A two-step continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles under metal- and azide-free conditions

Article abstract of DOI:10.1039/c6ra19022g

A green, general and efficient I₂/TBHP mediated synthetic method toward 1,4-disubstituted 1,2,3-triazoles via the reactions of acetophenones, tosylhydrazine and anilines within 35 min in a two-step continuous flow system has been developed. The

Full text of DOI:10.1039/c6ra19022g

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DOI: 10.1039/C6RA19022G
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ARTICLE
A two-step continuous flow synthesis of 1,4-disubstituted 1,2,3-
triazoles under metal- and azide-free conditions
Jiajia Gu, a Zheng Fang, *a Zhao Yang, b Xin Li, a Ning Zhu, a Li Wan, a Ping Wei a and Kai Guo *a, c
Received 00th January 20xx,
Accepted 00th January 20xx
A green, general and efficient I2/TBHP mediated synthetic method toward 1,4-disubstituted 1,2,3-triazoles via the
reactions of acetophenones, tosylhydrazine and anilines within 35min in a two-step continuous flow system has been
developed. The reaction proceeds smoothly to afford 1,4-disubstituted 1,2,3-triazoles in moderate to good yield under
metal- and azide-free conditions by using I2 as a catalyst.
DOI: 10.1039/x0xx00000x
www.rsc.org/
which were explosive and toxic. Therefore, it is important to
develop an efficient and straightforward method to synthesis
1,2,3-triazoles from simple, readily accessible, and inexpensive
Introduction
The formation of heterocyclic frameworks is an important
part of programs in drug discovery. As an important
compounds, 1,2,3-triazoles have been widely used in organic
synthesis,1 biochemistry,2 and material science.3 Therefore, it
is important to develop general and efficient methods for their
synthesis.4 The pioneer work on the synthesis of 1,2,3-triazole
can be dated back to the 1960s, Huisgen and co-workers
reported the approach for the synthesis of these compounds
through thermal dipolar cycloaddition between alkynes and
azides.5 However, the regioselectivity of this method is poor,
which limits its application. Afterward, Sharpless6 and Meldal7
reported a Cu-catalyzed azide−alkyne cycloaddition (CuAAC)
method for the synthesis of 1,2,3-triazole, which was high
efficiency and had excellent regioselectivity. And 1,2,3-
triazoles can also be prepared by RuAAC,8 IrAAC,9 and Pd-
catalyzed reactions of alkenyl bromides with azides.10 However,
these reactions mentioned above shared a common drawback,
which was that they utilized heavy metals, which limited its
practical application.
materials.
Scheme 1 A proposed route to 1,2,3-triazoles under metal- and azide-free conditions
To overcome this problem, another method was developed
by using organic catalyst instead of metal catalyst.11 And a lot
of 1,2,3-triazoles had been readily obtained through the
incorporation of azides with different reaction partners. For
example the reaction of azides with enols and enamines, 12 the
nitromethylene-based three-component synthesis13 and the
Lewis based-catalyzed azide-zwitterion reaction.14 However,
these reactions required sodium azides or organic azides,
With the striking advances of 1,2,3-triazole synthesis, the
most challenge is to develop a metal- and azide-free method,
which is quite attractive from the economical and green
chemistry points of view. In 2013, Zhang and coworkers
provided a copper-mediated method to achieve the desired
1,4-disubstituted 1,2,3-triazoles without the use of azides.15
Westermann improved Sakai’s reaction and reported the
synthesis of 1,4-disubstituted 1,2,3-triazoles under metal-free
conditions (Scheme 1a).16 Recently, Ramasastry summarized
the synthetic methods for 1,2,3-triazoles.17 To the best of our
knowledge, only few literatures reported chemoselective
formation of 1,4-disubstituted 1,2,3-triazoles under metal- and
azide-free conditions. Ji and coworkers reported the synthesis
of 1,4-disubstituted and 1,5-disubstituted 1,2,3-triazoles
through the cycloaddition of α-chlorotosylhydrazones with
arylamines under metal- and azide-free conditions (Scheme
a.College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
b.School of Engineering, China Pharmaceutical University, No.639 Longmian
Avenue, Nanjing 211198, China.
c. State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
Email: guok@njtech.edu.cn (K. Guo), fzcpu@163.com (Zh. Fang), Tel +86 25 5813
9926, Fax +86 25 5813 9935.
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1 Optimization of the reaction conditions of the first step a
DOI: 10.1039/C6RA19022G
1b).18 Wang and coworkers reported the I2/TPBP mediated
synthesis of 1,4-disubstituted 1,2,3-triazoles. However, the
View Article Online
19
starting materials of these methods were not readily available.
They were always obtained through the reaction of ketones
with tosylhydrazine, which added the step to get the desired
products. And the added step in multistep batch reactions was
not only troublesome, but also time-consuming and less
efficient.
The use of continuous flow microreactors provides a
valuable platform for the development of multistep syntheses.
Because it integrates multiple unit operations into one single
operation and eliminates the handling of intermediate
species.20 Recently, our group had researched the oxidation
amination of alcohol to amide in a two-step continuous flow
reactor with metal-free catalyst.21 In the process, we
successfully integrates alcohol oxidation and amide bond
formation, which are usually accomplished separately, into a
single operation. Here we report a I2/TBHP metdiated two-step
continuous flow synthesis of 1,4-disubstituted 1,2,3-triazoles
(Scheme 1c).
Entry
1
2
Equiv. number
T1 (°C)
25
50
80
50
50
50
50
t (min)
10
10
10
5
20
10
10
Yield (%) b
1:1
1:1
1:1
1:1
1:1
86
98
96
95
98
96
94
3
4c
5d
6e
7f
1:1.2
1.2:1
a
Reaction conditions: solution A: 0.1M of 1a in dioxane, flow rate 0.1mL/min;
solution B: 0.1M of tosylhydrazine in dioxane, flow rate 0.1mL/min, unless
otherwise noted. Isolated yield. solution A: 0.1M of 1a, flow rate 0.2mL/min;
solution B: 0.1M of tosylhydrazine in dioxane, flow rate 0.2mL/min. d solution A:
0.1M of 1a, flow rate 0.05mL/min; solution B: 0.1M of tosylhydrazine in dioxane,
flow rate 0.05mL/min. solution A: 0.1M of 1a, flow rate 0.1mL/min; solution B:
0.12M of tosylhydrazine in dioxane, flow rate 0.1mL/min. solution A: 0.12M of
1a, flow rate 0.1mL/min; solution B: 0.1M of tosylhydrazine in dioxane, flow rate
b
c
e
f
0.1mL/min.
Since the continuous flow system was fit for the multistep
reaction, we designed a two-step continuous flow reactor
system, as shown in Figure 1. It consists of three syringe
pumps, two T-piece micromixers and two microreactors. The
volume of the syringe and two microreactors are 20mL, 2mL
and 10mL, respectively. The mole ratio of reactants and
reaction time can be modulated by changing the flow rate of
syringes. And the temperature was controlled by oil bath.
Table 2 Optimization of the reaction conditions of the second step a
Catalyst
(mol%)
I2 (10)
KI (10)
NIS (10)
I2 (10)
Oxidant
(equiv.)
TBHP (2)
TBHP (2)
TBHP (2)
H2O2 (2)
m-CPBA
(2)
T1
(°C)
50
50
50
50
T2
(°C)
80
80
80
80
t1
(min)
10
10
10
t2
(min)
25
25
25
Yield
(%) b
41
23
38
Entry
1
2
3
4
10
25
Trace
5
6
I2 (10)
I2 (10)
50
50
80
80
10
10
25
25
NP c
TEMPO
(2)
NP
7
8
9
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (20)
I2 (50)
-
50
50
50
50
50
50
50
80
50
10
10
10
10
10
10
10
25
25
25
16.7
33.3
25
Trace
25
64
48
64
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
100
100
100
100
100
10d
11e
12f
13g
Figure 1 A two-step continuous flow reactor system
85
86
25
a
Results and Discussion
At the beginning, a model reaction of acetophenone (1a),
tosylhydrazine and p-aminotoluene (2a) to form 4-phenyl-1-p-
Reaction conditions: solution A: 0.1M of 1a in dioxane, flow rate 0.1mL/min;
solution B: 0.1M of tosylhydrazine in dioxane, flow rate 0.1mL/min; solution C:
0.06M of 2a, 0.005M of catalyst, 0.1M of oxidant in dioxane, flow rate 0.2mL/min,
unless otherwise noted. Isolated yield. NP=No Product. d solution C: 0.03M of
b
c
e
2a, 0.5mM of I2, 0.05M of TBHP in dioxane, flow rate 0.4mL/min. solution C:
0.12M of 2a, 0.01M of I2, 0.1M of TBHP in dioxane, flow rate 0.1mL/min.
solution C: 0.06M of 2a, 0.01M of I2, 0.1M of TBHP in dioxane, flow rate
0.2mL/min. g solution C: 0.06M of 2a, 0.025M of I2, 0.1M of TBHP in dioxane, flow
rate 0.2mL/min.
tolyl-1H-1,2,3-triazole
(3a) were chosen to identify the
f
reaction system. Firstly, we optimized the first step of the
reaction in continuous flow reactor. The results were
summarized in Table 1. Before we started the experiment in
microreactor, a solvent screen in batch experiment was
needed, which indicated that 1,4-dioxane was the optimal
solvent due to the solubility of product. From Table 1 we can
see that the reaction temperature and reaction time of the
first step were 50°C (Table 1, entries 1-3) and 10min (Table 1,
entry 2, 4, 5) , respectively.
Then we continued to optimize the second step which was
initiated by treating acetophenone (1a), tosylhydrazine and p-
aminotoluene (2a) with I2 (10 mol %) in the presence of TBHP
(2.0 equiv), 80 °C for 35min. The yield of the product 3a was
41%. To improve the yield of the product, different catalysts,
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oxidants, reaction temperature and reaction time were tested.
And the results were shown in Table 2. The reaction commercially available anilines was used to investigate the
proceeded less efficiently in other iodine-containing catalysts substrate scope of this method. And the results were shown in
such as KI and NIS (Table 2, entries 1-3). And when other Table 3. Moderate to good yields were obtained in most cases.
oxidants were used instead of TBHP, the results were really The reactions of aniline or 4-substituted anilines afforded
ARTICLE
With the optimized conditions in hand, an array of
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DOI: 10.1039/C6RA19022G
bad (Table 2, entries 1, 4-7). Next, the temperature was corresponding product 3a-3d in 72%-85% yields. And fluoro,
investigated and we observed that when increasing the chloro, and bromo group could be tolerated in the reaction
temperature to 100°C, it led to a significant improvement in conditions to generate the desired functionalized 1,4-
the amount of product 3a. Thus, 100°C was regarded as the disubstituted 1,2,3-triazoles in good yields (Table 3, 3e
optimum temperature (Table 2, entry 1, 8, 9). The reaction What’s more, the reaction was not affected by the position of
time (Table 2, entry 1, 10, 11) and equiv. number of catalyst the substituents on the aromatic ring of anilines (Table 3, 3h
(Table 2, entry 1, 12, 13) were also investigated, which led to 3j). When more sterically hindered substrate ([1,1′-biphenyl]-
best reaction conditions. 2-amine) was applied, the reaction proceeded smoothly (Table
Optimized reaction conditions for a two-step continuous 3, 3k).
−3g).
-
flow synthesis of 1,2,3- triazole had been obtained. And we
Next, a wide range of acetophenones had also been used to
used the similar conditions to investigate the same reaction in test the substrate scope of the reaction, and the results were
batch. The yield of the product was only up to 43%, which was shown in Table 4. Both electron-deficient and electron-rich
much lower than that in continuous flow system. And the substrates could react smoothly to afford the desired products
reaction time in batch was 15 h, which was much longer than in good yields (Table 4, 3m
35 min. Most importantly, the reaction in batch was much acetonaphthone were good substrates for this reaction (Table
more troublesome. The two steps needed to be accomplished 4, 3t 3u). Furthermore, triazoles with heterocyclic substituents,
separately, p-aminotoluene, I2 and TBHP in dioxane were such as furyl and thiophenyl groups, were obtained in high
-3s). 1-acetonaphthone and 2-
,
added to the reaction liquid when acetophenone (1a) and yields (Table 4, 3w, 3x).
tosylhydrazine were reacted completely and isolated, which
Table 4 Scope of acetophenones a
led to time-consuming and less efficient. From these results
we can see that the continuous flow system was fit for the
multistep reaction.
Table 3 Scope of anilines a
a
Reaction conditions: solution A: 0.1M of 1 in dioxane, flow rate 0.1mL/min;
solution B: 0.1M of tosylhydrazine in dioxane, flow rate 0.1mL/min, T1=50°C;
solution C: 0.06M of 2a, 0.005M of I2, 0.1M of TBHP in dioxane, flow rate
0.2mL/min, T2=100°C.
a
Reaction conditions: solution A: 0.1M of 1a in dioxane, flow rate 0.1mL/min;
solution B: 0.1M of tosylhydrazine in dioxane, flow rate 0.1mL/min, T1=50°C;
solution C: 0.06M of 2, 0.005M of I2, 0.1M of TBHP in dioxane, flow rate
0.2mL/min, T2=100°C.
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extracted with ethyl acetate, washed with H2O.ViTewheArtioclregOannlinice
DOI: 10.1039/C6RA19022G
layer was dried over anhydrous sodium sulfate and solvent
was removed under vacuum. And the crude product was
purified by flash chromatography on silica gel by gradient
elution with ethyl acetate in petroleum ether to obtain the
product 3.
4-phenyl-1-p-tolyl-1H-1,2,3-triazole (3a): White solid; 1H
NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H),
7.67 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.36 (dd, J = 14.0,
7.8 Hz, 3H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 146.25,
137.90, 129.26, 128.43, 127.90, 127.35, 124.84, 119.46, 117.79,
116.59, 20.11; HRMS (ESI) m/z calcd for C15H13N3 [M+H]+
236.1182, found 236.1195.
Scheme 2 A large-scale reaction in continuous flow system
To show the application of this new methodology, we
conducted a large-scale reaction in continuous flow system
under the best reaction conditions. And the desired product
was obtained successfully in 83% yield (Scheme 2).
1,4-diphenyl-1H-1,2,3-triazole (3b): White solid; 1H NMR
(400 MHz, CDCl3) δ 8.20 (s, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.81 (d,
J = 7.7 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.47 (t, J = 6.5 Hz, 3H),
7.38 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 147.42,
136.09, 129.24, 128.79, 127.93, 127.78, 127.44, 124.87, 119.56,
116.61; HRMS (ESI) m/z calcd for C14H11N3 [M+H]+ 222.1047,
found 222.1053.
Conclusions
In conclusion, a green, efficient and direct method for the
synthesis of 1,4- disubstituted 1,2,3-triazoles in a two-step
continuous flow system has been developed. This metal- and
azide-free method uses commercial available starting
materials and integrates multistep reactions, which are usually
accomplished separately, into a single operation. And the yield
of the corresponding products was good. It also clearly shows
the major advantage of continuous multistep systems to allow
reaction parameters to be independently adjusted.
1-(4-isopropylphenyl)-4-phenyl-1H-1,2,3-triazole (3c): White
1
solid; H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.94–7.88 (m,
2H), 7.70 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (dd, J =
15.2, 7.9 Hz, 3H), 3.00 (dt, J = 13.8, 6.9 Hz, 1H), 1.31 (d, J = 6.9
Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 148.25, 130.29, 128.92,
128.39, 127.73, 125.87, 120.64, 117.66, 33.87, 23.91; HRMS
(ESI) m/z calcd for C17H17N3 [M+H]+ 264.1495, found 264.1509.
1-(4-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (3d): Light
1
yellow solid; H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.93–
7.88 (m, 2H), 7.71–7.65 (m, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t,
J = 7.4 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 130.38, 128.92, 128.35, 125.85, 122.24,
117.86, 114.83, 55.66; HRMS (ESI) m/z calcd for C15H13N3O
[M+H]+ 252.1131, found 252.1146.
Experimental
General details
Reaction solvents were obtained commercially, and used
without further purification. Commercial reagents were used
as received. Reaction were monitored by thin-layer
chromatography (TLC) on 0.25mm precoated Merck Silica Gel
1-(4-fluorophenyl)-4-phenyl-1H-1,2,3-triazole
(3e): White
1
solid; H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.91 (d, J = 7.9
Hz, 2H), 7.78 (dd, J = 8.8, 4.5 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H),
7.38 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 147.56, 129.10, 127.95, 124.86, 121.57, 121.48,
116.72, 115.87, 115.64; HRMS (ESI) m/z calcd for C14H10N3F
[M+H]+ 240.0932, found 240.0958.
60 F254, visualizing with ultraviolet light. H/13C NMR spectra
1
were recorded on 400’54 ascend purchased from Bruker
Biospin AG, operating at 400/100 MHz, respectively. Chemical
shifts (δ) are reported in parts per million (ppm) downfield
from tetramethylsilane (TMS), which was used as internal
standard. High-resolution mass spectra (HRMS) were obtained
from an Agilent 6520 LC-MS instrument. Flash column
chromatography was performed on Merck Silica Gel 60 (200-
300mesh) using petroleum ether and ethyl acetate.
General procedure for synthesis of compound 3: 5mmol of
acetophenones (1) was dissolved in 50mL dioxane, which was
placed into syringe A. And 5mmol of tosylhydrazine was
dissolved in 50mL dioxane, which was placed into syringe B.
Anilines (2, 3mmol, 1.2eq), I2 (0.25mmol, 0.2eq) and TBHP
1-(4-chlorophenyl)-4-phenyl-1H-1,2,3-triazole
(3f): Light
1
yellow solid; H NMR (400 MHz, DMSO) δ 7.97–7.93 (m, 4H),
7.66–7.60 (m, 2H), 7.54 –7.48 (m, 4H); 13C NMR (101 MHz,
DMSO) δ 167.82, 132.82, 130.75, 129.91, 129.22, 129.02,
128.53, 125.32, 121.65, 119.71; HRMS (ESI) m/z calcd for
C14H10N3Cl [M+H]+ 256.0636, found 256.0664.
1-(4-bromophenyl)-4-phenyl-1H-1,2,3-triazole
(3g): White
1
solid; H NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 7.99–7.90 (m,
4H), 7.90–7.82 (m, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4
Hz, 1H); 13C NMR (101 MHz, DMSO) δ 145.20, 135.82, 132.84,
130.07, 129.02, 128.33, 125.33, 121.87, 119.65; HRMS (ESI)
m/z calcd for C14H10N3Br [M+H]+ 300.0131, found 300.0131.
4-phenyl-1-m-tolyl-1H-1,2,3-triazole (3h): White solid; 1H
NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.95–7.89 (m, 2H), 7.64
(s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.50–7.34 (m, 5H), 2.47 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 140.05, 130.32, 129.56, 128.92,
(70wt% in water, 5mmol, 2eq) were dissolves in 50mL dioxane,
which was placed into syringe C. The flow rate of syringes A, B
and
C
were 0.1mL/min, 0.1mL/min, and 0.2mL/min,
respectively. And the temperature of the two oil baths was set
in 50˚C and 80˚C, respectively. The reaction liquid was
collected, and then quenched by NaHSO3 solution and
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128.40, 125.88, 121.24, 117.63, 21.45; HRMS (ESI) m/z calcd 137.32, 136.09, 128.75, 128.59, 127.69, 126.37, 124.73, 119.50,
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+
for C15H13N3 [M+H]+ 236.1182, found 236.1208.
116.21, 20.32; HRMS (ESI) m/z calcd DfOoIr: 10C.1150H3913/CN63RA[1M90+2H2]G
1-(3-methoxyphenyl)-4-phenyl-1H-1,2,3-triazole (3i): White 236.1143, found 236.1175.
solid; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.92 (dd, J = 5.2,
1-phenyl-4-m-tolyl-1H-1,2,3-triazole (3q): White solid; 1H
3.3 Hz, 2H), 7.50–7.35 (m, 5H), 7.32 (dd, J = 8.0, 1.1 Hz, 1H), NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.83–7.76 (m, 3H), 7.69
6.99 (dd, J = 8.3, 1.8 Hz, 1H), 3.91 (s, 3H); 13C NMR (101 MHz, (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.50–7.44 (m, 1H),
CDCl3) δ 159.65, 147.36, 137.10, 129.54, 129.23, 127.91, 7.36 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 2.43 (s, 3H); 13
C
127.43, 124.87, 116.64, 113.63, 111.38, 105.38, 54.65; HRMS NMR (101 MHz, CDCl3) δ 137.63, 134.56, 132.62, 128.77,
(ESI) m/z calcd for C15H13N3O [M+H]+ 252.1131, found 128.22, 127.81, 127.76, 125.53, 121.93, 119.52, 116.56, 20.46;
252.1125.
4-phenyl-1-o-tolyl-1H-1,2,3-triazole (3j): light yellow oil; H 236.1164.
HRMS (ESI) m/z calcd for C15H13N3 [M+H]+ 236.1143, found
1
NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.92 (d, J = 7.2 Hz, 2H),
1-phenyl-4-o-tolyl-1H-1,2,3-triazole (3r): light yellow solid;
7.46 (t, J = 7.6 Hz, 2H), 7.43 (d, J = 6.4 Hz, 1H), 7.35-7.42 (m, 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.80-7.85 (m, 3H),
3H), 2.28 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.6, 136.5, 7.56 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 2.8 Hz,
133.7, 131.5, 130.3, 129.9, 128.9, 128.3, 126.8, 125.9, 125.8, 3H), 2.55 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.81, 137.03,
121.1, 17.9; HRMS (ESI) m/z calcd for C15H13N3 [M+H]+ 135.72, 130.91, 129.84, 129.52, 129.03, 128.72, 128.42, 126.13,
236.1182, found 236.1198.
1-(biphenyl-2-yl)-4-phenyl-1H-1,2,3-triazole (3k): White solid; [M+H]+ 236.1143, found 236.1154.
1H NMR (400 MHz, CDCl3) δ 7.66–7.57 (m, 3H), 7.53–7.45 (m,
4-(4-methoxyphenyl)-1-phenyl-1H-1,2,3-triazole (3s): White
120.51, 119.72, 21.43; HRMS (ESI) m/z calcd for C15H13N3
1
3H), 7.31 (dd, J = 9.4, 5.3 Hz, 3H), 7.25–7.20 (m, 4H), 7.10–7.06 solid; H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.85 (d, J = 8.7
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 146.40, 136.29, 135.95, Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.8 Hz, 2H), 7.46 (t, J
134.26, 130.13, 129.30, 128.87, 127.76, 127.74, 127.60, 127.50, = 7.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H); 13C NMR
127.15, 127.04, 125.50, 124.74, 120.68; HRMS (ESI) m/z calcd (101 MHz, CDCl3) δ 158.78, 147.25, 134.95, 128.75, 127.67,
for C20H15N3O [M+H]+ 298.1339, found 298.1377.
126.16, 121.88, 119.48 , 115.76, 113.31, 54.34; HRMS (ESI) m/z
1-(naphthalen-1-yl)-4-phenyl-1H-1,2,3-triazole
(
3l): Brown calcd for C15H13N3O [M+H]+ 252.1092, found 252.1104.
1
oil; H NMR (400 MHz, CDCl3) δ 8.18–8.10 (m, 2H), 8.05 (d, J =
4-(naphthalen-1-yl)-1-phenyl-1H-1,2,3-triazole (3t): brown
8.0 Hz, 1H), 7.98 (dd, J = 6.7, 5.2 Hz, 2H), 7.73–7.53 (m, 4H), yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 9.4 Hz, 1H),
7.49 (dd, J = 7.8, 4.2 Hz, 3H), 7.40 (t, J = 6.8 Hz, 1H); 13C NMR 8.27 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 7.8 Hz, 2H),
(101 MHz, CDCl3) δ 147.77, 134.23, 133.76, 130.48, 130.21, 7.82 (d, J = 7.0 Hz, 1H), 7.64–7.52 (m, 5H), 7.49 (t, J = 7.2 Hz,
129.00, 128.48, 128.40, 128.33, 127.96, 127.13, 125.93, 125.04, 1H); 13C NMR (101 MHz, CDCl3) δ 146.58, 136.02, 132.89,
123.60, 122.33; HRMS (ESI) m/z calcd for C18H13N3O [M+H]+ 130.13, 128.85, 128.19, 127.86, 127.51, 126.57, 126.42, 125.78,
272.1182, found 272.1196.
125.09, 124.37, 124.33, 119.60; HRMS (ESI) m/z calcd for
3m): White C18H13N3 [M+H]+ 272.1143, found 272.1154.
4-(naphthalen-2-yl)-1-phenyl-1H-1,2,3-triazole
4-(4-fluorophenyl)-1-phenyl-1H-1,2,3-triazole
(
solid; 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.89 (dd, J = 8.5,
(3u): light
1
5.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.7 Hz, 2H), 7.47 brown yellow solid; H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H),
(t, J = 7.4 Hz, 1H), 7.16 (t, J = 8.6 Hz, 2H); 13C NMR (101 MHz, 8.33 (s, 1H), 8.04–7.98 (m, 1H), 7.97–7.90 (m, 2H), 7.90–7.81
CDCl3) δ 163.05, 160.59, 146.54, 135.98, 128.81, 127.86, (m, 3H), 7.61–7.45 (m, 5H); 13C NMR (101 MHz, CDCl3) δ
126.64, 126.56, 125.44, 125.40, 119.53, 116.38, 115.05, 114.83; 133.95, 132.53, 132.24, 128.81, 127.83, 127.68, 127.24, 126.79,
HRMS (ESI) m/z calcd for C14H10N3F [M+H]+ 240.0892, found 126.52, 125.53, 125.29, 123.66, 122.82, 119.57; HRMS (ESI)
240.0896.
m/z calcd for C18H13N3 [M+H]+ 272.1143, found 272.1147.
4-(4-chlorophenyl)-1-phenyl-1H-1,2,3-triazole
(3n): White
4-(biphenyl-4-yl)-1-phenyl-1H-1,2,3-triazole (3v): White solid;
1
solid; H NMR (400 MHz, DMSO) δ 9.38 (s, 1H), 7.97 (t, J = 8.4 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.00 (d, J = 8.3 Hz, 2H),
Hz, 4H), 7.69–7.50 (m, 5H); 13C NMR (101 MHz, DMSO) δ 7.82 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.2
146.20, 136.53, 132.67, 130.20, 129.96, 129.14, 129.09, 128.82, Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.47 (t, J = 7.7 Hz, 3H), 7.38 (t, J
126.99, 120.02; HRMS (ESI) m/z calcd for C14H10N3Cl [M+H]+ = 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 128.80, 127.83,
256.0563, found 256.0576.
127.82, 126.00, 126.50, 126.00, 125.24, 119.54, 117.48, 116.57;
4-(4-bromophenyl)-1-phenyl-1H-1,2,3-triazole
(
3o): White HRMS (ESI) m/z calcd for C18H13N3 [M+H]+ 298.1300, found
1
solid; H NMR (400 MHz, DMSO) δ 9.39 (s, 1H), 7.94 (dd, J = 298.1327.
16.4, 8.0 Hz, 4H), 7.73 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.9 Hz, 2H),
4-(furan-2-yl)-1-phenyl-1H-1,2,3-triazole (3w): White solid;
7.54 (t, J = 7.4 Hz, 1H); 13C NMR (101 MHz, DMSO) δ 146.27, 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.78 (d, J = 8.1 Hz, 2H),
136.57, 131.99, 129.96, 129.48, 128.83, 127.27, 121.25, 120.02; 7.55 (t, J = 7.7 Hz, 2H), 7.47 (dd, J = 13.3, 5.7 Hz, 2H), 6.94 (d, J
HRMS (ESI) m/z calcd for C14H10N3Br [M+H]+ 300.0038, found = 3.3 Hz, 1H), 6.53 (dd, J = 3.2, 1.7 Hz, 1H); 13C NMR (101 MHz,
300.0064.
CDCl3) δ 144.83, 141.30, 140.11, 135.82, 128.80, 127.88,
1-phenyl-4-p-tolyl-1H-1,2,3-triazole (3p): White solid; 1H 119.51, 116.06, 110.58, 106.16; HRMS (ESI) m/z calcd for
NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.86–7.75 (m, 4H), 7.56 C12H9N3O [M+H]+ 212.0779, found 212.0787.
(dd, J = 10.5, 5.0 Hz, 2H), 7.46 (dd, J = 10.6, 4.3 Hz, 1H), 7.30–
1-phenyl-4-(thiophen-2-yl)-1H-1,2,3-triazole (3x): White solid;
7.26 (m, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 147.46, 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H),
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Journal Name
12 (a) D. B. Ramachary, K. Ramakumar, V. V. Narayana, Chem. -
7.55 (t, J = 7.7 Hz, 2H), 7.47 (dd, J = 12.5, 5.0 Hz, 2H), 7.35 (dd, J
= 5.1, 0.9 Hz, 1H), 7.12 (dd, J = 5.0, 3.6 Hz, 1H); 13C NMR (101
MHz, CDCl3) δ 142.91, 135.86, 131.42, 128.79, 127.89, 126.72,
124.39, 123.55, 119.54, 116.07; HRMS (ESI) m/z calcd for
C12H9N3S [M+H]+ 228.0551, found 228.0583.
View Article Online
Eur. J., 2008, 14, 9143; (b) M. Belkheira, D. E. Abed, J.-M.
Pons, C. Bressy, Chem. - Eur. J., 2011,DO17I:,101.21093197/;C6(cR)A1L9.0J2.2TG.
Danence, Y. Gao, M. Li, Y. Huang, J. Wang, Chem. - Eur. J.,
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Karthik, Angew. Chem., Int. Ed., 2014, 53, 10420; (e) W. Li, Q.
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Acknowledgements
The research has been supported by the National Natural
Science Foundation of China (Grant No.21522604, U1463201
and 21402240); the youth in Jiangsu Province Natural Science
Fund (Grant No.BK20150031, BK20130913 and BY2014005-03);
13 J. Thomas, J. John, N. Parekh, W. Dehaen, Angew. Chem., Int.
Ed., 2014, 53, 10155.
a
Project Funded by the Priority Academic Program
14 W. Li, J. Wang, Angew. Chem., Int. Ed., 2014, 53, 14186.
15 Z. K. Chen, Q. Q. Yan, Z. X. Liu, Y. M. Xu, Y. H. Zhang, Angew.
Chem., Int. Ed. 2013, 52, 13324.
Development of Jiangsu Higher Education Institutions (PAPD).
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6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA19022G
A new method for the formation of 1,4-disubstituted 1,2,3-triazoles in continuous flow
system under metal- and azide-free conditions has been developed. And the
corresponding products were obtained in moderate to good yields.
O
oil bath
R1
oil bath
TsNHNH2
NH2
R2
I2 TBHP
syringe pump
Tube reactor (ID=0.5mm)
N
N
micromixer
N
R2
R1
metal-free,
25min, 67%-90%