Facile one-pot synthesis of monosubstituted 1-aryl-1h-1,2,3-triazoles from arylboronic acids and prop-2-ynoic acid (=propiolic acid) or calcium acetylide (=calcium carbide) as acetylene source

Article abstract of DOI:10.1002/hlca.201100256

The synthesis of monosubstituted 1-aryl-1H-1,2,3-triazoles was achieved in a one-pot reaction from arylboronic acids and prop-2-ynoic acid or calcium acetylide (=calcium carbide), respectively, as a source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction conditions were successfully applied to arylboronic acids, including analogs with various functionalities. Unexpectedly, the 1,2,3-triazole moiety promoted a regioselective hydrodebromination (Scheme 2). Copyright

Full text of DOI:10.1002/hlca.201100256

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Helvetica Chimica Acta – Vol. 95 (2012)
Facile One-Pot Synthesis of Monosubstituted 1-Aryl-1H-1,2,3-triazoles from
Arylboronic Acids and Prop-2-ynoic Acid (¼ Propiolic Acid) or Calcium
Acetylide (¼Calcium Carbide) as Acetylene Source
by Qing Yang*a), Yubo Jiangb), and Chunxiang Kuangb)
a) Department of Biochemistry, School of Life Sciences, Fudan University, Handan Road 220, Shanghai
200433, P. R. China (phone/fax: þ 86-21-65643446; e-mail: yangqing68@fudan.edu.cn)
b) Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P. R. China
The synthesis of monosubstituted 1-aryl-1H-1,2,3-triazoles was achieved in a one-pot reaction from
arylboronic acids and prop-2-ynoic acid or calcium acetylide (¼calcium carbide), respectively, as a
source of acetylene, with yields ranging from moderate to excellent (Scheme 1, Table 2). The reaction
conditions were successfully applied to arylboronic acids, including analogs with various functionalities.
Unexpectedly, the 1,2,3-triazole moiety promoted a regioselective hydrodebromination (Scheme 2).
Introduction. – The 1H-1,2,3-triazole unit is an important structure unit in a number
of pharmaceuticals, agrochemicals, and chemical reagents, and has also found
widespread applications in the fields of material science and molecular structure
design [1]. Deriving from the robust Cu-catalyzed Huisgen 1,3-dipolar cycloaddition,
1,4-disubstituted 1H-1,2,3-triazoles can be synthesized efficiently [2]. However, there
are few efficient methodologies described concerning the synthesis of 1-monosub-
stituted 1H-1,2,3-triazoles via this useful ꢀclick reactionꢁ. One strategy was the decarboxy-
lation of triazoles bearing a carboxylic acid substituent, but the reaction required
extreme temperatures and long reaction times [3]. Another method was the cyclo-
addition of azides to acetylene [2f] and its equivalents such as acetylides (ethynyl-
trimethylsilane and ethynyltributylstannane) [4] and vinyl compounds (vinyl acetate,
vinyl ethers, vinylamines, and vinyl sulfoxides) [5]. Very recently, calcium acetylide
(¼calcium carbide; CaC2), and prop-2-ynoic acid (¼ propiolic acid) were also reported
to be used as a safe and inexpensive acetylene source [6]. However, all of these methods
employed poisonous and potentially explosive organic azides as starting materials, which
has limited their applications in the synthesis of 1-monosubstituted 1H-1,2,3-triazoles.
Herein, we would like to describe a convenient and efficient one-pot protocol for
the preparation of monosubstituted 1-aryl-1H-1,2,3-triazoles 2 (Scheme 1). In this
method, arylboronic acids 1 were involved as the starting materials to generate organic
Scheme 1. Synthesis of Monosubstituted 1-Aryl-1H-1,2,3-triazoles 2
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢃrich

Helvetica Chimica Acta – Vol. 95 (2012)
449
azides in situ according to Liuꢁs report [7], and CaC2 or prop-2-ynoic acid were used as
the source of acetylene, respectively. Thus, the isolation of the poisonous and unstable
organic azides was avoided.
Results and Discussion. – An initial investigation of the reaction conditions was
conducted with phenylboronic acid (1a; 0.3 mmol), NaN3 (1.1 equiv.), and prop-2-
ynoic acid (1.2 equiv.) as the starting materials, in which decarboxylation may occur in
situ [6c]. The reaction was carried out in the presence of different amounts of CuI and
additives (DBU (¼1,8-diazabicyclo[5.4.0]undec-7-ene), Et3N, and Et2NH) in different
solvents (DMF and CH2Cl2) at 808. However, the first step of the reaction failed when
pure DMF was applied as the solvent (Table 1, Entry 1). When dioxane or DMSO was
used as the solvent, the reaction worked, but the yield of the triazole 2a was low
(Entries 2 and 3). To our surprise, the improved yield of 40% of 2a was obtained when
H2O alone was used as the medium (Entry 4). Inspiringly, the product yield was
improved further when a moderate amount of H2O was added to DMF as a co-solvent
(Entries 5 – 8). The yield was increased up to 68% when CuI (0.1 equiv.), NaN3
(1.1 equiv.), sodium ascorbate (0.2 equiv.), DBU (0.5 equiv.), and prop-2-ynoic acid
(1.2 equiv.) were added to the solvent DMF/H2O 6 :1. Additionally, the first step of the
Table 1. Optimization of the Synthesis of 1-Phenyl-1H-1,2,3-triazole (2a)a)
Entry
CuI [equiv.]
Base (equiv.)
Solvent (v/v)
Yield [%] of 2ab)
1c)
2
3
4
5
6
7
8
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.3
0.2
0.2
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
Et3N (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.5)
DBU (0.3)
DBU (0.5)
DBU (0.8)
DBU (0.5)
DMF
dioxane
DMSO
H2O
0
32
36
40
48
56
68
51
37
79
88
80
72
82
76
42
DMF/H2O 2 : 1
DMF/H2O 4 : 1
DMF/H2O 6 : 1
DMF/H2O 8 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
DMF/H2O 6 : 1
9
10
11d)e)
12f)e)
13d)e)
14d)e)
15d)e)
16d)g)
a) Conditions unless indicated otherwise: a mixture of PhB(OH)2 (0.3 mmol), NaN3 (0.33 mmol), and
CuI in solvent (2 ml) was heated to 808 and stirred until PhB(OH)2 was consumed. After the mixture was
cooled to r.t., DBU, sodium ascorbate (0.06 mmol), and prop-2-ynoic acid were added, and the reaction
was then conducted at 808 until PhN3 was consumed (TLC monitoring). b) Yield of isolated product.
c) The second step was not conducted. d) 0.45 mmol of prop-2-ynoic acid was used. e) 0.16 mmol of
f
sodium ascorbate was used. ) 0.54 mmol of propiolic acid was used. g) No sodium ascorbate was used.

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Helvetica Chimica Acta – Vol. 95 (2012)
reaction ran smoothly and finished within 0.5 h (Entry 7). The base Et3N seems not as
efficient as DBU under these conditions (Entry 9). Our study also showed that
increasing the amount of CuI to 0.2 equiv. or prop-2-ynoic acid to 1.5 equiv. was
beneficial to the yield (Entries 10 and 11), while an overabundance of CuI or prop-2-
ynoic acid was unfavorable (Entries 12 and 14). Reducing the amount of DBU caused a
decline of the yield (Entry 13) as well. An additionally important discovery was that the
presence of sodium ascorbate in the reaction mixture was absolutely necessary to
obtain a higher yield, as the yield dropped near to half in the absence of sodium
ascorbate (Entry 16). Finally, the yield of 2a was increased to up to 88% when the
optimal conditions were applied to the reaction at 808, i.e., CuI (0.2 equiv.), NaN3 (1.1
equiv), sodium ascorbate (0.4 equiv.), DBU (0.5 equiv.), and prop-2-ynoic acid
(1.5 equiv.) in DMF/H2O 6 :1 (Entry 11).
The optimized conditions were then also applied to CaC2 instead of prop-2-ynoic
acid as an alternative source of acetylene for the synthesis of the monosubstituted 1-
phenyl-1H-1,2,3-triazole (2a; Table 2, Entry 1); under the effect of CuI, phenyl azide
was formed in situ and then treated with CaC2, generating the expected product in 86%
yield.
This methodology (with prop-2-ynoic acid or CaC2) led to monosubstituted 1H-
1,2,3-triazoles, while polysubstituted 1H-1,2,3-triazoles were generated in previously
described methods [8], in which arylboronic acids and NaN3 were also involved as the
Table 2. Synthesis of 1-Momosubstitued 1,2,3-Triazoles 2a)
Entry
Ar
Product 2
Yield [%]b)
Time [h]b)
Yield [%]c)
Time [h]c)
1
2
3
4d)
5
6
7
8
9
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
88
89
85
76
86
82
71
72
92
94
90
69
4
4
5
8
4
5
4
4
2.5
3
1.5
8
86
86
82
81
85
87
69
76
84
93
82
78
4.5
5
6
7
5.5
6
6
4
3
3
4-MeꢀC6H4
3-MeꢀC6H4
2-MeꢀC6H4
4-MeOꢀC6H4
3-MeOꢀC6H4
4-HOꢀC6H4
3-NH2ꢀC6H4
4-CHOꢀC6H4
4-FꢀC6H4
10
11
12
2j
2k
2l
3-NO2ꢀC6H4
Naphthalen-1-yl
2
7
a) Conditions: arylboronic acid 1 (0.3 mmol), NaN3 (0.33 mmol), and CuI (0.06 mmol) were added to
DMF/H2O 6 : 1 (2 ml). The mixture was heated to 808 and stirred until the ArB(OH)2 was consumed.
After cooling to r.t., DBU (0.15 mmol), sodium ascorbate (0.12 mmol), and prop-2-ynoic acid
(0.45 mmol) or CaC2 (0.45 mmol) were added, and the reaction was then conducted at 808 until the ArN3
was consumed (TLC monitoring). b) Yield of isolated product by using prop-2-ynoic acid, and time of
c
the second step. ) Yield of isolated product by using CaC2, and time of the second step. d) Conducted at
1208.

Helvetica Chimica Acta – Vol. 95 (2012)
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starting materials. Under the optimized reaction conditions, also a series of arylboronic
acids was subjected to the reaction with prop-2-ynoic acid and CaC2, respectively,
affording monosubstitued 1-aryl-1H-1,2,3-triazoles (Table 2). The results showed that
arylboronic acids carrying either an electron-donating substituent such as a Me, MeO,
OH, or NH2 group (Table 2, Entries 2 – 8) or an electron-withdrawing group including a
formyl, F, or NO2 group (Entries 9 – 11) proceeded successfully. Substrates bearing
either an electron-donating or an electron-withdrawing group at the para- or meta-
position gave all the corresponding monosubstitued 1-aryl-1H-1,2,3-triazole in good to
excellent yields at 808. Though the arylboronic acids bearing an ortho-substituent
suffered from a low reaction rate due to the steric hindrance effect (Entries 4 and 12),
their reaction proceeded successfully by raising the temperature up to 1208. Addition-
ally, groups such as OH, formyl, and NH2 of the arylboronic acids were tolerated
(Entries 7 – 9). It is especially worth noting that this procedure is also suitable for the
preparation of 1-aryl-1H-1,2,3-triazoles bearing an amino group at the benzene moiety.
Furthermore, the entire procedure of synthesizing 1-aryl-1H-1,2,3-triazoles 2 could
also be achieved by a one-pot ꢀone-stepꢁ manipulation (Table 3). Monosubstitued 1-
aryl-1H-1,2,3-triazoles with either an electron-donating substituent such as Me or MeO
(Table 3, Entries 2 and 3) or an electron-withdrawing group such as F (Entry 4) could
be obtained through this one-pot ꢀone-stepꢁ procedure; but the yields were slightly
lower than those of the one-pot ꢀtwo-stepꢁ procedure (Table 2).
Table 3. Synthesis of 1-Aryl-1H-1,2,3-triazoles 2 by a One-Pot ꢀOne-Stepꢁ Procedurea)
Entry
1
Product
Yield [%]b)
72
Time [h]b)
4
Yield [%]c)
68
Time [h]c)
4.5
2a
2c
2e
2j
2
3
4
75
66
82
5
4
3
80
72
86
6
5.5
3
a) Conditions: arylboronic acid 1 (0.3 mmol), NaN3 (0.33 mmol), CuI (0.06 mmol), sodium ascorbate
(0.12 mmol), prop-2-ynoic acid (0.45 mmol), or CaC2 (0.45 mmol) and DBU (0.15 mmol) were added to
DMF/H2O 6 : 1 (2 ml). The reaction was then conducted at 808 until arylboronic acid and ArN3 were
consumed (TLC monitoring). b) Yield of isolated product by using prop-2-ynoic acid and reaction time.
c) Yield of isolated product by using CaC2 and reaction time.
Additionally, a copper-catalyzed hydrodebromination directed by the 1,2,3-triazole
moiety was observed during the present study. Not the expected 1-(2-bromophenyl)-
1H-1,2,3-triazole (2m) but 1-phenyl-1H-1,2,3-triazole (2a) was obtained in 36% yield
when (2-bromophenyl)boronic acid (1m) was used as the substrate (Scheme 2).
To elucidate the role of the 1,2,3-triazole moiety in this hydrodebromination, 1-(2,4-
dibromophenyl)-1H-1,2,3-triazole (3) was employed directly under the above con-

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Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 2. Reaction of (2-Bromophenyl)boronic Acid (1m)
ditions (Scheme 3). The product of the debromination was not 1-phenyl-1H-1,2,3-
triazole (2a) but 1-(4-bromophenyl)-1H-1,2,3-triazole (4, 83% yield). Thus, the 1,2,3-
triazole moiety seems to act as the directing group, which promoted the regioselective
hydrodebromination of the ortho-Br substituent in the substrate.
Scheme 3. 1,2,3-Triazole-Promoted Hydrodebromination of 1-(2,4-Dibromophenyl)-1H-1,2,3-triazole
(3)
In summary, we demonstrated a facile and efficient protocol for the synthesis of
monosubstitued 1-aryl-1H-1,2,3-triazoles from arylboronic acids and prop-2-ynoic acid
or CaC2, respectively, as the source of acetylene. This protocol provided a convenient
and mild access to these 1H-1,2,3-triazoles, which are important heterocyclic
compounds in medicinal chemistry and material science. Unexpectedly, a 1,2,3-
triazole-promoted regioselective hydrodebromination was observed, and the study of
its application is ongoing.
This work was supported by the Natural Science Foundation of China (No. 30873153), the Key
Projects of Shanghai in Biomedicine (No.08431902700), and the Scientific Research Foundation of the
State Education Ministry for the Returned Overseas Chinese Scholars. We would like to thank the Center
for Instrumental Analysis, Tongji University, China. We thank Dr. Y. Hefner (1278 Avenida Miguel,
Encinitas, CA 92024, U.S.A.) for helpful discussion and critical reading as well as editing this manuscript.
Experimental Part
General. Commercially obtained reagents were used without further purification. TLC: Huanghai
GF254 silica-gel coated plates. Column chromatography (CC): SiO2 (300 – 400 mesh), at medium
1
pressure. H-NMR Spectra: Bruker-AM-500 spectrometer in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz.

Helvetica Chimica Acta – Vol. 95 (2012)
453
Monosubstitued 1-Aryl-1H-1,2,3-triazoles 2: General Procedure. A soln. of arylboronic acid 1
(0.3 mmol), NaN3 (22 mg, 0.33 mmol), and CuI (11 mg, 0.06 mmol) in DMF/H2O 6 :1 (2 ml) was stirred
at 808 until 1 was consumed completely (TLC monitoring). Then, the mixture was cooled to r.t., sodium
ascorbate (24 mg, 0.12 mmol), prop-2-ynoic acid (32 mg, 0.45 mmol), and DBU (23 mg, 0.15 mmol)
were added, and the stirred mixture was heated to 808 until the reaction was completed. The mixture was
allowed to cool to r.t., then quenched with H2O (15 ml), and extracted with AcOEt (3 ꢁ 10 ml). The
combined org. layer was washed with brine (3 ꢁ 5 ml), dried (Na2SO4), and concentrated and the crude
product purified by CC (silica gel, AcOEt/hexane 1:2): 2.
1-Phenyl-1H-1,2,3-triazole (2a) [6a]. 1H-NMR (500 MHz, CDCl3): 8.00 (d, J ¼ 0.9, 1 H); 7.86 (d, J ¼
0.9, 1 H); 7.76 – 7.74 (m, 2 H); 7.56 – 7.53 (m, 2 H); 7.45 (t, J ¼ 16.0, 1 H).
1
1-(4-Methylphenyl)-1H-1,2,3-triazole (2b) [6a]. H-NMR (500 MHz, CDCl3): 7.95 (d, J ¼ 1.0, 1 H);
7.83 (d, J ¼ 1.0, 1 H); 7.62 (d, J ¼ 8.0, 2 H); 7.32 (d, J ¼ 8.0, 2 H); 2.43 (s, 3 H).
1
1-(3-Methylphenyl)-1H-1,2,3-triazole (2c) [2f]. H-NMR (500 MHz, CDCl3): 7.98 (d, J ¼ 0.7, 1 H);
7.84 (d, J ¼ 0.7, 1 H); 7.59 (s, 1 H); 7.52 (d, J ¼ 8.0, 1 H); 7.42 (d, J ¼ 8.0, 1 H); 7.27 – 7.25 (m, 1 H); 2.46 (s,
3 H).
1
1-(2-Methylphenyl)-1H-1,2,3-triazole (2d) [6a]. H-NMR (500 MHz, CDCl3): 7.86 (d, J ¼ 0.9, 1 H);
7.76 (d, J ¼ 0.9, 1 H); 7.43 – 7.34 (m, 4 H); 2.20 (s, 3 H).
1-(4-Methoxyphenyl)-1H-1,2,3-triazole (2e) [2f]. 1H-NMR (500 MHz, CDCl3): 7.91 (d, J ¼ 0.8, 1 H);
7.83 (d, J ¼ 0.8, 1 H); 7.64 (d, J ¼ 6.8, 2 H); 7.03 (d, J ¼ 6.8, 2 H,); 3.87 (s, 3 H).
1-(3-Methoxyphenyl)-1H-1,2,3-triazole (2f) [4c]. 1H-NMR (500 MHz, CDCl3): 8.00 (s, 1 H); 7.84 (s,
1 H); 7.43 – 7.36 (m, 2 H); 7.27 (dd, J ¼ 2.3, 7.4, 1 H); 6.98 (dd, J ¼ 2.4, 8.3, 1 H); 3.88 (s, 3 H).
1
4-(1H-1,2,3-Triazol-1-yl)phenol (2g) [6a]. H-NMR (500 MHz, (D6)DMSO): 9.91 (s, 1 H); 8.63 (d,
J ¼ 1.0, 1 H); 7.90 (d, J ¼ 1.0, 2 H); 7.66 (q, J ¼ 9.0, 2 H); 6.93 (d, J ¼ 9.0, 2 H).
3-(1H-1,2,3-Triazol-1-yl)benzenamine (2h) [9a]. 1H-NMR (500 MHz, CDCl3): 7.95 (d, J ¼ 1.1, 1 H);
7.82 (d, J ¼ 1.0, 1 H); 7.27 (t, J ¼ 8.0, 8.0, 1 H); 7.14 (t, J ¼ 2.1, 2.1, 1 H); 7.02 (ddd, J ¼ 0.8, 2.0, 8.0, 1 H);
6.73 (ddd, J ¼ 0.8, 2.3, 8.1, 1 H); 3.95 (s, 2 H).
4-(1H-1,2,3-Triazol-1-yl)benzaldehyde (2i) [9b]. 1H-NMR (500 MHz, CDCl3): 10.09 (s, 1 H); 8.12 (d,
J ¼1.1, 1 H); 8.08 (d, J ¼ 8.69, 2 H); 7.99 (d, J ¼ 8.56, 2 H); 7.91 (d, J ¼ 1.1, 1 H).
1
1-(4-Fluorophenyl)-1H-1,2,3-triazole (2j) [6a]. H-NMR (500 MHz, CDCl3): 7.95 (d, J ¼ 1.0, 1 H);
7.85 (d, J ¼ 1.0, 1 H); 7.73 (d, J ¼ 9.0, 2 H); 7.23 (d, J ¼ 7.6, 2 H).
1-(3-Nitrophenyl)-1H-1,2,3-triazole (2k) [2f]. 1H-NMR (500 MHz, CDCl3): 8.61 (t, J ¼ 2.0, 1 H);
8.34 – 8.31 (m, 1 H); 8.23 – 8.21 (m, 1 H); 8.12 (d, J ¼ 1.0, 1 H); 7.92 (d, J ¼ 1.0, 1 H); 7.77 (t, J ¼ 8.2, 1 H).
1
1-(Naphthalen-1-yl)-1H-1,2,3-triazole (2l) [9c]. H-NMR (500 MHz, CDCl3): 8.05 – 8.02 (m, 1 H);
7.98 – 7.95 (m, 3 H); 7.61 – 7.53 (m, 5 H).
1-(2,4-Dibromophenyl)-1H-1,2,3-triazole (3) [9d]. A soln. of 1-azido-2,4-dibromobenzene (277 mg,
1 mmol), CaC2 (128 mg, 2 mmol), CuI (38 mg, 0.2 mmol), and sodium ascorbate (80 mg, 0.4 mmol) in
MeCN/H2O 3 :1 (6 ml) was stirred at 808 until the starting 1-azido-2,4-dibromobenzene was consumed
completely (TLC monitoring). The mixture was allowed to cool to r.t. and the reaction quenched with
H2O (15 ml). The mixture was extracted with AcOEt (3 ꢁ 10 ml), and the combined org. layer washed
with brine (3 ꢁ 5 ml), dried (Na2SO4), and concentrated and the crude product purified by CC (silica gel,
1
AcOEt/hexane 1:2): 3 (83%). H-NMR (400 MHz, CDCl3): 7.97 (s, 1 H); 7.94 (d, J ¼ 2.0, 1 H); 7.87 (s,
1 H); 7.64 (dd, J ¼ 2.0, 8.4, 1 H); 7.44 (d, J ¼ 8.46, 1 H).
Regioselective Hydrodebromination of 3 Affording 4. To a soln. of 3 (91 mg, 0.3 mmol) in DMF/H2O
6 :1 (2 ml) was added CuI (11 mg, 0.06 mmol), sodium ascorbate (24 mg, 0.12 mmol), and DBU (23 mg,
0.15 mmol). The mixture was heated to 1208 and stirred until 3 was consumed completely (TLC
monitoring). The mixture was cooled to r.t., and then H2O (10 ml) was added. The mixture was extracted
with AcOEt (3 ꢁ 10 ml), the combined org. layer washed with brine (3 ꢁ 5 ml), dried (Na2SO4), and
concentrated, and the crude product purified by CC (SiO2, AcOEt/hexane 1:2): 1-(4-bromophenyl)-1H-
1,2,3-triazole [2f] (4; 83%). 1H-NMR (400 MHz, CDCl3): 7.98 (s, 1 H); 7.87 (s, 1 H); 7.68 (d, J ¼ 9.1, 2 H);
7.65 (d, J ¼ 9.1, 2 H).

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Helvetica Chimica Acta – Vol. 95 (2012)
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Received June 18, 2011