Copper-catalyzed synthesis of aryl azides and 1-aryl-1,2,3-triazoles from boronic acids

Article abstract of DOI:10.1016/j.tetlet.2007.03.107

A catalytic method was developed to synthesize aryl and vinyl azides from the corresponding boronic acids under mild and operationally simple conditions. In addition, a new one-pot procedure was developed to synthesize 1-aryl- and 1-vinyl-1,2,3-triazoles directly from boronic acids and alkynes, which avoided the need to isolate unstable azide intermediates.

Full text of DOI:10.1016/j.tetlet.2007.03.107

Tetrahedron Letters 48 (2007) 3525–3529
Copper-catalyzed synthesis of aryl azides and
1-aryl-1,2,3-triazoles from boronic acids
Chuan-Zhou Tao, Xin Cui, Juan Li, Ai-Xiang Liu, Lei Liu* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 8 January 2007; revised 19 March 2007; accepted 20 March 2007
Available online 23 March 2007
Abstract—A catalytic method was developed to synthesize aryl and vinyl azides from the corresponding boronic acids under mild
and operationally simple conditions. In addition, a new one-pot procedure was developed to synthesize 1-aryl- and 1-vinyl-1,2,3-
triazoles directly from boronic acids and alkynes, which avoided the need to isolate unstable azide intermediates.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Aryl and vinyl azides are useful intermediates in the syn-
thesis of various heterocyclic compounds and transition
metal complexes.1–3 More recently they have also been
utilized to constitute important components in many
functional materials such as the photoaffinity labelling
agents for proteins.4 Despite these interesting applica-
tions, very few synthetic methods have been developed
to synthesize aryl and vinyl azides from readily available
starting materials.5 Therefore, at the present time these
types of compounds are still prepared mainly by using
an old-fashioned and inconvenient approach, that is,
replacement of diazonium salts by inorganic azides.
In the present study we sought to further improve the
one-pot synthesis of 1-aryl-1,2,3-triazoles by using alter-
native starting materials to replace the aryl halides. As a
result we became interested in the recent discovery by
Lam et al., who reported that aryl boronic acids could
be coupled to a variety of organic nucleophiles mediated
by copper acetate.12 An important advantage of this
method is that much milder reaction conditions are
allowed (such as room temperature, aerobic environ-
ment, and moisture-containing solvent). Furthermore,
the fact that many aryl and vinyl boronic acids are
now commercially available makes this method more
practically appealing, particularly for generation of
combinatorial synthesis of triazole libraries.
To improve the synthesis of aryl and vinyl azides, Zhu
and Ma reported in 2004 a very interesting and creative
method in which a copper catalyst was developed to
promote the coupling of aryl and vinyl iodides with
sodium azides.6 On the basis of this finding several
groups subsequently developed one-pot synthetic meth-
ods for the preparation of 1-aryl-1,2,3-triazoles directly
from aryl iodides, sodium azide, and terminal alky-
nes.7–9 The significance of these studies is manifested
by the fact that 1,2,3-triazoles have recently found wide-
spread use in pharmaceuticals and agrochemicals.10,11
Nonetheless, it is worth noting that the above methods
usually suffer from long reaction times (ꢀovernight)
even at elevated temperature (ꢀ70 ꢁC) due to the slow
azidonation of aryl halides.7–9
Noteworthy, a number of N-centered nucleophiles such
as amines, amides, imides, carbamates, and sulfon-
amides have been previously reported to be utilizable
in the coupling reaction with boronic acids.13 Neverthe-
less, none of the previous studies has considered the use
of an inorganic salt such as sodium azide as the nucleo-
phile. Thus, in order to find out whether the coupling
reaction could proceed with an inorganic azide, we de-
signed an array of reaction conditions in a systematic
fashion (Table 1). To our great satisfaction, we found
that the proposed azidonation reaction occurred
smoothly in the presence of several different Cu salts
including Cu(OAc)2, CuSO4, CuI, and CuCl. The high-
est isolated yield (93%) was obtained with 10 mol % of
CuSO4 catalyst in MeOH (entry 2). The addition of
water to the reaction media decreased the yield to 69%
(entry 8). On the other hand, less polar solvents such
as dichloromethane could not be used to mediate the
*
Corresponding authors. Tel.: +86 5513607466; fax: +86 5513606689
(L.L); e-mail: leiliu@ustc.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.107

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C.-Z. Tao et al. / Tetrahedron Letters 48 (2007) 3525–3529
Table 1. Copper catalyzed coupling between 4-methoxyphenylboronic acid (1) and sodium azidea
OH
copper salts
+
NaN3
O
B
O
N3
r.t. air
OH
Entry
Boronic acid (mmol)
NaN3 (mmol)
Catalyst (mol %)
Solvent (3 mL)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.1
1.0
Cu(OAc)2ÆH2O (10)
CuSO4 (10)
CuI (10)
MeOH
MeOH
MeOH
MeOH
DCM
THF
EtOH
MeOH/H2O = 1:1
H2O
MeOH
MeOH
MeOH
MeOH
MeOH
5
5
5
5
5
5
5
5
5
5
5
5
5
91
93
93
91
Trace
Trace
65
69
50
93
76
93
89
CuCl (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
CuSO4 (20)
CuSO4 (5)
CuSO4 (10)
CuSO4 (10)
CuSO4 (10)
10
84
a Isolated yield.
coupling reaction (entry 5). It is important to note that
the present reaction was accomplished at room temper-
ature and in the air, in contrast to the conditions for the
azidonation of aryl halides where the reaction had to be
performed at elevated temperature under inert gas
protection.6
The above results demonstrated that CuSO4 constituted
an efficient catalyst for the cross coupling of aryl boro-
nic acid with sodium azide under mild reaction condi-
tions. In order to examine the scope of this newly
discovered reaction, we next examined the isolated
yields for the cross coupling of a number of representa-
Table 2. Copper catalyzed cross-coupling between sodium azide and various aryl and vinyl boronic acidsa
OH
CuSO4 10%mol
NaN3
R
N3
R
B
MeOH, r.t., air
OH
Entry
1
Reactant
Product
Time (h)
5
Yieldb (%)
93
B(OH)2
N3
MeO
MeO
B(OH)2
N3
2
3
4
5
14
14
24
14
90
92
70
92
N3
B(OH)2
B(OH)2
N3
Cl
Cl
B(OH)2
N3
N3
B(OH)2
OMe
6
7
5
5
90
98
OMe
N3
B(OH)2
B(OH)2
N3
8
14
86
a Conditions: Boronic acid = 1.0 mmol, NaN3 = 1.2 mmol, CuSO4 = 10 mol %, MeOH = 3 mL, room temperature, in air.
b Isolated yield.

C.-Z. Tao et al. / Tetrahedron Letters 48 (2007) 3525–3529
3527
tive aryl and vinyl boronic acids with sodium azide
(Table 2). It was found that both the electron-rich
(i.e., 4-methoxyphenyl-boronic acid) and electron-poor
(4-chlorophenyl-boronic acid) substrates could be effi-
ciently converted to the desired products in high yields
(entries 1–4). Furthermore, sterically hindered
substrates could be well tolerated to some degree since
2-substituted aryl boronic acids could also provide the
desired products in over 90% yields (entries 5–6). In
addition to the phenyl boronic acids, other aromatic
substrates were also utilizable such as naphthalen-1-
ylboronic acid (entry 7). Finally, vinyl boronic acids
such as (E)-styrylboronic acid could be successfully con-
verted to vinyl azides using the same approach (entry 8).
Again, we need to stress that these reactions were
achieved under very mild conditions at room tempera-
ture, in an aerobic environment, and without require-
ment for any anhydrous solvent. This represented a
Table 3. Copper-catalyzed one-pot synthesis of 1-aryl- and 1-vinyl-1,2,3-triazoles from boronic acidsa
OH
OH
1. NaN3. CuSO4
2. RCCH
R
Ar
N
Ar
B
N
N
Entry
1
Boronic acid
Alkyne
Product
Time
12
Temperature
rt
Yieldb (%)
95
B(OH)2
OMe
MeO
N
N
N
N
B(OH)2
2
3
4
17
17
41
rt
rt
rt
92
95
63
N
N
B(OH)2
N
N
N
N
Cl
B(OH)2
N
N
Cl
B(OH)2
5
6
33
12
rt
rt
81
92
N
N
N
MeO
B(OH)2
OMe
N
N
N
B(OH)2
7
12
rt
96
N
N
N
N
B(OH)2
8
9
17
15
20
20
rt
rt
rt
rt
64
96
90
93
N
N
OMe
B(OH)2
C6H13
N
N
MeO
N
N
B(OH)2
C6H13
10
11
N
N
B(OH)2
C6H13
N
N
N
a Conditions: Boronic acid = 1.0 mmol, NaN3 = 1.1 mmol, CuSO4 = 10 mol %, MeOH = 3 mL, water = 3 mL, room temperature, in air.
b Isolated yield.

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C.-Z. Tao et al. / Tetrahedron Letters 48 (2007) 3525–3529
valuable improvement over the previously reported Cu-
catalyzed azidonation reaction of aryl halides which had
to be performed at elevated temperature under inert gas
protection.6
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
03.107.
Having successfully developed a new and mild method
for the preparation of aryl and vinyl azides,14 we next
sought to develop a new one-pot protocol to synthesize
1-aryl- and 1-vinyl-1,2,3-triazoles. Such a one-pot ap-
proach is considered to be valuable because organic
azides are often unstable to heat and light. Thus, a meth-
odology that avoids the isolation of organic azides is
desirable. Previous studies have shown that aryl iodides
could be used to couple with sodium azide and an al-
kyne to afford the triazoles.7–9 In our approach, we at-
tempted to utilize both aryl and vinyl boronic acids as
the starting material. The following one-pot experiments
were carried out with an aryl boronic acid (1 equiv), a
terminal alkyne (1.1 equiv), NaN3 (1.1 equiv), and
CuSO4 (0.1 equiv) at room temperature.15 The products
were normally obtained by simple filtration. As seen in
Table 3, both aromatic and aliphatic alkynes could be
used in this one-pot reaction. Besides, a variety of func-
tional groups on aryl and alkenyl boronic acids were
fully tolerated. It is significant to note that even steri-
cally hindered aryl boronic acids carrying an ortho sub-
stituent (entries 5–6) could be successfully converted to
the desired product in high yields. In comparison to
our approach, the previous one-pot method using aryl
iodides was found to be unsuccessful with sterically hin-
dered starting materials (i.e., ortho-substituted aryl iod-
ides) even at a high temperature.8 This evidently shows
the advantage of using boronic acids as the starting
material where both the reaction condition and scope
were better than the aryl halide case.
References and notes
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To conclude, in the present study we reported a novel
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sponding boronic acids. Compared to the very recent
procedures using aryl halides, our new method showed
a milder reaction condition and improved substrate tol-
erance. On the basis of this finding, we next developed a
one-pot procedure to prepare 1-aryl- and 1-vinyl-1,2,3-
triazoles directly from boronic acids and alkynes. This
one-pot method was advantageous not only because it
was operationally simple and high yielding, but also be-
cause it completely avoided the isolation of relatively
unstable aryl and vinyl azides. Given the fact that many
aryl and vinyl boronic acids have now become commer-
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organic material design, where the triazole-type com-
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Acknowledgement
This research was supported by the NSFC (No.
20472079).

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petroleum ether or purified by a pad of silicon gel to give
the desired aryl or vinyl azide.
15. Typical experimental procedure for the one-pot triazole
synthesis: NaN3 (78 mg, 1.2 mmol), CuSO4 (0.1 mmol,
16 mg), and boronic acids (1.0 mmol) were reacted in
methanol (3 mL) as described above for 5–14 h. Then
water (3 mL), sodium ascorbate (0.5 mmol), and
phenylacetylene (1.1 mmol) were added into the reaction
mixture. The resulting mixture was stirred vigorously at
room temperature for 2–4 h (as monitored by TLC
analysis). Some precipitate was formed and collected
by a simple filtration. After the precipitate was washed
with water (3 · 25 mL), it was dried in air or further
purified by flash chromatography to afford the pure
product.
14. Typical experimental procedure for the azidonation reac-
tion: NaN3 (78 mg, 1.2 mmol) and CuSO4 (0.1 mmol,
16 mg) were placed in an oven-dried round-bottomed
flask. Subsequently methanol (3 mL) and boronic acids
(1.0 mmol) were added. The reaction mixture was stirred
vigorously at room temperature for a certain time (mon-
itored by TLC analysis). The resulting mixture was
concentrated in vacuo, and the residue was extracted with
16. Chao, J.-P.; Wu, W.-Q.; Luo, X.-D.; Ling, Y.-Z. Chin. J.
Org. Chem. 2006, 26, 1004.