A Practical Synthesis of 5-Substituted 1 H -Tetrazoles from Aldoximes Employing the Azide Anion from Diphenyl Phosphorazidate

Article abstract of DOI:10.1055/s-0036-1591851

5-Substituted 1 H -tetrazoles were effectively synthesized from aldoximes and diphenyl phosphorazidate (DPPA) under reflux conditions in xylenes. Various aldoximes underwent the cycloaddition reaction to afford the corresponding 5-substituted 1 H -tetrazoles in short reaction times and in good yields. Chiral aldoximes derived from amino acids also gave aminotetrazoles with almost no racemization.

Full text of DOI:10.1055/s-0036-1591851

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
K. Ishihara et al.
Paper
Synthesis
A Practical Synthesis of 5-Substituted 1H-Tetrazoles from Aldoximes
Employing the Azide Anion from Diphenyl Phosphorazidate
Kotaro Ishiharaa
(PhO)2P(O)N3
(DPPA; 1.5 equiv)
DBU (3.0 equiv)
Mayumi Kawashimaa
Takatoshi Matsumotob
Takayuki Shioiria
N
N
N
N
OH
R
R
N
H
xylenes, reflux, 2–16 h
24 examples
43–99% yield
R = aryl, heteroaryl, alkyl
R
Masato Matsugi*a
R
a Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi,
Tempaku, Nagoya 468-8502, Japan
DPPA, DBU
PG
N
PG
N
N
N
OH
N
H
no or little racemization
H
matsugi@meijo-u.ac.jp
HN
N
b Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, 2-1-1, Katahira, Aobaku, Sendai 980-8577,
Japan
33
Received: 13.09.2017
the presence of copper32 or InCl3 catalysts have also been
reported. However, some methods have disadvantages such
as the need for toxic metals and explosive azide sources.
Recently, we reported the synthesis of 5-substituted
1H-tetrazoles from aldoximes by using diphenyl phos-
phorazidate [DPPA, (PhO)2P(O)N3].34,35 This method is safe
and environmentally friendly as it does not require toxic
metals or explosive azide sources. However, the yields of
the desired products were unsatisfactory and longer reac-
tion times were required when sterically hindered sub-
strates were used. Subsequent DFT (B3LYP) calculations in-
dicated that the thermal energy was insufficient to exceed
the activation energy barrier in these cases. Increasing the
reaction temperature appeared to improve the reactivity.
Herein, we report the entire study, including an improve-
ment in the reaction conditions for the rapid synthesis of
5-substituted 1H-tetrazoles in good yields, and the applica-
tion in chiral 1H-tetrazole synthesis by using optically ac-
tive substrates derived from amino acids.
We initially thought to optimize the reaction conditions
using benzaldoxime in a model reaction. The reaction con-
ditions were examined by investigating various parameters,
including base, solvent, temperature, and reaction time. To
investigate the effect of temperature on the reactivity, the
reaction was performed at various temperatures and with
different solvents (Table 1, entries 1–9). While the desired
tetrazole was not obtained at room temperature, the yields
improved with increasing reaction temperature in toluene.
Elevation of the reaction temperature by using xylenes,
which has a higher boiling point, increased the yield and
the reaction was complete in four hours. The use of DMF
also afforded the desired product in a short time and in a
high yield when the reaction temperature was increased,
but the use of other solvents with lower boiling points de-
creased the yields. Other bases were also screened (entries
10–12). The use of pyridine, triethylamine, or N,N-diisopro-
Accepted after revision: 07.11.2017
Published online: 12.12.2017
DOI: 10.1055/s-0036-1591851; Art ID: ss-2017-f0595-op
Abstract 5-Substituted 1H-tetrazoles were effectively synthesized
from aldoximes and diphenyl phosphorazidate (DPPA) under reflux con-
ditions in xylenes. Various aldoximes underwent the cycloaddition reac-
tion to afford the corresponding 5-substituted 1H-tetrazoles in short re-
action times and in good yields. Chiral aldoximes derived from amino
acids also gave aminotetrazoles with almost no racemization.
Keywords diphenyl phosphorazidate, aldoximes, azides, cycloaddi-
tion, tetrazoles
Tetrazoles make up an important class of synthetic het-
erocyclic compounds. Lately, tetrazole components have at-
tracted increasing attention due to their wide range of ap-
plications in various areas of science.1 Especially in medici-
nal chemistry, tetrazole rings have been utilized as
bioisosteres for carboxyl groups owing to their similar
properties.2 Therefore, the tetrazole functionality is found
in pharmaceuticals, such as in antihypertensive,3 antiallergic,4
antibiotic,5 antineoplastic,6 and antiviral agents.7 They have
also been used in agrochemicals,8 as ligands in coordination
chemistry,9 and in materials science.10
Numerous methods have been developed for the syn-
thesis of tetrazoles;11–14 5-substituted 1H-tetrazoles have
been generally synthesized by the [3+2]-cycloaddition re-
action between nitriles and azides in the presence of vari-
ous catalysts, such as copper (CuI,15a CuO,15b Cu2O,15c and
CuFe2O415d), iron [Fe(OAc)216a and FeCl3–SiO216b], zinc (ZnCl2
17a
and ZnBr217b–d), AlCl3;18 CdCl2,19 boron compounds
20a
[BF3·OEt2
and B(C6F5)320b], cyanuric chloride,21 CAN,22
TABF,23 BaWO4,24 Ln(OTf)3–SiO2,25 NaHSO4–SiO2,26 meso-
porous ZnS nanospheres,27 Zn/Al hydrotalcite,28 amberlyst-15,29
COY zeolite,30 and clay.31 Methods for the synthesis of 5-
substituted 1H-tetrazoles from aldoximes or aldehydes in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
K. Ishihara et al.
Paper
Synthesis
pylethylamine decreased the yields relative to 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU). Although bis(p-nitrophenyl)
phosphorazidate (p-NO2DPPA)36 is more reactive than DPPA
in the direct conversion of alcohols into azides, it was unex-
pectedly less reactive than DPPA in this tetrazole synthesis
(entry 13). The yield was scarcely decreased when the
quantities of DPPA and DBU were reduced (entry 14). As a
result, the reaction proceeded smoothly with DBU in hot
xylenes.
thesize these compounds (entry 12). Similarly, aliphatic al-
doximes afforded improved yields under these conditions
(entries 20–24). In particular, a sterically hindered aldoxime
dramatically increased the yield (entry 24). Using an aldox-
ime with a nitro group did not change the yield owing to
decomposition of the product (entry 6). Using a substrate
containing a cyano group also did not improve the yield,
due to formation of a byproduct (entry 13). Vinylic aldox-
ime did not afford the desired tetrazole in either solvent,
because of undesirable side reactions (entry 19).
Next, we conducted an experiment to apply this method on
gram scale. The substrate was used on gram scale in this reac-
tion to afford the desired product in high yield (Scheme 1).
Table 1 Optimization of Reaction Conditions
DPPA (1.5 equiv)
N
N
N
N
OH
base (3.0 equiv)
N
solvent, temp, time
H
DPPA (1.2 equiv)
N
N
N
N
OH
E/Z = 10:1a
DBU (2.4 equiv)
xylenes, reflux, 4 h
99%
N
H
E/Z = 10:1a
Entry
Base
Solvent
Temp (°C)
Time (h) Yield (%)
1.21 g
1.44 g
1
2
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
pyridine
Et3N
DIPEA
DBU
DBU
toluene
toluene
toluene
toluene
xylenes
DMF
r.t.
16
16
16
16
4
n.d.b
9
Scheme 1 Gram-scale synthesis of 5-substituted 1H-tetrazole. a Deter-
70
mined by 1H NMR.
3
90
43
93
99
70
92
16
30
43
40
25
56
93
4
110
We then demonstrated the application of this method
to the synthesis of optically active chiral substrates derived
from amino acids and investigated racemization in this
reaction. As shown in Scheme 2, both substrates were con-
verted into the corresponding aminotetrazoles in moderate
yields. The aldoxime derived from proline was reacted un-
der optimized conditions to give the desired product with-
out loss of enantiomeric purity (Scheme 2, a). The aldoxime
derived from leucine afforded the tetrazole with a little
racemization. In this case, the reaction was conducted at
90°C in toluene because of decomposition of the product at
high temperatures (Scheme 2, b). These tetrazoles were
methylated to measure the enantiomeric excess by HPLC.17c
By employing this method, optically active aldoximes can
be converted into the corresponding tetrazoles with no or
little racemization. This method would be useful for the
synthesis of optically active 1H-tetrazoles.
5
138–144
110
6
16
4
7
DMF
140
8
THF
66
16
16
4
9
MeCN
82
10
11
12
13c
14d
xylenes
xylenes
xylenes
toluene
xylenes
138–144
138–144
138–144
110
4
4
16
4
138–144
a E/Z ratio determined by 1H NMR.
b n.d. = not determined.
c p-NO2DPPA was used instead of DPPA.
d DPPA (1.0 equiv) and DBU (2.0 equiv) were used.
With the optimal reaction conditions in hand, the sub-
strate scope was investigated using various aldoximes in
toluene or xylenes, as shown in Table 2. The desired prod-
ucts were not obtained in good yields and a long reaction
time was needed when toluene was used, while the use of
xylenes afforded the desired products in good yields and in
a short reaction time even when inert substrates were used.
Aromatic and heteroaromatic aldoximes gave the desired
tetrazoles in high yields after short reaction times (entries
1–18). It is noteworthy that the reaction proceeded suc-
cessfully even for substrates with substituent groups at the
ortho positions when xylenes are used as solvent (entries
10, 12, 15 and 18). Since it is known that some biologically
active compounds have the same skeleton, such as losartan
or candesartan,3 this method can be used to effectively syn-
DPPA (1.5 equiv)
DBU (3.0 equiv)
N
N
(a)
N
N
OH
N
xylenes, reflux, 16 h
58%
Boc
HN
Boc
N
E/Z = 1:1a
>99% eeb
>99% eec
DPPA (1.5 equiv)
DBU (3.0 equiv)
(b)
Cbz
N
Cbz
N
toluene, 90 °C, 16 h
68%
N
N
N
OH
H
H
HN
N
E/Z = 1:1a
>99% eeb
97% eec
Scheme 2 Application to chiral aldoximes. a Determined by 1H NMR. b
Determined by chiral HPLC. c Determined by chiral HPLC of the methyl-
ated derivative.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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K. Ishihara et al.
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Synthesis
Table 2 Synthesis of 5-Substituted 1H-Tetrazoles from Aldoximes
DPPA (1.5 equiv)
DBU (3.0 equiv)
N
N
N
N
OH
R
R
N
H
solvent, reflux, time
Entry
1
Substrate (E/Z)a
Product
Toluene
Xylenes
Time (h)
16
Yield (%)
93
Time (h)
Yield (%)
N
N
OH
N
4
99
N
N
N
H
(10:1)
2
3
16
16
89
81
4
99
OH
N
N
Cl
Cl
N
N
H
(16:1)
4
87
Cl
N
Cl
OH
N
N
N
N
N
H
(10:1)
4
5
16
16
16
16
16
81
4
4
2
4
4
95
OH
N
N
N
N
Br
Br
N
H
(6:1)
73
88
OH
N
N
N
MeO2C
O2N
MeO
MeO2C
N
H
(17:1)
(10:1)
(13:1)
6
77
79
N
OH
N
N
O2N
N
N
H
7
81
98
N
N
OH
N
MeO
N
N
H
8
18a (20)a,b
18a (44)a,b
OMe
OMe
OH
N
OH
N
N
N
N
N
N
N
H
N
H
(4:1)
9
16
16
85
19
4
94
70
N
N
OH
N
N
N
H
(10:1)
N
10
16
OH
N
N
N
N
N
H
(7:1)
11
12
16
16
80
14
4
96
77
OH
N
N
N
N
H
(10:1)
N
16
OH
N
N
N
N
H
(4:1)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
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Synthesis
Table 2 (continued)
Entry
Substrate (E/Z)a
Product
Toluene
Time (h)
Xylenes
Yield (%)
38 (20)c
Time (h)
Yield (%)
43 (28)c
13
16
4
N
N
N
OH
OH
N
N
NC
NC
N
H
(10:1)
(3:7)
14
15
16
90
51
4
99
N
N
N
N
H
16
4
80
N
N
N
OH
N
N
H
(10:1)
16
17
16
16
92
83
4
4
98
99
N
OH
O
N
O
N
N
N
H
(2:1)
H
H
N
OH
N
N
N
N
N
N
H
(5:2)
18
19
16
16
35
4
4
74
N
N
OH
N
N
N
H
HN
HN
(4:1)
complex
mixture
complex
mixture
OH
N
N
N
N
N
H
(6:4)
20
21
48
48
71
65
16
16
86
83
N
N
N
OH
N
N
H
N
(1:1)
OH
N
N
N
N
H
(1:1)
22
23
48
48
40
33
16
16
89
88
N
N
OH
OH
N
N
N
n-C6H13
n-C6H13
(1:1)
N
H
N
N
N
N
H
(3:1)
N
24
16
trace
16
68
N
OH
N
N
N
H
(1:0)
a Determined by 1H NMR.
b Yield of 2-(1H-tetrazol-5-yl)phenol shown in parentheses.
c Yield of 1,4-di(1H-tetrazol-5-yl)benzene shown in parentheses.
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A plausible reaction mechanism for this cycloaddition is
shown in Scheme 3. The aldoxime is initially deprotonated
by DBU and attacks DPPA to form a phosphate intermediate,
which activates the C=N bond. The phosphate intermediate
is isomerized by heat to assume the cis configuration favor-
able for cycloaddition. Subsequently, cycloaddition of the
free azide anion across the C=N bond followed by elimina-
tion and tautomerism affords the desired tetrazole. That the
free azide anion was generated in situ was confirmed by the
reddish-brown color reaction when ferric(III) nitrate was
added to the reaction mixture. The phosphate intermediate
derived from the aldoxime could not be confirmed owing to
its instability. Conversely, the phosphate derived from ke-
toxime could be isolated. Therefore, it seems that aldoxime
would also form the phosphate.
plates. Purification by column chromatography was performed on
silica gel 60N (spherical, neutral, 63–210 μm, Kanto Chemical Co.,
Inc.). Melting points were determined in open-ended capillaries using
a Bibby Scientific Ltd. Stuart® SMP30 instrument and are uncorrected.
All NMR spectra were recorded on a JEOL JNM-EX270 spectrometer.
High-resolution mass spectra (HRMS) were measured by EI using
JEOL MS-700. High-resolution EI mass spectra were calibrated with
PFK. All high-performance liquid chromatography (HPLC) analyses
were performed on Hitachi UV L-2140 and L-2400 detectors with a
Hitachi L-2130 pump. The chiral HPLC conditions (column, mobile
phase, flow rate, and detection wavelength) are indicated in the text.
5-Substituted 1H-Tetrazoles; General Procedure
DPPA (0.15 mmol) and DBU (0.30 mmol) were added to a solution of
the appropriate aldoxime (0.10 mmol) in xylenes (0.5 mL). After stir-
ring for 2–16 h at reflux, the mixture was cooled to r.t. and sat. aq
NaHCO3 (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 N aq HCl to pH 2. The aqueous layer
was extracted with EtOAc (2 × 30 mL) and the combined organic ex-
tracts were washed with brine (30 mL) and dried over Na2SO4. Con-
centration of the solvent in vacuo followed by purification of the resi-
due on a short column (silica gel, EtOAc–n-hexane, 1:1 to 3:1) gave
the desired tetrazole.
O
R
DBU
N
H
O
O
DPPA
OH
PhO
P
OPh
N
R
N
R
N
N3
N
2–N
N
N
O
N
N
N
N3
O
P
N
5-Phenyl-1H-tetrazole (Table 2, entry 1)18b
O
OPh
OPh
N
Δ
OPh
O
R
R
P
Yield: 14.5 mg (99%); white solid; mp 214 °C.
OPh
N
1H NMR (270 MHz, DMSO-d6): δ = 7.60–7.66 (m, 3 H), 8.03–8.07 (m, 2 H).
N
H
N
H
H+ (workup)
N
N
DBU
N
N
5-(4-Chlorophenyl)-1H-tetrazole (Table 2, entry 2)18b
R
R
N
N
Yield: 17.8 mg (99%); white solid; mp 249–250 °C.
N
1H NMR (270 MHz, DMSO-d6): δ = 7.70 (d, J = 8.6 Hz, 2 H), 8.06 (d,
J = 9.2 Hz, 2 H).
Scheme 3 Plausible reaction mechanism
5-(2-Chlorophenyl)-1H-tetrazole (Table 2, entry 3)13
This reaction presumably does not involve nitrile for-
mation, because the nitrile product was not observed, and
this reaction was suppressed when using p-NO2DPPA. If the
reaction proceeded via a nitrile, the phosphate intermedi-
ate derived from p-NO2DPPA would accelerate the forma-
tion of the nitrile intermediate due to its higher elimination
ability compared to DPPA phosphate.
In summary, we have achieved an efficient synthesis of
5-substituted 1H-tetrazoles by using DPPA and performing
the reaction under reflux condition in xylenes. Various
aldoximes were easily converted into the corresponding
5-substituted 1H-tetrazoles in short times, and good yields
were obtained even when sterically hindered substrates
were used. Optically active chiral aldoximes derived from
amino acids afforded the corresponding aminotetrazoles
with no or little racemization. This method is a practical
synthetic method that is easy to perform and does not re-
quire toxic metals or explosive azide sources.
Yield: 15.7 mg (87%); pale yellow solid; mp 170–171 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.57 (t, J = 7.6 Hz, 1 H), 7.65
(t, J = 7.6 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.82 (d, J = 7.6 Hz, 1 H).
5-(4-Bromophenyl)-1H-tetrazole (Table 2, entry 4)18b
Yield: 21.3 mg (95%); pale yellow solid; mp 257–258 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.84 (d, J = 7.3 Hz, 2 H), 7.99
(d, J = 6.5 Hz, 2 H).
Methyl 4-(1H-Tetrazol-5-yl)benzoate (Table 2, entry 5)37
Yield: 18.0 mg (88%); white solid; mp 224–225 °C.
1H NMR (270 MHz, DMSO-d6): δ = 3.91 (s, 3 H), 8.12 (s, 4 H).
5-(4-Nitrophenyl)-1H-tetrazole (Table 2, entry 6)18b
Yield: 15.1 mg (79%); yellow solid; mp 216 °C.
1H NMR (270 MHz, DMSO-d6): δ = 8.32 (d, J = 9.2 Hz, 2 H), 8.47
(d, J = 9.2 Hz, 2 H).
5-(4-Methoxyphenyl)-1H-tetrazole (Table 2, entry 7)18b
Yield: 17.3 mg (98%); white solid; mp 227 °C.
1H NMR (270 MHz, DMSO-d6): δ = 3.85 (s, 3 H), 7.17 (d, J = 8.6 Hz, 2
H), 7.99 (d, J = 8.6 Hz, 2 H).
All the laboratory chemicals were purchased and used without purifi-
cation unless it is stated otherwise. All reactions were magnetically
stirred and monitored by thin-layer chromatography using silica gel
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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K. Ishihara et al.
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Synthesis
5-(2-Methoxyphenyl)-1H-tetrazole32e and 2-(1H-Tetrazol-5-
5-(1H-Pyrrol-2-yl)-1H-tetrazole (Table 2, entry 17)40
yl)phenol13 as mixture (Table 2, entry 8)
Yield: 13.4 mg (99%); pale gray solid; mp 230 °C.
1H NMR (270 MHz, DMSO-d6): δ = 6.24–6.27 (m, 1 H), 6.80 (s, 1 H),
7.03 (s, 1 H), 12.02 (br s, 1 H).
5-(2-Methoxyphenyl)-1H-tetrazole
Yield: 3.1 mg (18%); white solid.
1H NMR (270 MHz, DMSO-d6): δ = 3.97 (s, 3 H), 7.16 (t, J = 7.3 Hz, 1 H),
7.28 (d, J = 8.4 Hz, 1 H), 7.59 (t, J = 8.1 Hz, 1 H), 8.10 (d, J = 5.9 Hz, 1 H).
3-(1H-Tetrazol-5-yl)-1H-indole (Table 2, entry 18)6b
Yield: 13.7 mg (74%); white solid; mp 229 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.20–7.29 (m, 2 H), 7.53–7.56 (m, 1
H), 8.07 (d, J = 3.2 Hz, 1 H), 8.20–8.23 (m, 1 H), 11.86 (br s, 1 H).
2-(1H-Tetrazol-5-yl)phenol
Yield: 7.1 mg (44%); white solid.
1H NMR (270 MHz, DMSO-d6): δ = 7.01 (t, J = 7.8 Hz, 1 H), 7.07 (d,
J = 8.1 Hz, 1 H), 7.41 (t, J = 6.9 Hz, 1 H), 7.99 (d, J = 5.9 Hz, 1 H).
5-Benzyl-1H-tetrazole (Table 2, entry 20)18b
Yield: 13.7 mg (86%); white solid; mp 121–122 °C.
1H NMR (270 MHz, DMSO-d6): δ = 4.29 (s, 2 H), 7.20–7.38 (m, 5 H).
5-(p-Tolyl)-1H-tetrazole (Table 2, entry 9)18b
Yield: 15.0 mg (94%); white solid; mp 243 °C.
1H NMR (270 MHz, DMSO-d6): δ = 2.39 (s, 3 H), 7.42 (d, J = 8.4 Hz,
2 H), 7.93 (d, J = 7.8 Hz, 2 H).
5-Phenethyl-1H-tetrazole (Table 2, entry 21)12
Yield: 14.5 mg (83%); white solid; mp 97–98 °C.
1H NMR (270 MHz, DMSO-d6): δ = 3.04 (t, J = 7.7 Hz, 2 H), 3.19
(t, J = 7.3 Hz, 2 H), 7.16–7.31 (m, 5 H).
5-(o-Tolyl)-1H-tetrazole (Table 2, entry 10)13
Yield: 11.2 mg (70%); white solid; mp 150 °C.
1H NMR (270 MHz, DMSO-d6): δ = 2.49 (s, 3 H), 7.37–7.53 (m, 3 H),
7.69 (d, J = 7.8 Hz, 1 H).
5-n-Hexyl-1H-tetrazole (Table 2, entry 22)12
Yield: 13.7 mg (89%); white solid; mp 40–41 °C.
1H NMR (270 MHz, DMSO-d6): δ = 0.85 (t, J = 6.6 Hz, 3 H), 1.24–1.31
(m, 6 H), 1.63–1.72 (m, 2 H), 2.86 (t, J = 7.2 Hz, 2 H).
5-(4-Isopropylphenyl)-1H-tetrazole (Table 2, entry 11)21
Yield: 18.0 mg (96%); white solid; mp 189 °C.
1H NMR (270 MHz, DMSO-d6): δ = 1.24 (d, J = 7.3 Hz, 6 H), 2.93–3.03
(m, 1 H), 7.49 (d, J = 7.8 Hz, 2 H), 7.97 (d, J = 7.8 Hz, 2 H).
5-Cyclohexyl-1H-tetrazole (Table 2, entry 23)12
Yield: 13.4 mg (88%); white solid; mp 127–128 °C.
1H NMR (270 MHz, DMSO-d6): δ = 1.22–1.58 (m, 5 H), 1.65–1.77 (m, 3
H), 1.98 (t, J = 5.9 Hz, 2 H), 2.92–3.03 (m, 1 H).
5-([1,1′-Biphenyl]-2-yl)-1H-tetrazole (Table 2, entry 12)38
Yield: 17.2 mg (77%); white solid; mp 141–142 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.07–7.11 (m, 2 H), 7.29–7.34
(m, 3 H), 7.58 (t, J = 7.5 Hz, 2 H), 7.65–7.73 (m, 2 H).
5-(tert-Butyl)-1H-tetrazole (Table 2, entry 24)41
Yield: 8.6 mg (68%); white solid; mp 206–207 °C.
1H NMR (270 MHz, DMSO-d6): δ = 1.37 (s, 9 H).
4-(1H-Tetrazol-5-yl)benzonitrile (Table 2, entry 13)31
tert-Butyl (S)-2-(1H-Tetrazol-5-yl)pyrrolidine-1-carboxylate
Yield: 7.4 mg (43%); white solid; mp 188–189 °C.
1H NMR (270 MHz, DMSO-d6): δ = 8.10 (d, J = 7.8 Hz, 2 H), 8.22
(d, J = 8.4 Hz, 2 H).
(Scheme 2, a)13
DPPA (0.15 mmol) and DBU (0.30 mmol) were added to a solution of
tert-butyl
(S)-2-[(hydroxyimino)methyl]pyrrolidine-1-carboxylate
(0.10 mmol) in xylenes (0.5 mL). After stirring for 16 h at reflux, the
mixture was cooled to r.t. and sat. aq NaHCO3 (2.0 mL) was added. Af-
ter 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 aq HCl 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. Concentration of the sol-
vent in vacuo followed by purification of the residue on a column (sil-
ica gel, EtOAc–n-hexane, 3:1) gave the desired tetrazole.
5-(Naphthalen-2-yl)-1H-tetrazole (Table 2, entry 14)39
Yield: 19.5 mg (99%); white solid; mp 205 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.62–7.70 (m, 2 H), 8.02–8.18
(m, 4 H), 8.68 (s, 1 H).
5-(Naphthalen-1-yl)-1H-tetrazole (Table 2, entry 15)30
Yield: 15.7 mg (80%); white solid; mp 210 °C.
1H NMR (270 MHz, DMSO-d6): δ = 7.63–7.74 (m, 3 H), 7.99 (d, J = 7.3
Hz, 1 H), 8.09 (d, J = 9.2 Hz, 1 H), 8.20 (d, J = 8.1 Hz, 1 H), 8.55–8.58
(m, 1 H).
Yield: 13.8 mg (58%); white solid; mp 124–125 °C.
1H NMR (270 MHz, CDCl3): δ = 1.50 (s, 9 H), 2.00–2.18 (m, 2 H), 2.26–
2.40 (m, 1 H), 2.94–3.04 (m, 1 H), 3.39–3.44 (m, 2 H), 5.03–5.07 (m, 1
H), 13.43 (br s, 1 H).
5-(Furan-2-yl)-1H-tetrazole (Table 2, entry 16)23
Yield: 13.4 mg (98%); white solid; mp 202–203 °C.
tert-Butyl (S)-2-(1-Methyl-1H-tetrazol-5-yl)pyrrolidine-1-carbox-
1H NMR (270 MHz, DMSO-d6): δ = 6.78–6.80 (m, 1 H), 7.28 (d, J = 3.2
Hz, 1 H), 8.05 (d, J = 1.9 Hz, 1 H).
ylate
MeI (0.116 mmol) and K2CO3 (0.116 mmol) were added to a solution
of the tetrazole (0.058 mmol) in DMF (2 mL). After stirring for 16 h at
r.t., the mixture was diluted with EtOAc (25 mL). The mixture was
washed with sat. aq NaHCO3 and brine (25 mL), and dried over
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
K. Ishihara et al.
Paper
Synthesis
Na2SO4. Concentration of the solvent in vacuo followed by purifica-
tion of the residue on a column (silica gel, EtOAc–n-hexane, 1:1) gave
the desired 1-Me isomer (43%) and 2-Me isomer (52%), respectively.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591851.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Yield: 6.3 mg (43%); white solid; mp 98–99 °C.
Chiral HPLC: column: Daicel CHIRAL OD-3, 4.6 × 150 mm; solvent:
i-PrOH–n-hexane, 10:90; flow rate: 1.0 mL/min; detector wave-
length: 210 nm; retention time (S): 7.58 min; >99% ee
References
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l
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1H NMR (270 MHz, CDCl3): δ = 1.32 (d, J = 43.5 Hz, 9 H), 2.00–2.52 (m,
4 H), 3.44–3.64 (m, 2 H), 4.11 (d, J = 41.0 Hz, 3 H), 5.07 (d, J = 8.1 Hz, 1
H).
HRMS (EI): m/z [M]+ calcd for C11H19N5O2: 253.1539; found:
253.1552.
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Benzyl (S)-[3-Methyl-1-(1H-tetrazol-5-yl)butyl]carbamate
(Scheme 2, b)17d
DPPA (0.15 mmol) and DBU (0.30 mmol) were added to a solution of
benzyl (S)-[1-(hydroxyimino)-4-methylpentan-2-yl]carbamate (0.10
mmol) in toluene (0.5 mL). After stirring for 16 h at 90 °C, the mixture
was cooled to r.t. and sat. aq NaHCO3 (2.0 mL) was added. After stir-
ring for 5 min, the mixture was diluted with water (20 mL). The aque-
ous layer was then washed with EtOAc (25 mL) and acidified with 1.0
N aq HCl 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. Concentration of the solvent in vacuo fol-
lowed by purification of the residue on a column (silica gel, EtOAc–n-
hexane, 1:1) gave the desired tetrazole.
Yield: 19.6 mg (68%); colorless gummy oil.
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1.57–1.72 (m, 1 H), 1.93 (t, J = 7.6 Hz, 2 H), 4.99–5.27 (m, 3 H), 6.07 (d,
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Benzyl (S)-[3-Methyl-1-(2-methyl-2H-tetrazol-5-yl)butyl]carba-
mate and Benzyl (S)-[3-Methyl-1-(1-methyl-1H-tetrazol-5-yl)bu-
tyl]carbamate Mixture
MeI (0.20 mmol) and K2CO3 (0.20 mmol) were added to a solution of
the tetrazole (0.10 mmol) in DMF (2 mL). After stirring for 16 h at r.t.,
the mixture was diluted with EtOAc (30 mL). The mixture was washed
with sat. aq NaHCO3 and brine (25 mL), and dried over Na2SO4. Con-
centration of the solvent in vacuo followed by purification of the resi-
due on a column (silica gel, EtOAc–n-hexane, 1:2) gave the desired
1-Me and 2-Me isomers as a mixture.
Yield: 29.6 mg (98%); white solid; mp 56–57 °C.
Chiral HPLC: column: Daicel CHIRAL OD-3, 4.6 × 150 mm; solvent:
i-PrOH–n-hexane, 10:90; flow rate: 1.0 mL/min; detector wave-
length: 210 nm; retention times (R) 9.97 min, (S) 11.63 min, (S) 12.17
min, and (R) 25.19 min; 97% ee.
1H NMR (270 MHz, CDCl3): δ = 0.96 (dd, J = 3.8, 6.5 Hz, 6 H), 1.56–1.70
(m, 1 H), 1.74–1.79 (m, 1 H), 1.84–1.98 (m, 1 H), 4.13 (s, 1.3 H (1-Me)),
4.32 (s, 1.7 H (2-Me)), 5.02–5.26 (m, 4 H), 7.30–7.38 (m, 5 H).
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303.1684.
try and Properties;
3
V
o.
l
Attanasi, O. A.; Spinelli, D., Eds.; Italian
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Funding Information
(13) Aureggi, V.; Sedelmeier, G. Angew. Chem. Int. Ed. 2007, 46, 8440.
(14) Treitler, D. S.; Leung, S.; Lindrud, M. Org. Process Res. Dev. 2017,
21, 460.
This work was supported by JSPS Grant-in-Aid for Scientific Research
(C), 26450145, and Prof. Y. Uozumi’s JST-ACCEL program (JPM-
JAC1401).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
K. Ishihara et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H