Preparation of 5-Aryl-2-Alkyltetrazoles with Aromatic Aldehydes, Alkylhydrazine, Di-tert-butyl Azodicarboxylate, and [Bis(trifluoroacetoxy)iodo]benzene

Article abstract of DOI:10.1021/acs.joc.6b00606

A variety of 5-aryl-2-methyltetrazoles and 5-aryl-2-benzyltetrazoles were directly prepared in good to moderate yields by the reaction of aromatic aldehydes with methylhydrazine and benzylhydrazine, followed by treatment with di-tert-butyl azodicarboxylate and [bis(trifluoroacetoxy)iodo]benzene in a mixture of dichloromethane and 2,2,2-trifluoroethanol at room temperature. The present method is a novel one-pot preparation of 5-aryl-2-methyltetrazoles and 5-aryl-2-benzyltetrazoles through a [2N + 2N] combination under transition metal-free and mild conditions.

Full text of DOI:10.1021/acs.joc.6b00606

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Note
Preparation of 5-Aryl-2-Alkyltetrazoles with
Aromatic Aldehydes, Alkylhydrazine, Di-t-butyl
Azodicarboxylate, and [bis(trifluoroacetoxy)iodo]benzene
Taro Imai, Ryo Harigae, Katsuhiko Moriyama, and Hideo Togo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00606 • Publication Date (Web): 14 Apr 2016
Downloaded from http://pubs.acs.org on April 19, 2016
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The Journal of Organic Chemistry
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Preparation of 5-Aryl-2-Alkyltetrazoles with Aromatic
Aldehydes, Alkylhydrazine, Di-t-butyl
Azodicarboxylate, and
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[bis(trifluoroacetoxy)iodo]benzene
Taro Imai†, Ryo Harigae†, Katsuhiko Moriyama†‡, and Hideo Togo*†
†Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
‡Molecular Chirality Research Center, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522,
Japan
togo@faculty.chiba-u.jp
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Abstract:
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R
1) RNHNH2
MeOH, r.t., 3 h
N
O
N
N
N
2) tBuO2CN=NCO2 Bu
PhI(O2CCF3)2
Ar
H
t
Ar
R = Me, CH2Ph
DCM, TFE, r.t., 0.5 h
A variety of 5-aryl-2-methyltetrazoles and 5-aryl-2-benzyltetrazoles were directly prepared in good to
moderate yields by the reaction of aromatic aldehydes with methylhydrazine and benzylhydrazine,
followed by treatment with di-t-butyl azodicarboxylate and [bis(trifluoroacetoxy)iodo]benzene in a
mixture of dichloromethane and 2,2,2-trifluoroethanol at room temperature. The present method is a
novel one-pot preparation of 5-aryl-2-methyltetrazoles and 5-aryl-2-benzyltetrazoles through a [2N +
2N] combination under transition metal-free and mild conditions.
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Tetrazoles are one of the most important heterocyclic units because they can be considered as
bioisosteres of amides and carboxylic acids having high lipophilicity.1 For example, Losartan using as
an hypertensive drug is a 5-aryl-1H-tetrazole,1h and Candesartan Cilexetil using as an angiotensin II
receptor blocker (ARB) is also a 5-aryl-1H-tetrazole.2 Other 5-aryl-1H-tetrazoles possessing anti-
allergic, anti-asthmatic, antiviral, and anti-inflammatory activities have also been reported.3 The most
common method for the preparation of 5-substituted 1H-tetrazoles is the reaction of nitriles with sodium
azide [type: 1N + 3N] in the presence of acid catalysts, such as NH4Cl, transition-metal catalysts, such
as Cu2O, ZnO, ZnBr2, and Bu2SnO, or microwave-irradiation, etc., as shown in Scheme 1 (eq. 1).1
Recent reports for the preparation of tetrazoles with [type: 1N + 3N] are as follows; 5-aryl-1H-
tetrazoles from aromatic nitriles with sodium azide in the presence of 4-(N,N-dimethylamino)pyridinium
acetate without solvent at 100 °C,4a 5-amino-1-aryltetrazoles from selenourea and sodium azide in the
presence of (diacetoxyiodo)benzene (DIB) at room temperature,4b 5-aryl- or 5-alkyl-1H-tetrazoles from
aromatic or aliphatic nitriles with sodium azide in the presence of Yb(OTf)3 in DMF at 100-120 °C,4c 5-
substituted 1H-tetrazoles from thiocyanates or nitriles and sodium azide with ZnCl2 in propanol at 95-
110 °C,4d 5-aryl- or 5-alkyl-1H-tetrazoles from aromatic or aliphatic nitriles with sodium azide in the
presence of Amberlyst 15 in DMSO at 85 °C,4e and 1,5-disubstituted tetrazoles using the Ugi reaction
from isocyanides, trimethylsilyl azide, and ketimines in methanol at room temperature.4f,4g However,
most of the reactions require sodium azide or azide derivatives. In particular, hydrazoic acid, which is
prepared from sodium azide with an acid catalyst, is extremely toxic and explosive. On the other hand,
studies for the preparation of tetrazoles through [type: 2N + 2N] are quite limited. Typical reports for
the preparation of tetrazoles with [type: 2N + 2N] are as follows; the dimerization of α-
diazoacetophenone derivatives with t-BuOK to form 1,5-disubstituted tetrazoles,5a the reaction of N-
phenylsulfonylbenzhydrazidoyl chloride and arylhydrazines with K2CO3 to form 2,5-diaryltetrazoles,5b
the reaction of arenediazonium salts and 2,2,2-trifluorodiazoethane with AcOAg and Cs2CO3 to form 2-
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aryl-5-trifluoromethyltetrazoles,5c and the reaction of arenediazonium salts and amidines, followed by
the reaction with I2-KI to form 2,5-disubstituted tetrazoles.5d
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Scheme 1. Preparation of Tetrazoles.
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General Method [type: 1N + 3N]
N
NH
N
ArCN + M-N3
M = H+, Na+,TMS, etc.
Ar
1)
N
Present Method [type: 2N + 2N]
RNHNH2
DBAD
PIFA
NNR
N
N
NR
N
Ar CHO
2)
Ar
Ar
H
Scheme 1. Preparation of Tetrazoles
Here, as part of our synthetic study of heterocycles with trivalent iodines,6 we would like to report a
novel preparation of 2-alkyl-5-aryltetrazoles that involved the reaction of aromatic aldehydes with
alkylhydrazine, followed by the reaction with di-t-butyl azodicarboxylate (DBAD) and
[bis(trifluoroacetoxy)iodo]benzene through [type: 2N + 2N], as shown in eq. 2 of Scheme 1.
First, treatment of 4-chlorobenzaldehyde 1a with methylhydrazine (1.2 equiv) in methanol at 60 °C
generated the corresponding N-methylhydrazone IAa quantitatively. After removal of methanol by
evaporation, dichloromethane (DCM), 1,2-dichloroethane (DCE), acetonitrile, toluene, DMSO, and
2,2,2-trifluoroethanol (TFE), which cannot be easily oxidized by [bis(trifluoroacetoxy)iodo]benzene
(PIFA), were added to the residue, respectively. Then, di-t-butyl azodicarboxylate (DBAD, 1.3 equiv)
and PIFA (2.2 equiv) were added to the solution, and the mixture was stirred at room temperature for
0.5 h to give 5-(4’-chlorophenyl)-2-methyltetrazole 2Aa. The yield was dependent on the solvent used,
as shown in Table 1 (Table 1, entries 1~6), and TFE was the most effective solvent, giving compound
2Aa in 59% yield (Table 1, entry 6). To improve the yield of compound 2Aa, mixed solvents were
examined at the second reaction step, and it was found that the mixture of DCM and TFE (1:1) is the
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best solvent, providing compound 2Aa in 68% yield (Table 1, entry 7 in entries 7~11). Use of TFE
instead of MeOH at the first reaction step and the addition of dichloromethane at the second reaction
step without evaporation resulted in a low yield of compound 2Aa (Table 1, entry 12). Acid additives,
such as trifluoroacetic acid (TFA) and BF3•OEt2, had a detrimental effect on the reaction (Table 1,
entries 13 and 14). Use of other trivalent iodines, such as (diacetoxyiodo)benzene (DIB) and
[(hydroxy)(tosyloxy)iodo]benzene (HTIB), instead of PIFA at the second reaction step was not effective
at all (Table 1, entries 15 and 16). Finally, it was found that treatment of p-chlorobenzaldehyde 1a and
methylhydrazine in methanol at room temperature for 3 h at the first reaction step, followed by the
reaction with DBAD (1.3 equiv) and PIFA (2.5 equiv) in a mixture of DCM and TFE (1:1) at room
temperature at the second reaction step was the best choice, giving compound 2Aa in 74% yield (Table
1, entry 18). Reducing the amount of TFE decreased the yield of compound 2Aa slightly (Table 1,
entries 19 and 20), and increasing the amount of TFE had almost no effect on the yield of compound
2Aa (Table 1, entries 21 and 22). Increasing the amount of DBAD (2.0 equiv) under the same
procedure and conditions was also not effective (Table 1, entry 23).
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Table 1. One-pot Preparation of 5-(4'-Chlorophenyl)-2-methyltetrazole from 4-Chlorobenzaldehyde.
Me
evaporation;
DBAD (1.3 equiv)
"I(III)" (X equiv)
N
N
H
H
N
O
NNHMe
MeNHNH2
(1.2 equiv)
N
solvents (0.5 M)
r.t., 0.5 h
MeOH (1.0 M)
60 °C, 1 h
Cl
Cl
IAa
1a
Cl
2Aa
entry
“I(III)” (X) solvent
yield (%)
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3
4
5
6
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
DCM
DCE
11
11
17
8
MeCN
PhMe
DMSO
TFE
18
59
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PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
PIFA (2.2)
DIB (2.2)
DCM:TFE=1:1
68
60
64
62
1
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8
8
DCE:TFE=1:1
MeCN:TFE=1:1
PhMe:TFE=1:1
9
10
11
DMSO:TFE=1:1 50
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12a
13b
14c
15
DCM:TFE=1:1
DCM:TFE=1:1
DCM:TFE=1:1
DCM:TFE=1:1
25
44
16
1
16
HTIB (2.2) DCM:TFE=1:1
1
17
PIFA (2.5)
PIFA (2.5)
PIFA (2.5)
PIFA (2.5)
PIFA (2.5)
PIFA (2.5)
PIFA (2.5)
DCM:TFE=1:1
DCM:TFE=1:1
DCM:TFE=3:1
DCM:TFE=3:2
DCM:TFE=2:3
DCM:TFE=1:3
DCM:TFE=1:1
71
74
68
70
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18d
19d
20d
21d
22d
23d,e
a TFE (1.0 M) was used instead of MeOH at the 1st reaction step, and the solvent was not evaporated at
the 2nd reaction step. TFA (1.0 equiv) was added at the 2nd reaction step. BF3∙OEt2 (1.0 equiv) was
added at the 2nd reaction step. The 1st reaction step was carried out at r.t. for 3 h. DBAD (2.0 equiv)
was used.
b
c
d
e
Based on those results, several aromatic aldehydes 1b~1q were treated with methylhydrazine in MeOH at
room temperature for 3 h, and then the solvent was removed. Dichloromethane (DCM) and TFE (1:1) were
added to the residue, and the addition of DBAD (1.3 equiv) and PIFA (2.5 equiv) to the residue at room
temperature provided 5-aryl-2-methyltetrazoles 2Ab~2Aq in good to moderate yields, as shown in Table 2.
The reactivity of 2-naphthoaldehyde 1r was low because the formation of N-methylhydrazone did not
proceed smoothly.
Treatment of electron-deficient heteroaromatic aldehydes, such as 3-
pyridinecarboxaldehyde and 4-quinolinecarboxaldehyde, with methylhydrazine and then TBAD and PIFA
under the same procedure and conditions furnished 2-methyl-5-(3’-pyridyl)tetrazole 2As and 2-methyl-5-(4’-
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quinolyl)tetrazole 2At in moderate yields. However, when less electron-deficient heteroaromatic aldehydes,
such as benzofuran-3-carboxaldehyde and benzothiopene-3-carboxaldehyde, than 3-
1
2
3
4
5
6
7
8
pyridinecarboxyaldehyde were treated with methylhydrazine and then DBAD and PIFA under the same
procedure and conditions, the corresponding tetrazoles were obtained in low yield, i.e., 12% and 11% yields,
respectively.
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The same treatment of several aromatic aldehydes 1a, 1b, 1d, 1g~1i, and 1l with benzylhydrazine
instead of methylhydrazine in DCM at room temperature, followed by evaporation and the subsequent
reaction with DBAD (1.3 equiv) and PIFA (2.5 equiv) together with addition of DCM and TFE (1:1) at
room temperature also gave the corresponding 5-aryl-2-benzyltetrazoles 2Ba, 2Bb, 2Bd, 2Bg~2Bi, and
2Bl in good to moderate yields, as shown in Table 2. However, when p-chlorobenzaldehyde was
treated with hydrazine, phenylhydrazine, and tosylhydrazine instead of methylhydrazine under the same
procedure and conditions, 5-(4’-chlorophenyl)tetrazole, 5-(4’-chlorophenyl)-2-phenyltetrazole, and 5-
(4’-chlorophenyl)-2-tosyltetrazole were not obtained at all, respectively.
The structure of 2-methyl-5-(4’-nitrophenyl)tetrazole 2Ag was supported by X-ray crystallographic
analysis (see supporting information).
On the other hand, when aliphatic aldehydes, such as cyclohexanecarboxaldehyde and 1-
adamantanecarboxaldehyde, were treated with methylhydrazine and then DBAD and PIFA under the
same procedure and conditions, the corresponding tetrazoles were not obtained at all. The reactions
gave complex mixtures containing cyclohexanecarboxylic acid and 1-adamantanecarboxylic acid,
respectively.
Table 2. One-pot Preparation of 2-Alkyl-5-aryltetrazoles from Aromatic Aldehydes.
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R
evaporation;
DBAD (1.3 equiv)
PIFA (2.5 equiv)
N
N
H
H
N
1
2
O
NNHR
RNHNH2
(1.2 equiv)
N
3
4
5
6
DCM:TFE = 1:1
(0.5 M)
r.t., 0.5 h
MeOH (1.0 M)
r.t., 3 h
X
X
X
A: R = Me,
B: R = CH2Ph
I
1
2
7
8
product, yield
R
R
R
N
N
9
N
N
N
N
N
Cl
N
N
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Cl
N
N
N
Cl
2Aa,74%
2Ab,76%
2Ac,61%
2Ba,72%e
2Bb,49%e
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
F
Br
F3C
2Ad,75%
2Bd,61%e
2Ae,62%
2Af,71%
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
O2N
NC
MeO2SO
Et
MeO2C
2Ag,51%a
2Bg,64%e
2Ah,68%
2Bh,61%e
2Ai,70%
2Bi, 51%e
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
MeO2S
2Aj,42%
2Ak,69%
2Al,70%
2Bl,59%e
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
Me
MeO
2Am,58%
2An,53%
2Ao,51%
R
R
R
N
N
N
N
N
N
N
N
N
N
N
N
Ph
O
Ph
2Ap,72%
2Aq,45%
2Ar,35%b,c
R
R
N
N
N
N
N
N
N
N
N
N
2As,55%b,c
2At,46%b,d
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a The 2nd reaction step was carried out in 0.25 M solution. b MeCN (0.25 M) was used instead of MeOH
1
2
3
4
d
at the 1st reaction step and the reaction was carried out at 70 °C. c PIFA (2.1 equiv) was used. MeCN :
TFE = 1:3 (0.5 M) was used as the solvent at the 2nd reaction step. e CH2Cl2 (0.25 M) was used instead
of MeOH at the 1st reaction step.
5
6
7
8
9
Scheme 2. Plausible Reaction Mechanism for Formation of Tetrazoles
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Boc
Path 1
N
N
Boc
NHR
O
RNHNH2
(-H2O)
N
Ar
H
Ar
H
1
I
R = Me, CH2Ph
R
N N
R
Boc
N
HN
N
NBoc
HN
Boc
N
Ar
H
Ar
Boc
III
II
(-PhI)
PIFA
(-CF3CO2H)
R
R
PIFA
N
N
N
N
NH
N
(-PhI)
N
H
N
Ar
(-CF3CO2H)
Ar
2
IV
Path 2
NHR
O
RNHNH2
N
(-H2O)
Ar
H
Ar
H
1
I
R = Me, CH2Ph
(-PhI)
PIFA
(-CF3CO2H)
R
N
Boc
Boc
Boc
Ar
N
N
N
N
N
N
R
N
Boc
Ar
VI
V
(-PhI)
PIFA
(-CF3CO2H)
R
N
N
N
2
N
Ar
The plausible reaction mechanism for the formation of tetrazoles is shown in Scheme 2. Aromatic
aldehyde 1 reacts with methylhydrazine or benzylhydrazine to form methylhydorazone or
benzylhydrazone I. The amino group of hydrazone I adds to an azo group of DBAD to form adduct II,
which further cyclizes to compound III via the nucleophilic 5-endo-trig cyclization mode. Practically,
when methylhydrazone prepared from the reaction of p-chlorobenzaldehyde and methylhydrazine was
treated with DBAD, compound III was isolated [HRMS (ESI) Calcd. for C18H28O4N4Cl (M+H)+
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399.1794, Found 399.1789]. PIFA oxidizes adduct III and induces the deprotection of BOC groups to
give 5-aryl-2-methyltetrazole or 5-aryl-2-benzyltetrazole 2, as shown in Path 1. On the other hand,
another mechanism Path 2 may be possible. Thus, methylhydrazone or benzylhydrazone I is oxidized
to diazomethine ylide V by PIFA. Once diazomethine ylide V is formed, it reacts with DBAD via 1,3-
dipolar cycloaddition to form 5-aryl-2-methyltetrazole or 5-aryl-2-benzylterazole 2 through the
oxidative deprotection of BOC groups in compound VI by PIFA. However, when the present second
reaction step was carried out in the presence of diphenylacetylene (3.0 equiv.) or dimethyl
acetylenedicarboxylate (3.0 equiv) under the same procedure and conditions, the corresponding
cycloaddition product, 1-methyl-3-(4’-chlorophenyl)-4,5-diphenylpyrazole or 1-methyl-3-(4’-
chlorophenyl)-4,5-di(methoxycarbonyl)pyrazole, was not obtained at all. Instead of that, tetrazole
compound 2Aa was obtained in 57% and 63% yields, respectively. Therefore, we are of the opinion
that the present reaction mainly proceeds through the mechanism Path 1 shown in Scheme 2.
In conclusion, treatment of various aromatic aldehydes with alkylhydrazines, such as methylhydrazine
and benzylhydrazine, followed by the reaction with di-t-butyl azodicarboxylate and
[bis(trifluoroacetoxy)iodo]benzene at room temperature gave directly the corresponding 2-alkyl-5-
aryltetrazoles, such as 5-aryl-2-methyltetrazoles and 5-aryl-2-benzyltetrazoles, respectively, in good to
moderate yields via [type: 2N + 2N] process in one pot. We believe the present method would be useful
for the preparation of tetrazole derivatives from aromatic aldehydes with alkylhydrazine under
transition-metal-free and mild conditions.
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Experimental Section
1
General Information. H NMR spectra were measured on 400 MHz spectrometers. Chemical shifts
were recorded as follows: chemical shift in ppm from internal tetramethylsilane on the δ scale,
multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad), coupling
constant (Hz), integration, and assignment. 13C NMR spectra were measured on 100 MHz
spectrometers. Chemical shifts were recorded in ppm from the solvent resonance employed as the
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internal standard (deuterochloroform at 77.0 ppm). High-resolution mass spectra (HRMS) were
measured on orbitrap mass spectrometers. Characteristic peaks in the infrared (IR) spectra were
recorded in wave numbers, cm–1. Melting points were uncorrected. Thin-layer chromatography (TLC)
was performed using 0.25 mm silica gel plates (60F-254). The products were purified by short column
chromatography on silica gel 60 (63–200 mesh).
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General Procedure for the Preparation of 5-Aryl-2-Methyltetrazoles (Table 1, entry 18 and Table
2). To a solution of 4-chlorobenzaldehyde 1a (70.3 mg, 0.5 mmol) in methanol (0.5 mL) was added
methylhydrazine (31.7 µL, 0.6 mmol) at room temperature. The mixture was stirred at r.t. for 3 h. Then,
the solvent was removed, and di-tert-butyl azodicarboxylate (149.7 mg, 0.65 mmol),
[bis(trifluoroacetoxy)iodo]benzene (537.6 mg, 1.25 mmol), dichloromethane (0.5 mL), and
trifluoroethanol (0.5 mL) were added, and the obtained mixture was stirred at room temperature for 0.5
h. The reaction mixture was quenched with sat. aq. Na2SO3 and was extracted with CHCl3 (3 × 10 mL).
The organic layer was washed with brine and dried over Na2SO4. Purification by short column
chromatography on silica gel (hexane/AcOEt = 4:1) yielded 5-(4’-chlorophenyl)-2-methyltetrazole 2Aa
(72.0 mg, 74%).
5-(4’-Chlorophenyl)-2-methyltetrazole (2Aa)7a: Colorless Solid (71.7 mg, 74% yield): mp 107-108 °C
(mp 108-109 °C); IR (neat) 2952, 1605, 1448, 1134, 1016 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.40
(s, 3H), 7.46 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 39.5, 125.8,
128.0, 129.2, 136.3, 164.4; HRMS (APCI) Calcd for C8H8N4Cl (M+H)+ 195.0432, Found 195.0429.
5-(3’-Chlorophenyl)-2-methyltetrazole (2Ab): Colorless Solid (74.3 mg, 76% yield): mp 85-86 °C; IR
(neat) 3043, 1577, 1453, 1192, 1051 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.41 (s, 3H), 7.40-7.46 (m,
2H), 8.00-8.05 (m, 1H), 8.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ = 39.6, 124.8, 126.9, 129.0, 130.2,
130.3, 134.9, 164.1; HRMS (APCI) Calcd for C8H8N4Cl (M+H)+ 195.0432, Found 195.0427.
5-(2’-Chlorophenyl)-2-methyltetrazole (2Ac)7a: Colorless Oil (59.7 mg, 61% yield); IR (neat) 2987,
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1602, 1441, 1193, 1036 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 4.44 (s, 3H), 7.35-7.44 (m, 2H), 7.51-
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7.57 (m, 1H), 7.91-7.95 (m, 1H); C NMR (100 MHz, CDCl3) δ = 39.6, 126.4, 126.9, 130.8, 131.1,
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131.3, 132.9, 163.4.
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5-(4’-Bromophenyl)-2-methyltetrazole (2Ad)7b: Colorless Solid (89.1 mg, 75% yield): mp 126-127 °C
(mp 124-126 °C); IR (neat) 2972, 1603, 1449, 1132, 1013 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.40
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(s, 3H), 7.63 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 39.5, 124.6,
126.2, 128.2, 132.1, 164.4.
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5-(4’-Fluorophenyl)-2-methyltetrazole (2Ae)7c: Colorless Solid (55.3 mg, 62% yield): mp 88-89 °C;
IR (neat) 2987, 1602, 1458, 1156, 1046 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.40 (s, 3H), 7.18 (t, J =
8.9 Hz, 2H), 8.13 (dd, J = 8.9, 5.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 39.6, 116.0 (d, JC-F = 22.5
Hz), 123.6 (d, JC-F = 2.8 Hz), 128.8 (d, JC-F = 8.5 Hz), 164.0 (d, JC-F = 249.8 Hz), 164.4.
5-(4’-Trifluoromethylphenyl)-2-methyltetrazole (2Af): Colorless Solid (83.2 mg, 71% yield): mp
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113-114 °C; IR (neat) 2969, 1546, 1427, 1160, 1017 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 4.43 (s,
3H), 7.75 (d, J = 8.1 Hz, 2H), 8.26 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 39.7, 123.9 (q,
JC-F = 272.5 Hz), 126.0 (q, JC-F = 3.8 Hz), 127.1, 130.8, 132.1 (q, JC-F = 32.9 Hz), 164.1; HRMS (APCI)
Calcd for C9H8N4F3 (M+H)+ 229.0696, Found 229.0698
2-Methyl-5-(4’-nitrophenyl)tetrazole (2Ag)7d: Colorless Solid (52.4 mg, 51% yield): mp 169-170 °C
(mp 171-172 °C); IR (neat) 2973, 1604, 1454, 1310, 1195, 1008 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
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4.46 (s, 3H), 8.31-8.37 (m, 4H); C NMR (100 MHz, CDCl3) δ = 39.7, 124.2, 127.5, 133.2, 148.8,
163.3.
5-(4’-Cyanophenyl)-2-methyltetrazole (2Ah)7b: Colorless Solid (62.7 mg, 68% yield): mp 127-128 °C
(mp 126-128 °C); IR (neat) 2987, 2223, 1536, 1419, 1133, 1006 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
4.44 (s, 3H), 7.79 (d, J = 7.8 Hz, 2H), 8.26 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 39.7,
113.7, 118.3, 127.2, 131.4, 132.7, 163.6.
Methyl 4-(2’-Methyl-2’H-tetrazol-5’-yl)benzoate (2Ai): Colorless Solid (76.0 mg, 70%yield): mp
181-183 °C; IR (neat) 2960, 1709, 1424, 1274, 1197, 1108 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 3.96
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(s, 3H), 4.43 (s, 3H), 8.16 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
= 39.6, 52.3, 126.7, 130.2, 131.4, 131.6, 164.4, 166.5.; HRMS (APCl) Calcd for C10H11O2N4 (M+H)+
219.0877, Found 219.0876.
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2-Methyl-5-(4’-(methylsulfonyl)phenyl) tetrazole (2Aj): Colorless Solid (50.0 mg, 42%yield):mp
214-215 °C; IR (neat) 2923, 1416, 1290, 1149, 1131, 1085 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 3.11
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(s, 3H), 4.45 (s, 3H), 8.08 (d, J = 8.6 Hz, 2H), 8.36 (d, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
= 39.7, 44.5, 127.6, 128.1, 132.4, 141.8, 163.6.; HRMS (APCl) Calcd for C9H11O2N4S (M+H)+
239.0597, Found 239.0600.
4-(2’-Methyl-2’H-tetrazol-5’-yl)phenyl Methanesulfonate (2Ak): Colorless Solid (87.3 mg, 69%
yield): mp 141-142 °C ; IR (neat) 2924, 1608, 1455, 1360, 1151 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =
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3.20 (s, 3H), 4.42 (s, 3H), 7.42 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 9.0 Hz, 2H); C NMR (100 MHz,
CDCl3) δ = 37.6, 39.6, 122.6, 126.6, 128.5, 150.4, 164.1.; HRMS (ESI) Calcd for C9H11O3N4S (M+H)+
255.0546, Found 255.0545.
2-Methyl-5-phenyltetrazole (2Al)7e: Colorless Oil (56.5 mg, 70% yield); IR (neat) 2953, 1722, 1449,
1195, 1045 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.36 (s, 3H), 7.50-7.43 (m, 3H), 8.16-8.09 (m, 2H);
13C NMR (100 MHz, CDCl3) δ = 39.4, 126.7, 127.3, 128.8, 130.2, 165.2.
2-Methyl-5-(4’-methylphenyl)tetrazole (2Am)7a: Colorless Solid (50.3 mg, 58% yield): mp 104-105
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°C (mp 108-109 °C); IR (neat) 2920, 1618, 1457, 1173, 1005 cm-1; H-NMR (CDCl3 : 400 MHz) δ =
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2.41 (s, 3H), 4.38 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H); C NMR (100 MHz,
CDCl3) δ = 21.5, 39.4, 124.5, 126.7, 129.6, 140.4, 165.3.
5-(4’-Ethylphenyl)-2-methyltetrazole (2An): Colorless Oil (49.6 mg, 53% yield); IR (neat) 2966,
1737, 1618, 1463, 1369, 1182 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 1.28 (t, J = 7.7 Hz, 3H), 2.72 (q, J
= 7.7 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 15.3,
28.8, 39.4, 124.7, 126.7, 128.4, 146.7, 165.3.; HRMS (APCl) Calcd for C10H13N4 (M+H)+ 189.1135,
Found 189.1134.
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5-(4’-Methoxyphenyl)-2-methyltetrazole (2Ao)7b: Colorless Solid (48.6 mg, 51% yield): mp 85-87 °C
(mp 85-86 °C); IR (neat) 2963, 1616, 1466, 1170, 1001 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 3.87 (s,
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2-Methyl-5-(p-biphenyl)tetrazole (2Ap): Colorless Solid (85.5 mg, 72% yield): mp 139-140 °C; IR
(neat) 3036, 1614, 1543, 1446, 1415, 1048 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.40 (s, 3H), 7.38 (t,
J = 7.41 Hz, 1H), 7.47 (dd J = 7.41, 7.18 Hz, 2H), 7.65 (d, J = 7.18 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H),
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8.21 (d, J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl3) δ = 39.5, 126.2, 127.1, 127.2, 127.5, 127.7,
128.9, 140.2, 143.0, 165.0.; HRMS (APCl) Calcd for C14H13N4 (M+H)+ 237.1135, Found 237.1135.
2-Methyl-5-(4’-benzoylphenyl)tetrazole (2Aq): Colorless Solid (59.2 mg, 45% yield): mp 162-163
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°C; IR (neat) 1650, 1442, 1418, 1308, 1047 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 4.44 (s, 3H), 7.52
(dd, J = 8.2, 7.5 Hz, 2H), 7.63 (tt, J = 1.4, 7.5 Hz, 1H), 7.84 (dd, J = 8.2, 1.4 Hz, 2H), 7.93 (d, J = 8.6
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Hz, 2H), 8.27 (d, J = 8.6 Hz, 2H); C NMR (100 MHz, CDCl3) δ = 39.6, 126.6, 128.4, 130.0, 130.5,
130.8, 132.6, 137.2, 138.9, 164.3, 196.0.; HRMS (ESI) Calcd for C15H13ON4 (M+H)+ 265.1084, Found
265.1082.
2-Methyl-5-(naphthalen-2’-yl) tetrazole (2Ar): Colorless Solid (36.7 mg, 35% yield): mp 117-118 °C;
IR (neat) 1526, 1492, 1434, 1376, 1324, 1200 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 4.44 (s, 3H), 7.53-
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7.57 (m, 2H), 7.87-7.90 (m, 1H), 7.95-7.97 (m, 2H), 8.21 (dd, J = 8.5, 1.8 Hz, 1H), 8.68 (s, 1H); C
NMR (100 MHz, CDCl3) δ = 39.5, 123.8, 124.6, 126.6, 126.6, 127.1, 127.8, 128.6, 128.7, 133.2, 134.2,
165.4.; HRMS (ESI) Calcd for C12H11N4 (M+H)+ 211.0978, Found 211.0978.
2-Methyl-5-(3’-pyridyl)tetrazole (2As)7f: Colorless Solid (44.3 mg, 55% yield): mp 125-126 °C; IR
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(neat) 1602, 1440, 1427, 1361, 1322, 1190 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 4.44 (s, 3H), 7.44
(ddd, J = 7.9, 4.9, 0.91 Hz, 1H), 8.42 (dt, J = 7.9, 2.0 Hz, 1H), 8.72 (dd, J = 4.9, 2.0 Hz, 1H), 9.37 (dd, J
= 2.0, 0.91 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 39.6, 123.6, 123.7, 134.0, 148.1, 151.2, 163.0.
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2-Methyl-5-(4’-quinolyl)tetrazole (2At): Colorless Solid (48.8 mg, 46% yield): mp 106-107 °C; IR
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(neat) 1589, 1485, 1427, 1337, 1193, 1161 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 4.54 (s, 3H), 7.67-
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0.90 ,8.3 Hz, 1H), 9.07 (d, J = 4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ = 39.8, 121.1, 124.8, 125.9,
127.8, 129.8, 130.1, 131.9, 149.0, 150.0, 163.6.; HRMS (ESI) Calcd for C11H10N5 (M+H)+ 212.0931,
Found 212.0927.
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General Procedure for the Preparation of 5-Aryl-2-benzyltetrazoles (Table 2).
To a solution of 4-chlorobenzaldehyde 1a (70.3 mg, 0.5 mmol) in dichloromethane (2.0 mL) was added
benzylhydrazine (65.0 µL, 0.55 mmol) at room temperature. The mixture was stirred at r.t. for 3 h.
Then, the solvent was removed, and dichloromethane (0.5 mL), trifluoroethanol (0.5 mL) and di-tert-
butyl azodicarboxylate (149.7 mg, 0.65 mmol) were added. After the obtained mixture was stirred at
room temperature for 1 h, [bis(trifluoroacetoxy)iodo]benzene (537.6 mg, 1.25 mmol) was added, and
the mixture was stirred at room temperature for 0.5 h. The reaction mixture was quenched with sat. aq.
Na2SO3 and was extracted with CHCl3 (3 × 10 mL). The organic layer was washed with brine and dried
over Na2SO4. Purification by short column chromatography on silica gel (hexane/AcOEt = 10:1) yielded
5-(4’-chlorophenyl)-2-benzyltetrazole 2Ba (97.1 mg, 72%).
2-Benzyl-5-(4’-chlorophenyl)tetrazole (2Ba): Colorless Solid (97.1 mg, 72% yield): mp 109-111 °C;
IR (neat) 1455, 1417, 1345, 1201, 1139, 1039 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ =5.80 (s, 2H), 7.36-
7.43 (m, 5H), 7.45 (d, J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 59.6,
125.8, 128.1, 128.4, 128.8, 129.0, 129.1, 133.2, 136.3, 164.6.; HRMS (APCl) Calcd for C14H12N4Cl
(M+H)+ 271.0745, Found 271.0743.
2-Benzyl-5-(3’-chlorophenyl)tetrazole (2Bb): Colorless Solid (65.7 mg, 49% yield): mp 74-76 °C; IR
(neat) 1454, 1435, 1198, 1077, 1048 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 5.81 (s, 2H), 7.40-7.44 (m,
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7H), 8.03 (ddd, J = 6.8, 2.2, 1.6 Hz, 1H), 8.13-8.15 (m, 1H); C NMR (100 MHz, CDCl3) δ = 57.0,
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125.0, 127.0, 128.5 (2C), 129.2 (2C), 130.3, 130.4, 133.2, 135.0, 164.4.; HRMS (APCl) Calcd for
C14H12N4Cl (M+H)+ 271.0745, Found 271.0742.
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2-Benzyl-5-(4’-bromophenyl)tetrazole (2Bd): Colorless Solid (95.4 mg, 61% yield): mp 105-107 °C;
IR (neat) 1596, 1453, 1348, 1197, 1001 cm-1; 1H-NMR (CDCl3 : 400 MHz) δ = 5.80 (s, 2H), 7.36-7.44
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(m, 5H), 7.60 (d, J = 8.61 Hz, 2H), 8.01 (d, J = 8.61 Hz, 2H); C NMR (100 MHz, CDCl3) δ = 57.0,
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124.8, 126.4, 128.5, 128.5, 128.9, 129.1, 132.2, 133.3, 164.7.; HRMS (APCl) Calcd for C14H12N4Br
(M+H)+ 315.0240, Found 315.0237.
2-Benzyl-5-(4’-nitrophenyl)tetrazole (2Bg): Colorless Solid (89.9 mg, 64% yield): mp 140-141 °C; IR
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(neat) 1516, 1337, 1041, 867 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 5.84 (s, 2H), 7.38-7.46 (m, 5H),
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8.33 (s, 4H); C NMR (100 MHz, CDCl3) δ = 57.2, 124.3, 127.8, 128.6, 129.2, 129.3, 133.0, 133.3,
148.9, 163.7.; HRMS (APCl) Calcd for C14H12O2N5 (M+H)+ 282.0986, Found 282.0983.
2-Benzyl-5-(4’-cyanophenyl)tetrazole (2Bh): Colorless Solid (79.7 mg, 61% yield): mp 110-112 °C;
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IR (neat) 2229, 1464, 1201, 1043, 856 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 5.83 (s, 2H), 7.37-7.45
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(m, 5H), 7.77 (d, J = 8.15 Hz, 2H), 8.26 (d, J = 8.15 Hz, 2H); C NMR (100 MHz, CDCl3) δ = 57.0,
113.6, 118.3, 127.2, 128.4, 128.9, 129.0, 131.4, 132.6, 132.8, 163.7.; HRMS (APCl) Calcd for C15H12N5
(M+H)+ 262.1087, Found 262.1090.
Methyl 4-(2’-Benzyl-2H-tetrazol-5’-yl)benzoate (2Bi): Colorless Solid (75.1 mg, 51% yield): mp 145-
1
146 °C; IR (neat) 1715, 1441, 1277, 1197, 1113, 1046 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 3.95 (s,
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3H), 5.82 (s, 2H), 7.37-7.45 (m, 5H), 8.14 (d, J = 8.83 Hz, 2H), 8.22 (d, J = 8.83 Hz, 2H); C NMR
(100 MHz, CDCl3) δ = 52.4, 57.1, 126.9, 128.5, 129.2 (2C), 130.2, 131.5, 131.7, 133.2, 164.7, 166.6;
HRMS (APCl) Calcd for C16H15O2N4 (M+H)+ 295.1190, Found 295.1187.
2-Benzyl-5-phenyltetrazole (2Bl): Colorless Solid (70.2 mg, 59% yield): mp 66-68 °C; IR (neat) 1713,
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1449, 1334, 1274, 1200, 1161 cm-1; H-NMR (CDCl3 : 400 MHz) δ = 5.81 (s, 2H), 7.37-7.46 (m, 8H),
8.14 (dd, J = 1.8, 8.1Hz, 2H); 13C NMR (100 MHz, CDCl3) δ = 56.9, 127.0, 127,4 128.5, 128.9, 129.0,
129.1, 130.4, 133.5, 165.5.; HRMS (APCl) Calcd for C14H13N4 (M+H)+ 237.1135, Found 237.1132.
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Isolation of Di-tert-butyl 5-(4’-chlorophenyl)-3-methyltetrazolidine-1,2-dicarboxylate (III) with p-
Chlorobenzaldehyde, Methylhydrazine, and Di-tert-butyl Azodicarboxylate (Scheme 2).
To a solution of 4-chlorobenzaldehyde 1a (70.3 mg, 0.5 mmol) in methanol (0.5 mL) was added
methylhydrazine (31.7 µL, 0.6 mmol) at room temperature. The mixture was stirred at r.t. for 3 h.
Then, the solvent was removed, and di-tert-butyl azodicarboxylate (149.7 mg, 0.65 mmol),
dichloromethane (0.5 mL), and trifluoroethanol (0.5 mL) were added, and the obtained mixture was
stirred at room temperature for 0.5 h. Then, the solvent was removed, and the residue was purified by
short column chromatography on silica gel (hexane/AcOEt = 6:1) to give di-tert-butyl 5-(4’-
chlorophenyl)-3-methyltetrazolidine-1,2-dicarboxylate (176.3 mg, 88%).
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Di-tert-butyl 5-(4’-chlorophenyl)-3-methyltetrazolidine-1,2-dicarboxylate (III): Colorless Solid
(176.3 mg, 88%yield): a mixture of two rotamers (5:3); mp 130-133 °C; IR (neat) 3288, 1738, 1683,
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1394, 1153, 810 cm-1 ; H-NMR (CDCl3 : 400 MHz) δ = 1.16 (brs, 9H, minor), 1.30 (brs, 9H, major),
1.45 (brs, 9H, minor), 1.48 (brs, 9H, major), 3.91 (brs, 3H, major), 3.92 (brs, 3H, minor), 5.97 (brs, 1H,
minor), 6.20 (brs, 1H, major), 7.33-7.45 (m, 4H) ; HRMS (ESI) Calcd for C18H28O4N4Cl (M+H)+
399.1794, Found 399.1789.
Acknowledgments:
Financial support in the form of a Grant-in–Aid for Scientific Research (No. 15K05418) from the
Ministry of Education, Culture, Sports, Science, and Technology in Japan and Iodine Research Project
in Chiba University is gratefully acknowledged.
Supporting Infomation:
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The supporting Information is available free of charge on the ACS Publications website at DOI:
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http://pubs.acs.org. NMR charts of all 5-aryl-2-alkyltetrazoles 2 and X-ray analytical data of 2Ag.
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References:
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