Regioselective synthesis of carboxylic and fluoromethyl tetrazoles enabled by silver-catalyzed cycloaddition of diazoacetates and aryl diazonium salts

Article abstract of DOI:10.1016/j.tet.2020.131063

Here we present a dipolar [3 + 2] cycloaddition transformation of diazoacetates with arenediazonium salts under silver catalysis, thus offering a straightforward approach for the regioselective construction of carboxylic tetrazoles. Several merits are accompanied with this reaction including readily available starting reagents, broad coupling scope, high yields, and friendly reaction conditions. The synthetic value is further showcased by one-pot conversion of commercially available primary arylamines to tetrazoles and successful transformations of the cycloadducts into valuable 5-fluoromethyltetrazoles and an analogue of P2X3 receptor antagonist.

Full text of DOI:10.1016/j.tet.2020.131063

Journal Pre-proof
Regioselective synthesis of carboxylic and fluoromethyl tetrazoles enabled by silver-
catalyzed cycloaddition of diazoacetates and aryl diazonium salts
Ming-Yang Xiao, Zhen Chen, Fa-Guang Zhang, Jun-An Ma
PII:
S0040-4020(20)30178-2
https://doi.org/10.1016/j.tet.2020.131063
TET 131063
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 January 2020
Revised Date: 17 February 2020
Accepted Date: 19 February 2020
Please cite this article as: Xiao M-Y, Chen Z, Zhang F-G, Ma J-A, Regioselective synthesis of carboxylic
and fluoromethyl tetrazoles enabled by silver-catalyzed cycloaddition of diazoacetates and aryl
diazonium salts, Tetrahedron (2020), doi: https://doi.org/10.1016/j.tet.2020.131063.
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Regioselective synthesis of carboxylic and
fluoromethyl tetrazoles enabled by silver-
catalyzed cycloaddition of diazoacetates and
aryl diazonium salts
Leave this area blank for abstract info.
Ming-Yang Xiao, Zhen Chen, Fa-Guang Zhang,* and Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin
Collaborative Innovation Centre of Chemical Science & Engineering, Tianjin University, Tianjin 300072; and
Joint School of NUS & TJU, International Campus of Tianjin University, Fuzhou 350207, P. R. of China.

1
Tetrahedron
journal homepage: www.elsevier.com
Regioselective Synthesis of Carboxylic and Fluoromethyl Tetrazoles Enabled by
Silver-Catalyzed Cycloaddition of Diazoacetates and Aryl Diazonium Salts
Ming-Yang Xiao,† Zhen Chen,† Fa-Guang Zhang, and Jun-An Ma
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Centre of Chemical Science &
Engineering, Tianjin University, Tianjin 300072; and Joint School of NUS & TJU, International Campus of Tianjin University, Fuzhou 350207, P. R. of China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Here we present a dipolar [3 + 2] cycloaddition transformation of diazoacetates with
arenediazonium salts under silver catalysis, thus offering a straightforward approach for the
regioselective construction of carboxylic tetrazoles. Several merits are accompanied with this
reaction including readily available starting reagents, broad coupling scope, high yields, and
friendly reaction conditions. The synthetic value is further showcased by one-pot conversion of
commercially available primary arylamines to tetrazoles and successful transformations of the
cycloadducts into valuable 5-fluoromethyltetrazoles and an analogue of P2X3 receptor
antagonist.
Available online
Keywords:
tetrazoles
fluoromethyl groups
diazonium salts
cycloaddition
diazoacetates
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
a) Previous Work:
Ar
N
N
Diazoacetates are an important class of building blocks in the
realm of synthetic chemistry.1 By harnessing their versatile
reactivity, a large variety of organic transformations have been
reported over the past decades, among which are X-Y insertions
(X = C, O, N, S, Si etc.; Y = H, O, N, S, etc.),2
cyclopropanation,3 migration,4 ylide rearrangement,5 and multi-
component reactions (MCR).6 In particular, diazoacetates can
also serve as competitive 1,3-dipoles to undergo direct dipolar
cycloaddition (DPC) reactions.7 Notably, such DPC
transformations could fully entail the diazo group for the efficient
preparation of various pharmaceutically important N-containing
heterocycles, which is arguably in line with the tenet of atom
economy and green chemistry. However, simple hydrocarbon
dipolarophiles such as alkenes and alkynes have been extensively
studied in most previous reports en route to pyrazolines and
pyrazoles, whereas the 1,3-dipolar reactivity of diazoacetates
with other hybrid reaction components remains far less
investigated. In this context, our group recently demonstrated that
aryl diazonium tetrafluoroborate8 could serve as a feasible dipo-
larophile to react with trifluorodiazoethane (CF3CHN2) and
masked difluorodiazoethane (PhSO2CF2CHN2) to produce
different functionalized tetrazole architectures, respectively
(Scheme 1a).9 From a diversity-oriented synthetic point of view,
the development of efficient methods to produce
monofluoromethyl tetrazoles by means of this strategy
undoubtedly would be equally desirable.10 More importantly, the
N2
Ag catalyst
N
N
+
CF3
Ar
N
N
H
H
CF3
BF4
Ar
Ar
Ar
N
N2
N
N
N
N
Ag catalyst
N
N
N
+
N
CF2SO2Ph
N
BF4
CF2SO2Ph
CHF2
b) This Work:
Ar
Ar
Ar
N
N
N
N
N2
Ag catalyst
N
N
N
+
N
N
N
H
COR
BF4
CH2F
COR
Scheme 1. Synthesis of CF3-, CHF2-, and CH2F-tetrazoles from
aryl diazonium salts and diazo compounds.
tetrazole derivatives have been extensively utilized in a wide
range of pharmaceuticals, agrochemicals, and materials science at
a remarkably increasing level.11 Therefore, herein we report our
exhaustive investigation of the silver-catalyzed [3
+ 2]
cycloaddition reactions of diazoacetates and α-diazo
acetophenones with aryl diazonium salts including optimization
of reaction conditions, substrate scope evaluation in terms of both
diazocarbonyl compounds and aryl diazonium salts, as well as
further synthetic transformations to 5-fluoromethyltetrazoles
———
Corresponding author. zhangfg1987@tju.edu.cn; majun_an68@tju.edu.cn.
†These authors contribute equally.

2
Tetrahedron
which are otherwise difficult to access via conventional
improvement was observed (entries 11–17). Reducing the
methods (Scheme 1b).
loadings of AgOAc or ethyl diazoacetate both resulted in inferior
yields (entries 18 and 19), and control experiments revealed that
both the silver catalyst and base are pivotal for the success of this
reaction (entries 20 and 21). Further examination on the solvent
effect (entries 22–26) demonstrated that THF proved to be a
better reaction medium and the yield could be finally increased to
86% (entry 22).
2. Results and discussion
As an outset of this study, we first evaluated the effect of
various base on the reactivity of phenyl diazonium tetra-
fluoroborate 1a with ethyl diazoacetate under the catalysis of
AgOAc (5 mol%) in a co-solvent of THF and DMF (v/v, 20/1) at
0
oC (entries 1–10, Table 1). Compared with Cs2CO3, which
The substrate scope of arenediazonium salts 1 with ethyl
diazoacetate was then investigated under the established
conditions. As depicted in Scheme 2, for general phenyl
diazonium salts, a broad spectrum of substituents including alkyl
(2a–2h), alkoxyl (2i–2k), phenyl (2l), nitro (2m and 2n),
trifluoromethyl (2o), acetyl (2p), alkoxylcarbonyl (2q) and cyano
(2r–2t) were all well tolerated to give the expected di-substituted
carboxylic tetrazoles in moderate to high yields (46–92%).
successfully promoted this reaction to give cycloadduct 2a in
75% yield in our primary report (entry 1),9 stronger bases led to
significantly decreased yields (entries 2–4), whereas weaker
bases brought about comparable or even better results (entries 5–
10), and Na2CO3 proved to be the optimal choice to deliver the
desired 2,5-disubstituted tetrazole 2a in 82% yield as a single
regio-isomer (entry 6). Subsequent catalyst screening indicated
that when other silver salts such as AgNO3, AgOTf, AgSbF6,
AgBF4, Ag2CO3, Ag3PO4 and AgF were used, no obvious
N2
N
BF4
N
N
N
AgOAc (5 mol%), Na2CO3
THF, 0 °C, 12 h
COR
R
+
N
Table 1. Screening studies. a
H
N
Ar
Ar
1
2
O
CO2Et
CO2Et
R = 4-Me, 2b, 89%
N
N
N
N
CO2Et
R = 3-Me, 2c, 66%
N
N
N
N
N
R = 2-Me, 2d, 87%
N
N
R = 2,4-Me2, 2e, 92%
R = 3,5-Me2, 2f, 77%
R = 4-iPr, 2g, 71%
R = 4-tBu, 2h, 64%
N
Entry
Catalyst
Base
Solvent
Yield
(%)b)
R
2a, 86%
79% at gram-scale
OMe
2i, 90%
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgNO3
AgOTf
AgSbF6
AgBF4
Ag2CO3
Ag3PO4
AgF
Cs2CO3
NaOH
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF+DMF
THF
75
nr
CO2Et
2
N
3
EtONa
tBuOK
K2CO3
Na2CO3
Li2CO3
NaHCO3
NaOAc
KOAc
62
nr
N
N
N
4
5
77
82
76
76
79
74
71
64
63
37
trace
trace
nr
6
MeO
OMe
7
OMe
2j, 71%
8
9
CO2Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
N
N
R = 4-NO2, 2m, 61%
R = 3-NO2, 2n, 72%
R = 4-CF3, 2o, 46%
R = 4-Ac, 2p, 73%
R = 4-CO2Me, 2q, 58%
R = 2-CN, 2r, 82%
CO2Et
CO2Et
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
-
N
N
N
N
N
N
N
N
N
N
Ph
Br
R
R = 3-CN-4-Me, 2s, 77%
R = 3-CN-4-OMe, 2t, 75%
OMe
2k, 74%
2l, 76%
CO2Et
CO2Et
CO2Et
R = 4-F, 2u, 91%
R = 3-F, 2v, 83%
R = 4-Cl, 2w, 67%
R = 3-Cl, 2x, 68%
R = 2-Cl, 2y, 61%
N
AgOAc
AgOAc
-
44
60
nr
N
N
N
N
N
N
N
N
N
N
N
CO2Me
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
nr
R = 3-Cl-4-F, 2z, 63%
R = 4-Br, 2a', 58%
R
N
S
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
86
67
21
48
62
2b', 71%
2c', 52%
DMF
CO2Et
t
CO2 Bu
CH2Cl2
N
CO2Bn
O
R
N
N
N
N
MeCN
N
N
N
N
N
N
toluene
N
N
N
N
a General [3 + 2] DPC conditions: phenyl diazonium tetrafluoroborate 1a (0.3
N
R = H, 2g', 77%
N
mmol), N2CHCO2Et (0.6 mmol), silver salt (5 mol%) and base (0.6 mmol) in
3 mL of indicated solvent at 0 C for 12 h; THF/DMF = 20:1 was used as
o
R = 4-Me, 2h', 82%
R = 4-Cl, 2i', 75%
mixed solvent unless otherwise noted.
b Yield of isolated product.
c AgOAc (1 mol%).
2e', 63%
2f', 78%
2d', 53%
Scheme 2. Regioselective synthesis of carboxylic tetrazoles from
arenediazonium salts 1 and diazoacetates.
d N2CHCO2Et (0.45 mmol).

3
Cycloadduct 2a could also be prepared in a gram-scale despite
with a slightly decreased yield (79%). Notably, various halogen-
containing phenyl diazonium salts participated in the [3 + 2]
cycloaddition transformation to furnish 2u–2a’ in 58–91% yields,
which provides new opportunity for further elaborations on these
tetrazole derivatives via transition-metal-mediated cross-coupling
reactions. In addition, steric effect has no obvious influence on
the reaction outcome as evident by the observed high yields for
ortho-substituted substrates (2d, 2e, 2l, 2r and 2y). Furthermore,
hetero-aryl diazonium salts such as 3-thienyl, 3-pyridyl, and 3-
quinolyl ones, also proved to be compatible coupling partners,
thereby affording the expected products 2b’–2d’ in decent yields.
As far as diazo compounds are concerned, the substrate scope is
not only limited to ethyl diazoacetate. Other diazo reagents such
as tert-butyl or benzyl diazo-acetate as well as α-diazo
acetophenones also proved to be viable 1,3-dipolar partners, and
the corresponding tetrazoles 2e’–2i’ were routinely afforded in
practical to high yields. It should be noted that exclusive
regioselectivity was observed in all cases among the tested
substrates. The molecular structure was further unambiguously
determined via X-ray analysis of 2j, and the other compounds are
assigned by analogy.12
CH2F
CO2Et
CH2OH
N
N
N
N
N
N
N
N
N
DIBAL-H
THF, rt, 4 h
N
PyFluor, MTBD
toluene, rt, 24 h
N
N
R
R
R
4
2
3
CH2F
CH2OH
CH2F
CH2OH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
4b, 70%
Me
3b, 84%
4a, 72%
3a, 88%
CH2OH
CH2F
CH2OH
CH2F
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NO2
3d, 64%
NO2
4d, 66%
F
F
3c, 96%
4c, 77%
N
N
N
N
N
N
CH2F
CH2OH
N
N
N
N
4e, 62%
3e, 78%
F
OH
N
N
N
N
N
N
N
N
4f, 54%
3f, 90%
Scheme 4. Scope of (2-Aryl-2H-tetrazol-5-yl)methanol 3 and 5-
(Fluoromethyl)-2-aryl-2H-tetrazole 4.
Scheme 3. Regioselective synthesis of free alcohol- or amino ac-
id-containing tetrazoles.
Since arenediazonium salts are not commercially obtainable,
and some of them are difficult to separate and purify, we then
evaluate the feasibility of performing a one-pot synthesis of 2-
aryl tetrazolic esters directly from primary arylamines. As a proof
of concept, we chose 4-hydroxylmethylaniline as the starting
material, with which we failed to separate the corresponding aryl
diazonium salt. To our delight, the tandem diazotiza-
tion/cycloaddition transformation in one-pot operation readily
proceeded to yield the expected cycloadduct 2j’ with good
efficiency (Scheme 3). Notably, phenylalanine-derived
diazonium salts were also well compatible with the current
platform, and the desired amino-acid-containing tetrazoles 2k’
and 2l’ were isolated in 55% and 40% yield, respectively. It
should be mentioned that the incorporation of tetrazole motif into
amino acids may offer novel bioorthogonal chemical handles for
fluorescent labelling in biological studies.13
S
cheme 5. Preparation of CH2F-functionalized P2X3 receptor an-
tagonist.
(DIBAL-H) readily reduced the cycloadducts
2 into the
corresponding tetrazolic alcohols 3 in 64–96% yields under mild
conditions, and the hydroxyl moiety could then be successfully
converted to fluorine in the presence of 2-pyridinesulfonyl
Introducing fluorine atoms into organic small molecules has
recognized as a powerful approach to alter physico-chemical and
biological properties of parent targets.14 Compared with the
recent progress in accessing trifluoromethyl- and difluoromethyl-
tetrazoles,9 the corresponding monofluoromethyl tetrazole
analogues still remain a curiosity. Therefore, we continued our
study in transforming cycloadducts 2 to monofluoromethyl te-
trazoles. As outlined in Scheme 4, diisobutylaluminum hydride
fluoride (PyFluor) and
a bicyclic strong guanidine base
(MTBD).15 As a result, a series of 2-aryl-5-fluoromethyltetrazole
derivatives 4 were ultimately obtained in 42–74% total yields
over two steps. Among them, fluoromethyl tetrazole 4b was
crystallized and analyzed by X-ray diffraction.12 Ketone-
substituted tetrazole 2g’ could also be easily converted to

4
Tetrahedron
o
corresponding α-phenyl fluoromethyl tetrazole 4f in 49% total
yield.
0.4 mmol, 2.0 equiv.) at 0 C. The reaction mixture was allowed
to stir at room temperature for 4 hours until completion indicated
by TLC. The obtained solution was subsequently quenched with
To further showcase the practicality of this protocol, we
o
1N HCl solution at 0 C, extracted with EtOAc, and the organic
devoted our attention to the synthesis of CH2F-functionalized
P2X3 receptor antagonist.16 As depicted in Scheme 5, tetrazole-
carboxylate 2m’ could be smoothly prepared in 52% yield by
treating easily accessible primary aryl amine 5 under standard
one-pot conditions. Subsequently,
sequence reaction of 2m’ occurred to deliver the target
monofluoromethyltetrazole analogue 4g in 52% total yield.
phase was washed with brine, dried over MgSO4 and
concentrated under reduced pressure. The residue was further
purified by a silica gel column chromatography (eluant:
petroleum ether/ethyl acetate = 5:1) to afford the expected
products 3. To a solution of 3 (0.3 mmol) in toluene (2 mL) was
added Pyfluor (2-pyridinesulfonyl fluoride, CAS 878376-35-3,
0.33 mmol, 1.1 equiv.) and MTBD (7-Methyl-1,5,7-
triazabicyclo-[4.4.0]dec-5-ene, CAS 84030-20-6, 0.45 mmol, 1.5
equiv.) dropwise at room temperature. The resulting mixture was
stirred at the same temperature for 24 hours until completion
indicated by TLC. The obtained solution was subsequently
a
reduction/fluorination
In conclusion,
a
[3
+
2] DPC transformation of
arenediazonium salts with diazoacetates and α-diazo
acetophenones was established via silver catalysis. Under gentle
reaction conditions,
a
broad array of 2-aryltetrazole-5-
o
quenched with saturated sodium bicarbonate solution at 0 C,
carboxylates and 2-aryltetrazole-5-ketones were regioselectively
achieved in good to high yields. This protocol’s practicality was
further highlighted via convenient one-pot protocol directly from
primary arylamines, and facile transformation of the
cycloadducts into 5-monofluoromethyltetrazoles as well as an
analogue of a P2X3 receptor antagonist. Future investigations on
the mechanistic elucidation and applications of these
functionalized tetrazoles are underway in our laboratory.
extracted with DCM, and the organic phase was washed with
brine, dried over MgSO4, and concentrated under vacuum. The
residue was purified by a silica gel column chromatography
(eluant: petroleum ether/ethyl acetate = 30:1) to afford the
desired products 4.
Ethyl 2-phenyl-2H-tetrazole-5-carboxylate (2a). Light yellow
solid; (56 mg, 86%); m.p.: 68-69 . 1H NMR (400 MHz, CDCl3)
δ 8.15 (d, J = 7.5 Hz, 2H), 7.67 – 7.41 (m, 3H), 4.54 (q, J = 7.1
Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
157.8, 136.4, 130.7, 129.9, 120.3, 62.8, 14.3. HR-MS (ESI-TOF)
m/z: [M + H]+ calcd for [C10H11N4O2]+ 219.0877; Found
219.0885.
3. Experimental section
3.1. Synthesis of tetrazoles 2 from the corresponding
arenediazonium salts 1 (Method A).
An oven-dried Schlenk tube equipped with a magnetic stir bar
was charged with AgOAc (2.6 mg, 0.015 mmol, 5 mol%) and
Na2CO3 (63.6 mg, 0.6 mmol, 2 equiv). Then THF (3 mL) and
N2CHCO2Et (68.5 mg, 0.6 mmol, 2 equiv) were added. The
resulting suspension was stirred at 0 oC for 10 minutes before the
aryl diazonium salts 1 (0.3 mmol) was added in one portion. The
Ethyl 2-(p-tolyl)-2H-tetrazole-5-carboxylate (2b). Yellow solid;
1
(62 mg, 89%); m.p.: 62-63 . H NMR (400 MHz, CDCl3) δ
8.08 – 7.77 (m, 2H), 7.25 (d, J = 8.3 Hz, 2H), 4.45 (q, J = 7.1 Hz,
2H), 2.33 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 158.0, 157.7, 141.2, 134.3, 130.4, 120.3, 62.8, 21.4,
14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C11H13N4O2]+
233.1033; Found 233.1035.
o
resulting mixture was allowed to stir at 0 C for 12 hours. Then
the mixture was filtered through a Celite plug, rinsed with ethyl
acetate. The resulting clear organic solution was concentrated
under reduced pressure, and the residue was further purified by a
silica gel column chromatography (eluant: petroleum ether/ethyl
acetate = 30:1) to yield the corresponding ethyl 2-aryl-2H-
tetrazole-5-carboxylate 2.
Ethyl 2-(m-tolyl)-2H-tetrazole-5-carboxylate (2c). Yellow
1
liquid; (46 mg, 66%). H NMR (400 MHz, CDCl3) δ 8.06 – 7.93
(m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 4.57
(q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 158.0, 157.8, 140.6, 136.5, 131.5,
129.7, 120.9, 117.6, 62.9, 21.5, 14.3. HR-MS (ESI-TOF) m/z: [M
+ H]+ calcd for [C11H13N4O2]+ 233.1033; Found 233.1038.
3.2. Synthesis of tetrazoles 2 from the corresponding aniline
derivatives (Method B).
An oven-dried Schlenk tube equipped with a magnetic stir bar
was charged with anilines (0.2 mmol), then dry THF (4 mL) were
added. To the resulting solution which was precooled to 0 C,
aqueous HBF4 (30 ꢀL, 50% in water, 0.4 mmol, 2.0 equiv) was
added. After 5 minutes, BuONO (54 ꢀL, 0.4 mmol, 2.0 equiv)
Ethyl 2-(o-tolyl)-2H-tetrazole-5-carboxylate (2d). Yellow liquid;
(60.5 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.0,
1.4 Hz, 1H), 7.48 (td, J = 7.5, 1.4 Hz, 1H), 7.43 – 7.34 (m, 2H),
4.56 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 158.0, 157.8, 136.1, 133.3, 132.1,
131.1, 127.1, 125.6, 62.9, 18.7, 14.3. HR-MS (ESI-TOF) m/z: [M
+ H]+ calcd for [C11H13N4O2]+ 233.1033; Found 233.1042.
o
t
was added subsequently. The mixture was allowed to stir at 0 oC
for 15 minutes before N2CHCO2Et (45.7 mg, 0.4mmol, 2 equiv.)
was added. After that, AgOAc (1.7 mg, 0.01 mmol, 5 mol%) and
Na2CO3 (63.6 mg, 0.6 mmol, 3 equiv) were added together. After
addition was complete, the mixture was stirred at 0 oC for
additional 12 hours. Then the mixture was filtered through a
Celite plug, rinsed with ethyl acetate. The resulting clear organic
solution was concentrated under reduced pressure, and the
Ethyl 2-(2, 4-dimethylphenyl)-2H-tetrazole-5-carboxylate (2e).
Yellow solid; (68 mg, 92%); m.p.: 66-68 . 1H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 8.1 Hz, 1H), 7.23 – 7.14 (m, 2H), 4.56 (q, J
= 7.1 Hz, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 158.1, 157.7, 141.5, 133.8, 133.0,
132.6, 127.7, 125.4, 62.9, 21.4, 18.6, 14.4. HR-MS (ESI-TOF)
m/z: [M + Na]+ calcd for [C12H14N4NaO2]+ 269.1009; Found
269.1008.
residue was further purified by
chromatography (eluant: petroleum ether/ethyl acetate = 10:1) to
yield the corresponding ethyl 2-aryl-2H-tetrazole-5-carboxylate 2.
a
silica gel column
3.3. Synthesis of fluoromethyl tetrazoles 4 from the
corresponding carboxylic tetrazoles 2.
Ethyl 2-(3, 5-dimethylphenyl)-2H-tetrazole-5-carboxylate (2f).
1
White solid; (57 mg, 77%); m.p.: 70-71 . H NMR (400 MHz,
To a solution of compounds 2 (0.2 mmol, 1.0 equiv.) in 3 mL
THF was added dropwise DIBAL-H in hexane (0.4 mL, 1.0 N,
CDCl3) δ 7.81 (d, J = 1.6 Hz, 2H), 7.15 (s, 1H), 4.57 (q, J = 7.1
Hz, 2H), 2.42 (s, 6H), 1.49 (t, J = 7.1 Hz, 3H). 13C NMR (101

5
MHz, CDCl3) δ 158.0, 157.8, 140.1, 136.4, 132.4, 118.1, 62.9,
21.4, 14.4. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C12H15N4O2]+ 247.1190; Found 247.1194.
(ESI-TOF) m/z: [M + Na]+ calcd for [C10H9N5NaO4]+ 286.0547;
Found 286.0541.
Ethyl 2-(4-(trifluoromethyl)phenyl)-2H-tetrazole-5-carboxylate
(2o). Light yellow solid; (39.5 mg, 46%). m.p.: 113-115 °C. H
1
Ethyl 2-(4-isopropylphenyl)-2H-tetrazole-5-carboxylate (2g).
Yellow liquid; (55 mg, 71%). 1H NMR (400 MHz, CDCl3)δ 8.28
– 7.92 (m, 2H), 7.47 – 7.34 (m, 2H), 4.57 (q, J = 7.1 Hz, 2H),
3.01 (hept, J = 6.9 Hz, 1H), 1.49 (t, J = 7.2 Hz, 3H), 1.30 (d, J =
6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 158.0, 157.8, 152.1,
134.5, 127.9, 120.5, 62.9, 34.1, 23.9, 14.4. HR-MS (ESI-TOF)
m/z: [M + H]+ calcd for [C13H17N4O2]+ 261.1346; Found
261.1351.
NMR (400 MHz, CDCl3) δ 8.58 – 8.22 (m, 2H), 7.95 – 7.77 (m,
2H), 4.58 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 158.2, 157.5, 138.6, 132.6 (q, J = 33.3 Hz),
127.2 (q, J = 3.8 Hz), 123.3 (q, J = 272.6 Hz), 120.6, 63.0, 14.2.
19F NMR (376 MHz, CDCl3) δ -62.87. HR-MS (ESI-TOF) m/z:
[M + Na]+ calcd for [C11H9F3N4NaO2]+ 309.0570; Found
309.0574.
Ethyl 2-(4-(tert-butyl)phenyl)-2H-tetrazole-5-carboxylate (2h).
Red liquid; (52.5 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.24 –
8.00 (m, 2H), 7.67 – 7.51 (m, 2H), 4.58 (q, J = 7.1 Hz, 2H), 1.49
(t, J = 7.1 Hz, 3H), 1.38 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
158.1, 157.9, 154.4, 134.2, 126.9, 120.2, 62.9, 35.2, 31.4, 14.4.
HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C14H19N4O2]+
275.1503; Found 275.1510.
Ethyl 2-(4-acetylphenyl)-2H-tetrazole-5-carboxylate (2p). White
solid; (60 mg, 73%). m.p. 95-96 °C. 1H NMR (400 MHz, CDCl3)
δ 8.42 – 8.23 (m, 2H), 8.22 – 8.01 (m, 2H), 4.55 (q, J = 7.1 Hz,
2H), 2.65 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 196.4, 158.2, 157.6, 139.1, 138.5, 130.1, 120.4, 63.0,
26.8, 14.3. HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for
[C12H12N4NaO3]+ 283.0802; Found 283.0799.
Ethyl 2-(4-methoxyphenyl)-2H-tetrazole-5-carboxylate (2i).
White solid; (67 mg, 90%); m.p.: 75-76 . H NMR (400 MHz,
Ethyl
2-(4-(methoxycarbonyl)phenyl)-2H-tetrazole-5-
1
1
carboxylate (2q). White solid; (48 mg, 58%). m.p.: 96-97 °C. H
NMR (400 MHz, CDCl3) δ 8.27 (q, J = 8.5 Hz, 4H), 4.57 (q, J =
7.1 Hz, 2H), 3.96 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 165.7, 158.2, 157.7, 139.3, 132.2, 131.5, 120.2,
63.1, 52.7, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C12H13N4O4]+ 277.0931; Found 277.0942.
CDCl3) δ 8.08 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.1 Hz, 2H), 4.55
(q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 161.3, 158.0, 157.7, 129.9, 122.0,
114.9, 62.8, 55.8, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd
for [C11H13N4O3]+ 249.0982; Found 249.0990.
Ethyl
2-(3,4,5-trimethoxyphenyl)-2H-tetrazole-5-carboxylate
Ethyl
2-(2-cyanophenyl)-2H-tetrazole-5-carboxylate
(2r).
1
(2j). White solid; (65.5 mg, 71%); m.p.: 145-146 . H NMR
(400 MHz, CDCl3) δ 7.40 (s, 2H), 4.54 (q, J = 7.1 Hz, 2H), 3.93
(s, 6H), 3.87 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 157.9, 157.7, 154.0, 139.9, 132.0, 97.9, 62.9,
61.1, 56.6, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C13H17N4O5]+ 309.1193; Found 309.1202.
Yellow solid; (60 mg, 82%); m.p. 76-77 °C. 1H NMR (400 MHz,
CDCl3) δ 8.09 (dd, J = 8.2, 1.2 Hz, 1H), 7.96 (dd, J = 7.8, 1.4 Hz,
1H), 7.87 (td, J = 7.9, 1.5 Hz, 1H), 7.74 (td, J = 7.7, 1.2 Hz, 1H),
4.57 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 158.4, 157.4, 137.0, 135.3, 134.3, 131.3, 124.8,
114.9, 107.3, 63.2, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd
for [C11H10N5O2]+ 244.0829; Found 244.0830.
Ethyl 2-(3-bromo-4-methoxyphenyl)-2H-tetrazole-5-carboxylate
(2k). White solid; (72 mg, 74%); m.p.: 107-108 °C. H NMR
1
Ethyl 2-(3-cyano-4-methylphenyl)-2H-tetrazole-5-carboxylate
(2s). White solid; (59 mg, 77%). m.p.: 118-119 °C. H NMR
1
(400 MHz, CDCl3) δ 8.41 (d, J = 2.7 Hz, 1H), 8.12 (dd, J = 8.9,
2.6 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H),
3.98 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 157.7, 157.7, 157.7, 130.0, 125.4, 120.5, 112.6, 111.9,
62.8, 56.7, 14.2. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C11H12N4O3Br]+ 327.0093; Found 327.0100.
(400 MHz, CDCl3) δ 8.44 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 8.5,
2.4 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H),
2.65 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 158.1, 157.5, 144.8, 134.6, 132.1, 124.1, 123.9, 116.4,
114.7, 63.1, 20.6, 14.3. HR-MS (ESI-TOF) m/z: [M + Na]+ calcd
for [C12H11N5NaO2]+ 280.0805; Found 280.0800.
Ethyl 2-([1,1'-biphenyl]-2-yl)-2H-tetrazole-5-carboxylate (2l).
Red liquid; (67 mg, 76%). H NMR (400 MHz, CDCl3) δ 7.64
1
Ethyl 2-(3-cyano-4-methoxyphenyl)-2H-tetrazole-5-carboxylate
(2t). Light yellow solid; (61.5 mg, 75%). m.p. 133-134 °C. H
1
(ddd, J = 16.8, 7.8, 1.5 Hz, 2H), 7.57 (ddd, J = 15.0, 7.9, 1.5 Hz,
2H), 7.26 (dd, J = 5.0, 1.9 Hz, 3H), 7.14 – 7.02 (m, 2H), 4.50 (q,
J = 7.1 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 157.8, 157.6, 138.7, 136.9, 134.7, 131.6, 131.6, 128.6,
128.4, 128.4, 128.1, 126.6, 62.7, 14.2. HR-MS (ESI-TOF) m/z:
[M + H]+ calcd for [C16H15N4O2]+ 295.1195; Found 295.1197.
NMR (400 MHz, CDCl3) δ 8.49 – 8.27 (m, 2H), 7.19 (d, J = 9.1
Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.48 (t, J = 7.1
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.5, 158.1, 157.6,
129.6, 126.3, 125.7, 114.6, 112.6, 103.5, 63.1, 57.0, 14.3. HR-
MS (ESI-TOF) m/z: [M + Na]+ calcd for [C12H11N5NaO3]+
296.0754; Found 296.0755.
Ethyl
2-(4-nitrophenyl)-2H-tetrazole-5-carboxylate
(2m).
1
Yellow solid; (52 mg, 66%); m.p. 136-137 °C. H NMR (400
MHz, CDCl3) δ 8.51 – 8.40 (m, 4H), 4.57 (q, J = 7.1 Hz, 2H),
1.48 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.5,
157.4, 148.7, 140.2, 125.7, 121.2, 63.3, 14.3. HR-MS (ESI-TOF)
m/z: [M + Na]+ calcd for [C10H9N5NaO4]+ 286.0547; Found
286.0553.
Ethyl
2-(4-fluorophenyl)-2H-tetrazole-5-carboxylate
(2u).
1
White solid; (64 mg, 91%). m.p.: 65-66 °C. H NMR (400 MHz,
CDCl3) δ 8.28 – 8.14 (m, 2H), 7.33 – 7.19 (m, 2H), 4.57 (q, J =
7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 163.7 (d, J = 252.1 Hz), 158.0, 157.8, 132.8 (d, J = 3.0
Hz), 122.6 (d, J = 8.8 Hz), 117.1 (d, J = 23.5 Hz), 63.0, 14.3. 19
F
NMR (376 MHz, CDCl3) δ -108.86 (ddd, J = 12.5, 8.2, 4.7 Hz).
HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C10H10FN4O2]+
237.0782; Found 237.0784.
Ethyl 2-(3-nitrophenyl)-2H-tetrazole-5-carboxylate (2n). Red
liquid; (57 mg, 72%). H NMR (400 MHz, CDCl3) δ 9.05 (t, J =
2.1 Hz, 1H), 8.57 (dd, J = 8.1, 2.1 Hz, 1H), 8.41 (dd, J = 8.3, 2.2
Hz, 1H), 7.84 (t, J = 8.2 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.48
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4, 157.4,
149.1, 137.0, 131.3, 125.7, 125.2, 115.7, 63.2, 14.3. HR-MS
1
Ethyl
2-(3-fluorophenyl)-2H-tetrazole-5-carboxylate
(2v).
Yellow liquid; (59 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.02
(dd, J = 8.3, 2.0 Hz, 1H), 7.94 (dt, J = 9.0, 2.3 Hz, 1H), 7.56 (td,
J = 8.3, 5.8 Hz, 1H), 7.25 (tdd, J = 8.2, 2.5, 0.9 Hz, 1H), 4.56 (q,

6
Tetrahedron
J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
Ethyl 2-(quinolin-3-yl)-2H-tetrazole-5-carboxylate (2d’). White
solid; (43 mg, 53%). m.p. 128-129 °C. 1H NMR (400 MHz,
CDCl3) δ 9.71 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.20
(d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.84 (t, J = 7.7 Hz,
1H), 7.68 (t, J = 7.5 Hz, 1H), 4.59 (q, J = 7.1 Hz, 2H), 1.49 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.3, 157.6, 148.6,
142.1, 131.6, 129.9, 129.9, 128.7, 128.7, 127.0, 126.8, 63.1, 14.3.
HR-MS (ESI-TOF) m/z: [M + Na]+ calcd for [C13H11N5NaO2]+
292.0805; Found 292.0806.
CDCl3) δ 162.9 (d, J = 249.8 Hz), 157.9, 157.6, 137.3 (d, J =
10.3 Hz), 131.4 (d, J = 8.7 Hz), 117.7 (d, J = 21.2 Hz), 115.9 (d,
J = 3.5 Hz), 108.2 (d, J = 27.4 Hz), 62.9, 14.2. 19F NMR (376
MHz, CDCl3) δ -108.93 (td, J = 8.6, 5.8 Hz). HR-MS (ESI-TOF)
m/z: [M + Na]+ calcd for [C10H9FNaN4O2]+ 259.0602; Found
259.0607.
Ethyl 2-(4-chlorophenyl)-2H-tetrazole-5-carboxylate (2w).
Light yellow solid; (50 mg, 66%). m.p.: 95- 96 °C. 1H NMR (400
MHz, CDCl3) δ 8.31 – 7.94 (m, 2H), 7.75 – 7.48 (m, 2H), 4.56
(q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 158.1, 157.7, 136.8, 134.9, 130.2, 121.7, 63.0,
Tert-butyl 2-phenyl-2H-tetrazole-5-carboxylate (2e’). Yellow
solid; (46 mg, 63%). m.p.: 65-66 °C. 1H NMR (400 MHz,
CDCl3) δ 8.21 – 8.16 (m, 2H), 7.61 – 7.51 (m, 3H), 1.68 (s, 9H).
13C NMR (101 MHz, CDCl3) δ 158.9, 157.0, 136.6, 130.6, 129.9,
120.4, 84.7, 28.2. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C12H15N4O2]+ 247.1190; Found 247.1193.
14.3. HR-MS (ESI-TOF) m/z: [M
+
H]+ calcd for
[C10H10ClN4O2]+ 253.04087; Found 253.04089.
Ethyl 2-(3-chlorophenyl)-2H-tetrazole-5-carboxylate
(2x).
Yellow solid; (51 mg, 68%). m.p.: 60-61 °C. 1H NMR (400
MHz, CDCl3) δ 8.24 (t, J = 1.5 Hz, 1H), 8.12 (td, J = 4.2, 3.6, 2.1
Hz, 1H), 7.58 – 7.46 (m, 2H), 4.57 (q, J = 7.1 Hz, 2H), 1.49 (t, J
= 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.1, 157.7,
137.2, 136.0, 131.1, 130.9, 120.7, 118.5, 63.1, 14.3. HR-MS
(ESI-TOF) m/z: [M + Na]+ calcd for [C10H9ClN4NaO2]+
275.0306; Found 275.0309.
Benzyl 2-phenyl-2H-tetrazole-5-carboxylate (2f’). Yellow solid;
(66 mg, 78%). m.p.: 80-81 °C. H NMR (400 MHz, CDCl3) δ
1
8.24 – 8.09 (m, 2H), 7.62 – 7.47 (m, 5H), 7.45 – 7.31 (m, 3H),
5.54 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 157.8, 157.8,
136.5, 134.8, 130.8, 130.0, 128.9, 128.9, 128.8, 120.5, 68.3. HR-
MS (ESI-TOF) m/z: [M + Na]+ calcd for [C15H12N4NaO2]+
303.0852; Found 303.0854.
Ethyl
2-(2-chlorophenyl)-2H-tetrazole-5-carboxylate
(2y).
Phenyl(2-phenyl-2H-tetrazol-5-yl)methanone
(2g’).
Light
Yellow liquid; (46 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 7.63
(ddd, J = 7.8, 4.1, 1.6 Hz, 2H), 7.57 (td, J = 7.7, 1.7 Hz,1H), 7.48
(td, J = 7.7, 1.5 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.0, 157.7, 134.5,
132.6, 131.3, 130.1, 127.9, 127.8, 63.0, 14.3. HR-MS (ESI-TOF)
m/z: [M + Na]+ calcd for [C10H9ClN4NaO2]+ 275.0306; Found
275.0302.
yellow solid; (58 mg, 77%). m.p.: 74-75 °C. 1H NMR (400 MHz,
CDCl3) δ 8.46 – 8.37 (m, 2H), 8.28 – 8.20 (m, 2H), 7.72 – 7.66
(m, 1H), 7.63 – 7.51 (m, 5H). 13C NMR (101 MHz, CDCl3) δ
182.5, 162.6, 136.5, 135.6, 134.5, 130.8, 130.7, 130.0, 128.8,
120.5. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C14H11N4O]+
251.0933; Found 251.0937.
(2-phenyl-2H-tetrazol-5-yl)(p-tolyl)methanone (2h’). Yellow
solid; (65 mg, 82%). m.p.: 73-74 °C. 1H NMR (400 MHz,
CDCl3) δ 8.42 – 8.28 (m, 2H), 8.25 – 8.20 (m, 2H), 7.64 – 7.52
(m, 3H), 7.36 (d, J = 8.1 Hz, 2H), 2.46 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 182.1, 162.7, 145.7, 136.6, 133.1, 131.0, 130.7,
130.0, 129.6, 120.5, 22.0. HR-MS (ESI-TOF) m/z: [M + H]+
calcd for [C15H13N4O]+ 265.1089; Found 265.1083.
Ethyl 2-(3-chloro-4-fluorophenyl)-2H-tetrazole-5-carboxylate
(2z). Yellow solid; (49 mg, 61%). m.p.: 69-71 °C. H NMR (400
1
MHz, CDCl3) δ 8.32 (dd, J = 6.2, 2.7 Hz, 1H), 8.12 (dt, J = 9.2,
3.3 Hz, 1H), 7.37 (t, J = 8.6 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H),
1.48 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -110.94
(td, J = 7.2, 6.8, 4.2 Hz). 13C{1H} NMR (101 MHz, CDCl3) δ
159.4 (d, J = 239.7 Hz), 158.0, 157.6, 132.9 (d, J = 3.3 Hz),
123.3, 123.1, 120.3 (d, J = 7.9 Hz), 118.0 (d, J = 23.1 Hz), 63.1,
(4-chlorophenyl)(2-phenyl-2H-tetrazol-5-yl)methanone
(2i’).
1
White solid; (64 mg, 75%). m.p.: 85-86 °C. H NMR (400 MHz,
CDCl3) δ 8.44 – 8.38 (m, 2H), 8.29 – 8.19 (m, 2H), 7.65 – 7.49
(m, 5H). 13C{1H} NMR (101 MHz, CDCl3) δ 181.1, 162.4, 141.2,
136.5, 133.9, 132.3, 130.8, 130.0, 129.2, 120.5. HR-MS (ESI-
TOF) m/z: [M + H]+ calcd for [C14H10N4OCl]+ 285.0543; Found
285.0537.
14.3. HR-MS (ESI-TOF) m/z: [M
+
H]+ calcd for
[C10H9FClN4O2]+ 271.9308; Found 271.9303.
Ethyl 2-(4-bromophenyl)-2H-tetrazole-5-carboxylate (2a’).
Yellow solid; (47 mg, 53%). m.p.: 92-93 °C. 1H NMR (400
MHz, CDCl3) δ 8.12 – 8.06 (m, 2H), 7.75 – 7.69 (m, 2H), 4.57
(q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 157.9, 157.6, 135.3, 133.1, 124.8, 121.7, 62.9,
Ethyl 2-(4-(hydroxymethyl)phenyl)-2H-tetrazole-5-carboxylate
(2j’). Yellow solid; (45 mg, 60%). m.p.: 77-78 °C. 1H NMR (400
MHz, CDCl3) δ 8.21 – 8.10 (m, 2H), 7.58 (d, J = 8.3 Hz, 2H),
4.82 (s, 2H), 4.57 (q, J = 7.1 Hz, 2H), 2.09 (s, 1H), 1.49 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.9, 157.9, 143.9,
135.7, 128.1, 120.6, 64.4, 63.0, 14.3. HR-MS (ESI-TOF) m/z: [M
+ H]+ calcd for [C11H13N4O3]+ 249.0988; Found 249.0995.
14.2. HR-MS (ESI-TOF) m/z: [M
+
H]+ calcd for
[C10H10BrN4O2]+ 296.9983; Found 296.9987.
Ethyl
2-(2-(methoxycarbonyl)thiophen-3-yl)-2H-tetrazole-5-
carboxylate (2b’). Red liquid; (60 mg, 71%). 1H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 5.3 Hz, 1H), 7.36 (d, J = 5.3 Hz,
1H), 4.56 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 1.47 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 159.7, 157. 7, 157.7, 135.8,
131.1, 128.9, 126.3, 63.0, 52.9, 14.3. HR-MS (ESI-TOF) m/z: [M
+ H]+ calcd for [C10H11N4O4S]+ 283.0501; Found 283.0502.
Ethyl (R)-2-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-
oxopropyl)phenyl)-2H-tetrazole-5-carboxylate (2k’). Yellow
1
solid; (69 mg, 55%). m.p.: 103-104 °C. H NMR (400 MHz,
CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 5.06
(d, J = 8.1 Hz, 1H), 4.63 (q, J = 5.9 Hz, 1H), 4.56 (q, J = 7.1 Hz,
2H), 3.73 (s, 3H), 3.24 (dd, J = 13.8, 5.9 Hz, 1H), 3.12 (dd, J =
13.7, 6.2 Hz, 1H), 1.48 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H). 13C
NMR (101 MHz, CDCl3) δ 172.0, 157.9, 155.1, 139.5, 135.4,
130.9, 120.5, 116.4, 80.4, 62.9, 54.4, 52.6, 38.3, 28.4, 14.3. HR-
MS (ESI-TOF) m/z: [M + H]+ calcd for [C19H26N5O6]+ 420.1183;
Found 420.1186.
Ethyl 2-(pyridin-3-yl)-2H-tetrazole-5-carboxylate (2c’). Light
yellow liquid; (34 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 9.49
(d, J = 2.5 Hz, 1H), 8.82 (dd, J = 4.8, 1.5 Hz, 1H), 8.50 (ddd, J =
8.3, 2.6, 1.5 Hz, 1H), 7.57 (ddd, J = 8.4, 4.8, 0.8 Hz, 1H), 4.58
(q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ 158.4, 157.6, 151.8, 141.8, 133.2, 127.8, 124.3,
63.2, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C9H10N5O2]+ 220.0834; Found 220.0837.

7
Ethyl (R)-2-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-
120.1, 74.6 (d, J = 169.1 Hz). HR-MS (ESI-TOF) m/z: [M +
oxopropyl)phenyl)-2H-tetrazole-5-carboxylate (2l’). Yellow
H]+ calcd for [C8H8FN4]+ 179.0733; Found 179.0732.
1
liquid; (49 mg, 40%). H NMR (400 MHz, CDCl3) δ 8.20 – 7.97
5-(fluoromethyl)-2-(p-tolyl)-2H-tetrazole (4b). Light yellow
solid; (27 mg, 70%). m.p.: 59-60 °C. 1H NMR (400 MHz,
CDCl3) δ 8.12 – 7.90 (m, 2H), 7.41 – 7.31 (m, 2H), 5.70 (d, J =
47.4 Hz, 2H), 2.45 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -
217.03 (t, J = 47.1 Hz). 13C NMR (101 MHz, CDCl3) δ 161.7 (d,
J = 20.3 Hz), 140.6, 134.6, 130.4, 120.1, 74.7 (d, J = 169.1 Hz),
21.4. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C9H10FN4]+
193.0889; Found 193.0893.
(m, 2H), 7.45 – 7.34 (m, 2H), 7.30 – 7.24 (m, 2H), 7.21 (q, J =
3.9 Hz, 3H), 4.56 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 13.2 Hz, 1H),
3.67 (s, 3H), 3.63 (d, J = 13.2 Hz, 1H), 3.55 (dd, J = 7.3, 6.3 Hz,
1H), 3.08 – 2.95 (m, 2H), 1.84 (s, 1H), 1.48 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 174.8, 157.9, 157.9, 140.8, 139.4,
135.1, 130.8, 128.5, 128.3, 127.3, 120.3, 62.9, 61.7, 52.2, 52.0,
39.4, 14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C21H24N5O4]+ 410.1828; Found 410.1831.
5-(fluoromethyl)-2-(4-fluorophenyl)-2H-tetrazole (4c). White
solid; (30 mg, 70%). m.p.: 50-51 °C. 1H NMR (400 MHz,
CDCl3) δ 8.20 – 8.09 (m, 2H), 7.33 – 7.18 (m, 2H), 5.70 (d, J =
47.3 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -109.85 (ddd, J =
12.7, 8.1, 4.6 Hz), -217.50 (t, J = 47.3 Hz). 13C NMR (101 MHz,
CDCl3) δ 163.4 (d, J = 251.2 Hz), 161.9 (d, J = 20.5 Hz), 133.0
(d, J = 3.4 Hz), 122.2 (d, J = 8.8 Hz), 117.0 (d, J = 23.5 Hz), 74.6
(d, J = 169.4 Hz). HR-MS (ESI-TOF) m/z: [M + H]+ calcd for
[C8H7F2N4]+ 197.0639; Found 197.0637.
(2-phenyl-2H-tetrazol-5-yl) methanol (3a). White solid; (31 mg,
88%). m.p.: 102-103 °C. H NMR (400 MHz, CDCl3) δ 8.17 –
7.99 (m, 2H), 7.54 – 7.38 (m, 3H), 5.06 (d, J = 6.4 Hz, 2H), 3.66
(td, J = 6.7, 2.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 166.0,
136.8, 129.9, 129.8, 120.0 56.1. HR-MS (ESI-TOF) m/z: [M +
H]+ calcd for [C8H9N4O]+ 177.0776; Found 177.0781.
1
(2-(p-tolyl)-2H-tetrazol-5-yl) methanol (3b). Light yellow solid;
1
(32 mg, 84%). m.p.: 97-98 °C. H NMR (400 MHz, CDCl3) δ
8.06 – 7.84 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 5.05 (d, J = 6.3 Hz,
2H), 3.38 (t, J = 6.5 Hz, 1H), 2.42 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.8, 140.3, 134.6, 130.3, 119.9, 56.2, 21.3. HR-MS
(ESI-TOF) m/z: [M + H]+ calcd for [C9H11N4O]+ 191.0933;
Found 191.0934.
5-(fluoromethyl)-2-(4-nitrophenyl)-2H-tetrazole (4d). White
solid; (29 mg, 66%). m.p.: 114-115 °C. H NMR (400 MHz,
1
CDCl3) δ 8.50 – 8.43 (m, 2H), 8.40 – 8.35 (m, 2H), 5.74 (d, J =
47.1 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -218.61 (t, J = 47.1
Hz). 13C NMR (101 MHz, CDCl3) δ 162.6 (d, J = 20.4 Hz),
148.4, 140.4, 125.7, 120.7, 74.5 (d, J = 170.3 Hz). HR-MS (ESI-
TOF) m/z: [M + H]+ calcd for [C8H7FN5O2]+ 224.0584; Found
224.0585.
(2-(4-fluorophenyl)-2H-tetrazol-5-yl) methanol (3c). Light
1
yellow solid; (37 mg, 96%). m.p.: 99-100 °C. H NMR (400
MHz, CDCl3) δ 8.19 – 7.98 (m, 2H), 7.27 – 7.16 (m, 2H), 5.05
(d, J = 6.2 Hz, 2H), 3.44 (t, J = 6.4 Hz, 1H). 19F NMR (376 MHz,
CDCl3) δ -110.24 (tt, J = 8.6, 4.6 Hz). 13C NMR (101 MHz,
CDCl3) δ 166.1, 163.2 (d, J = 250.8 Hz), 133.0 (d, J = 2.8 Hz),
122.0 (d, J = 8.8 Hz), 116.9 (d, J = 23.4 Hz), 56.1. HR-MS (ESI-
TOF) m/z: [M + H]+ calcd for [C8H8FN4O]+ 195.0682; Found
195.0687.
3-(5-(fluoromethyl)-2H-tetrazol-2-yl)quinoline (4e). White
1
solid; (28 mg, 62%). m.p.: 140-141 °C. H NMR (400 MHz,
CDCl3) δ 9.71 (d, J = 2.5 Hz, 1H), 8.89 (d, J = 2.5 Hz, 1H), 8.26
– 8.20 (m, 1H), 8.03 – 7.93 (m, 1H), 7.85 (ddd, J = 8.5, 6.9, 1.5
Hz, 1H), 7.70 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 5.77 (d, J = 47.2
Hz, 2H). 19F NMR (376 MHz, CDCl3) δ -217.96 (t, J = 47.3 Hz).
13C NMR (101 MHz, CDCl3) δ 162.4 (d, J = 20.4 Hz), 148.5,
142.2, 131.4, 130.1, 129.9, 128.7, 127.1, 126.3, 74.6 (d, J = 169.9
Hz). HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C11H9FN5]+
230.0842; Found 230.0847.
(2-(4-nitrophenyl)-2H-tetrazol-5-yl) methanol (3d). Orange
1
solid; (28 mg, 64%). m.p.: 135-137 °C. H NMR (400 MHz,
CDCl3) δ 8.50 – 8.40 (m, 2H), 8.36 (d, J = 9.2 Hz, 2H), 5.09 (d, J
= 6.3 Hz, 2H), 2.60 (t, J = 6.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 166.7, 148.2, 140.6, 125.6, 120.6, 56.3. HR-MS (ESI-
TOF) m/z: [M + H]+ calcd for [C8H8N5O3]+ 222.0627; Found
222.0632.
5-(fluoro(phenyl)methyl)-2-phenyl-2H-tetrazole (4f). Light
1
yellow liquid; (27.5 mg, 54%). H NMR (400 MHz, CDCl3) δ
8.19 – 8.04 (m, 2H), 7.61 (dt, J = 7.9, 1.5 Hz, 2H), 7.58 – 7.49
(m, 3H), 7.49 – 7.40 (m, 3H), 6.86 (d, J = 45.6 Hz, 1H). 19F
NMR (376 MHz, CDCl3) δ -171.05 (d, J = 45.6 Hz). 13C NMR
(101 MHz, CDCl3) δ 164.9 (d, J = 26.4 Hz), 136.8, 136.1 (d, J =
21.9 Hz), 130.2, 129.8, 129.6 (d, J = 2.2 Hz), 128.9, 127.0 (d, J =
5.8 Hz), 120.2, 86.8 (d, J = 174.1 Hz). HR-MS (ESI-TOF) m/z:
[M + H]+ calcd for [C14H12FN4]+ 255.1046; Found 255.1047.
(2-(quinolin-3-yl)-2H-tetrazol-5-yl) methanol (3e). White solid;
1
(35.5 mg, 78%). m.p.: 177-178 °C. H NMR (400 MHz, DMSO-
d6) δ 9.58 (d, J = 2.5 Hz, 1H), 9.12 (d, J = 2.6 Hz, 1H), 8.26 (dd,
J = 8.2, 1.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.91 (ddd, J = 8.5,
6.8, 1.5 Hz, 1H), 7.77 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 5.85 (t, J =
6.1 Hz, 1H), 4.86 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz,
DMSO-d6) δ 167.0, 147.4, 142.1, 131.2, 129.8, 129.1, 128.9,
128.3, 126.9, 126.3, 54.3. HR-MS (ESI-TOF) m/z: [M + H]+
calcd for [C11H10N5O]+ 228.0885; Found 228.0877.
5-amino-N-(1-(furan-2-yl)ethyl)-4'-methyl-[1,1'-biphenyl]-3-
carboxamide (5). White solid; (141 mg, 88%). m.p.: 70-71 °C.
1H NMR (400 MHz, CDCl3) δ 7.45 – 7.39 (m, 2H), 7.34 (d, J =
1.8 Hz, 1H), 7.28 (t, J = 1.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H),
7.04 (t, J = 1.9 Hz, 1H), 6.93 (t, J = 1.9 Hz, 1H), 6.63 (d, J = 8.3
Hz, 1H), 6.31 (dd, J = 3.3, 1.9 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H),
5.42 (p, J = 7.1 Hz, 1H), 3.87 (s, 2H), 2.37 (s, 3H), 1.57 (d, J =
6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.5, 154.8, 148.8,
143.6, 142.3, 139.3, 136.5, 134.9, 131.8, 130.1, 127.1, 124.2,
119.8, 110.5, 106.3, 44.0, 21.3, 19.6. HR-MS (ESI-TOF) m/z: [M
+ H]+ calcd for [C20H21N2O2]+ 321.1603; Found 321.1608.
phenyl(2-phenyl-2H-tetrazol-5-yl) methanol (3f). White solid;
1
(45.5 mg, 90%). m.p.: 112-113 °C. H NMR (400 MHz, CDCl3)
δ 8.12 – 8.01 (m, 2H), 7.58 – 7.53 (m, 2H), 7.53 – 7.42 (m, 3H),
7.39 – 7.28 (m, 3H), 6.26 (d, J = 5.5 Hz, 1H), 3.97 (d, J = 5.6 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 168.3, 140.2, 136.7, 129.9,
129.7, 128.7, 128.5, 126.8, 120.0, 69.1. HR-MS (ESI-TOF) m/z:
[M + Na]+ calcd for [C14H12N4ONa]+ 275.0909; Found 275.0903.
5-(fluoromethyl)-2-phenyl-2H-tetrazole (4a). White solid; (25.5
1
mg, 72%). m.p.: 68-69 °C. H NMR (400 MHz, CDCl3) δ 8.20 –
Ethyl
2-(5-((1-(furan-2-yl)ethyl)carbamoyl)-4'-methyl-[1,1'-
8.01 (m, 2H), 7.60 – 7.43 (m, 3H), 5.70 (d, J = 47.3 Hz, 2H). 19
F
biphenyl]-3-yl)-2H-tetrazole-5-carboxylate (2m’). Yellow solid;
NMR (376 MHz, CDCl3) δ -217.20 (t, J = 47.3 Hz). 13C NMR
(101 MHz, CDCl3) δ 161.7 (d, J = 20.4 Hz), 136.7, 130.2, 129.8,
(46 mg, 52%). m.p.: 91-92 °C. H NMR (400 MHz, CDCl3) δ
1
8.52 (t, J = 1.9 Hz, 1H), 8.45 (t, J = 1.8 Hz, 1H), 8.22 (t, J = 1.7
Hz, 1H), 7.60 – 7.55 (m, 2H), 7.38 (d, J = 1.8 Hz, 1H), 7.30 (d, J

8
Tetrahedron
2. For a selected review, see: Li YP, Li ZQ, Zhu SF. Tetrahedron
Lett. 2018; 59: 2307-2316.
= 7.9 Hz, 2H), 6.61 (d, J = 8.2 Hz, 1H), 6.35 (dd, J = 3.3, 1.8
Hz, 1H), 6.30 (d, J = 3.3 Hz, 1H), 5.49 (p, J = 7.1 Hz, 1H), 4.59
(q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.66 (d, J = 6.9 Hz, 3H), 1.50 (t,
J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 164.9, 158.0,
157.8, 154.9, 143.9, 142.2, 139.0, 137.0, 136.9, 135.4, 130.0,
128.1, 127.1, 121.1, 116.7, 110.4, 106.3, 63.1, 43.9, 21.3, 19.6,
14.3. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C24H24N5O4]+
446.1828; Found 446.1833.
3. For selected reviews, see: (a) Lebel H, Marcoux JF, Molinaro C,
Charette AB. Chem. Rev. 2003; 103: 977-1050;
(b) Wu W, Lin M, Jiang H. Org. Biomol. Chem. 2018; 16: 7315-
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PA. Chem. Soc. Rev. 2001; 30: 50-61.
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Adv. Syn. Catal. 2019; 361: 919-944.
N-(1-(furan-2-yl)eth-yl)-5-(5-(hydroxymethyl)-2H-tetrazol-2-
yl)-4'-methyl-[1,1'-biphenyl]-3-carboxamide (3g). Yellow solid;
(71 mg, 88%). m.p.: 177-178 °C. 1H NMR (400 MHz, DMSO-d6)
δ 9.24 (d, J = 8.2 Hz, 1H), 8.54 (t, J = 1.7 Hz, 1H), 8.43 (t, J =
1.8 Hz, 1H), 8.37 (t, J = 1.6 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H),
7.61 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 6.42 (dd, J =
3.2, 1.8 Hz, 1H), 6.35 (d, J = 3.3 Hz, 1H), 5.81 (t, J = 6.1 Hz,
1H), 5.35 (p, J = 7.1 Hz, 1H), 4.83 (d, J = 6.0 Hz, 2H), 2.38 (s,
3H), 1.54 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ
166.8, 163.8, 155.8, 142.1, 142.0, 138.2, 136.8, 136.5, 135.1,
129.8, 126.9, 126.4, 119.8, 117.5, 110.3, 105.6, 54.2, 42.7, 20.7,
18.9. HR-MS (ESI-TOF) m/z: [M + H]+ calcd for [C22H22N5O3]+
404.1723; Found 404.1728.
7. For selected reviews, see: (a) Burtoloso ACB, Dias RMP,
Bernardim B. Acc. Chem. Res. 2015; 48: 921-934;
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5-(5-(fluoromethyl)-2H-tetrazol-2-yl)-N-(1-(furan-2-yl)ethyl)-
4'-methyl-[1,1'-biphenyl]-3-carboxamide (4g). White solid; (34
mg, 42%). m.p.: 183-184 °C. 1H NMR (400 MHz, CDCl3) δ 8.43
(dt, J = 19.5, 1.9 Hz, 2H), 8.16 (d, J = 1.7 Hz, 1H), 7.56 (d, J =
7.8 Hz, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H),
6.65 (d, J = 8.2 Hz, 1H), 6.34 (t, J = 2.5 Hz, 1H), 6.29 (d, J = 3.3
Hz, 1H), 5.72 (d, J = 47.2 Hz, 2H), 5.48 (p, J = 7.2 Hz, 1H), 2.41
(s, 3H), 1.65 (d, J = 7.0 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -
217.67 (t, J = 47.2 Hz). 13C NMR (101 MHz, CDCl3) δ 165.1,
162.0 (d, J = 20.6 Hz), 154.9, 143.9, 142.3, 139.0, 137.1, 136.9,
135.6, 130.0, 127.5, 127.2, 120.9, 116.5, 110.5, 106.3, 74.6 (d, J
= 169.5 Hz), 43.9, 21.3, 19.7. HR-MS (ESI-TOF) m/z: [M + H]+
calcd for [C22H21FN5O2]+ 406.1679; Found 406.1686.
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This work was financially supported by the National Key
10. The cycloaddition reaction of monofluorodiazoethane or masked
monofluorodiazoethane with aryl diazonium salts would be a
direct way to produce monofluoromethyl tetrazoles, but until now
no monofluoromethyldiazo reagent has been reported. For selected
examples on the synthesis of monofluoromethyl molecules, see:
(a) Himo F, Demko ZP, Noodleman L, Sharpless KB. J. Am.
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Research
and
Development
Program
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China
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China (Nos. 21772142, 21901181, and 21961142015), and
Tianjin Municipal Science
(19JCQNJC04700).
&
Technology Commission
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12. The X-ray crystallographic structure for 2j and 4b have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC), under deposition numbers CCDC 1945349 and 1968330,
respectively. Data can be obtained free of charge from the

9
Cambridge
Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/data_request/cif.
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Electronic Supplementary Material
See the Supporting Information for detailed experimental
procedures and NMR spectra.

Highlights
1, A silver-catalyzed regioselective cycloaddition reaction between
diazoacetates with arenediazonium salts has been developed.
2, Expedient access to both carboxylic and fluoromethyl tetrazoles.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: