substituted 1H-Tetrazoles from Aldoximes Using
Diphenyl Phosphorazidate
Kotaro Ishihara
O
Mayumi Kawashima
PhO
P
OPh
Takayuki Shioiri
N3
Masato Matsugi*
DPPA (1.5 equiv)
N
N
N
N
OH
DBU (3.0 equiv)
toluene, reflux
R
Department of Applied Biological Chemistry, Faculty of Agriculture,
Meijo University, 1-501 Shiogamaguchi, Tempaku-ku, Nagoya 468-
8502, Japan
R
N
H
20 examples
up to 93% yield
matsugi@meijo-u.ac.jp
Received: 13.04.2016
Accepted after revision: 16.05.2016
Published online: 22.06.2016
15;22 and COY zeolite.23 Recently, methods for the synthesis
of 5-substituted 1H-tetrazoles by the reaction of aldoximes
or aldehydes with azide sources in the presence of copper24
DOI: 10.1055/s-0035-1561668; Art ID: st-2016-u0255-l
25
or InCl3 catalyst have been reported; however, these
Abstract A novel method for the synthesis of 5-substituted 1H-tetra-
zoles using diphenyl phosphorazidate (DPPA) has been developed. Aro-
matic and aliphatic aldoximes underwent cycloaddition to afford the
corresponding 5-substituted 1H-tetrazoles with ease and efficiency.
methods suffer from disadvantages because of the use of
toxic metals and explosive azide sources. Therefore, safe
and environmentally friendly methods for the synthesis of
tetrazoles are preferable.
Key words diphenyl phosphorazidate, aldoximes, azides, cycloaddi-
On the other hand, diphenyl phosphorazidate [DPPA,
(C6H5O)2P(O)N3]26 is less explosive because of the stabiliza-
tion from the phosphorus atom. Thus, the application of
DPPA to the synthesis of 5-substituted 1H-tetrazoles would
be desirable. Herein, we report an easy and efficient meth-
od for the synthesis of 5-substituted 1H-tetrazoles from al-
doximes using DPPA. This method enables the preparation
of tetrazoles without the use of toxic metals and explosive
azide sources, and the synthetic procedure is very simple.
We initially explored the optimum reaction conditions
through the reaction of benzaldoxime with DPPA as a mod-
el reaction. The reaction conditions were optimized by in-
vestigating various parameters, such as temperature, equiv-
alents of reagents, base, and solvent. To investigate the ef-
fect of temperature on the reactivity, the reaction was
performed at various temperatures in toluene (Table 1, en-
tries 1–4). While the desired tetrazole was not obtained at
room temperature, yields were improved as the reaction
temperature increased. As a result, the desired tetrazole
was obtained in high yield at 110 °C (at reflux). The amount
of reagents was also investigated. The reaction smoothly
tion, tetrazoles
Tetrazoles are heterocyclic compounds comprising a
five-membered ring with one carbon and four nitrogen at-
oms and are unknown in nature. The interest in tetrazole
chemistry over the recent decade has increased rapidly be-
cause tetrazoles have found a wide range of applications in
various areas of science. In medicinal chemistry, they are
utilized as bioisosteres because the tetrazole ring can act as
a biological equivalent to a carboxyl group.1 The tetrazole
functionality shows biological activities, such as in angio-
tensin II antagonists2 and antiallergic,3 antibiotic,4 and anti-
viral agents.5 Moreover, tetrazoles have played a significant
role as ligands in coordination chemistry6 and materials sci-
ence.7
The general method for the synthesis of 5-substituted
1H-tetrazoles is the [3+2]-cycloaddition reaction between
nitriles and azides. Various methods have been developed
for the synthesis of 5-substituted 1H-tetrazoles. These
methods used various catalysts such as copper (CuI,8a
CuO,8b Cu2O,8c and CuFe2O48d); iron [Fe(OAc)2 and FeCl3-
proceeded when
a
large excess of 1,8-diazabicy-
9a
SiO29b]; ZnCl2;10 AlCl3;11 CdCl2;12 boron compounds
clo[5.4.0]undec-7-ene (DBU) relative to DPPA was used (Ta-
ble 1, entries 4–6). The use of triethylamine (Et3N) or N,N-
diisopropylethylamine (DIPEA) as a base decreases the yield
relative to DBU (Table 1, entries 7, 8).
13a
[BF3·OEt2
and B(C6H5)313b]; cyanuric chloride;14 CAN;15
TABF;16 BaWO4;17 Ln(OTf)3-SiO2;18 NaHSO4-SiO2;19 meso-
porous ZnS nanospheres;20 Zn/Al hydrotalcite;21 amberlyst-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
K. Ishihara et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditions
formation because the nitrile product was not observed,
and this reaction was suppressed with the use of p-NO2DPPA.
If the reaction proceeded via a nitrile, the phosphate inter-
mediate derived from p-NO2DPPA would accelerate the for-
mation of the nitrile intermediate by the higher elimination
ability than DPPA phosphate.
N
N
OH
N
N
DPPA, base
N
H
solvent, temp., 16 h
(E/Z =10/1)a
Entry DPPA (equiv) Base (equiv)
Solvent
Temp (°C) Yield (%)
Table 2 Synthesis of 5-Substituted 1H-Tetrazoles from Aldoximes
1
2
1.5
1.5
1.5
1.5
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (2.5)
DBU (2.5)
Et3N (3.0)
DIPEA (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
r.t.
n.d.
9
70
DPPA (1.5 equiv)
N
N
N
DBU (3.0 equiv)
N
OH
3
90
43
93
83
86
43
51
70
16
30
56
R
R
N
toluene, reflux, 16 h
4
110
110
110
110
110
110
66
H
5
Entry Substrate (E/Z)a
Product
Yield (%)
93
6
N
OH
N
7
N
1
N
N
H
8
(10/1)
9
N
OH
N
10
11
12b
THF
N
Cl
Cl
2
89
81
81
77
73
38
85
80
N
MeCN
82
N
H
(16/1)
toluene
110
N
OH
a Determined by 1H NMR spectroscopy.
N
N
N
Br
b p-NO2DPPA was used instead of DPPA.
Br
3
N
H
(6/1)
The desired tetrazole was obtained in high yield, but it
was tried to further optimize the reaction conditions by in-
vestigating different solvents (Table 1, entries 9–11). How-
ever, the use of other solvents decreased the yield com-
pared with toluene. Although bis(p-nitrophenyl) phos-
phorazidate (p-NO2DPPA)27 proved to be more effective
than DPPA in the direct conversion of alcohols into azides, it
was unexpectedly less reactive than DPPA in this tetrazole
synthesis (Table 1, entry 12).
Encouraged by these results, the substrate scope was in-
vestigated using various aldoximes, as shown in Table 2. Ar-
omatic and heteroaromatic aldoximes gave the desired
products in high yields, whereas aliphatic aldoximes need-
ed a long reaction time to afford the corresponding tetra-
zoles in moderate yields. Aliphatic aldoximes afforded low-
er yields than aromatic ones. This observation was in accor-
dance with previous reports using other azide
sources.24a,b,25 Aromatic aldoximes containing an electron-
withdrawing group decrease the yields (Table 2, entries 5–
7), and sterically hindered aldoximes resulted in extremely
low yields (Table 2, entries 10, 20). In these cases, the reac-
tions did not proceed completely. Allylic aldoxime also did
not afford the desired tetrazoles because of undesirable
side reactions (Table 2, entry 15).
N
N
OH
N
N
N
MeO
MeO
O2N
MeO2C
4
N
H
(13/1)
OH
N
N
O2N
5
N
N
H
(10/1)
N
OH
N
N
N
MeO2C
6
N
H
(17/1)
N
OH
N
N
NC
NC
7
8
9
N
N
H
(10/1)
N
OH
N
N
N
N
H
(10/1)
N
OH
N
N
N
N
H
(10/1)
OH
N
N
N
N
N
H
The proposed reaction mechanism for this cycloaddi-
tion is shown in Scheme 1.24a The reaction presumably pro-
ceeds via a phosphate intermediate; DPPA activates the C=N
bond through an interaction of the oxygen atom of aldox-
ime. Subsequently, the cycloaddition of the azide ion across
the C=N bond followed by elimination affords the desired
tetrazole. This reaction presumably does not involve nitrile
10
14
(4/1)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
K. Ishihara et al.
Letter
Synlett
Table 2 (continued)
In conclusion, we have developed a novel method for
the synthesis of 5-substituted 1H-tetrazole using DPPA.28,29
Various aldoximes were easily converted into the corre-
sponding 5-substituted 1H-tetrazoles. The advantages of
this method are (1) the replacement of toxic metals and ex-
plosive azide sources with DPPA, and (2) the synthetic pro-
cedure is very simple.
Entry Substrate (E/Z)a
Product
Yield (%)
90
N
OH
N
N
N
11
N
H
(3/7)
N
OH
O
O
N
N
N
12
13
92
83
N
H
Acknowledgment
(2/1)
This work was supported by JSPS Grant-in-Aid for Scientific Research
(C), 26450145, and Prof. Y. Uozumi’s JST-ACCEL program.
H
N
H
N
N
OH
N
N
N
N
H
(5/2)
Supporting Information
N
N
OH
Supporting information for this article is available online at
N
N
14
35
N
http://dx.doi.org/10.1055/s-0035-1561668.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
H
HN
HN
(4/1)
N
References and Notes
OH
N
N
N
complex
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15
16
17
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N
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DPPA
DBU
O
OPh
N3
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P
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N
OPh
O
OPh
OPh
–N3
O
R
R
N
P
O
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H+ (work-up)
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N
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DBU
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OPh
OPh
N
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O
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Scheme 1 Proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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K. Ishihara et al.
Letter
Synlett
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(28) General Procedure
DPPA (0.30 mmol) and DBU (0.60 mmol) were added to a solu-
tion of aldoxime (0.20 mmol) in toluene (1.0 mL). After stirring
for 16 h at reflux, the mixture was cooled to room temperature
and sat. NaHCO3 aq (2.0 mL) was added. After stirring for 5 min,
the mixture was diluted with water (20 mL). The aqueous layer
was then washed with EtOAc (25 mL) and acidified with 1.0 N
HCl aq to pH 2. The aqueous layer was extracted with EtOAc (2 ×
30 mL), and the combined organic extracts were washed with
brine (30 mL) and dried over Na2SO4. The concentration of the
solvent in vacuo followed by the purification of the residue
through a short silica gel column (EtOAc–n-hexane = 1:1 to 3:1)
gave the desired tetrazole.
Analytical Data for 5-Phenyl-1H-tetrazole (Table 2, Entry 1)
White solid; mp 214 °C. 1H NMR (270 MHz, DMSO-d6): δ =
7.60–7.66 (m, 3 H), 8.03–8.07 (m, 2 H).
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