One-pot synthesis of 1-monosubstituted-1, 2, 3-triazoles from 2-methyl-3-butyn-2-ol

Article abstract of DOI:10.1016/j.tetlet.2018.01.012

An efficient method for the synthesis of 1-monosubstituted-1, 2, 3-triazoles from 2-methyl-3-butyn-2-ol under copper catalyst conditions has been developed through a one-step one-pot sequence. This method provides a concise and efficient pathway to synthesize 1-monosubstituted-1, 2, 3-triazole derivatives in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2018.01.012

Accepted Manuscript
One-pot synthesis of 1-monosubstituted-1, 2, 3-triazoles from 2-methyl-3-bu-
tyn-2-ol
Yaowen Liu, Chunmei Han, Xinyuan Ma, Jianhua Yang, Xuepu Feng, Yubo
Jiang
PII:
S0040-4039(18)30024-8
https://doi.org/10.1016/j.tetlet.2018.01.012
TETL 49599
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
4 November 2017
30 December 2017
4 January 2018
Please cite this article as: Liu, Y., Han, C., Ma, X., Yang, J., Feng, X., Jiang, Y., One-pot synthesis of 1-
monosubstituted-1, 2, 3-triazoles from 2-methyl-3-butyn-2-ol, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.01.012
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Graphical Abstract
One-pot synthesis of 1-monosubstituted-1, 2, 3-triazoles Leave this area blank for abstract info.
from 2-methyl-3-butyn-2-ol
Yaowen Liu a, Chunmei Han a, Xinyuan Ma a, Jianhua Yang a, Xuepu, Feng a, Yubo Jiang a,

1
Tetrahedron Letters
One-pot synthesis of 1-monosubstituted-1, 2, 3-triazoles from 2-methyl-3-butyn-2-ol
Yaowen Liu a, Chunmei Han a, Xinyuan Ma a, Jianhua Yang a, Xuepu Feng a, Yubo Jiang a, 
a Faculty of Science, Kunming University of Science and Technology, Kunming 650500, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient method for the synthesis of 1-monosubstituted-1, 2, 3-triazoles from 2-methyl-3-
butyn-2-ol under copper catalyst conditions has been developed through a one-step one-pot
Received in revised form
Accepted
sequence. This method provides
monosubstituted-1, 2, 3-triazole derivatives in good to excellent yields.
a concise and efficient pathway to synthesize 1-
Available online
Keywords:
One-pot
1-Monosubstituted- 1, 2, 3-triazoles
Aryl azides
Copper catalyst
2-Methyl-3-butyn-2-ol
Introduction
cycloaddition of organic azide and alkyne is an important
complement to copper catalyzed 1, 3-dipolar cycloaddition
reactions, which are the essence of click chemistry. In 2007,
Fokin13 group found that ruthenium complexes can effectively
catalyze organic azide and alkyne cycloaddition reaction, and
specifically to generate 1, 5-disubstituted 1, 2, 3-triazoles. From
then on these compounds come to the limelight, bringing
researchers to explore more effective methods using different
approaches to respectively obtain 1, 4-disubstituted 1, 2, 3-
triazoles and 1, 5-disubstituted 1, 2, 3-triazoles.14 However, The
construction of the ring of monosubstituted 1, 2, 3-triazoles is
more difficult than that of the other kinds of these heterocycles,
owing to the special request for the structure of “alkyne source”
and the relatively rigorous reaction conditions required in the
system. As early as 1966, Kauer and Carboni15 were the first to
synthesize 1-(2-nitro phenyl)-1, 2, 3-triazole derivatives by using
acetylene and ortho nitro azide, achieving the construction of 1-
monosubstituted-1, 2, 3-triazole. One strategy is the
decarboxvlation of triazoles bearing a carboxylic acid substituent,
which requires long reaction times and extreme temperatures.16
Another protocol is the cycloaddition of azides to acetylene17 and
its analogs such as acetylides18 and vinyl compounds.19
Afterwards, Spagnolo, Zanirato20 and Liang21 groups optimized
the above method but are mainly limited to the acetylene gas.
Thus, the synthesis of 1-monosubstituted-1, 2, 3-triazoles by
using other alkyne sources attracts much attention continuously.
During 2009, Jensen22 group reported 1-monosubstituted-1, 2, 3-
triazole was successfully constructed under microwave
irradiation by ethylene acetate as alkyne source. Kuang23 group
reported a novel and usefu1 protocol for the synthesis of 1-
The class of heterocyclic compounds containing five-
membered ring with three nitrogen atoms are known as triazoles;
among triazole family, the 1, 2, 3-triazoles possess the diverse
applications as potential bioactive compound and frequently used
for the preparation of new drugs with diverse biological
activities.1 Recently, 1, 2, 3-triazoles were widely applied in
various fields such as organic synthesis,2 materials,3 medicinal
chemistry,4 food additives5 and biological science,6 especially in
medicinal chemistry field such as anti-HIV,7 anticancer8 and
antifungal9 activities, although the structures were not found in
natural products (Fig. 1).
Fig. 1. 1-Monosubstituted-1, 2, 3-triazoles pharmaceutical activities.
As the 1, 2, 3-triazole derivatives were used in many
expanding areas,10 its preparation has attracted much attention
and obtained encouraging progress in recent years. Thus, it is
significant to develop general and efficient methods for their
fabrication. The first method to form 1, 2, 3-triazole was the
Huisgen dipolar cycloaddition, giving 1,4- and 1,5-disubstituted
regioisomers.11 In 2002, Sharpless12 group found a copper-
catalyzed 1,3-dipolar cycloaddition reaction (CuAAC) between
alkynes and azides, allowing the regioselective formation of the 1,
monosubstitued 1, 2, 3-triazoles by click reaction
/
decarboxylationl under mild conditions. In 2011, the group24
achieved metal-free synthesis of 1-monosubstituted-1, 2, 3-
4-disubstituted 1, 2, 3-triazoles. Ruthenium catalyzed
———
 Corresponding author.
e-mail: ybjiang@kmust.edu.cn

2
Tetrahedron Letters
triazoles from acetylene sodium. During 2013, the samegroup25
was conducted at 120oC in solvent of PhMe-MeOH (1:1 in
volume) under the base of K3PO4 (Table 1, entry 1). To our
delight, addition of other base to the reaction leads to
significantly improved efficiencies (Table 1, entries 2−7).
Among the bases screened, KOH (5 eq.) was observed to be the
most effective, producing 3b in 61% yield (Table 1, entry 7).
Then, other solvents including single toluene or CH3OH seemed
ineffective for the system (Table 1, entries 8−9). Further
screening of the volume ratios of the mixture solvent showed that
1:3 for Toluene-CH3OH was the best choice (Table 1, entries
10−13). Subsequently, we investigated the effects of temperature
and found that the yield could not be improved when the reaction
temperature was adjusted to a lower temperature of 110oC (Table
1, entry 14). To gain the ideal yield, the reaction temperature was
raised and it turned out that the 130oC could bring a highest yield
of 79% than others including 140oC and 150oC (Table 1, entries
15-17). Additionally, the amount of KOH was also examined and
reducing the amount of KOH to 3.0 equiv and 4.0 equiv or
increasing it to 6.0 equiv and 7.0 equiv could not raise the yield
evidently. After further optimization, the best results were
obtained using a treatment of 5 mol% CuI, 10 mol% NaAsc and
5 equiv of KOH in Toluene-CH3OH (1:3, v:v) at 130oC for 48 h,
affording the desired 1-monosustituted-1, 2, 3-triazole 3b in 79%
yield (Table1, entry 15).
developed an easy one-pot synthesis of l-monosubstituted
aliphatic 1, 2, 3-triazoles from aliphatic halides (C1 and Br),
sodium azide and propiolic acid by a click cycloaddition /
decarboxylation process. Another method has also been
developed for the synthesis of monosubstitued1-aryl 1-H-1, 2, 3-
triazoles from arylboronic acids and prop-2-ynoic acid or CaC2.26
Owing to the development of facile synthesis and modification of
1, 2, 3-triazole compounds, therefore these widely applications
strongly attracted enormous interests.27
Herein, we would like to describe a convenient and efficient
one-pot method for the preparation of 1-monosubstituted-1, 2, 3-
triazoles. In this method, the aryl azides and 2-methyl-3-butyn-
2-ol were involved directly as the starting materials under
copper-catalyst in the presence of KOH by a one-step one-pot
sequence.
Results and Discussion
An initial investigation of the reaction conditions was
conducted using 1-azido-4-methylbenzene 1b and 2-methyl-3-
butyn-2-ol
investigated the effects of base, solvent and temperature
respectively, as summarized in Table 1. No target molecule of 1-
(p-tolyl)-1H-1, 2, 3-triazole 3b was detected when the reaction
Table 1. Selected Optimization of the Reaction Conditions.a
2 as the starting materials. We respectively
Entry
1
Base (eq.)
K3PO4 (5.0)
t-BuOK (5.0)
CH3ONa (5.0)
NaH (5.0)
Solvent
Temp (oC)
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
140
150
130
130
130
130
Yield (%)b
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene / CH3OH = 1 / 1
Toluene
0
2
25
32
28
45
47
61
0
3
4
5
CsOH (5.0)
NaOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (5.0)
KOH (3.0)
KOH (4.0)
KOH (6.0)
KOH (7.0)
6
7
8
9
CH3OH
0
10
11
12
13
14
15
16
17
18
19
20
21
Toluene / CH3OH = 3 / 1
Toluene / CH3OH = 2 / 1
Toluene / CH3OH = 1 / 2
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
Toluene / CH3OH = 1 / 3
51
54
55
65
32
79
74
72
50
61
77
78
a Reaction conditions unless noted: 1-azido-4-methylbenzene 1b (0.3 mmol), 2-methyl-3-butyn-2-ol 2 (0.3 mmol), CuI (0.015 mmol), NaAsc (0.03 mmol)
and base (1.5 mmol) were added to 2 mL of solvent and stirred at 130 oC for 48 h.
b Isolated yield
With the optimized reaction conditions in hand, a series of aryl
azides 1 and 2-methyl-3-butyn-2-ol 2 were then subjected to the
reaction, affording the corresponding 1-monosubstituted-1, 2, 3-
triazole 3. The results summarized in Table 2 showed that aryl
azides carrying either an electron donating substituent or an
electron withdrawing group could proceed well and generated the
desired products 3 in good to excellent yields (Table 2, 3a-3o).
The substrates with electron-donating groups (-CH3, -OMe)
could react well and afford good yields (Table 2, 3b-3f), and
those with an electron-withdrawing groups (-NO2, -F, -Br, -Cl,)
could also produce the desired compounds in moderate to good
yields (Table 2, 3h-3q). Azides with electron-donating groups or
electron-withdrawing groups at meta- or ortho-position could
only produce the corresponding products in lower yields

3
compared with those from substrates bearing a group at para-
position, probably owning to the steric effect (Table 2, 3c and 3d
vs. 3b, 3f vs. 3e, 3i vs. 3h, 3j vs. 3k, 3l and 3m vs. 3n, 3o and 3p
vs. 3q). Moreover, the substrates with electron-donating group (-
OMe) are superior to those with CH3 on the same position (para
or ortho) of N-1 aryl (Table 2, 3e and 3f vs. 3b and 3c). And, the
substrates with electron-withdrawing group (-NO2) on the same
position produced only lower yields in comparison with those
bearing halogens (-F, -Br, -Cl), probably owning to the electronic
effects (3h vs. 3k, 3n and 3q, 3i vs. 3j, 3l and 3o). It should be
noted that the substrate possessing sulfonamido was also
tolerated in the system and good yield was also obtained (3g).
To gain mechanistic insight into the reactions, several control
experiments were carried out (Scheme 2). Firstly, the 2-methyl-3-
butyn-2-ol 2 was consumed completely when heated to 130 C
o
for 48 hours at the existence of KOH in the solvent of PhMe-
MeOH (1:3) (eq. 1). And the generated acetylene 4 could
smoothly combine with 1-azido-4-methylbenzene 1b to form the
target molecules 3b in 73% yield under the standard conditions
without KOH (eq. 2). Meanwhile, the intermediate 2-(1-(p-tolyl)-
1H-1, 2, 3-triazol-4-yl)propan-2-ol 5 could be obtained from the
cycloaddition of 1-azido-4-methylbenzene 1b and 2-methyl-3-
butyn-2-ol 2 in 90% yield (eq. 3), which could also be converted
to the target molecule 3b in 79% yield mediated by KOH in the
same solvent (eq. 4).
Table 2. Substrates Scope a, b
Scheme 2. Controlled Experiments.
On the basis of above results, two plausible routes may be
involved in the construction of 1, 2, 3-triazoles (Scheme 3). In
route I, elimination of 2-methyl-3-butyn-2-ol 2 firstly happened
mediated by KOH, generating acetylene 4, which underwent the
Cu-catalyzed alkyne-azide cycloaddition to form the product 3b.
In route II, the starting material 2 experienced the Cu-catalyzed
cycloaddition for the first step to form 2-(1-(p-tolyl)-1H-1, 2, 3-
triazol-4-yl)propan-2-ol 5, which transformed to the final product
through an elimination process in the action of KOH.
a
Reaction conditions unless noted: aryl azides 1 (0.3 mmol), 2-methyl-3-
butyn-2-ol 2 (0.3 mmol), CuI (0.015 mmol), NaAsc (0.03 mmol) and KOH
(1.5 mmol) were added to 2 mL of solvent and stirred at 130 oC for 48 h.
b Yield of isolated product after column chromatography.
To test the scalability of the current method, the reaction of 1-
azido-4-methylbenzene 1b (7.45 mmol, 1.0 g) and 2-methyl-3-
butyn-2-ol 2(7.45 mmol, 0.6 g) as the starting materials was
carried out on a gram scale, and the product 3b was isolated in
74% yield (Scheme 1).
Scheme 3. Plausible Routes.
Conclusions
In summary, we have developed a highly efficient protocol for
the synthesis of 1-monosustituted-1, 2, 3-triazoles using aryl
azides and 2-methyl-3-butyn-2-ol as the starting materials, in
which a one-step one-pot sequence was involved under the
optimization reaction. It is a facile method for the preparation of
Scheme 1. Gram-Scale Synthesis of Product (3b)

4
Tetrahedron
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Acknowledgments
The authors like to thank the National Natural Science
Foundation of China (Nos. 21262020 and 21662020) for the
financial support.
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5
Highlights
• 2-Methyl-3-butyn-2-ol as the alkyne
source
• Synthesis of 1-monosubstituted-1, 2, 3-
triazoles.
• One-step one-pot sequence.