Efficient one-pot synthesis of 1-aryl 1,2,3-triazoles from aryl halides and terminal alkynes in the presence of sodium azide

Article abstract of DOI:10.1055/s-2005-921887

An efficient one-pot synthesis of 1-aryl 1,2,3-triazoles from aryl bromides/iodides and terminal alkynes in the presence of sodium azide is described. In the case of aryl iodides, the reactions proceeded at room temperature. The reactions normally gave hi

Full text of DOI:10.1055/s-2005-921887

LETTER
2941
Efficient One-Pot Synthesis of 1-Aryl 1,2,3-Triazoles from Aryl Halides and
Terminal Alkynes in the Presence of Sodium Azide
One-Pot
S
a
ynthesis of
c
1-Aryl 1, 2,
o
3-Triazoles b Andersen,a Simon Bolvig,b Xifu Liang*a
d
Department of Medicinal Chemistry, LEO Pharma, Industriparken 55, 2750 Ballerup, Denmark
Fax +45(7226)3320; E-mail: xifu.liang@leo-pharma.com
e
Department of Spectroscopy and Physical Chemistry, LEO Pharma, Industriparken 55, 2750 Ballerup, Denmark
Received 1 September 2005
1,3-dipolar addition between aryl azides and terminal
alkynes. The reaction between 4-azido-2-methylaniline
and ethynylbenzene was chosen as a prototype reaction
(Figure 1). The reactions were performed with 4-azido-2-
methylaniline (1 equiv), ethynylbenzene (1 equiv), CuI
(0.1 equiv), sodium ascorbate, and ligand A (trans-N,N¢-
dimethyl-1,2-cyclohexanediamine) at room temperature
under an argon atmosphere. The conversions were deter-
Abstract: An efficient one-pot synthesis of 1-aryl 1,2,3-triazoles
from aryl bromides/iodides and terminal alkynes in the presence of
sodium azide is described. In the case of aryl iodides, the reactions
proceeded at room temperature. The reactions normally gave high
yields.
Key words: 1,2,3-triazoles, one-pot, copper, 1,3-dipolar cycloaddi-
tion, catalyst
1
mined by H NMR after quenching the reactions at
various times.
1,2,3-Triazoles have found widespread use in pharmaceu-
ticals and agrochemicals.1 The discovery2 of Cu(I)-cata-
lyzed 1,3-dipolar cycloaddition of azides and terminal
alkynes has further triggered the use of 1,2,3-triazoles in
bioconjungation, drug discovery,3 materials science4 and
combinatorial chemistry.5
In one of our ongoing medicinal chemistry projects, we
need a convenient and efficient method for the preparation
of 1-aryl 1,2,3-triazoles. Recently, for concerns about the
safety of working with low molecular weight organic
azides and convenience, several groups have developed
one-pot procedures to prepare 1,2,3-triazoles from in situ
generated organic azides and terminal alkynes.6 One such
method,6c developed by Fokin et al, for the preparation of
1-aryl 1,2,3-triazoles from the aryl iodides, sodium azide,
and terminal alkynes, attracted our attention. In this meth-
od, the Cu(I)-catalyzed azidonation of aryl halides7 and
the 1,3-dipolar cycloaddition between aryl azides and
alkynes were elegantly combined into a one-pot proce-
dure, which tolerates a wide variety of functional groups.
The method, however, suffers even at 65 °C from long
reaction times, supposedly due to the slow azidonation of
aryl iodide. Moreover, it is limited to the use of the aryl
iodides. This is unfortunate because many more aryl
bromides are commercially available. We have published
an efficient method for the preparation of aryl azides from
the corresponding aryl halides.8 We felt that our method
could further be developed into an efficient one-pot pro-
cedure to prepare 1-aryl 1,2,3-triazoles from aryl halides
via in situ formation of aryl azides. Herein, we report this
one-pot synthesis of 1-aryl 1,2,3-triazoles.
Figure 1 The effect of sodium ascorbate and ligand A on the Cu(I)-
catalyzed 1,3-dipolar cycloaddition
No conversion was observed within 90 minutes in the
absence of CuI, suggesting that Cu(I) is essential for this
transformation. As shown in Figure 1, an increase in the
amount of sodium ascorbate from 10 mol% to 15 mol%
caused a slight decrease in the reaction rate. The same
phenomenon was previously observed by using tris(car-
boxyethyl)phosphine (TCEP) as a reducing agent.9 The
reactions both in the presence and in the absence of ligand
A had more or less the same reaction rate. These results
suggest that ligand A does not have a negative effect on
the reaction. This is important information, because
ligand A plays a crucial role in the azidonation of aryl
halides.8 Note that the reaction conditions for the 1,3-di-
polar cycloaddition are clearly different from the previous
ones that require acetonitrile as co-solvent and at least
one equivalent of a nitrogen base, such as 2,6-lutidine,
To begin with, we examined whether our catalyst system
for azidonation of aryl halides has a catalytic effect on the
SYNLETT 2005, No. 19, pp 2941–2947
0
1
.1
2
.2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-921887; Art ID: D26505ST
© Georg Thieme Verlag Stuttgart · New York

2942
J. Andersen et al.
LETTER
triethylamine, diisopropylethylamine, DBU or pyridine, is quite unstable under reaction conditions. Surprisingly,
when CuI is used as catalyst.2a,10 The reason might be that in contrast to the azidonation, which was sluggish, the re-
complexation with acetonitrile and a base prevents oxida- action proceeded smoothly with 4-iodobenzonitrile
tion of Cu(I) to Cu(II).11 Sodium ascorbate has the same (Table 1, entry 10). The strong electron-withdrawing nitro
stabilizing effect as we observed in the azidonation of aryl group on the aryl iodide was well tolerated (Table 1, entry
halides.
15). Reaction with aryl iodide bearing an amino group in
ortho position was sluggish, indicating that the reaction is
sensitive to sterically hindered aryl halides (Table 1, entry
11). This steric effect was further confirmed by a compar-
ison between azidonation of 2-iodotoluene and 4-iodotol-
uene (Scheme 1). When the 4-iodotoluene was subjected
to the azidonation, the reaction went to completion in 15
minutes, giving 91% yield. In comparison, the azidona-
tion of 2-iodotoluene gave only 63% yield after 150 min-
utes.12 Aryl alkynes bearing both electron-withdrawing
groups, such as trifluoromethyl and nitrile (Table 1, entry
8 and 10), and electron-donating groups, such as ether,
hydroxy and aniline (Table 1, entry 5, 11 and 15) under-
went the 1,3-dipolar cycloaddition.
Since our previous8 and present results clearly proved that
the catalytic system is effective for both the azidonation
and the 1,3-dipolar cycloaddition, a two-step one-pot
preparation of 1-aryl 1,2,3-triazoles from the correspond-
ing aryl halides seemed to be possible. The following one-
pot experiments were carried out with an aryl iodide (1
equiv), a terminal alkyne (1 equiv), NaN3 (1 equiv), CuI
(0.1 equiv), sodium ascorbate (0.1 equiv), and ligand A
(0.15 equiv) in DMSO–H2O (5:1) at room temperature.
The products were normally obtained by simple filtration.
As can be seen in Table 1, a variety of functional groups
on aryl iodides, as well as on terminal alkynes were toler-
ated in this one-pot reaction. But, entry 3 is a noticeable
exception. In this reaction, not only the desired product
(38%), but also a by-product, 4-unsubstituted compound,
was obtained. This indicates that the trimethylsilyl group
Table 1 1-Aryl 1,2,3-Triazoles from Aryl Iodides via in situ Generated Aryl Azides
N
N
I
R2
NaN3 (1.05 equiv), CuI (0.1 equiv)
N
R2
R1
+
R1
ligand A (0.15 equiv)
sodium ascorbate (0.1 equiv)
DMSO/H2O 5:1, r.t., Ar
Entry
1
Product
Time (min)
90
Yield (%)a
99
OH
OH
N
N
N
2
90
83
N
N
N
N
EtO2C
EtO2C
3b
overnight
38
76
94
N
Si
N
4
90
90
N
N
N
5
NH2
N
N
N
N
6
90
84
N
N
Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 1-Aryl 1,2,3-Triazoles
2943
Table 1 1-Aryl 1,2,3-Triazoles from Aryl Iodides via in situ Generated Aryl Azides (continued)
N
N
I
R2
NaN3 (1.05 equiv), CuI (0.1 equiv)
N
R2
R1
+
R1
ligand A (0.15 equiv)
sodium ascorbate (0.1 equiv)
DMSO/H2O 5:1, r.t., Ar
Entry
7
Product
Time (min)
90
Yield (%)a
77
N
N
N
N
Br
8
9
90
86
88
88
43
N
N
CF3
N
N
90
N
N
EtO2C
10
11
90
N
N
CN
HO
overnight
OMe
N
N
NH2
N
CO2Me
12
60
90
89
54
N
N
N
NC
13c,d
OMe
N
N
N
HO2C
14
15
90
60
68
97
N
N
N
H2N
OH
N
N
N
O2N
HO
16
60
97
N
N
N
a Isolated yield.
b The procedure is a slight different from the general one-pot procedure for Table 1, because of the volatile ethynyltrimethylsilane (see exper-
imental section).
c NaOH (1 equiv) was used.
d Some product might be lost during work-up.
Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York

2944
J. Andersen et al.
LETTER
I
required 12 hours. Again, a variety of functional groups
were compatible with the reaction. The reactions general-
ly gave good to excellent yields.
N3
R2
NaN3 (2 equiv), CuI (0.1 equiv)
R1
R2
R1
ligand A (0.15 equiv),
sodium ascorbate (0.05 equiv)
DMSO/H2O 5:1, r.t., Ar
We wondered whether this one-pot procedure could be
used for aryl chlorides. As we tried this reaction, we ob-
served that sodium azide and ethynyl benzonitrile under-
went [3+2] cycloaddition and an N-unsubstituted 1,2,3-
triazole instead of a 1-aryl 1,2,3-triazole, was produced,13
suggesting that the reactivity of aryl chlorides were insuf-
ficient for this type of reaction under the present reaction
conditions (Scheme 2).
R1 = H, R2 = Me: 150 min, 63% yield
1 = Me, R2 = H: 15 min, 91% yield
R
Scheme 1 Azidonation of iodotoluenes
The one-pot reaction was also extended to the use of aryl
bromides (Table 2). However, at room temperature, the
reaction turned out to be very slow and needed several
days to be complete. Gratifyingly, as the temperature was
raised to 70 °C, the reactions went to completion within
two hours except for the reaction for entry 1, which
N
N
Cl
N
CN
NaN3 (1.05 equiv),
CuI (0.1 equiv)
+
ligand A (0.15 equiv)
sodium ascorbate
(0.1 equiv)
N
N
CN
HN
Table 2 1-Aryl 1,2,3-Triazoles Prepared from Aryl Bromides via in
situ Generated Aryl Azides
DMSO/H2O 5:1,
100 °C, 5 h, Ar
NC
N
NaN3 (1.05 equiv)
CuI (0.1 equiv)
N
Br
R2
Scheme 2
N
R2
R1
+
R1
ligand A (0.15 equiv)
sodium ascorbate
(0.1 equiv)
In summary, we have developed a mild and efficient one-
pot procedure for the preparation of 1-aryl 1,2,3-triazoles
from the corresponding aryl halides and terminal alkynes
in the presence of sodium azide. This method has some
advantages – fast reaction and low temperature – over the
known method.6c Moreover, aryl bromides can be also
used in this procedure. We found that 10 mol% of sodium
ascorbate can efficiently stabilize the Cu(I) source. Our
method opens a way to conveniently prepare a large array
of 1-aryl 1,2,3-triazoles under mild conditions.
DMSO/H2O 5:1,
70 °C, Ar
Entry Product
Time
(min)
Yield
(%)a
1
overnight 98
NH2
N
N
N
H2N
N
2
120
120
89
89
N
O
General One-Pot Procedure for Table 1
N
Aryl iodide (2 mmol), NaN3 (2.1 mmol), alkyne (2 mmol), sodium
ascorbate (0.2 mmol), CuI (0.2 mmol), ligand A (0.3 mmol), and
DMSO–H2O (5:1, 6 mL) were introduced into a two-necked round-
bottom flask equipped with a stirring bar. After it was degassed, and
then introduced under an argon atmosphere, the reaction mixture
was stirred at r.t. and the progress of the reaction was followed by
TLC. A precipitate was usually formed during the reaction. When
the starting material was completely consumed, or when the
progress of the reaction had stopped, H2O was poured into the crude
mixture, and the obtained mixture was cooled down on an ice bath.
The precipitate was isolated by filtration, washed with H2O, and
dried in vacuo, giving the desired product. In some cases, chroma-
tography was necessary (vide infra).
3
N
N
N
Cl
NC
4
N
120
120
60
74
83
77
N
N
O
5
N
N
N
General One-Pot Procedure for Table 2
Aryl bromide (2 mmol), NaN3 (2.1 mmol), alkyne (2 mmol), sodi-
um ascorbate (0.2 mmol), CuI (0.2 mmol), ligand A (0.3 mmol), and
6 mL DMSO–H2O (5:1) were introduced into a two-necked round-
bottom flask equipped with a stirring bar. After it was degassed, and
then introduced under an argon atmosphere, the reaction mixture
was stirred at 70 °C and the progress of the reaction was followed
by TLC. When the starting material was completely consumed, or
when the progress of the reaction had stopped, H2O was poured into
the crude mixture, and the obtained mixture was cooled down on an
ice bath. The formed precipitate was isolated by filtration, washed
with H2O, and dried in vacuo, to obtain the desired product.
CN
Cl
6b
N
N
N
SiMe3
a Isolated yield.
b The procedure is slightly different from the general one-pot proce-
dure for Table 2, because of the volatile trimethyl(propargyl)silane
(see experimental section).
Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 1-Aryl 1,2,3-Triazoles
2945
4-{1-Phenyl-[1,2,3]triazol-4-yl}butan-1-ol (Table 1, entry 1)
Yield 99%; yellow oil; Rf = 0.23 (PE–EtOAc, 1:3).
1H NMR (300 MHz, CDCl3): d = 7.75 (s, 1 H), 7.71 (dt, J = 7.3, 1.1
Hz, 2 H), 7.50 (tt, J = 7.3, 1.1 Hz, 2 H), 7.41 (tt, J = 7.3, 1.1 Hz, 1
H), 3.70 (t, J = 6.1 Hz, 2 H), 2.84 (t, J = 7.3 Hz, 2 H), 2.11 (br s, 1
H), 1.91–1.79 (m, 2 H), 1.75–1.63 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 149.2, 137.5, 130.1, 128.9,
120.8, 119.4, 62.8, 41.4, 32.5, 25.7.
MS (ES+): m/z (%) = 218 (57) [M + H+], 240 (100) [M + Na+].
4-(4-Butyl-phenyl)-1-phenyl-[1,2,3]triazole (Table 1, entry 6)
Yield 84%; pale yellow solid; mp 118–121 °C; Rf = 0.16 (PE–
EtOAc, 10:1).
1H NMR (300 MHz, DMSO): d = 9.25 (s, 1 H), 7.96 (d, J = 8.0 Hz,
2 H), 7.86 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 2 H), 7.51 (t,
J = 7.3 Hz, 1 H), 7.31 (d, J = 7.3 Hz, 2 H), 2.62 (t, J = 7.6 Hz, 2 H),
1.59 (quin, J = 7.6 Hz, 2 H), 1.32 (hex, J = 7.6 Hz, 2 H), 0.91 (t,
J = 7.6 Hz, 3 H).
13C NMR (75.4 MHz, DMSO): d = 147.4, 142.4, 136.6, 129.8,
128.8, 128.6, 127.7, 125.2, 119.9, 119.1, 34.5, 32.9, 21.7, 13.7.
3-{4-Hydroxymethyl-[1,2,3]triazol-1-yl}benzoic Acid Ethyl
HRMS (EI+): m/z [M+] calcd for C18H19N3: 277.1529; found:
Ester (Table 1, entry 2)
277.1577.
Yield 83%; yellow solid; mp 135–137 °C; Rf = 0.24 (PE–EtOAc,
1:3).
1-Phenyl-4-(4-trifluoromethylphenyl)-[1,2,3]triazole (Table 1,
entry 8)
1H NMR (300 MHz, DMSO): d = 8.82 (s, 1 H), 8.43 (t, J = 1.9 Hz,
1 H), 8.20 (ddd, J = 0.8, 1.9, 8.0 Hz, 1 H), 8.04 (dt, J = 0.8, 8.0 Hz,
1 H), 7.76 (t, J = 8.0 Hz, 1 H), 5.35 (t, J = 5.4 Hz, 1 H), 4.64 (d,
J = 5.4 Hz, 2 H), 4.40 (q, J = 6.9 Hz, 2 H), 1.37 (t, J = 6.9 Hz, 3 H).
13C NMR (75.4 MHz, DMSO): d = 169.7, 149.7, 136.9, 131.5,
130.5, 128.8, 124.3, 121.2, 120.0, 61.2, 54.9, 14.0.
Yield 86%; pale yellow solid; mp 224–228 °C; Rf = 0.14 (PE–
EtOAc, 10:1)
1H NMR (300 MHz, DMSO): d = 9.49 (s, 1 H), 8.18 (d, J = 8.0 Hz,
2 H), 7.97 (dd, J = 7.3, 1.2 Hz, 2 H), 7.88 (d, J = 8.0 Hz, 2 H), 7.66
(t, J = 7.3 Hz, 2 H), 7.54 (tt, J = 7.3, 1.2 Hz, 1 H).
13C NMR (75.4 MHz, DMSO): d = 145.8, 136.4, 134.2, 133.3,
129.9 (2 C), 128.3 (q, J = 31 Hz), 125.9 (q, J = 3 Hz, 2 C), 125.8 (2
C), 124.1 (q, J = 271 Hz), 120.9, 120.1 (2 C).
HRMS (EI+): m/z [M+] calcd for C12H13N3O3: 247.0957; found:
247.0965.
3-{4-Trimethylsilanyl-[1,2,3]triazol-1-yl}benzoic Acid Ethyl
Ester (Table 1, entry 3) and 3-[1,2,3]triazol-1-yl-benzoic Acid
Ethyl Ester (By-product)
HRMS (EI+): m/z [M+] calcd for C15H10F3N3: 289.0827; found:
289.0830.
Ethyl 3-iodobenzoate (552 mg, 2.0 mmol), ligand A (43 mg, 0.3
mmol), sodium ascorbate (40 mg, 0.2 mmol), and NaN3 (130 mg,
2.0 mmol) were taken up in DMSO–H2O (5:1, 6 mL) and degassed
with argon. Then, CuI (39 mg, 0.2 mmol) and ethynyltrimethylsi-
lane (295 mg, 3 mmol) were added at r.t. The reaction solution was
stirred at the same temperature under an argon atmosphere over-
night. Then the solution was poured into H2O and extracted with
EtOAc. The combined organic phases were concentrated in vacuo
together with silica gel. The residue was purified by chromatogra-
phy (PE–EtOAc, 4:1 → EtOAc), giving a desired compound as a
colorless oil (220 mg, 38%) and a by-product as a white solid (70
mg, 16%).
4-{1-(4-Hydroxymethylphenyl)-[1,2,3]triazol-4-yl}benzonitrile
(Table 1, entry 10)
Yield 88%; orange solid; mp 222–224 °C; Rf = 0.04 (PE–EtOAc,
3:1).
1H NMR (300 MHz, DMSO): d = 9.47 (s, 1 H), 8.14 (d, J = 8.8 Hz,
2 H), 7.98 (d, J = 8.4 Hz, 2 H) 7.90 (d, J = 8.4 Hz, 2 H), 7.57 (d,
J = 8.8 Hz, 2 H), 5.37 (t, J = 5.4 Hz, 1 H), 4.60 (d, J = 5.4 Hz, 1 H).
13C NMR (75.4 MHz, DMSO): d = 146.0, 144.0, 139.2, 135.4,
133.4, 128.0, 126.2, 121.7, 120.3, 119.1, 110.8, 62.6.
HRMS (EI+): m/z [M+] calcd for C16H12N4O: 276.1011; found:
276.1031.
Data for the desired compound:
4-Amino-3-{4-(3-methoxyphenyl)-[1,2,3]triazol-1-yl}benzoic
Acid Methyl Ester (Table 1, entry 11)
Purified by flash chromatography (PE–EtOAc, 10:1 → 3:1).
Rf = 0.64 (PE–EtOAc, 1:1).
1H NMR (300 MHz, DMSO): d = 8.33 (t, J = 1.9 Hz, 1 H), 8.10 (dt,
J = 1.5, 7.6 Hz, 1 H), 8.04 (ddd, J = 1.0, 3.3, 8.0 Hz, 1 H), 8.02 (s,
1 H), 7.61 (t, J = 8.0 Hz, 1 H), 4.44 (q, J = 7.2 Hz, 2 H), 1.43 (t,
J = 7.2 Hz, 3 H), 0.40 (s, 9 H).
13C NMR (75.4 MHz, DMSO): d = 165.4, 147.8, 137.2, 132.2,
129.9, 129.4, 127.1, 125.1, 121.3, 61.6, 14.3, –1.1.
Yield 43%; off-white solid; mp 128–130 °C; Rf = 0.11 (PE–EtOAc,
1:3).
1H NMR (300 MHz, CDCl3): d = 8.15 (s, 1 H), 8.00 (d, J = 1.9 Hz,
1 H), 7.90 (dd, J = 8.4, 1.9 Hz, 1 H), 7.51 (t, J = 2.3 Hz, 1 H), 7.44
(d, J = 7.7 Hz, 1 H), 7.36 (t, J = 7.7 Hz, 1 H), 6.93 (dm, J = 7.6 Hz,
1 H), 6.88 (d, J = 8.4 Hz, 1 H), 5.15 (br s, 2 H), 3.89 (s, 6 H).
HRMS (EI+): m/z [M+] calcd for C14H19N3O2Si: 289.1247; found:
289.1234.
13C NMR (75.4 MHz, CDCl3): d = 166.1, 160.2, 147.7, 144.9,
131.4, 131.2, 130.1, 125.6, 121.8, 120.2, 119.6, 118.3, 116.8, 114.8,
110.9, 55.4, 52.0.
HRMS (EI+): m/z [M+] calcd for C17H16N4O3: 324.1222; found:
324.1187.
Data for the by-product:
Mp 81–83 °C; Rf = 0.50 (PE–EtOAc, 1:1).
1H NMR (300 MHz, DMSO): d = 8.96 (d, J = 1.2 Hz, 1 H), 8.43 (dd,
J = 1.2, 2.3 Hz, 1 H), 8.20 (ddd, J = 1.2, 2.3, 7.7 Hz, 1 H), 8.05 (dt,
J = 1.2, 7.7 Hz, 1 H), 8.01 (d, J = 1.2 Hz, 1 H), 7.76 (t, J = 7.7 Hz,
1 H), 4.37 (q, J = 6.9 Hz, 2 H), 1.35 (t, J = 6.9 Hz, 3 H).
13C NMR (75.4 MHz, DMSO): d = 165.2, 137.3, 135.0, 131.9,
130.9, 129.3, 125.0, 123.8, 120.7, 61.7, 14.5.
4-{4-(4-Butylphenyl)-[1,2,3]triazol-1-yl}benzonitrile (Table 1,
entry 12)
Yield 88%; orange solid; mp 144–149 °C; Rf = 0.37 (PE–EtOAc,
1:3).
1H NMR (300 MHz, DMSO): d = 9.39 (s, 1 H), 8.20 (d, J = 8.6 Hz,
2 H), 8.13 (d, J = 8.6 Hz, 2 H), 7.85 (d, J = 8.0 Hz, 2 H), 7.32 (d,
J = 8.0 Hz, 2 H), 2.62 (t, J = 7.3 Hz, 2 H), 1.59 (quin, J = 7.3 Hz, 2
H), 1.32 (hex, J = 7.3 Hz, 2 H), 0.91 (t, J = 7.3 Hz, 3 H).
HRMS (EI+): m/z [M+] calcd for C11H11N3O2: 217.0851; found:
217.0863.
Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York

2946
J. Andersen et al.
LETTER
5-{4-(3-Aminophenyl)-[1,2,3]triazol-1-yl}-2-methylphenyl-
amine (Table 2, entry 1)
Yield 98%; pale green solid; mp 177–181 °C; Rf = 0.20 (PE–
13C NMR (75.4 MHz, DMSO): d = 147.8, 142.7, 139.5, 134.2,
128.8, 127.2, 125.3, 120.2, 119.2, 118.0, 110.9, 34.5, 32.9, 21.7,
13.7.
EtOAc, 1:3).
HRMS (EI+): m/z [M+] calcd for C19H18N4: 302.1531; found:
302.1541.
1H NMR (300 MHz, DMSO): d = 8.92 (s, 1 H), 7.24–7.19 (m, 2 H),
7.11 (t, J = 7.7 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H), 7.04 (dm, J = 7.7
Hz, 1 H), 6.95 (dd, J = 8.0, 2.3 Hz, 1 H), 6.58 (dm, J = 7.7 Hz, 1 H),
5.28 (s, 2 H), 5.18 (s, 2 H), 2.12 (s, 3 H).
3-{4-(3-Methoxyphenyl)-[1,2,3]triazol-1-yl}benzoic Acid(Table
1, entry 13)
The reaction mixture was acidified to pH 1 with 4 M HCl before
cooling down on ice-bath.
13C NMR (75.4 MHz, DMSO): d = 148.9, 147.7, 147.6, 135.5,
130.8, 130.6, 129.3, 121.5, 118.7, 113.7, 113.2, 110.5, 107.0, 104.9,
17.0.
Yield 54%; off-white solid; mp 219–220 °C; Rf = 0.07 (PE–EtOAc,
1:3 + 1% AcOH).
HRMS (EI+): m/z [M+] calcd for C15H15N5: 265.1327; found:
265.1318.
1H NMR (500 MHz, DMSO, 60 °C): d = 13.4 (br s, 1 H), 9.18 (s, 1
H), 8.44 (br s, 1 H), 8.09 (d, J = 6.1 Hz, 1 H), 7.94 (br s, 2 H), 7.54
(s, 1 H), 7.51 (br s, 1 H), 7.38 (t, J = 7.9 Hz, 1 H), 6.94 (dd, J = 8.2,
1.8 Hz, 1 H), 3.86 (s, 3 H).
1-{4-(4-Phenyl-[1,2,3]triazol-1-yl)-phenyl}ethanone (Table 2,
entry 2)
Yield 89%; off-white solid; mp 141–143 °C; Rf = 0.17 (PE–EtOAc,
3:1).
1H NMR (300 MHz, DMSO): d = 9.45 (s, 1 H), 8.46 (t, J = 1.9 Hz,
1 H), 8.25 (dm, J = 8.0 Hz, 1 H), 8.09 (dm, J = 8.0 Hz, 1 H), 7.98
(td, J = 7.7, 1.5 Hz, 2 H), 7.80 (t, J = 8.0 Hz, 1 H), 7.52 (td, J = 7.7,
1.5 Hz, 2 H), 7.40 (tt, J = 7.7, 1.5 Hz, 1 H), 2.70 (s, 3 H).
13C NMR (75.4 MHz, DMSO): d = 159.7, 147.4, 131.4, 130.1,
123.7, 119.9, 117.6, 114.0, 110.5, 55.1. Not all signals were ob-
served on the NMR time scale due to the slow internal rotation.
HRMS (EI+): m/z [M+] calcd for C16H13N3O3: 295.0957; found:
295.0937.
2-Methyl-4-{4-phenyl-[1,2,3]triazol-1-yl}phenylamine (Table 1,
entry 14)
13C NMR (75.4 MHz, DMSO): d = 197.0, 147.4, 138.2, 136.9,
130.4, 130.1, 128.9, 128.2, 128.2, 125.3, 124.2, 119.7, 119.0, 26.9.
Purified by flash chromatography (PE–EtOAc, 3:1 → 1:3).
HRMS (EI+): m/z [M+] calcd for C16H13N3O: 263.1059; found:
Yield 68%; off-white solid; mp 153–155 °C; Rf = 0.08 (PE–EtOAc,
263.1078.
3:1).
4-{4-(4-Chlorophenyl)-[1,2,3]triazol-1-yl}benzonitrile (Table 2,
entry 3)
Yield 89%; yellow solid; mp 188–190 °C; Rf = 0.28 (PE–EtOAc,
3:1).
1H NMR (300 MHz, DMSO): d = 9.48 (s, 1 H), 8.18 (d, J = 9.2 Hz,
2 H), 8.13 (d, J = 9.2 Hz, 2 H), 7.95 (d, J = 8.4 Hz, 2 H), 7.58 (d,
J = 8.4 Hz, 2 H).
13C NMR (75.4 MHz, DMSO): d = 146.9, 139.8, 134.7, 133.3,
129.5, 129.1, 127.4, 120.7, 120.5, 118.4, 111.5.
1H NMR (300 MHz, DMSO): d = 9.02 (s, 1 H), 7.93 (d, J = 6.9 Hz,
2 H), 7.53–7.43 (m, 3 H), 7.43 (dd, J = 8.4, 2.7 Hz, 1 H), 7.36 (tt,
J = 6.9, 1.2 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 5.28 (s, 2 H), 2.17
(s, 3 H).
13C NMR (75.4 MHz, DMSO): d = 147.3, 146.6, 130.6, 128.8,
127.8, 126.0, 125.1, 122.1, 121.7, 119.1, 118.9, 113.7, 17.4.
HRMS (EI+): m/z [M+] calcd for C15H14N4: 250.1218; found:
250.1222.
3-{1-(4-Nitrophenyl)-[1,2,3]triazol-4-yl}phenol (Table 1, entry
HRMS (EI+): m/z [M+] calcd for C15H9ClN4: 280.0516; found:
15)
280.0501.
Yield 97%; brown solid; mp 239–243 °C; Rf = 0.09 (PE–EtOAc,
3:1).
4-{1-(4-Chlorophenyl)-[1,2,3]triazol-4-yl}butyronitrile (Table
2, entry 5)
1H NMR (500 MHz, DMSO, 80 °C): d = 9.12 (s, 1 H), 9.05 (br s, 1
H), 8.41 (d, J = 9.2 Hz, 2 H), 8.21 (d, J = 9.2 Hz, 2 H), 7.39 (s, 1 H),
7.34 (d, J = 7.6 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 6.80 (d, J = 7.63
Hz, 1 H).
13C NMR (75.4 MHz, DMSO, 80 °C): d = 158.8, 149.2, 148.1,
142.0, 132.1, 130.7, 126.1, 121.8, 120.6, 117.7, 116.7, 113.9.
Yield 83%; off-white solid; mp 70–72 °C; Rf = 0.51 (PE–EtOAc,
1:3).
1H NMR (300 MHz, DMSO): d = 8.67 (s, 1 H), 7.92 (d, J = 8.8 Hz,
2 H), 7.66 (d, J = 8.8 Hz, 2 H), 2.83 (t, J = 7.3 Hz, 2 H), 2.61 (t,
J = 7.3 Hz, 2 H), 1.98 (p, J = 7.3 Hz, 2 H).
13C NMR (75.4 MHz, DMSO): d = 146.6, 135.5, 132.6, 129.7,
121.4, 120.6, 120.3, 24.5, 23.9, 15.7.
HRMS (EI+): m/z [M+] calcd for C12H11ClN4: 246.0672; found:
HRMS (EI+): m/z [M+] calcd for C14H10N4O3: 282.0753; found:
282.0757.
3-{4-Phenyl-[1,2,3]triazol-1-yl}phenol (Table 1, entry 16)
Yield 97%; pale green solid; mp 227–231 °C; Rf = 0.14 (PE–
EtOAc, 3:1).
1H NMR (300 MHz, DMSO): d = 10.07 (br s, 1 H), 9.25 (s, 1 H),
7.98 (d, J = 7.6 Hz, 2 H), 7.58–7.19 (m, 6 H), 6.91 (br s, 1 H).
13C NMR (75.4 MHz, DMSO): d = 147.1, 130.8 (br), 130.2, 128.9,
128.1, 125.3, 119.5, 110.5 (br). Not all signals were observed on the
NMR time scale due to the slow internal rotation.
246.0650.
1-p-Tolyl-4-trimethylsilanylmethyl-[1,2,3]triazole (Table 2,
entry 6)
4-Bromotoluene (342 mg, 2.0 mmol), ligand A (43 mg, 0.3 mmol),
sodium ascorbate (40 mg, 0.2 mmol), and NaN3 (130 mg, 2.0 mmol)
were taken up in DMSO–H2O (5:1, 6 mL) and degassed with argon.
Then, CuI (39 mg, 0.2 mmol) was added. After the mixture was
heated to 70 °C, trimethyl(propargyl)silane (purity: 85%, 396 mg, 3
mmol) was added. The reaction solution was stirred at the same
temperature for 1 h. Then the solution was poured into H2O and
extracted with CH2Cl2. The combined organic phases were concen-
trated in vacuo together with silica gel. The residue was purified by
HRMS (EI+): m/z [M+] calcd for C14H11N3O: 237.0902; found:
237.0896.
Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of 1-Aryl 1,2,3-Triazoles
2947
chromatography (PE–EtOAc, 3:1), giving the title compound as a
white solid (372 mg, 77%); mp 89–90 °C.
1175. (d) Parent, M.; Mongin, O.; Kamada, K.; Katan, C.;
Blanchard-Desce, M. Chem. Commun. 2005, 2029. (e) van
Steenis, D. J. V. C.; David, O. R. P.; van Strijdonck, G. P. F.;
van Maarseveen, J. H.; Reek, J. N. H. Chem. Commun. 2005,
4333.
Rf = 0.52 (PE–EtOAc, 3:1).
1H NMR (300 MHz, DMSO): d = 8.28 (s, 1 H), 7.74 (d, J = 8.4 Hz,
2 H), 7.36 (d, J = 8.4 Hz, 2 H), 2.32 (s, 3 H), 2.07 (s, 2 H), 0.04 (s,
9 H).
13C NMR (75.4 MHz, DMSO): d = 145.9, 138.0, 135.0, 130.5,
119.9, 119.1, 20.9, 14.9, 1.3.
(5) (a) Löber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett.
2003, 5, 1753. (b) Harju, K.; Vahermo, M.; Mutikainen, I.;
Yli-Kauhaluoma, J. J. Comb. Chem. 2003, 5, 826.
(c) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb.
Chem. 2004, 6, 884. (d) Tornoe, C. W.; Sanderson, S. J.;
Mottram, J. C.; Coombs, G. H.; Meldal, M. J. Comb. Chem.
2004, 6, 312.
MS (ES+): m/z (%) = 246 (100) [M + H+].
(6) (a) Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seibel, W.
L.; Srivastava, A. Tetrahedron Lett. 2003, 44, 2153.
(b) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett.
2004, 6, 3897. (c) Appukkuttan, P.; Dehaen, W.; Fokin, V.
V.; Van der Eycken, E. Org. Lett. 2004, 6, 4223.
(d) Kacprzak, K. Synlett 2004, 943. (e) Chittaboina, S.; Xie,
F.; Wang, Q. Tetrahedron Lett. 2005, 46, 2331.
(7) Zhu, W.; Ma, D. Chem. Commun. 2004, 888.
(8) Andersen, J.; Madsen, U.; Björkling, F.; Liang, X. Synlett
2005, 2209.
(9) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless,
K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192.
(10) Biling, J. F.; Nilsson, U. J. J. Org. Chem. 2005, 70, 4847.
(11) Sharpless, K. B.; Fokin, V.; Rostovtsev, V.; Green, L.;
Himo, F. PCT Int. Appl. WO200310172, 2003.
(12) The steric effect was also observed by others. For examples,
see: Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X.
Tetrahedron Lett. 2005, 46, 7295.
Acknowledgment
The Department of Spectroscopy and Physical Chemistry at LEO
Pharma is acknowledged for the assistance in the characterization of
the compounds prepared herein.
References
(1) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles 2003,
60, 1225.
(2) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org.
Chem. 2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.;
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(3) Kolb, H. C.; Sharpless, K. B. Drug Discov. Today 2003, 8,
1128; and reference cited therein.
(4) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.;
Scheel, A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K.
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(13) For a Cu(I)-catalyzed synthesis of N-unsubstituted 1,2,3-
triazoles, see: Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org.
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Synlett 2005, No. 19, 2941–2947 © Thieme Stuttgart · New York