Cu(OH)(TMEDA)2Cl2-catalyzed regioselective 2-arylation of 5-substituted tetrazoles with boronic acids under mild conditions

Article abstract of DOI:10.1021/jo500862t

A mild and regioselective 2-arylation of 5-substituted tetrazoles is described. The reaction proceeds regioselectively with a variety of arylboronic acids in the presence of [Cu(OH)(TMEDA)]₂Cl₂ to afford 2,5-disubstituted tetrazoles. This is the first report of highly regioselective arylation of 5-alkyltetrazoles.

Full text of DOI:10.1021/jo500862t

Note
pubs.acs.org/joc
[Cu(OH)(TMEDA)]2Cl2‑Catalyzed Regioselective 2‑Arylation of
5‑Substituted Tetrazoles with Boronic Acids under Mild Conditions
Takuya Onaka,*,† Hideaki Umemoto,† Yasuyoshi Miki,‡ Akira Nakamura,‡ and Tomohiro Maegawa*,‡
†Fujimoto Chemicals Co., Ltd., 1-2-38, Kinrakuji-cho, Amagasaki, Hyogo 660-0806, Japan
‡School of Pharmaceutical Sciences, Kinki University, 3-4-1, Kowakae, Higashi-Osaka, Osaka 577-8502, Japan
S
* Supporting Information
ABSTRACT: A mild and regioselective 2-arylation of 5-
substituted tetrazoles is described. The reaction proceeds
regioselectively with a variety of arylboronic acids in the
presence of [Cu(OH)(TMEDA)]2Cl2 to afford 2,5-disubsti-
tuted tetrazoles. This is the first report of highly regioselective
arylation of 5-alkyltetrazoles.
and avoiding high reaction temperatures is necessary. In
etrazoles are versatile, N-containing heterocyclic com-
Tpounds used in pharmaceuticals, agrochemicals, and addition, only 5-aryltetrazoles were used as substrates.
materials science.1 Moreover, 1-aryl-5-substituted tetrazoles
We report herein the catalytic and highly regioselective 2-
arylation of 5-alkyl- and aryl-substituted tetrazoles under mild
conditions. 5-Methyltetrazole was employed as a substrate, and
the reaction was investigated using phenylboronic acid at room
temperature in an O2 atmosphere (Table 1). CuCl and CuCl2
were initially selected as the catalytic copper salts, but no
reaction occurred (entries 1 and 2). The use of N,N,N′,N′-
tetramethylethylenediamine (TMEDA) as a coordinating
ligand promoted the coupling reaction to afford 2-phenyl-5-
methyltetrazole in a moderate yield (46%) and high regio-
selectivity (99:1) (entries 3 and 4). Under Han’s conditions,15
the coupling reaction of 5-methyltetrazole and phenylboronic
acid afforded a mixture of 2-phenyl and 1-phenyl-5-methyl-
tetrazoles.17 The other coordinating ligands, N,N′-dimethyl-
ethylenediamine (DMEDA) and N,N,N′,N′-tetramethyl-
propylenediamine (TMPDA), appeared to be less effective
than TMEDA (entries 5 and 6). A suitable steric environment
around the ligand may be necessary for high regioselectivity.
Other copper salts, such as CuBr, CuI, CuO, Cu2O, CuOAc,
and Cu(OAc)2, gave poor results under the same conditions.
The use of di-μ-hydroxobis[(N,N,N′,N′-tetramethylethylene-
diamine) copper(II)] chloride18 ([Cu(OH)(TMEDA)]2Cl2) as
a catalyst led to a better result, although even less catalyst (6%)
was used (entry 7). The best result was obtained using 12 mol
% of catalyst (entry 8). Further exploration of the base and
solvent systems showed that a combination of K2CO3 as the
base and CH2Cl2 as the solvent was most effective. In addition,
O2 is required as an oxidant, and the reaction gave low yields in
air or a N2 atmosphere (entries 9 and 10).
are particularly useful as synthetic intermediates in biological
research and medicinal chemistry,2 with 1,3-dipolar cyclo-
addition reactions being the most common means of
constructing 1,5-disubstituted tetrazoles. Such reactions include
sodium azide with imidoylbenzotriazole3 or sodium azide with
nitriles.4 Recently, the direct introduction of an aryl group into
1-substituted 5-bromotetrazole was achieved using a Suzuki−
Miyaura coupling reaction.5
Historically, 2-aryl-5-substituted tetrazoles have been re-
garded as less important than 1-aryl-5-substituted tetrazoles.
However, the former have recently exhibited remarkable
biological properties such as hepatitis C serine protease
inhibition,6 metabotropic glutamate receptor antagonism,7
inhibition of stearoyl-coenzyme A delta-9 desaturase,8 and G-
protein-coupled receptor agonism.9 Despite these findings,
however, reported methods for synthesizing 2-aryl-5-substi-
tuted tetrazoles are few. Kakehi’s synthesis10 is a representative
method employing phenylsulfonylhydrazones and arene-
diazonium salts, both of which must also be synthesized.
Several transition-metal-catalyzed direct 2-arylations of 5-
substituted tetrazoles have been reported. A stoichiometric
amount of Cu(OAc)2 was found to mediate the cross-coupling
of arylboronic acid and 5-phenyltetrazole,11 and Ph2ICl and 2-
(tributylstannyl)tetrazole.12 A catalytic version of Cu(OAc)2
was achieved using Ph3Bi(OAc)2 and 5-phenyltetrazole.13 Pd-
and Cu-catalyzed 2-arylation has also been reported using Na
salts of tetrazoles and Ar2IBF4 as substrates.14 Although 2,5-
disubstituted tetrazoles were selectively obtained, the process
was complicated by the availability of substrates and wastes
after the reaction. Han and co-workers15 recently reported the
synthesis of 2-aryl-5-substituted tetrazoles through the coupling
of N−H-free 5-substituted tetrazoles with arylboronic acid in
the presence of a catalytic amount of copper(II) oxide at 100
°C. Note, however, that tetrazoles are potentially explosive,1,16
The plausible mechanism is shown in Scheme 1, which is
similar to that mentioned by Collman and co-workers.18 First,
copper(II) catalyst undergoes transmetalation with arylboronic
acid, then tetrazole activated with the base could coordinate to
Received: April 17, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo500862t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of the Reaction Conditions
a
entry
Cu catalyst (mol %)
CuCl (12)
oxid.
time (h)
yield (%) (2-Ar/1-Ar)
1
2
O2
O2
O2
O2
O2
O2
O2
O2
air
17
17
17
17
17
17
17
14
14
14
no reaction
no reaction
46 (99:1)
51 (99:1)
22 (94:6)
no reaction
57 (99:1)
CuCl2 (12)
3
CuCl (12)/TMEDA(12)
CuCl2 (12)/TMEDA(12)
CuCl2 (12)/DMEDA(12)
CuCl2 (12)/TMPDA(12)
[Cu(OH)(TMEDA)]2CI2 (6)
[Cu(OH)(TMEDA)]2Cl2 (12)
[Cu(OH)(TMEDA)]2Cl2 (12)
[Cu(OH)(TMEDA)]2Cl2 (12)
4
5
6
7
b
8
69 (67) (98:2)
9
23 (100:0)
10 (100:0)
10
none
a
b
Yield and 2-Ar/1-Ar ratio were determined by HPLC. Isolated yield is indicated in the parentheses.
Scheme 1
Table 2. Reaction of Various Tetrazoles with Phenylboronic
Acid
copper in the presence of O2 atomosphere to generate
copper(III) species. Although Collman and co-workers used
the same catalyst for coupling of imidazole, no reaction
occurred with tetrazole under the same conditions. The
addition of K2CO3 was essential for this reaction since the
nucleophilicity of tetrazoles and imidazoles is different. In
addition, at this point, two types of coordination of tetrazole
could be considered and the coordination with the 2-position of
tetrazole formed a more favorable transition state than that with
1-position of tetrazole because of steric repulsion between the
substituent on the 5-position and the aryl group. Then,
reductive elimination of the tetrazole and aryl group led to the
coupling product and the regeneration of a copper(II) catalyst.
After optimizing the reaction conditions, the generalities of
the reactions using various 5-substituted tetrazoles and
phenylboronic acid were explored (Table 2). The reaction of
5-benzyltetrazole was regioselective and gave 2-phenyl-5-
benzyltetrazole 1b with a 76% yield. The presence of a sulfur
atom had a negligible effect on the overall results, and the
desired 2-phenyl-5-methylthiotetrazole 1c was obtained with a
62% yield and high regioselectivity. Substrates bearing ester
groups or a halogen atom (Br) also yielded coupling products
(1d and 1e) and would be useful synthons for modified
tetrazoles. The coupling of 5-aryltetrazoles with phenylboronic
acid proceeded smoothly, giving the corresponding 2,5-
disubstituted products in good yields (1f−1h). The reaction
of 5-(4-pyridyl)tetrazole selectively produced 2-phenyl-5-
pyridyltetrazole 1i with an acceptable yield. Note that, in
these reactions, only the phenyl group was introduced at the 2-
position and that 1-phenyltetrazole was not observed, even
following reactions with compound 1i.
a
b
LiCl (0.5 equiv) was added. PhB(OH)2 (3.0 equiv) was used.
Reaction time 17 h.
Next, reactions with various arylboronic acids were used to
explore the influence of the aryl substituent (Table 3).
Phenylboronic acids bearing electron-donating groups such as
methyl, methoxy, and benzyloxy groups reacted with 5-
methyltetrazole with moderate yields (2a−2c). Reactions of
various halo-substituted phenylboronic acids yielded products
similar to those obtained with phenylboronic acid and afforded
the desired 2,5-disubstituted tetrazoles 2d−h with high
regioselectivity. 2-Aryl-substituted tetrazoles were the major
products in these cases, while 1-aryl-substituted tetrazoles were
not detected.
In summary, a novel method for the regioselective synthesis
of 2,5-disubstituted tetrazoles by direct coupling of 5-
substituted tetrazoles with arylboronic acids in the presence
of a catalytic amount of [Cu(OH)(TMEDA)]2Cl2 in an O2
atmosphere was developed. The reaction can be conducted at
room temperature and is applicable to both 5-aryltetrazoles and
5-alkyltetrazoles. The products were obtained as nearly pure
single regioisomers. This is the first report of such high
B
dx.doi.org/10.1021/jo500862t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
5-Methylthio-2-phenyl-2H-tetrazole (1c). 1c (120.5 mg, 62%)
was obtained from 5-methylthio-1H-tetrazole (116.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and phenylboronic acid (195.1 mg, 1.60 mmol): eluent,
Table 3. Reaction of 5-Methyltetrazole with Various
Arylboronic Acids
1
1:1 hexane/CH2Cl2; colorless oil; H NMR (400 MHz, CDCl3) δ
8.10−8.07 (2H, m), 7.57−7.46 (3H, m), 2.76 (3H, s); 13C NMR (100
MHz, CDCl3) δ 165.7, 136.7, 129.7, 119.6, 14.5; HRMS (ESI) calcd
for C8H9N4S [M + H]+ 193.0548, found 193.0546.
2-Phenyl-2H-tetrazole-5-carboxylic Acid Ethyl Ester (1d).22
1d (0.82 g, 53%) was obtained from 1H-tetrazole-5-carboxylic acid
ethyl ester (1.00 g, 7.04 mmol), K2CO3 (1.07 g, 7.74 mmol),
[Cu(OH)(TMEDA)]2Cl2 (0.39 g, 0.84 mmol), LiCl (0.15 g, 3.52
mmol), and phenylboronic acid (2.58 g, 21.12 mmol): eluent, 15:1
hexane/AcOEt; white solid; mp 72−73 °C (EtOH); IR (ATR) cm−1
1
1736; H NMR (400 MHz, CDCl3) δ 8.22−8.20 (2H, m), 7.62−7.53
(3H, m), 4.59 (2H, q, J = 7.2 Hz), 1.50 (3H, t, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 157.8, 136.4, 130.7, 129.9, 120.4, 62.8, 14.2;
HRMS (ESI) calcd for C10H11N4O2 [M + H]+ 219.0882, found
219.0886.
5-Bromo-2-phenyl-2H-tetrazole (1e). 1e (118.6 mg, 52%) was
obtained from 5-bromo-1H-tetrazole (149.0 mg, 1.00 mmol), K2CO3
(152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg, 0.12
mmol), and phenylboronic acid (195.1 mg, 1.60 mmol): eluent, 3:2
1
hexane/CH2Cl2; white solid; mp 49−50 °C (EtOH); H NMR (400
MHz, CDCl3) δ 8.12−8.08 (2H, m), 7.60−7.51 (3H, m); 13C NMR
(100 MHz, CDCl3) δ 143.3, 136.4, 130.4, 129.8, 119.7; HRMS (ESI)
calcd for C7H6BrN4 [M + H]+ 224.9776, found 224.9774.
regioselectivity in coupling reactions of 5-alkyltetrazoles. This
method therefore offers a facile and practical route to various
2,5-disubstituted tetrazoles.
2,5-Diphenyl-2H-tetrazole (1f).23 1f (180.4 mg, 81%) was
obtained from 5-phenyl-1H-tetrazole (146.2 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), LiCl (21.2 mg, 0.50 mmol), and phenylboronic acid
(195.1 mg, 1.60 mmol): eluent, 3:1 hexane/CH2Cl2; white solid; mp
102−103 °C (EtOH, lit.10 101−102 °C); 1H NMR (400 MHz,
CDCl3) δ 8.28−8.19 (4H, m), 7.61−7.49 (6H, m); 13C NMR (100
MHz, CDCl3) δ 165.2, 137.0, 130.6, 129.7, 129.6, 129.0, 127.2, 127.1,
119.9; HRMS (ESI) calcd for C13H11N4 [M + H]+ 223.0984, found
223.0984.
EXPERIMENTAL SECTION
■
General Information. Melting points were uncorrected. 1H NMR
spectra were recorded at 400 MHz, and 13C NMR spectra were
recorded at 100 MHz with tetramethylsilane as an internal standard.
IR spectra were recorded using an attenuated total reflectance
measurement. High-resolution mass spectra were recorded on a
time-of-flight instrument using electrospray ionization method.
Column chromatography was performed with silica gel 60N (40−
100 μm, spherical, neutral). Analytical high-performance liquid
chromatography was performed using Imtakt Unison UK-C18 column.
Materials. Unless otherwise noted, materials and solvents were
purchased and used without further purification. 5-Bromo-1H-
tetrazole19 and 1H-tetrazole-5-carboxylic acid ethyl ester20 were
prepared according to the reported procedure. Products 1b,21 1d,22
1f,23 1g,24 1h,12,14 and 1i23 are known in the literature.
5-(4-Methylphenyl)-2-phenyl-2H-tetrazole (1g).24 1g (187.6
mg, 79%) was obtained from 5-(4-methylphenyl)-1H-tetrazole (160.2
mg, 1.00 mmol), K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)-
(TMEDA)]2Cl2 (55.7 mg, 0.12 mmol), and phenylboronic acid
(195.1 mg, 1.60 mmol): eluent, 1:1 hexane/CH2Cl2; white solid; mp
94−95 °C (EtOH, lit.10 94−95 °C); H NMR (400 MHz, CDCl3) δ
1
8.21−8.13 (4H, m), 7.60−7.47 (3H, m), 7.33 (2H, d, J = 7.6 Hz), 2.44
(3H, s); 13C NMR (100 MHz, CDCl3) δ 165.3, 140.8, 137.0, 129.7,
129.5, 127.0, 124.4, 119.9, 21.5; HRMS (ESI) calcd for C14H13N4 [M
+ H]+ 237.1140, found 237.1134.
General Procedure. K2CO3 (1.1 equiv), [Cu(OH)-
(TMEDA)]2Cl2 (12 mol %), and arylboronic acid (1.6−3.0 equiv)
were added to a solution of a tetrazole in CH2Cl2 (0.1−0.2 M
solution) at room temperature. After the mixture stirred at room
temperature for 16 h under O2, 10% aqueous NH3 was added and
extracted with CH2Cl2. The organic layer was washed with 10%
aqueous NaCl, dried over Na2SO4, filtered, and evaporated in vacuo.
The residue was purified by flash SiO2 column chromatography to give
the 2,5-disubstituted tetrazole.
5-(4-Bromophenyl)-2-phenyl-2H-tetrazole (1h). 1h (228.2 mg,
75%) was obtained from 5-(4-bromophenyl)-1H-tetrazole (225.1 mg,
1.00 mmol), K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)-
(TMEDA)]2Cl2 (55.7 mg, 0.12 mmol), and phenylboronic acid
(195.1 mg, 1.60 mmol): eluent, 1:1 hexane/CH2Cl2; white solid; mp
113−114 °C (EtOH); 1H NMR (400 MHz, CDCl3) δ 8.21−8.12 (4H,
m), 7.68−7.49 (5H, m); 13C NMR (100 MHz, CDCl3) δ 164.4, 136.8,
132.2, 129.8, 129.7, 128.6, 126.1, 125.0, 119.9; HRMS (ESI) calcd for
C13H10BrN4 [M + H]+ 301.0089, found 301.0085.
5-Methyl-2-phenyl-2H-tetrazole (1a). 1a (108.8 mg, 67%) was
obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol), K2CO3
(152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg, 0.12
mmol), and phenylboronic acid (195.1 mg, 1.60 mmol): eluent, 1:2
4-(2-Phenyl-2H-tetrazol-5-yl)pyridine (1i).23 1i (69.9 mg, 31%)
was obtained from 5-(4-pyridyl)-1H-tetrazole (147.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and phenylboronic acid (195.1 mg, 1.60 mmol): eluent,
5:1 CH2Cl2/AcOEt; white solid; mp 142−143 °C (EtOH, lit.25
1
hexane/CH2Cl2; colorless oil; H NMR (400 MHz, CDCl3) δ 8.11−
8.08 (2H, m), 7.57−7.45 (3H, m), 2.64 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 163.2, 136.9, 129.6, 129.5, 119.7, 11.0; HRMS (ESI) calcd
for C8H9N4 [M + H]+ 161.0827, found 161.0825.
5-Benzyl-2-phenyl-2H-tetrazole (1b).21 1b (181.2 mg, 76%)
was obtained from 5-benzyl-1H-tetrazole (160.2 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and phenylboronic acid (195.1 mg, 1.60 mmol): eluent,
1
141.5−142.5 °C); H NMR (400 MHz, CDCl3) δ 8.82 (2H, dd, J =
4.4, 1.6 Hz), 8.22−8.19 (2H, m), 8.13 (2H, dd, J = 4.4, 1.6 Hz), 7.63−
7.53 (3H, m); 13C NMR (100 MHz, CDCl3) δ 163.3, 150.8, 136.7,
134.5, 130.1, 129.8, 120.9, 120.0; HRMS (ESI) calcd for C12H10N5 [M
+ H]+ 224.0936, found 224.0925.
1
2:3 hexane/CH2Cl2; colorless oil; H NMR (400 MHz, CDCl3) δ
8.11−8.08 (2H, m), 7.55−7.23 (8H, m), 4.34 (2H, s); 13C NMR (100
MHz, CDCl3) δ 165.8, 136.9, 136.6, 129.6, 129.5, 128.9, 128.7, 127.0,
119.9, 31.9; HRMS (ESI) calcd for C14H13N4 [M + H]+ 237.1140,
found 237.1135.
2-(4-Methylphenyl)-5-methyl-2H-tetrazole (2a). 2a (111.5 mg,
64%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and p-methylphenylboronic acid (217.5 mg, 1.60 mmol):
C
dx.doi.org/10.1021/jo500862t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
eluent, 1:2 hexane/CH2Cl2; white solid; mp 69−70 °C (EtOH); H
NMR (400 MHz, CDCl3) δ 7.96 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J =
8.4 Hz), 2.63 (3H, s), 2.43 (3H, s); 13C NMR (100 MHz, CDCl3) δ
163.0, 139.7, 134.7, 130.1, 119.6, 21.2, 11.0; HRMS (ESI) calcd for
C9H11N4 [M + H]+ 175.0984, found 175.0979.
HRMS (ESI) calcd for C9H10ClN4O [M + H]+ 225.0543, found
225.0542.
ASSOCIATED CONTENT
■
S
* Supporting Information
2-(4-Methoxyphenyl)-5-methyl-2H-tetrazole (2b). 2b (106.5
mg, 56%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00
mmol), K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2
(55.7 mg, 0.12 mmol), and p-methoxyphenylboronic acid (243.1 mg,
1.60 mmol): eluent, 1:6 hexane/CH2Cl2; white solid; mp 73−74 °C
1H and 13C NMR spectra of all compounds (1a−1i, 2a−2h).
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(EtOH); H NMR (400 MHz, CDCl3) δ 8.00 (2H, d, J = 9.6 Hz),
AUTHOR INFORMATION
7.03 (2H, d, J = 9.2 Hz), 3.88 (3H, s), 2.62 (3H, s); 13C NMR (100
MHz, CDCl3) δ 163.0, 160.4, 130.5, 121.3, 114.6, 55.6, 11.0; HRMS
(ESI) calcd for C9H11N4O [M + H]+ 191.0933, found 191.0937.
2-(4-Benzyloxyphenyl)-5-methyl-2H-tetrazole (2c). 2c (142.7
mg, 53%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00
mmol), K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2
(55.7 mg, 0.12 mmol), and 4-benzyloxyphenylboronic acid (364.9 mg,
1.60 mmol): eluent, 1:6 hexane/CH2Cl2; white solid; mp 113−114 °C
■
Corresponding Authors
*E-mail: t-onaka@fujimoto-chem.co.jp. Fax: (+81)-6-6482-
3115.
*E-mail: maegawa@phar.kindai.ac.jp. Fax: (+81)-6-6721-2505.
Notes
The authors declare no competing financial interest.
1
(EtOH); H NMR (400 MHz, CDCl3) δ 8.00 (2H, d, J = 8.8 Hz),
7.46−7.33 (5H, m), 7.10 (2H, d, J = 9.2 Hz), 5.14 (2H, s), 2.62 (3H,
s); 13C NMR (100 MHz, CDCl3) δ 163.0, 159.5, 136.3, 130.7, 128.7,
128.3, 127.5, 121.3, 115.6, 70.4, 11.0; HRMS (ESI) calcd for
C15H15N4O [M + H]+ 267.1246, found 267.1241.
REFERENCES
■
(1) (a) Butler, R. N. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
UK, 1996; Vol. 4. (b) Roh, J.; Vav
Chem. 2012, 6101−6118.
(2) (a) Frija, L. M. T.; Khmelinskii, I. V.; Cristiano, M. L. S.
Tetrahedron Lett. 2005, 46, 6757−6760. (b) Srihari, P.; Dutta, P.; Rao,
R. S.; Yadav, J. S.; Chandrasekhar, S.; Thombare, P.; Mohapatra, J.;
Chatterjee, A.; Jain, M. R. Bioorg. Med. Chem. Lett. 2009, 19, 5569−
5572. (c) Al-Hourani, B. J.; Sharma, S. K.; Mane, J. Y.; Tuszynski, J.;
Baracos, V.; Kniess, T.; Suresh, M.; Pietzsch, J.; Wuest, F. Bioorg. Med.
Chem. Lett. 2011, 21, 1823−1826.
́ ́ ́
rova, K.; Hrabalek, A. Eur. J. Org.
2-(4-Fluorophenyl)-5-methyl-2H-tetrazole (2d). 2d (102.8 mg,
57%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and p-fluorophenylboronic acid (223.9 mg, 1.60 mmol):
1
eluent, 1:2 hexane/CH2Cl2; white solid; mp 80−81 °C (EtOH); H
NMR (400 MHz, CDCl3) δ 8.12−8.06 (2H, m), 7.27−7.21 (2H, m),
2.64 (3H, s); 13C NMR (100 MHz, CDCl3) δ 164.1, 163.4, 161.6,
133.2, 121.7, 121.6, 116.8, 116.5, 11.0; HRMS (ESI) calcd for
C8H8FN4 [M + H]+ 179.0733, found 179.0730.
(3) (a) Thomas, E. W. Synthesis 1993, 767−768. (b) Artamonova, T.
V.; Zhivich, A. B.; Dubinskii, M. Yu.; Koldobskii, G. I. Synthesis 1996,
1428−1430. (c) Katritzky, A. R.; Cai, C.; Meher, N. K. Synthesis 2007,
1204−1208.
2-(4-Chlorophenyl)-5-methyl-2H-tetrazole (2e). 2e (115.2 mg,
59%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and p-chlorophenylboronic acid (250.2 mg, 1.60 mmol):
1
(4) (a) Demco, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
41, 2110−2113. (b) Demco, Z. P.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2113−2116.
eluent, 1:2 hexane/CH2Cl2; white solid; mp 84−85 °C (EtOH); H
NMR (400 MHz, CDCl3) δ 8.05 (2H, d, J = 9.2 Hz), 7.52 (2H, d, J =
8.8 Hz), 2.64 (3H, s); 13C NMR (100 MHz, CDCl3) δ 163.5, 135.3,
129.8, 120.9, 11.0; HRMS (ESI) calcd for C8H8ClN4 [M + H]+
195.0437, found 195.0439.
(5) Kaim, L. E.; Grimaud, L.; Patil, P. Org. Lett. 2011, 13, 1261−
1263.
(6) (a) Sun, Y.; Liu, D.; Or, Y. S.; Wang, Z. Patent WO 2008, 019,
289, 2008; Chem. Abstr. 2008, 148, 262901. (b) Sun, Y.; Liu, D.; Or, Y.
S.; Wang, Z. Patent WO 2008, 021, 733, 2008; Chem. Abstr. 2008, 148,
308635. (c) Sun, Y.; Liu, D.; Or, Y. S.; Wang, Z. Patent WO 2009, 064,
955, 2009; Chem. Abstr. 2009, 150, 555797.
2-(4-Bromophenyl)-5-methyl-2H-tetrazole (2f). 2f (142.4 mg,
59%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and p-bromophenylboronic acid (321.3 mg, 1.60 mmol):
1
eluent, 1:2 hexane/CH2Cl2; white solid; mp 92−93 °C (EtOH); H
(7) (a) Tehrani, L. R.; Smith, N. D.; Huang, D.; Poon, S. F.; Roppe,
J. R.; Seiders, T. J.; Chapman, D. F.; Chung, J.; Cramer, M.; Cosford,
N. D. P. Bioorg. Med. Chem. Lett. 2005, 15, 5061−5064. (b) Arora, J.;
Edwards, L.; Isaac, M.; Kers, A.; Staaf, K.; Slassi, A.; Stefanac, T.;
Wensbo, D.; Xin, T.; Holm, B. Patent WO 2005, 080, 386, 2005;
Chem. Abstr., 2005, 143, 266955. (c) Arzel, E.; Edwards, L.; Isaac, M.;
Mcleod, D. A.; Slassi, A.; Xin, T. Patent WO 2009, 051, 556, 2009;
Chem. Abstr., 2009, 150, 447953.
(8) Lachance, N.; Li, C. S.; Leclerc, J.-P.; Ramtohul, Y. K. Patent WO
2008, 128, 335, 2008; Chem. Abstr., 2009, 149, 513832.
(9) Wood, H. B.; Szewczyk, J. W.; Huang, Y.; Adams, A. D. Patent
WO 2009, 129, 036, 2009; Chem. Abstr., 2008, 151, 491142.
(10) (a) Ito, S.; Tanaka, Y.; Kakehi, A. Bull. Chem. Soc. Jpn. 1976, 49,
762−766. (b) Ito, S.; Tanaka, Y.; Kakehi, A.; Kondo, K. Bull. Chem.
Soc. Jpn. 1976, 49, 1920−1923.
NMR (400 MHz, CDCl3) δ 7.99 (2H, d, J = 8.8 Hz), 7.68 (2H, d, J =
9.2 Hz), 2.64 (3H, s); 13C NMR (100 MHz, CDCl3) δ 163.5, 135.8,
132.8, 123.3, 121.1, 11.0; HRMS (ESI) calcd for C8H8BrN4 [M + H]+
238.9932, found 238.9933.
2-(3-Bromophenyl)-5-methyl-2H-tetrazole (2g). 2g (123.3 mg,
51%) was obtained from 5-methyl-1H-tetrazole (84.1 mg, 1.00 mmol),
K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)(TMEDA)]2Cl2 (55.7 mg,
0.12 mmol), and m-bromophenylboronic acid (321.3 mg, 1.60 mmol):
1
eluent, 1:2 hexane/CH2Cl2; white solid; mp 65−66 °C (EtOH); H
NMR (400 MHz, CDCl3) δ 8.30 (1H, t, J = 2.0 Hz), 8.06 (1H, ddd, J
= 8.0, 2.0, 1.2 Hz), 7.61 (1H, ddd, J = 8.0, 2.0, 1.2 Hz), 7.42 (1H, t, J =
8.0 Hz), 2.65 (3H, s); 13C NMR (100 MHz, CDCl3) δ 163.5, 137.6,
132.5, 131.0, 123.2, 122.8, 118.2, 11.0; HRMS (ESI) calcd for
C8H8BrN4 [M + H]+ 238.9932, found 238.9928.
2-(3-Chloro-4-methoxyphenyl)-5-methyl-2H-tetrazole (2h).
2h (139.8 mg, 62%) was obtained from 5-methyl-1H-tetrazole (84.1
mg, 1.00 mmol), K2CO3 (152.0 mg, 1.10 mmol), [Cu(OH)-
(TMEDA)]2Cl2 (55.7 mg, 0.12 mmol), and 3-chloro-4-methoxy-
phenylboronic acid (298.2 mg, 1.60 mmol): eluent, 1:6 hexane/
(11) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M.
P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941−2944.
(12) Davydov, D. V.; Beletskaya, I. P.; Semenov, B. B.; Smushkevich,
Y. I. Tetrahedron Lett. 2002, 43, 6217−6219.
(13) Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett. 1999, 40, 2747−
2748.
1
CH2Cl2; white solid; mp 140−141 °C (EtOH); H NMR (400 MHz,
CDCl3) δ 8.15 (1H, d, J = 2.8 Hz), 7.97 (1H, dd, J = 8.8, 2.8 Hz), 7.06
(1H, d, J = 8.8 Hz), 3.98 (3H, s), 2.63 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 163.2, 155.9, 130.4, 123.6, 122.0, 119.1, 112.2, 56.5, 11.0;
(14) Beletskaya, I. P.; Davydov, D. V.; Gorovoy, M. S. Tetrahedron
Lett. 2002, 43, 6221−6223.
D
dx.doi.org/10.1021/jo500862t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(15) (a) Li, Y.; Gao, L.-X.; Han, F.-S. Chem. Commun. 2012, 48,
2719−2721. (b) Liu, C.-Y.; Li, Y.; Ding, J.-Y.; Dong, D.-W.; Han, F.-S.
Chem.Eur. J. 2014, 20, 2373−2381.
(16) Differential scanning calorimetry measurements indicated that
the onset temperature of decomposition of 2-phenyl-5-methylthio-
tetrazole was 128 °C (885 J/g).
(17) Coupling reactions were performed under Han’s15 conditions,
and the coupling products were obtained as 3:2 mixtures of 2-Ar and
1-Ar. Yields were determined by HPLC.
(18) [Cu(OH)(TMEDA)]2Cl2 is commercially available from TCI
(D2542). (a) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233−1236.
(b) Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem.
2001, 66, 1528−1531. (c) Collman, J. P.; Zhong, M.; Zhang, C.;
Costanzo, S. J. Org. Chem. 2001, 66, 7892−7897.
(19) Koldobskii, G. I.; Soldatenko, D. S.; Gerasimova, E. S.;
Khokhryakova, N. R.; Scherbini, M. B.; Lebedev, V. P.; Ostrovskii, V.
A. Russ. J. Org. Chem. 1997, 33, 1771−1783.
(20) Das, B.; Reddy, C. R.; Kumar, D. N.; Krishnaiah, M.; Narender,
R. Synlett 2010, 391−394.
(21) Zhou, T.; Chen, Z.-C. J. Chem. Res. 2004, 404−405.
(22) Wang, Y.; Lin, Q. Org. Lett. 2009, 11, 3570−3573.
(23) Reinov, M. V.; Yurovskaya, M. A.; Davydov, D. V.; Streletskii, A.
V. Chem. Heterocycl. Compd. 2004, 40, 188−193.
(24) Wang, Y.; Vera, C. I. R.; Lin, Q. Org. Lett. 2007, 9, 4155−4158.
(25) Wentrup, C.; Damerius, A.; Reichen, W. J. Org. Chem. 1978, 43,
2037−2041.
E
dx.doi.org/10.1021/jo500862t | J. Org. Chem. XXXX, XXX, XXX−XXX