C-H bonds as ubiquitous functionality: Preparation of multiple regioisomers of arylated 1,2,4-triazoles via C-H arylation

Article abstract of DOI:10.1021/jo3021677

We describe a general approach for the synthesis of complex aryl 1,2,4-triazoles. The electronic character of the C-H bonds and the triazole ring allows for the regioselective C-H arylation of 1-alkyl- and 4-alkyltriazoles under catalytic conditions. We have also developed the SEM and THP switch as well as trans-N-alkylation, which enable sequential arylation of the triazole ring to prepare 3,5-diaryltriazoles. This new strategy provides rapid access to a variety of arylated 1,2,4-triazoles and well complements existing cyclization methods.

Full text of DOI:10.1021/jo3021677

Note
pubs.acs.org/joc
C−H Bonds as Ubiquitous Functionality: Preparation of Multiple
Regioisomers of Arylated 1,2,4-Triazoles via C−H Arylation
Jung Min Joo, Pengfei Guo, and Dalibor Sames*
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York, 10027, United States
S
* Supporting Information
ABSTRACT: We describe a general approach for the
synthesis of complex aryl 1,2,4-triazoles. The electronic
character of the C−H bonds and the triazole ring allows for
the regioselective C−H arylation of 1-alkyl- and 4-
alkyltriazoles under catalytic conditions. We have also
developed the SEM and THP switch as well as trans-N-
alkylation, which enable sequential arylation of the triazole ring to prepare 3,5-diaryltriazoles. This new strategy provides rapid
access to a variety of arylated 1,2,4-triazoles and well complements existing cyclization methods.
1,2,4-Triazoles have emerged as an important heterocyclic class
with a growing number of applications in medicinal chemistry
and materials science.1 In particular, C-arylated triazoles display
a broad range of biological activities, including anticancer and
antipsychotic activities.2 In addition, conjugated triazoles and
polymeric forms have been widely studied for the development
of functional materials owing to interesting fluorescence and
light emitting properties.3
In the context of a broad C−H functionalization program,4
we have been developing new catalytic methods, based on
transition-metal carboxylate systems, for regioselective C−H
arylation of heteroarenes such as indoles, pyrroles, pyrazoles,
imidazoles, and pyridines.5−7 We herein report a general
approach for the selective and sequential arylation of 1,2,4-
Figure 1. Regioselectivity of the direct catalytic C−H arylation
governed by the electronic character of the C−H bonds and
triazoles. The synthesis of aryltriazoles typically relies on
multistep cyclocondensation reactions, which require direct
handling of hazardous hydrazines.1,8 Much less common are
cross-coupling reactions of halogenated 1,2,4-triazoles, which
achieved limited success in terms of efficiency and selectivi-
ty.2d,9
heteroarene rings.
have been reported, these protocols are mostly limited to 1-
methyltriazole.10−13
First, we examined a direct C−H arylation of 1-substituted
triazoles to develop a benchtop procedure using air-stable
phosphonium salts (Table 1). Screening experiments found
that DMA, typically employed for C−H arylation of azoles, was
not suitable for the reaction of 1,2,4-triazole in the presence of
air-stable phosphonium salts (entry 1). In toluene, however, a
weak base, such as pivalate, generated in situ by the addition of
a catalytic amount of pivalic acid and a stoichiometric amount
of potassium carbonate, was sufficient for the C-5 arylation of
1,2,4-triazoles (entry 2). The presence of the carboxylic acid
cocatalyst was essential to achieve efficiency (entry 3).5a,c,14 As
a ligand, [P(n-Bu)Ad2H]BF4 was superior to the corresponding
tricyclohexylphosphonium salt (entry 4). Consistent with our
previous report showing the importance of the steric bulk of
carboxylate base,5h bulkier and more soluble carboxylic acid
cocatalysts proved to be more efficient than pivalic acid
During our study on the Pd-catalyzed C−H arylation of
imidazoles, we observed that in the presence of a strong base
(NaO-t-Bu), the C-2 position of imidazoles is preferred over
the C-5 (Figure 1A).5g We also observed that in the arylation of
pyridines, the presence of electron-withdrawing groups
markedly increases the reactivity of the heteroarene ring
(Figure 1B).5h These results together suggest that 1,2,4-
triazoles, electron-deficient due to the presence of an additional
nitrogen atom (in comparison to imidazoles), should be
arylated at the C-5 position of 1H-triazoles and both C-3 and
C-5 of 4H-triazoles, even possibly in the presence of a weak base
(Figure 1C). Presumably, the deprotonation is facilitated by
complexation of the palladium complex to the N-4 nitrogen of
1H-triazoles and the N-1 (or N-2) of 4H-triazoles. In contrast,
a palladation at the C-3 of 1H-triazoles is disfavored due to
electronic repulsion between the C−Pd bond and nitrogen lone
pairs.5g,h Although catalytic C−H arylations of 1,2,4-triazoles
Received: October 9, 2012
© XXXX American Chemical Society
A
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Note
a c
−
Table 1. C−H Arylation of 1-Alkyl-1,2,4-triazoles
entry
R
X
ligand
base
solvent
2 (%)
1
2
3
4
5
6
7
8
SEM
SEM
SEM
SEM
SEM
SEM
Me
Br
Br
Br
Br
Br
Br
Br
Cl
I
[PCy3H]BF4
K2CO3/Me3CCO2H
K2CO3/Me3CCO2H
K2CO3
DMA
2a, 10
2a, 74
2a, 20
2a, 90
2a, 92
2a, 96
2b, 92
2b, 83
2b, 70
2c, 82
2d, 40
2d, 90
2d, 9
[PCy3H]BF4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMA
[PCy3H]BF4
[P(n-Bu)Ad2H]BF4
[P(n-Bu)Ad2H]BF4
[P(n-Bu)Ad2H]BF4
[P(n-Bu)Ad2H]BF4
[P(n-Bu)Ad2H]BF4
Pd(PPh3)2Cl2
[P(n-Bu)Ad2H]BF4
[P(n-Bu)Ad2H]BF4
P(n-Bu)Ad2
K2CO3/Me3CCO2H
K2CO3/EtMe2CCO2H
K2CO3/n-BuMe2CCO2H
K2CO3/EtMe2CCO2H
K2CO3/EtMe2CCO2H
Ag2CO3
Me
d
9
Me
10
11
Ph
Br
Br
Br
Br
Br
Br
Br
Br
K2CO3/EtMe2CCO2H
K2CO3/EtMe2CCO2H
NaOt-Bu
toluene
toluene
toluene
toluene
DMA
THP
THP
THP
SEM
THP
SEM
THP
e
12
e
13
[P(n-Bu)Ad2H]BF4
none
NaOt-Bu
14
15
16
17
K2CO3/Me3CCO2H
K2CO3/Me3CCO2H
K2CO3/Me3CCO2H
K2CO3/Me3CCO2H
2a, 0
none
DMA
2d, 0
none
toluene
toluene
2a, 0
none
2d, 0
a
b
1
All reactions were performed on a 0.5 mmol scale. Yield was determined by H NMR analysis of the crude product using (CHCl2)2 as internal
c
standard except entries 5, 7, 10, and 12 where yields of isolated products are reported. Reaction conditions unless otherwise noted: 1.5 equiv of
PhX, 5 mol % of Pd(OAc)2, 10 mol % of ligand, 3.0 equiv of K2CO3, 0.3 equiv of carboxylic acid, solvent (1.0 M), 120 °C, 16−20 h. Reaction
conditions: 1.5 equiv of PhI, 5 mol % of Pd(PPh3)2Cl2, 2.0 equiv of Ag2CO3, DMA (1.0 M), 120 °C, 18 h. Reaction conditions: 1.5 equiv of PhBr, 5
d
e
mol % of Pd(OAc)2, 7.5 mol % of P(n-Bu)Ad2, 2.0 equiv of NaOt-Bu, toluene (1.0 M), 100 °C, 2 h.
although the benefit was modest (entries 5 and 6). Hence,
readily available, inexpensive pivalic acid was used for the
examination of the substrate scope. Both bromobenzene and
chlorobenzene were competent haloarene donors for the
coupling of 1-methyltriazole (entries 7 and 8). While
iodobenzene did not perform well under the standard
conditions, a less activated catalytic system derived from
Pd(PPh3)2Cl2 and Ag2CO3 furnished the arylated product in
70% yield (entry 9). Not only 1-methyltriazole but also 1-
phenyltriazole can be transformed to the arylated product in
high yield (entry 10). We also investigated the bulkier, and thus
less reactive tetrahydropyranyl protecting group (THP), which
offers advantages over the SEM group in terms of cost and
Figure 2. Bromoarene scope.
deprotection strategy. The benchtop procedure gave the
desired product in moderate yield (entry 11), whereas the
conditions developed for the C2-arylation of imidazoles5g were
very efficient, leading to the formation of 2d in 90% yield after
heating at 100 °C for only 2 h (entry 12). In this protocol
based on NaO-t-Bu, the generation of the active Pd catalyst
from phosphonium salts was not practical (entry 13). It is also
notable that phosphine-free conditions were not effective for
this process, illustrating the importance of the generation of a
phosphine-ligated palladium complex in the arylation of
electron-deficient heterocycles (entries 14−17).5h
azoles and pyridines5f−h (see Figure 1). This regioselectivity
rationale for C−H arylation of azoles and azines, based on the
stability of the developing C−Pd bond, was recently supported
by an independent theoretical study.16 In order to address the
low reactivity of the C-3 position, we examined the SEM switch
in the context of 1,2,4-triazoles (Scheme 1). Similar to the SEM
switch of diazoles,5f,g the SEM group can be transposed from
N-1 to N-2 nitrogen in the presence of a catalytic amount of
SEM-Cl. While N-4 nitrogen is more nucleophilic than N-2, the
formation of a series of triazolium intermediates ultimately
leads to the isolation of the least sterically hindered 3-
aryltriazole 3a as a consequence of thermodynamic control (for
kinetic alkylation, vide infra). The alkylation at N-2, if it occurs,
also results in the formation of 3a via a 1,2-dialkyltriazolium
salt. Through this process, the unreactive C-3 position is
converted to the reactive C-5 position, where the second
arylation can take place to provide diaryltriazole 4a. Note that
The scope of haloarene donors was tested, revealing that
both electron-rich and electron-deficient aryl bromides can be
coupled with 1-SEM-1,2,4-triazoles (Figure 2). A variety of
functional groups, including methoxy, dimethylamino, ester,
and pyridyl groups, were tolerated.
However, the C-3 position of 1,2,4-triazoles shows very low
reactivity in the Pd-catalyzed reaction conditions,15 which is
consistent with the electronic argument we proposed for other
B
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Note
Scheme 1. SEM Switch
Scheme 3. trans-N-Alkylation and Arylation of a 4H-Triazole
more nucleophilic N-4 nitrogen to give the corresponding
triazolium salts 6, from which 4-alkyl-4H-triazole 7 can be
obtained by cleavage of the protecting groups.
The arylation of 4-alkyltriazoles presents a serious
challenge.18,19 Nonetheless, our protocol can be used for the
arylation of 4H-triazoles, giving diaryltriazole 8 in 71% yield.
This result represents the first catalytic C−H arylation of 4-
alkyl-4H-triazoles.
In conclusion, we have developed a new approach for the
synthesis of complex aryl 1,2,4-triazoles. Complementary to
cyclization methods and catalytic N-arylation reactions, the
direct C−H arylation of the 1,2,4-triazole ring provides rapid
access to a variety of arylated products. It is the electronic
character of the C−H bonds and triazole ring that allows for
the regioselective C-5 arylation under practical laboratory
conditions. It is also demonstrated that the protocol is quite
general and applicable to not only 1-alkyltriazoles but also
regioisomeric 4-alkyltriazoles. While the trans-N-alkylation was
limited to the preparation of 4-methyl-triazoles, our approach
based on direct C−H arylation enables the preparation of both
isomeric series of mono- and diarylated 1,2,4-triazoles.
the SEM group of the triazole can be easily removed under
mild acidic conditions.
Importantly, it was also found that the THP counterpart 2d
underwent a THP-switch to shift the THP group in a highly
efficient and regioselective manner (Scheme 2).17 The loss of
Scheme 2. THP Switch
EXPERIMENTAL SECTION
■
The arylation reaction was carried out in a capped glass vial (4 mL)
equipped with a magnetic stir bar and a Teflon-lined cap and heated in
a 34-well reaction block. All reagents were used as received unless
otherwise noted. Flash column chromatography was performed on
silica gel (40−63 μm) using the indicated solvent system. Nuclear
magnetic resonance spectra were recorded at 300 K on 300 or 400
Fourier transform NMR spectrometers in CDCl3 or DMSO. Proton
chemical shifts are expressed in parts per million (ppm, δ scale) and
are referenced to residual protium in the NMR solvent (CDCl3, δ
1
7.26; DMSO, δ 2.50). Data for H NMR are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet and/or multiple resonances, br = broad),
coupling constant (J) in Hertz, and integration. Carbon chemical shifts
are expressed in parts per million (ppm, δ scale) and are referenced to
the carbon resonance of the NMR solvent (CDCl3, δ 77.0; DMSO, δ
40.0). Infrared (IR) spectra were reported in frequency of the
absorption (cm−1). High-resolution mass spectra (HRMS) were
acquired on a high-resolution sector-type double-focusing mass
spectrometer (ionization mode: FAB or EI).
the THP group and reinstallation at the least hindered N-2
position produced 3-aryltriazole 3d. A subsequent C-5 arylation
and removal of the THP group at ambient temperature
provided (NH)-free triazole 5 in high yield.
Furthermore, the resulting 1-SEM- and 1-THP-5-aryltria-
zoles, 2a and 2d, can be employed for trans-N-alkylation to
furnish regioisomeric 4-methyl-4H-triazole 7 (Scheme 3).
Under kinetic control, the alkylation occurs selectively at the
1-Phenyl-1H-1,2,4-triazole (1c),20 1-methyl-5-phenyl-1H-1,2,4-tria-
zole (2b),10c 1-phenyl-5-phenyl-1H-1,2,4-triazole (2c),21 and 4-
methyl-3-phenyl-4H-1,2,4-triazole (7)22 are known compounds.
C−H Arylation of 1,2,4-Triazoles Using K2CO3 and Carbox-
ylic Acid on the Benchtop (Table 1, Figure 2, and Scheme 1).
To a 4 mL glass vial equipped with a magnetic stir bar were
sequentially added carboxylic acid (0.15 mmol), K2CO3 (207 mg, 1.5
mmol), triazole substrate (0.5 mmol), aryl halide (0.75 mmol), toluene
C
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Note
(0.5 mL, 1 M), Pd(OAc)2 (5.6 mg, 0.025 mmol), and [P(n-
Bu)Ad2H]BF4 (22.3 mg, 0.05 mmol). The reaction mixture was
100.0 mmol) and p-toluenesulfonic acid (951 mg, 5.0 mmol). Then
the reaction mixture was heated to 70 °C. After being stirred for 2 h at
70 °C, the reaction mixture was cooled to 25 °C and then washed with
saturated aqueous NaHCO3 solution (20 mL). The organic layer was
collected, and the aqueous layer was extracted with EtOAc (20 mL ×
3). The combined organic layers were dried over sodium sulfate and
filtered. The filtrate was concentrated, and the residue was purified by
flash column chromatography (EtOAc) to provide 1d as a colorless oil
(6.89 g, 90% yield): IR (film) 2947, 1506, 1276, 1046 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.26 (s, 1H), 7.93 (s, 1H), 5.45 (dd, J = 8.5, 3.5
Hz, 1H), 4.07−4.01 (m, 1H), 3.76−3.60 (m, 1H), 2.16−1.89 (m, 3H),
1.77−1.52 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 151.6, 141.9,
85.9, 67.5, 30.4, 24.7, 21.7; HRMS (FAB) calcd for C7H12N3O [M +
H]+ 154.0980, found 154.0982.
5-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole
(2a). Purification by flash column chromatography (hexanes/EtOAc =
8:2) provided 2a as a yellow oil (127 mg, 92% yield): IR (film) 2952,
1461, 1249, 1093 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H),
7.94−7.90 (m, 2H), 7.54−7.48 (m, 3H), 5.51 (s, 2H), 3.84−3.74 (m,
2H), 1.02−0.92 (m, 2H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 155.8, 150.7, 130.4, 129.0, 128.9, 127.5, 77.2, 67.4, 17.9, −1.5;
HRMS (FAB) calcd for C14H22N3OSi [M + H]+ 276.1532, found
276.1522.
5g
purged with argon through a Teflon-lined cap. Then the cap was
replaced with a new Teflon-lined solid cap. The reaction vial was
moved to a preheated reaction block (120 °C). After being stirred for
18 h at 120 °C, the reaction mixture was cooled to 25 °C and
concentrated. The residue was purified by flash column chromatog-
raphy to provide the desired arylated product.
C−H Arylation of 1-THP-1H-1,2,4-triazoles Using NaO-t-Bu
in the Glovebox (Table 1, Entry 12, and Scheme 2). To a 4 mL
glass vial equipped with a magnetic stir bar were sequentially added
triazole substrate (0.5 mmol), aryl halide (0.75 mmol), and toluene
(0.5 mL, 1 M). The reaction mixture was purged with argon through a
Teflon-lined cap. Then the reaction vial was moved to a glovebox.
Pd(OAc)2 (5.6 mg, 0.025 mmol), P(n-Bu)Ad2 (13.4 mg, 0.038 mmol),
and NaO-t-Bu (96 mg, 1.0 mmol), which were stored under argon in
the glovebox, were added to the reaction mixture. The cap was
replaced with a new Teflon-lined solid cap. The reaction vial was
removed from the glovebox and then moved to a preheated reaction
block (100 °C). After being stirred for 2 h at 100 °C, the reaction
mixture was cooled to 25 °C and concentrated. The residue was
purified by flash column chromatography to provide the desired
arylated product.
C−H Arylation of 4-Alkyl-4H-1,2,4-triazole Using K2CO3 and
Pivalic Acid in the Glovebox (Scheme 3). To a 4 mL glass vial
equipped with a magnetic stir bar were sequentially added pivalic acid
(15.3 mg, 0.15 mmol), K2CO3 (207 mg, 1.5 mmol), triazole substrate
(0.5 mmol), aryl halide (0.75 mmol), and toluene (0.5 mL, 1 M). The
reaction mixture was purged with argon through a Teflon-lined cap.
Then the reaction vial was moved to a glovebox. Pd(OAc)2 (5.6 mg,
0.025 mmol) and P(n-Bu)Ad2 (13.4 mg, 0.038 mmol), which were
stored under argon in the glovebox, were added to the reaction
mixture. The cap was replaced with a new Teflon-lined solid cap. The
reaction vial was removed from the glovebox and then moved to a
preheated reaction block (100 °C). After being stirred for 18 h at 100
°C, the reaction mixture was cooled to 25 °C and concentrated. The
residue was purified by flash column chromatography to provide the
desired arylated product.
trans-N-Alkylation (Scheme 3). To a stirred solution of 2a or 2d
(1.0 mmol) in CH2Cl2 (2 mL) at 25 °C was added trimethyloxonium
tetrafluoroborate (1.5 mmol). Then the reaction mixture was stirred at
25 °C until the starting material was completely consumed (∼2 h).
Then HCl in EtOH (1 N, 2 mL) was added to the reaction mixture.
After being stirred for 3 h at 25 °C, the reaction mixture was
neutralized with saturated aqueous Na2CO3 solution (10 mL). The
organic layer was collected, and the aqueous layer was extracted with
EtOAc (10 mL × 3). The combined organic layers were dried over
sodium sulfate and filtered. The filtrate was concentrated, and the
residue was purified by flash column chromatography to provide the
product 7.
5-Phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (2d). Pu-
rification by flash column chromatography (hexanes/EtOAc = 7:3)
provided 2d as a colorless oil (103 mg, 90% yield): IR (film) 2943,
1
1455, 1043 cm−1; H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.76
(dd, J = 6.5, 2.8 Hz, 2H), 7.55−7.48 (m, 3H), 5.34 (dd, J = 9.8, 2.4 Hz,
1H), 4.21−4.11 (m, 1H), 3.67 (td, J = 11.4, 2.1 Hz, 1H), 2.50 (qd, J =
13.6, 4.2 Hz, 1H), 2.17−2.05 (m, 1H), 1.93−1.83 (m, 1H), 1.82−1.72
(m, 1H), 1.66−1.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 155.5,
150.9, 130.3, 129.0, 128.8, 127.9, 83.9, 67.6, 29.6, 24.7, 22.4; HRMS
(EI) calcd for C13H16N3O [M + H]+ 230.1293, found 230.1304.
5-(4-Methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-
1,2,4-triazole (2e). Purification by flash column chromatography
(hexanes/EtOAc=6:4) provided 2e as a colorless oil (107 mg, 70%
1
yield): IR (film) 2953, 1613, 1492, 1252 cm−1; H NMR (400 MHz,
CDCl3) δ 7.90 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz,
2H), 5.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, J = 8.3 Hz, 2H), 0.97 (t, J =
8.3 Hz, 2H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.3,
155.7, 150.6, 130.5, 120.0, 114.3, 77.2, 67.3, 55.3, 17.9, −1.5; HRMS
(EI) calcd for C15H24N3O2Si [M + H]+ 306.1638, found 306.1648.
N,N-Dimethyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-tri-
azol-5-yl)aniline (2f). Purification by flash column chromatography
(hexanes/EtOAc = 6:4) provided 2f as a colorless oil (126 mg, 79%
1
yield): IR (film) 2952, 1606, 1492, 1278 cm−1; H NMR (400 MHz,
CDCl3) δ 7.97 (s, 1H), 7.41−7.32 (m, 1H), 7.30−7.26 (m, 1H),
7.25−7.22 (m, 1H), 6.87 (dd, J = 8.3, 2.5 Hz, 1H), 5.54 (s, 2H), 3.82
(t, J = 8.3 Hz, 2H), 3.02 (s, 6H), 0.99 (t, J = 8.3 Hz, 2H), 0.03 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 156.7, 150.6, 129.5, 128.1, 116.7,
1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (1a).23 To a
stirred solution of 1,2,4-triazole (1.39 g, 20.0 mmol) in THF (20.0 mL,
1.0 M) at 25 °C under argon atmosphere were sequentially added
NaH (60% in mineral oil, 800 mg, 20.0 mmol) and SEMCl (3.54 mL,
20.0 mmol). After being stirred for 16 h at 25 °C, the reaction mixture
was quenched with water (5 mL) and transferred to a 125 mL
separatory funnel that contained water (10 mL) and brine (10 mL).
The organic layer was collected, and the aqueous layer was extracted
with EtOAc (25 mL × 3). The combined organic layers were dried
over sodium sulfate and filtered. The filtrate was concentrated, and the
residue was purified by flash column chromatography (hexanes/EtOAc
= 1:1) to provide 1a as a colorless oil (2.74 g, 68% yield): IR (film)
2954, 1508, 1272, 1103 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.23 (s,
1H), 7.95 (s, 1H), 5.49 (s, 2H), 3.65−3.55 (m, 2H), 0.94−0.85 (m,
2H), −0.03 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 152.0, 143.6,
77.7, 67.5, 17.7, −1.5; HRMS (FAB) calcd for C8H18N3OSi [M + H]+
200.1219, found 200.1209.
114.2, 112.8, 77.2, 67.2, 40.4, 17.9, −1.5; HRMS (FAB) calcd for
C16H26N4OSi [M]+ 318.1876, found 318.1874.
Ethyl 3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-
yl)benzoate (2g). Purification by flash column chromatography
(hexanes/EtOAc = 6:4) provided 2g as a colorless oil (120 mg, 69%
1
yield): IR (film) 2953, 1722, 1247, 1108 cm−1; H NMR (400 MHz,
CDCl3) δ 8.61 (s, 1H), 8.19 (d, J = 7.1 Hz, 1H), 8.12 (d, J = 7.0 Hz,
1H), 7.98 (s, 1H), 7.63−7.57 (m, 1H), 5.51 (s, 2H), 4.41 (q, J = 7.2
Hz, 2H), 3.80 (t, J = 8.0 Hz, 2H), 1.40 (t, J = 7.4 Hz, 3H), 0.99 (t, J =
8.0 Hz, 2H), 0.00 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 165.8,
155.0, 150.8, 133.0, 131.4, 130.1, 129.0, 127.9, 77.3, 67.5, 61.3, 17.9,
14.3, −1.5; HRMS (EI) calcd for C17H26N3O3Si [M + H]+ 348.1743,
found 348.1736.
3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-
pyridine (2h). Purification by flash column chromatography (DCM)
provided 2h as a colorless oil (106 mg, 77% yield): IR (film) 2953,
1413, 1249, 1093 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H),
8.72 (d, J = 4.7 Hz, 1H), 8.27−8.21 (m, 1H), 7.97 (s, 1H), 7.43 (dd, J
= 7.9, 4.9 Hz, 1H), 5.50 (s, 2H), 3.77 (t, J = 8.2 Hz, 2H), 0.95 (t, J =
8.2 Hz, 2H), 0.02 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.1,
1-(Tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (1d). To a stirred
solution of 1,2,4-triazole (3.45 g, 50.0 mmol) in THF (25.0 mL, 2.0
M) at 25 °C were sequentially added 3,4-dihydro-2H-pyran (9.0 mL,
D
dx.doi.org/10.1021/jo3021677 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
151.2, 151.0, 149.6, 136.1, 123.8, 123.5, 77.3, 67.6, 17.8, −1.5; HRMS
(FAB) calcd for C13H21N4OSi [M + H]+ 277.1485, found 277.1474.
3-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole
(3a). To a 4 mL glass vial equipped with a magnetic stir bar were
sequentially added 2a (414 mg, 1.5 mmol), SEMCl (0.075 mmol), and
CH3CN (1.5 mL). Then the reaction mixture was heated to 80 °C.
After being stirred for 20 h at 80 °C, the reaction mixture was cooled
to 25 °C and concentrated. The residue was purified by flash column
chromatography (hexanes/EtOAc = 8:2) to provide 3a as an
amorphous white solid (394 mg, 95% yield): IR (film) 2953, 1496,
160.1, 130.6, 130.1, 129.4, 126.5, 118.9, 115.9, 111.6, 55.7; HRMS
(FAB) calcd for C15H14N3O [M + H]+ 252.1137, found 252.1143.
3-(4-Methoxyphenyl)-4-methyl-5-phenyl-4H-1,2,4-triazole (8).24
Purification by flash column chromatography (EtOAc/MeOH =
97:3) provided 8 as a white solid (94 mg, 71% yield): mp 205−208
1
°C; IR (film) 1614, 1482, 1255, 1028 cm−1; H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 4.6 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.52−7.46
(m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 3.85 (s, 3H), 3.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.0, 155.6, 155.6, 130.4, 130.0, 128.8,
127.0, 119.0, 114.3, 55.4, 33.3; HRMS (FAB) calcd for C16H16N3O [M
+ H]+ 266.1293, found 266.1290.
1
1249, 1103 cm−1; H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.13
(dd, J = 8.2, 1.5 Hz, 2H), 7.47−7.38 (m, 3H), 5.52 (s, 2H), 3.69 (t, J =
8.2 Hz, 2H), 0.95 (t, J = 8.2 Hz, 2H), −0.01 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 162.8, 144.4, 130.7, 129.4, 128.6, 126.4, 77.8, 67.5,
17.7, −1.5; HRMS (FAB) calcd for C14H22N3OSi [M + H]+ 276.1532,
found 276.1525.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
3-Phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (3d). To
a 4 mL glass vial equipped with a magnetic stir bar were sequentially
added 2d (345 mg, 1.5 mmol), 3,4-dihydro-2H-pyran (3.0 mmol), p-
toluenesulfonic acid (0.15 mmol), and THF (1.5 mL). Then the
reaction mixture was heated to 70 °C. After being stirred for 2 h at 70
°C, the reaction mixture was cooled to 25 °C, diluted with THF (10
mL), and then washed with saturated aqueous NaHCO3 solution (10
mL). The organic layer was collected, and the aqueous layer was
extracted with EtOAc (10 mL × 3). The combined organic layers were
dried over sodium sulfate and filtered. The filtrate was concentrated,
and the residue was purified by flash column chromatography
(hexanes/EtOAc = 6:4) to provide 3d as a white solid (327 mg,
95% yield): mp 52−56 °C; IR (film) 2944, 1494, 1441, 1043 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.28 (d, J = 3.3 Hz, 1H), 8.16−8.08 (m,
2H), 7.47−7.34 (m, 3H), 5.52−5.45 (m, 1H), 4.14−4.05 (m, 1H),
3.78−3.67 (m, 1H), 2.20−2.10 (m, 2H), 2.09−1.95 (m, 1H), 1.77−
1.58 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 142.7, 130.9,
129.2, 128.5, 126.4, 86.0, 67.6, 30.5, 24.7, 21.8; HRMS (EI) calcd for
C13H16N3O [M + H]+ 230.1293, found 230.1295.
5-(3-Methoxyphenyl)-3-phenyl-1-((2-(trimethylsilyl)ethoxy)-
methyl)-1H-1,2,4-triazole (4a). Purification by flash column chroma-
tography (DCM) provided 4a as a white solid (124 mg, 65% yield):
mp 79−82 °C; IR (film) 2953, 1609, 1516, 1091 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.23−8.16 (m, 2H), 7.57−7.52 (m, 2H), 7.50−7.38
(m, 4H), 7.09−7.04 (m, 1H), 5.54 (s, 2H), 3.91−3.84 (m, 2H), 3.89
(s, 3H), 1.01 (t, J = 8.2 Hz, 2H), 0.02 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 161.1, 159.8, 156.6, 130.9, 129.9, 129.3, 128.9, 128.5, 126.5,
121.3, 116.7, 114.0, 77.2, 67.3, 55.4, 17.9, −1.4; HRMS (FAB) calcd
for C21H28N3O2Si [M + H]+ 382.1951, found 382.1966.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sames@chem.columbia.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institute of General Medical Sciences
(GM60326) and the National Institute of Mental Health
(MH086545) for support of this work.
REFERENCES
■
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(144 mg, 86% yield): IR (film) 2941, 1605, 1485, 1043 cm−1; H
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7.07 (ddd, J = 7.7, 2.5, 1.8 Hz, 1H), 5.38 (dd, J = 9.7, 2.7 Hz, 1H),
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1.75 (m, 1H), 1.69−1.55 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
161.2, 159.8, 156.2, 131.0, 129.9, 129.1, 128.3, 126.6, 121.3, 116.6,
114.0, 84.0, 67.6, 55.3, 29.6, 24.7, 22.4; HRMS (FAB) calcd for
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2074, 1462, 1117 cm−1; H NMR (400 MHz, DMSO) δ 8.10 (d, J =
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E
dx.doi.org/10.1021/jo3021677 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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