Transition-metal-free direct alkylation of aryl tetrazoles via intermolecular oxidative C-N formation

Article abstract of DOI:10.1021/jo502283h

A transition-metal-free synthetic approach for constructing alkylated aryl tetrazoles has been developed using n-Bu₄NI as the catalyst and t-BuOOH as the oxidant. It involves the direct C-N bond formation through sp³ C-H activation. A wide range of benzylic C-H substrates (or alkyl ethers) and aryl tetrazoles undergo this reaction smoothly to deliver the corresponding products in good yields.

Full text of DOI:10.1021/jo502283h

Note
pubs.acs.org/joc
Transition-Metal-Free Direct Alkylation of Aryl Tetrazoles via
Intermolecular Oxidative C−N Formation
Liang Wang,* Kaiqiang Zhu, Qun Chen, and Mingyang He*
School of Petrochemical Engineering and Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Changzhou
University, Changzhou, 213164, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-free synthetic approach for constructing alkylated aryl tetrazoles has been developed using n-
Bu4NI as the catalyst and t-BuOOH as the oxidant. It involves the direct C−N bond formation through sp3 C−H activation. A
wide range of benzylic C−H substrates (or alkyl ethers) and aryl tetrazoles undergo this reaction smoothly to deliver the
corresponding products in good yields.
Meanwhile, hydrocarbons such as methylarenes are the most
cheap and readily available raw materials for chemical
industries. Therefore, the direct formation of C−C and C−X
bonds via C−H activation of methylarenes is of great
importance and is also a big challenge currently. As a part of
our continuous interest in the functionalization of tetrazoles,5c
herein, we report a metal-free alkylation of aryl tetrazoles with
benzylic C−H substrates or alkyl ethers by using n-Bu4NI as
catalyst and t-BuOOH as oxidant (Scheme 1, (d)).
Initially, toluene 1a and 5-phenyl-2H-tetrazole 2a were
chosen as the model substrates to optimize the reaction
conditions (Table 1). A 29% yield of product 3aa was obtained
using n-Bu4NI (0.2 equiv) as catalyst and TBHP (3 equiv) as
oxidant in ethyl acetate. Replacing TBHP by other oxidants
such as H2O2, DTBP, K2S2O8, or O2 resulted in the failure of
the reaction (Table 1, entries 2−5). Reactions in other solvents,
including N,N-dimethylformamide (DMF), dimethyl sulfoxide
(DMSO), 1,2-dichloroethane (DCE), and acetonitrile, gave the
desired product 3aa in much lower yields. Encouragingly, a
67% yield of 3aa was obtained under solvent-free conditions.
Increasing the amount of toluene improved the yield notably,
and the highest yield was obtained in 1 mL of toluene (ca. 30
equiv) (Table 1, entries 10−12). In addition, no product was
observed in the absence of either n-Bu4NI or TBHP (Table 1,
entries 13 and 14). Increasing the amount of TBHP to 5 equiv
led to a decreased yield. Other catalysts, such as n-Bu4NBr, n-
Bu4NCl, I2, and NaI, were also evaluated; however,
unsatisfactory results were obtained (Table 1, entries 17−20).
Finally, the survey on the reaction temperature showed that 80
°C was the optimum.
etrazoles are of great importance due to their wide
1
2
Tapplications in organic chemistry, medicinal chemistry,
and material science.3 For example, biphenyl tetrazoles are key
intermediates for preparation of sartan drugs, and 2-
arylcarbapenems are useful antibiotics.4 Recently, tetrazoles
were also utilized as directing groups in C−H activation
reactions. Seki reported an efficient Ru(III)-catalyzed synthesis
of angiotensin II receptor blockers (ARBs) using tetrazole as
the directing group (Scheme 1, (a)).5a Ackermann and co-
workers also disclosed highly efficient Ru(II)-catalyzed direct
ortho-arylations of aryl tetrazoles.5b Inspired by their work, we
developed a rhodium-catalyzed direct ortho C−H olefination
reaction of aryl tetrazoles (Scheme 1, (b)).5c
Despite the utilities of the tetrazole moiety, reaction for
preparation of alkylated tetrazoles has a limited scope.
Generally, they were synthesized by SN2 reaction between an
alkyl halide and a tetrazole. For example, Aridoss and Laali
reported a base-promoted the synthesis of alkylated tetrazoles
in refluxing acetonitrile (Scheme 1, (c)).6 The major drawbacks
associated with this procedure were the expensive alkyl halides,
moderate yields as well as the formation of isomeric dialkylated
mixtures.
Recently, the cross-dehydrogenative coupling (CDC) re-
action has arisen as an excellent synthetic method to construct
more complex compounds.7 The CDC strategy is very powerful
with high atomic economy since no prefunctionalization or
preactivation of starting materials is required. Among the
reported procedures, the metal-free n-Bu4NI/TBHP system
turns out to be the focus of current interest,8 and some
excellent protocols for C−O,9 C−N,10 and C−S11 bond
formation have been developed. However, the C−N bond
formation catalyzed by n-Bu4NI via sp3 C−H activation has not
been fully explored, especially for the synthesis or functional-
ization of N-containing heterocycles.
Received: October 6, 2014
© XXXX American Chemical Society
A
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Note
Scheme 1. Alkylation of 5-Aryl 1H-Tetrazoles and Their Functionalizations
a
Table 1. Optimization of Reaction Conditions
b
c
entry
catalyst (mol %)
oxidant (equiv)
T (°C)
solvent
yield (%)
1
2
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
TBHP (3)
H2O2 (3)
DTBP (3)
K2S2O8 (3)
O2
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
110
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
DMF
29
d
d
d
d
d
3
4
5
6
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
7
DMSO
DCE
trace
18
8
9
CH3CN
26
10
11
12
13
14
15
16
17
18
19
20
21
22
23
67
e
75
f
g
83 (81)
df
,
df
,
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (10)
n-Bu4NBr (10)
n-Bu4NCl (10)
I2 (10)
f
f
TBHP (5)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
74
76
f
trace
df
,
f
f
trace
trace
NaI (10)
f
n-Bu4NI (20)
n-Bu4NI (20)
n-Bu4NI (20)
38
f
71
f
68
a
b
Reaction conditions: 1a (3 mmol), 2a (0.3 mmol), solvent (1 mL), catalyst, and oxidant were heated in a sealed tube for 12 h. TBHP: tert-butyl
c
d
e
hydroperoxide 70% in water, H2O2 30% in water, DTBP: di-tert-butyl peroxide 98%. Isolated yields. Product not observed. Toluene (20 equiv).
f
g
Toluene (30 equiv, 1 mL). Toluene (1.5 mL).
With the optimized conditions in hand, a series of
methylarenes were employed for oxidative coupling with 2a
(Table 2). Generally, methylarenes bearing either electron-
donating or electron-withdrawing substituents reacted with 2a
smoothly to afford the desired products in moderate to good
yields (3aa−3la). Both xylenes and mesitylene were efficiently
B
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Note
a
Table 2. Reaction Scope for Methylarenes
a
Reaction conditions: 1 (9 mmol), 2a (0.3 mmol), TBAI (0.06 mmol, 20 mol %), TBHP (0.9 mmol, 3 equiv), 80 °C, 12 h. Isolated yields.
Scheme 2. Amination Reaction of Selected Alkyl Ethers
transformed to the corresponding products with high
selectivities, giving only mono-amination products (3ba−3ea).
Other para-substitued toluene substrates with functional groups
including t-butyl, chloro, bromo, fluoro, methoxyl, and nitro
were also tolerated under the conditions (3fa−3la). Compared
with the halo-substituted toluene substrates, the starting
materials 1j and 1l showed relatively lower activities. For
substrate 1j, a small amount of amination product on the
methoxyl group was also detected. Moreover, the steric
hindrance showed little influence on the reaction, and substrate
1k underwent this coupling reaction to deliver the product 3ka
in good yield. Other benzylic C−H substrates such as
ethylbenzene and diphenylmethane also proceeded smoothly
to furnish the corresponding products in 85% and 77% yields,
respectively.
As mentioned above, the amination reaction on the methoxyl
group of substrate 1j prompted us to extend this protocol to
the alkyl ethers (Scheme 2). Under the optimized conditions,
the selected alkyl ethers including dioxane, 1,2-dimethoxy-
ethane, and tetrahydro-2H-pyran were found to react smoothly
to generate the coupling products 5aa−5ca with moderate to
good yields. For the 1,2-dimethoxyethane, it was worth noting
that the amination reaction took place mainly on the methylene
group.
To further explore the scope of this protocol, a series of aryl
tetrazoles were investigated, and the results are summarized in
Table 3. To our delight, aryl tetrazoles with various substituents
C
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Note
a
Table 3. Reaction Scope for Tetrazoles
a
Reaction conditions: toluene (9 mmol), 2 (0.3 mmol), TBAI (0.06 mmol, 20 mol %), TBHP (0.9 mmol, 3 equiv), 80 °C, 12 h, isolated yields.
Scheme 3. Gram-Scale Reaction
coupled with toluene smoothly to afford the desired products in
good yields. Various functional groups, including methyl,
methoxyl, chloro, fluoro, trifluoromethyl, and nitro, survived
well under the reaction conditions. Negligible steric hindrance
influence was observed for the tetrazole substrate (3ad, 74%).
For the tetrazole substrate bearing methoxyl at the para
position, however, a lower yield was obtained (3ah, 63%). To
our delight, 5-(furan-2-yl)-2H-tetrazole worked well with
toluene to give the desired product 3aj in 70% yield.
Scheme 4. Control Experiments
Furthermore, a scale-up reaction was performed to
demonstrate the practicability of the developed protocol (10
mmol scale). The amination reaction proceeded smoothly
under the optimized conditions to provide the product 3aa in
72% yield (Scheme 3).
To gain insight into the mechanism, several control
experiments were performed (Scheme 4). Initially, when 1
equiv of radical inhibitor, BHT (2,6-di-tert-butyl-4-methylphe-
nol), was added to the reaction mixture, only a trace amount of
product 3aa was observed (Scheme 4, (a)). This result
indicated that a radical pathway may be involved in this
reaction. Next, the role of TBAI was investigated. The color of
the reaction mixture turned brown after addition of TBAI,
suggesting the generation of iodine. However, replacement of
TBAI with I2 inhibited the reaction (Scheme 4, (b)). A trace
amount of product 3aa was obtained by switching the catalyst
to NaI. Additionally, reaction of benzyl iodide and 2a led to a
mixture, which ruled out the possibility of nucleophilic
substitution of 2a to the benzyl iodide. Moreover, the kinetic
isotopic effect (KIE) experiment was studied (Scheme 4, (d)).
The result shows a significant kinetic isotope effect (kH/kD =
13.2), indicating that the C−H bond cleavage of toluene may
be the rate-determining step (see the Supporting Information).
On the basis of the above experimental results and literature
reports,9c,10e a plausible mechanism is proposed (Scheme 5).
Initially, the oxidation of TBAI by TBHP gives the tert-butoxyl
radical, iodine, and a hydroxyl anion (Scheme 5, step (i)).
Then, the tetrazole is deprotonated by hydroxyl anion to
provide anionic species A (Scheme 5, step (ii)). Meanwhile,
homolysis of the benzyl C−H bond is induced by tert-butoxyl
radical to give radical B, which is further oxidized by iodine to
produce the benzyl cation C (Scheme 5, step (iii)). Finally, aryl
tetrazole anion A reacted with benzyl cation C to form the
product 3 (Scheme 5, step (iv)). Thus, the I2/I− redox system
plays a vital role in this reaction.
D
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Note
δ 8.30−8.09 (m, 2H), 7.59−7.46 (m, 3H), 7.39−7.25 (m, 4H), 5.87 (s,
2H), 2.54 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.2, 136.9,
131.6, 130.8, 130.2, 129.7, 129.1, 128.8, 127.4, 126.8, 126.5, 54.7, 19.2
ppm; HRMS (ESI): Calcd for C15H14N4Na (M + Na)+ 273.1111,
found 273.1115.
Scheme 5. Plausible Mechanism
2-(3,5-Dimethylbenzyl)-5-phenyl-2H-tetrazole (3ea). White solid
(59.4 mg, 75%), mp 80−82 °C; 1H NMR (CDCl3, 400 MHz) δ 8.21−
8.10 (m, 2H), 7.55−7.38 (m, 3H), 7.03 (s, 2H), 6.99 (s, 1H), 5.72 (s,
2H), 2.31 (s, 6H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.3, 138.6,
133.1, 130.5, 130.2, 128.8, 127.4, 126.8, 126.0, 56.7, 21.1 ppm; HRMS
(ESI): Calcd for C16H16N4Na (M + Na)+ 287.1267, found 287.1270.
2-(4-(tert-Butyl)benzyl)-5-phenyl-2H-tetrazole (3fa). White solid
1
(61.3 mg, 70%), mp 122−124 °C; H NMR (CDCl3, 400 MHz) δ
8.25−8.03 (m, 2H), 7.51−7.43 (m, 3H), 7.39 (q, J = 8.5 Hz, 4H), 5.78
(s, 2H), 1.31 (s, 9H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.3,
152.0, 130.4, 130.2, 128.8, 128.1, 127.4, 126.8, 125.9, 56.5, 34.6, 31.2
ppm; HRMS (ESI): Calcd for C18H20N4Na (M + Na)+ 315.1580,
found 315.1583.
2-(4-Chlorobenzyl)-5-phenyl-2H-tetrazole (3ga). Light yellow
1
solid (67.4 mg, 83%), mp 69−70 °C; H NMR (CDCl3, 400 MHz)
In conclusion, an n-Bu4NI-catalyzed direct oxidative coupling
of methylarenes with aryl tetrazoles has been developed. This
protocol provides a simple and green approach for the
preparation of tetrazole derivatives. Substrates with various
functional groups proceeded smoothly to provide the
corresponding products in moderate to good yields. Notably,
alkyl ethers could also be employed as substrates in the present
protocol.
δ 8.20−8.04 (m, 2H), 7.52−7.41 (m, 3H), 7.35 (s, 4H), 5.76 (s, 2H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5, 135.0, 131.7, 130.4,
129.8, 129.2, 128.8, 127.2, 126.8, 99.9, 56.0 ppm; HRMS (ESI): Calcd
for C14H11ClN4Na (M + Na)+ 293.0564, found 293.0569.
2-(4-Bromobenzyl)-5-phenyl-2H-tetrazole (3ha). White solid
(83.2 mg, 88%), mp 80−82 °C; 1H NMR (CDCl3, 400 MHz) δ
8.20−8.07 (m, 2H), 7.53−7.43 (m, 5H), 7.29 (d, J = 8.4 Hz, 2H), 5.74
(s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5, 132.2, 132.1,
130.4, 130.0, 128.8, 127.1, 126.8, 123.2, 56.0 ppm; HRMS (ESI):
Calcd for C14H11BrN4Na (M + Na)+ 337.0059, found 337.0051.
2-(4-Fluorobenzyl)-5-phenyl-2H-tetrazole (3ia). White solid (68.6
EXPERIMENTAL SECTION
■
General Information. Chemicals were used as received without
1
special purification unless stated otherwise. H and 13C NMR were
1
mg, 90%), mp 61−63 °C; H NMR (CDCl3, 400 MHz) δ 8.24−8.04
(m, 2H), 7.55−7.36 (m, 5H), 7.06 (t, J = 8.6 Hz, 2H), 5.76 (s, 2H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5, 163.0 (d, JC−F = 247 Hz),
130.4 (d, JC−F = 8.6 Hz), 129.1, 128.8, 127.2, 126.8, 116.1, 116.0 (d,
JC−F = 21.8 Hz), 56.0 ppm; HRMS (ESI): Calcd for C14H11FN4Na (M
+ Na)+ 277.0860, found 277.0869.
2-(4-Methoxybenzyl)-5-phenyl-2H-tetrazole (3ja). White solid
(53.5 mg, 67%), mp 57−59 °C; 1H NMR (CDCl3, 400 MHz) δ
8.12 (d, J = 1.6 Hz, 2H), 7.51−7.40 (m, 3H), 7.38 (d, J = 8.6 Hz, 2H),
6.89 (d, J = 8.6 Hz, 2H), 5.73 (s, 2H), 3.78 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 165.3, 160.0, 130.2, 129.9, 128.8, 127.4, 126.8,
125.4, 114.3, 56.3, 55.2 ppm; HRMS (ESI): Calcd for C15H14N4NaO
(M + Na)+ 289.1060, found 289.1067.
2-(2-Chlorobenzyl)-5-phenyl-2H-tetrazole (3ka). White solid
(63.3 mg, 78%), mp 68−70 °C; 1H NMR (CDCl3, 400 MHz) δ
8.20−8.11 (m, 2H), 7.51−7.41 (m, 4H), 7.32−7.24 (m, 2H), 7.18 (dd,
J = 7.6, 1.5 Hz, 1H), 5.96 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz)
δ 165.4, 133.6, 131.2, 130.3, 130.2, 130.0, 129.8, 128.8, 127.3, 127.2,
126.9, 54.0 ppm; HRMS (ESI): Calcd for C14H11ClN4Na (M + Na)+
293.0564, found 293.0573.
2-(4-Nitrobenzyl)-5-phenyl-2H-tetrazole (3la). White solid (54.8
mg, 65%), mp 122−124 °C; 1H NMR (CDCl3, 400 MHz) δ 8.25 (d, J
= 8.6 Hz, 2H), 8.13 (dd, J = 6.6, 2.9 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H),
7.52−7.43 (m, 3H), 5.92 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz)
δ 165.9, 148.4, 140.0, 130.6, 129.2, 128.9, 126.9, 124.3, 55.7 ppm;
HRMS (ESI): Calcd for C14H11N5NaO2 (M + Na)+ 304.0805, found
304.0811.
recorded at ambient temperature on a 400 MHz NMR spectrometer.
NMR experiments are reported in δ units, parts per million (ppm),
and were referenced to CDCl3 (δ 7.26 or 77.0 ppm) as the internal
standard. The coupling constants J are given in Hz. Melting points
(mp) are determined with a MPA 100 apparatus and are not corrected.
High-resolution mass spectrometry (HRMS) was performed on a
TOF MS instrument with an ESI source.
General Procedure for the Alkylation of Aryl Tetrazoles. In a
sealed tube, n-Bu4NI (22.1 mg, 0.06 mmol) was added to the mixture
of methylarenes 1 or alkyl ethers (9 mmol), aryl tetrazole 2 (0.3
mmol), and t-BuOOH (70% aqueous, 0.9 mmol, 3 equiv) at room
temperature. The reaction mixture was stirred at 80 °C for 12 h. After
the reaction, the reaction mixture was allowed to cool to room
temperature. The solvent was then removed under vacuum, and the
residue was purified by silica gel chromatography using a mixture of
PE/EA to afford the desired product 3 and 5.
2-Benzyl-5-phenyl-2H-tetrazole (3aa).6 White solid (58.8 mg,
1
83%), mp 60−62 °C; H NMR (CDCl3, 400 MHz) δ 8.14−8.16 (m,
2H), 7.50−7.45 (m, 3H), 7.35−7.44 (m, 5H), 5.80 (s, 2H) ppm; 13C
NMR (CDCl3,100 MHz) δ 165.4, 133.3, 130.2, 129.0, 128.9, 128.7,
128.3, 127.3, 126.8, 56.7 ppm; HRMS (ESI): Calcd for C14H12N4Na
(M + Na)+ 259.0954, found 259.0960.
2-(4-Methylbenzyl)-5-phenyl-2H-tetrazole (3ba). White solid
(57.7 mg, 77%), mp 91−93 °C; 1H NMR (CDCl3, 400 MHz) δ
8.27−7.99 (m, 2H), 7.52−7.41 (m, 3H), 7.33 (d, J = 8.0 Hz, 2H), 7.18
(d, J = 7.9 Hz, 2H), 5.75 (s, 2H), 2.34 (s, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 165.3, 138.8, 130.2, 129.6, 128.7, 128.3, 127.3,
126.8, 56.5, 21.1 ppm; HRMS (ESI): Calcd for C15H14N4Na (M +
Na)+ 273.1111, found 273.1107.
5-Phenyl-2-(1-phenylethyl)-2H-tetrazole (3ma). Colorless oil
1
(63.8 mg, 85%); H NMR (CDCl3, 400 MHz) δ 8.17 (dd, J = 7.5,
1.6 Hz, 2H), 7.52−7.28 (m, 8H), 6.12 (q, J = 7.1 Hz, 1H), 2.11 (d, J =
7.1 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 164.9, 138.9, 130.1,
128.8, 128.7, 128.6, 127.5, 126.8, 126.6, 63.6, 21.1 ppm; HRMS (ESI):
Calcd for C15H14N4Na (M + Na)+ 273.1111, found 273.1119.
2-Benzhydryl-5-phenyl-2H-tetrazole (3na).12 White solid (72.1
mg, 77%), mp 111−113 °C; 1H NMR (CDCl3, 400 MHz) δ 8.17 (dd,
J = 7.4, 2.2 Hz, 2H), 7.50−7.46 (m, 3H), 7.41−7.34 (m, 11H) ppm;
13C NMR (CDCl3, 100 MHz) δ 165.3, 137.1, 130.3, 128.8, 128.7,
128.6, 128.3, 127.4, 126.9, 71.2 ppm; HRMS (ESI): Calcd for
C20H16N4Na (M + Na)+ 335.1267, found 335.1270.
2-(3-Methylbenzyl)-5-phenyl-2H-tetrazole (3ca). Light yellow
1
solid (46.5 mg, 62%), mp 61−63 °C; H NMR (CDCl3, 400 MHz)
δ 8.25 (dd, J = 7.4, 2.1 Hz, 2H), 7.65−7.49 (m, 3H), 7.46−7.12 (m,
4H), 5.87 (s, 2H), 2.45 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
165.4, 138.8, 133.2, 130.2, 129.6, 129.15,128.7, 127.4, 126.8, 125.4,
56.8, 21.3 ppm; HRMS (ESI): Calcd for C15H14N4Na (M + Na)+
273.1111, found 273.1104.
2-(2-Methylbenzyl)-5-phenyl-2H-tetrazole (3da). Light yellow
1
solid (61.5 mg, 82%), mp 49−50 °C; H NMR (CDCl3, 400 MHz)
E
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Note
2-(1,4-Dioxan-2-yl)-5-phenyl-2H-tetrazole (5aa). White solid
(48.0 mg, 69%), mp 51−53 °C; 1H NMR (CDCl3, 400 MHz) δ
8.24−8.11 (m, 2H), 7.48−7.47 (m, 3H), 6.09 (dd, J = 6.1, 2.9 Hz,
1H), 4.43 (dd, J = 12.0, 6.1 Hz, 1H), 4.16 (dd, J = 12.0, 2.9 Hz, 1H),
4.09 (dd, J = 9.8, 5.8 Hz, 1H), 3.98−3.92 (m, 1H), 3.90−3.85 (m, 2H)
ppm; 13C NMR (CDCl3,100 MHz) δ 165.2, 130.5, 128.8, 127.0, 126.9,
84.0, 67.1, 65.8, 64.9 ppm; HRMS (ESI): Calcd for C11H12N4NaO2
(M + Na)+ 255.0852, found 255.0860.
2-Benzyl-5-(3-nitrophenyl)-2H-tetrazole (3ai). Yellow solid (61.5
mg, 73%), mp 82−84 °C; 1H NMR (CDCl3, 400 MHz) δ 8.26 (d, J =
8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.46−7.38 (m, 5H), 5.82 (s,
2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 163.7, 148.8, 132.9, 132.5,
130.0, 129.1, 129.0, 128.5, 124.8, 121.8, 57.1 ppm; HRMS (ESI):
Calcd for C14H11N5NaO2 (M + Na)+ 304.0805, found 304.0813.
2-Benzyl-5-(furan-2-yl)-2H-tetrazole (3aj).6 Pale red oil (47.5 mg,
70%); 1H NMR (CDCl3, 400 MHz) δ 7.60 (d, J = 1.8 Hz, 1H), 7.47−
7.29 (m, 5H), 7.01 (d, J = 3.5 Hz, 1H), 6.70 (d, J = 3.5 Hz, 1H), 5.80
(s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 158.8 (two coinciding
carbon resonances), 144.3, 143.0, 133.1, 129.1, 128.4, 118.4, 111.5,
57.0 ppm; HRMS (ESI): Calcd for C12H10N4NaO (M + Na)+
249.0747, found 249.0752.
General Procedure for Gram-Scale Reaction of Toluene with
5-Phenyl-2H-tetrazole. n-Bu4NI (736.7 mg, 0.2 mmol) was added
to the mixture of toluene (30 mL), 5-phenyl-2H-tetrazole 2a (10
mmol), and t-BuOOH (70% aqueous, 30 mmol, 3 equiv) at room
temperature. The reaction mixture was stirred at 80 °C for 12 h. After
the reaction, the reaction mixture was transferred to a round-bottom
flask. The solvent was then removed under vacuum, and the residue
was purified by silica gel chromatography using a mixture of PE/EA to
afford the desired product 3aa (1.70 g, 72%).
2-(1,2-Dimethoxyethyl)-5-phenyl-2H-tetrazole (5ba). Colorless
1
oil (35.8 mg, 51%); H NMR (CDCl3, 400 MHz) δ 8.20 (dd, J =
7.4, 2.3 Hz, 2H), 7.55−7.43 (m, 3H), 5.97 (t, J = 6.1 Hz, 1H), 4.05 (d,
J = 6.1 Hz, 2H), 3.41 (s, 3H), 3.39 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz) δ 165.6, 130.5, 128.8, 127.2, 127.0, 91.5, 72.1, 59.5, 57.4
ppm; HRMS (ESI): Calcd for C11H14N4NaO2 (M + Na)+ 257.1009,
found 257.1017.
5-Phenyl-2-(tetrahydro-2H-pyran-2-yl)-2H-tetrazole (5ca). Color-
less oil (53.8 mg, 78%); 1H NMR (CDCl3, 400 MHz) δ 8.26−8.12 (m,
2H), 7.47 (dd, J = 5.0, 2.4 Hz, 3H), 6.05 (dd, J = 7.7, 2.8 Hz, 1H), 4.01
(dd, J = 9.6, 5.3 Hz, 1H), 3.88−3.74 (m, 1H), 2.49 (dd, J = 16.7, 8.9
Hz, 1H), 2.18−2.14 (m, 2H), 1.77−1.71 (m, 3H) ppm; 13C NMR
(CDCl3, 100 MHz) δ 164.9, 130.3, 128.8, 127.2, 126.9, 87.7, 66.8,
29.0, 24.5, 20.7 ppm; HRMS (ESI): Calcd for C12H14N4NaO (M +
Na)+ 253.1060, found 253.1054.
2-Benzyl-5-(p-tolyl)-2H-tetrazole (3ab).6 White solid (60.0 mg,
ASSOCIATED CONTENT
■
1
80%), mp 115−117 °C; H NMR (CDCl3, 400 MHz) δ 8.03 (d, J =
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all the compounds and
8.1 Hz, 2H), 7.48−7.31 (m, 5H), 7.30−7.25 (m, 2H), 5.79 (s, 2H),
2.40 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5, 140.4, 133.4,
129.5, 128.9, 128.8, 128.3, 126.8, 124.5, 56.7, 21.4 ppm; HRMS (ESI):
Calcd for C15H14N4Na (M + Na)+ 273.1111, found 273.1118.
2-Benzyl-5-(m-tolyl)-2H-tetrazole (3ac). White solid (57.0 mg,
kinetic isotope experiments are available in the Supporting
Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
76%), mp 116−118 °C; H NMR (CDCl3, 400 MHz) δ 8.11−7.81
AUTHOR INFORMATION
Corresponding Authors
*E-mail: lwcczu@126.com (L.W.).
*E-mail: hemingyangjpu@yahoo.com (M.H.).
(m, 2H), 7.45−7.32 (m, 6H), 7.27 (d, J = 6.2 Hz, 1H), 5.80 (s, 2H),
2.42 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5, 138.6, 133.4,
131.1, 129.0, 128.9, 128.7, 128.3, 127.4, 127.2, 124.0, 56.7, 21.3 ppm;
HRMS (ESI): Calcd for C15H14N4Na (M + Na)+ 273.1111, found
273.1102.
■
Notes
2-Benzyl-5-(o-tolyl)-2H-tetrazole (3ad). White solid (55.5 mg,
1
The authors declare no competing financial interest.
74%), mp 113−115 °C; H NMR (CDCl3, 400 MHz) δ 8.01−7.91
(m, 2H), 7.39 (m, 6H), 7.27 (d, J = 6.2 Hz, 1H), 5.80 (s, 2H), 2.42 (s,
3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 165.5,138.5, 133.4, 131.0,
129.0, 128.8, 128.7, 128.3, 127.4, 127.2, 124.0, 56.7, 21.3 ppm; HRMS
(ESI): Calcd for C15H14N4Na (M + Na)+ 273.1111, found 273.1107.
2-Benzyl-5-(4-chlorophenyl)-2H-tetrazole (3ae). Yellow solid
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21302014), the Natural Science
Foundation for Colleges and Universities of Jiangsu Province
(13KJB150002), and the Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology (BM2012110).
1
(68.2 mg, 84%), mp 119−121 °C; H NMR (CDCl3, 400 MHz) δ
8.07 (d, J = 8.6 Hz, 2H), 7.53−7.27 (m, 7H), 5.79 (s, 2H) ppm; 13C
NMR (CDCl3, 100 MHz) δ 164.5, 136.3, 133.2, 129.2, 128.9, 128.4,
128.1, 125.8, 56.8 ppm; HRMS (ESI): Calcd for C14H11ClN4Na (M +
Na)+ 293.0564, found 293.0570.
REFERENCES
■
2-Benzyl-5-(4-fluorophenyl)-2H-tetrazole (3af). Yellow solid (57.2
(1) Larock, R. C. Comprehensive Organic Transformations: A Guide to
Functional Group Preparations; VCH Publishers: New York, 1989.
(2) (a) Fernandez-Bachiller, M. I.; Perez, C.; Monjas, L.; Rademann,
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1
mg, 75%), mp 77−79 °C; H NMR (CDCl3, 400 MHz) δ 8.18−8.07
(m, 2H), 7.46−7.32 (m, 5H), 7.19−7.08 (m, 2H), 5.79 (s, 2H) ppm;
13C NMR (CDCl3, 100 MHz) δ 165.2, 164.2 (d, JC−F = 188.0 Hz),
133.2, 129.0 (d, JC−F = 4.2 Hz), 128.9, 128.8, 128.4, 119.4, 115.9 (d,
JC−F = 22.0 Hz), 56.8 ppm; HRMS (ESI): Calcd for C14H11FN4Na (M
+ Na)+ 277.0860, found 277.0871.
2-Benzyl-5-(4-(trifluoromethyl)phenyl)-2H-tetrazole (3ag).6
1
White solid (65.7 mg, 72%), mp 74−76 °C; H NMR (CDCl3, 400
MHz) δ 8.26 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.43−7.38
(m, 5H), 5.82 (s, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 164.2,
133.1, 132.0 (q, J = 33.2 Hz), 131.8, 130.7, 129.0, 128.4, 127.1, 125.8
(q, J = 3.7 Hz), 123.8 (q, J = 270.8 Hz), 57.0 ppm; HRMS (ESI):
Calcd for C15H11F3N4Na (M + Na)+ 327.0828, found 327.0821.
2-Benzyl-5-(4-methoxyphenyl)-2H-tetrazole (3ah).6 White solid
1
(50.3 mg, 63%), mp 121−122 °C; H NMR (CDCl3, 400 MHz) δ
8.07 (d, J = 8.9 Hz, 2H), 7.47−7.29 (m, 5H), 6.98 (d, J = 8.9 Hz, 2H),
5.78 (s, 2H), 3.85 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ
165.3, 161.2, 133.4, 129.0, 128.8, 128.3, 128.2, 119.9, 114.2, 56.6, 55.3
ppm; HRMS (ESI): Calcd for C15H14N4NaO (M + Na)+ 289.1060,
found 289.1048.
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