A flow strategy for the rapid, safe and scalable synthesis of N-H 1, 2, 3-triazoles via acetic acid mediated cycloaddition between nitroalkene and NaN3

Article abstract of DOI:10.1016/j.tet.2017.05.065

The N-unsubstituted 4-aryl-1H-1,2,3-triazoles were synthesized via the acetic acid promoted cycloaddition between β-nitrostyrenes with sodium azide under transition-metal-free conditions in a continuous flow microreactor. The continuous-flow microreactor provided a safe environment for the dangerous reagents NaN₃ and nitroalkene, and offered such a rapid procedure that the triazoles were formed in less than 4 min. In addition, the excess sodium azide was quenched by the by-product HNO₂ in the presence of acetic acid. The scale-up experiment proved again that the yield did not drop in the flow reaction. Moreover, the synthesis of N-unsubstituted 1,2,3-triazole was also explored via a one pot reaction with aldehyde, nitromethane and sodium azide, and this reaction was monitored with an “in-tube retention time gradient” (IT-RTG) technology, which may be a novel application of the continuous-flow microreactor.

Full text of DOI:10.1016/j.tet.2017.05.065

Accepted Manuscript
A flow strategy for the rapid, safe and scalable synthesis of N-H 1, 2, 3-triazoles via
acetic acid mediated cycloaddition between nitroalkene and NaN
3
Dong Li, Lei Liu, Yu Tian, Yongjian Ai, Zhike Tang, Hong-bin Sun, Gang Zhang
PII:
S0040-4020(17)30566-5
10.1016/j.tet.2017.05.065
TET 28731
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 March 2017
Revised Date: 18 May 2017
Accepted Date: 19 May 2017
Please cite this article as: Li D, Liu L, Tian Y, Ai Y, Tang Z, Sun H-b, Zhang G, A flow strategy for
the rapid, safe and scalable synthesis of N-H 1, 2, 3-triazoles via acetic acid mediated cycloaddition
between nitroalkene and NaN , Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.065.
3
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
A Flow Strategy for the Rapid, Safe and
Scalable Synthesis of N-H 1, 2, 3-Triazoles
via Acetic Acid Mediated Cycloaddition
between Nitroalkene and NaN3
Leave this area blank for abstract info.
Dong Li, ‡ Lei Liu, ‡ Yu Tian, Yongjian Ai,
Zhike Tang, Hong-bin Sun and Gang Zhang **
Department of Chemistry, Northeastern University,
Shenyang 110819, P. R. China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A Flow Strategy for the Rapid, Safe and Scalable Synthesis of N-H 1, 2, 3-
Triazoles via Acetic Acid Mediated Cycloaddition between Nitroalkene and
NaN3
Dong Li, ‡ Lei Liu, ‡ Yu Tian, Yongjian Ai, Zhike Tang, Hong-bin Sun and Gang Zhang **
a
Department of Chemistry, Northeastern University, Shenyang 110819, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
The N-unsubstituted 4-aryl-1H-1,2,3-triazoles were synthesized via the acetic acid promoted
cycloaddition between β-nitrostyrenes with sodium azide under transition-metal-free conditions
Received in revised form
Accepted
Available online
in a continuous flow microreactor. The continuous-flow microreactor provided a safe
environment for the dangerous reagents NaN3 and nitroalkene, and offered such a rapid
procedure that the triazoles were formed in less than 4 minutes. In addition, the excess sodium
azide was quenched by the by-product HNO2 in the presence of acetic acid. The scale-up
experiment proved again that the yield did not drop in the flow reaction. Moreover, the synthesis
of N-unsubstituted 1,2,3-triazole was also explored via a one pot reaction with aldehyde,
nitromethane and sodium azide, and this reaction was monitored with an "in-tube retention
time gradient" (IT-RTG) technology, which may be a novel application of the continuous-flow
microreactor.
Keywords:
continuous flow microreactor
1,2,3-triazole
nitroalkene
acid promote
2017 Elsevier Ltd. All rights reserved
.
in-tube retention time gradient
Introduction
The 1,2,3-triazoles are a class of vital heterocycle moieties
that display many biological activities,10 such as anti-HIV,11
antifungal,12 antiviral,13 and antimicrobial aitivities.14 So the
synthesis of 1,2,3-triazoles was concerned greatly in recent
years.15 The conventional method of generating triazoles is the
Huisgen 1,3-dipolar cycloaddition of alkynes with azides.16 The
Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was
independently developed by the Sharpless’ group and Meldal’ s
group to offer 1,4-disubstituted triazoles, and it was well-known
as “click chemistry” due to its high chemo and regioselectivity.17
Many works have revealed that the synthesis of triazole can
greatly benefit from continuous-flow processing.18 As the
triazole are usually synthesized as the pharmaceutical, in-line
metal scavenging, nontoxic metal catalyst and metal-free
synthesis have to be developed.19 In 2005, Quiclet-Sire and
Amantini respectively reported that nitroalkenes were utilized to
form the N-unsubstituted 4-aryl-1H-1,2,3-triazoles,20 which have
great potential in anticancer drugs.21 That bright an alternative
In the past decades, more and more research works have
concentrated in the development of microreactors and continuous
flow technology, because the continuous-flow microreactors
possess a great many of benefits towards conventional batch-
style reactor, such as easily controllable reaction parameters and
excellent scalability to industrial level by simple number-
amplification1. The continuous-flow microreactor have been
applied in many kinds of organic reactions such as selective
nitrification,2 catalytic hydrogenation,3 oxidation,4 Grignard
reaction,5 synthesis of heterocycles,6 C-C and C-N coupling.7
Moreover, because of the enhanced heat- and mass-transfer
ability, the flow reactor provides safe reaction environment to
avoid the potential explosion caused by regional overheating or
high active chemicals.8 In addition, the high surface area-to-
volume-ratio and low waste generation are also well-known
advantages of continuous-flow reactor.9
———
Corresponding author.
**Corresponding author.
Tel.: +862483671751; e-mail: sunhb@mail.neu.edu.cn
Tel.: +862483671751; e-mail: zhanggang99@126.com
‡ These authors contributed equally.

2
Tetrahedron
route to synthesize the triazole via the cyclization of
The detailed exploration for the amounts of the acetic acid is
ACCEPTED MANUSCRIPT
nitroalkenes with azides.22 However, hydrazoic acid may be
generated in the reactions, which is toxic and explosive
substance, and nitroalkenes are not as safe as the terminal
presented in the table S2.
It seems that the acidity of the reaction solution was a key
factor. The yield improved with the increasing amount of acid in
low acidity range, but too much acid would protonate NaN3 then
the cyclization was restrained because the [3+2] cycloaddition of
alkynes. Conducting the reaction in
a
continues-flow
microreactor will limit the contact of toxic intermediates,
because they can be consumed in situ.23 In 2010 and 2011,
Bernhard Gutmann and Prakash B. Palde have independently
reported the application of continuous-flow microreactor in the
synthesis of tetrazoles, which was the acid-promoted cyclization
of nitrile with the risky reagent NaN3.24 Therefore, we believe
that the continuous-flow manner will be a good strategy for the
cyclization of nitroalkenes with NaN3. In this paper, we describe
that acetic acid catalyzed to afford 4-aryl-1H-1,2,3-triazoles in a
concise self-made continuous-flow microreactor.
-
N3 to electro-deficient olefin is the critical step. So the optimal
amount of weak acid (2.5 equiv. acetic acid) can play the equal
role to a small amount of strong acid (0.5 equiv. TsOH 22b), and
the “lethal dose” of AcOH is several folds of TsOH (table 1,
entry 8 and 10). It’s interesting that the optimal dose for AcOH is
the “lethal dose” for TsOH. Because one molecule of HNO2
generates with the formation of triazole, the existence of
sufficient HOAc is helpful to consume the excess NaN3 due to
the following reaction (eq. 1):
Results and Discussion
eq.1
-
The conditions optimization in Batch. The synthesis of 4-
phenyl-NH-1,2,3-triazoles is selected as the model reaction, and
We estimated the residual N3 in the reaction mixture with the
Fe (III) colorimetry,25 and we found that most of the excess NaN3
had been destroyed along with the process of the reaction,
especially in high temperature reaction (table S3). That
highlights the safety of the acetic acid promoted synthetic
method.
it has been promoted by several acid catalyst, including
22b
pꢀ toluenesulfonic acid (TsOH)
and Amberlyst-15.22c
However, when the strong Bronst acids are employed as catalyst,
the releasing of toxic HN3 is inevitable. A weak acid such as
acetic acid may reduce this risk. In the initial exploration, a
mixture of β-nitrostyrene (1a, 0.3 mmol), sodium azide (0.6
mmol), 10 mol% acetic acid was dissolved in DMF then heated
at 60 oC for 1 hour. The 4-phenyl-NH-1,2,3-triazole was
obtained in 56% isolated yield. We optimized the reaction
conditions carefully in a sealed tube, and we found that the
amount of acetic acid was the key point (table 1). With the
optimal amount of acetic acid (2.5 equiv. to β-nitrostyrene), the
target product was obtained with >90% yield. Either more or less
acetic acid gave unsatisfactory yield, especially when the dosage
of acetic acid increased to 20 equivalents, the reaction did not
occur and no desired product was obtained, whereas a catalyst-
free reaction still afforded 40% yield of triazole.
Additionally, Lewis acids are less active than acetic acid, and
bases are ineffective. Various solvents were tested, such as
methanol, water, dichloromethane, acetone and toluene. The
polar non-protonic solvent gave the best result. That agreed with
the known report 22b (For full version of conditions optimization,
see supporting information).
Table 2. The optimization for the synthesis of 4-phenyl-NH-
1, 2, 3-triazoles in the continuous flow reactor and its
schematic diagram a
Table 1. Conditions optimization for the cyclization of ꢀ β-
nitrostyrene with NaN3 to afford 1,2,3-triazole in batch a
Entry
Amount of acetic acid (equiv.)
Yield (%)
Flow rate Retention
Temp
(oC)
Entry
Yield (%)
1
2
3
4
5
6
7
0.1
0.5
1.0
2.0
2.5
5.0
10
56
77
85
84
93
77
71
(mL/min)
time (min)
1
2
3
4
5
1.0
1.65
120
150
200
200
200
75
81
85
93
93
1.0
1.65
1.0
1.65
0.5
3.3
0.33
5.0
a Reaction conditions: 1a (10 mmol), NaN3 (2.0 equiv.), acetic acid (2.5
equiv.), DMF (66 mL), H2O (3 mL) in continuous flow equipment with a 54
bar back pressure regulator (BPR).
8
9
20
-
0
40
The optimization in continuous-flow microreactor. When
we replaced the batch reaction by a continuous-flow reactor, we
found that the solubility of sodium azide was a problem.
10
11
2.5 (TsOH)
0.5 (TsOH)
0
93 ref. [22b]
a Reaction conditions: 1a (0.3 mmol), NaN3 (2.0 equiv.), acid (indicated
amount) and solvent (2 mL) were heated at 60 oC for 60 minutes.

3
Table 3. AcOH-mediated 1, 3-dipolar cycloaddition of nitroolefins with NaN for the synthesis of 4-Aryl-NH-1,2,3-triazolesa
ACCEPTED MANUSC3RIPT
a Reaction conditions in batch: nitroolefins (0.3 mmol), NaN3 (2.0 equiv.), acetic acid (2.5 equiv.) and DMF (2 mL) were heated at 60 °C for 1 h in a sealed tube.
b Reaction conditions in continuous flow: a mixture of nitroolefins (3.0 mmol), NaN3 (2.0 equiv.), acetic acid (2.5 equiv.), DMF (20 mL) and H2O (1 mL) was
pumped to get through the microreactor at 200 °C with a retention time for 3.3 min. c The reaction was performed at 140 °C for 3 h in batch. d The corresponding
tetrazoles (4-(1H-tetrazole-5-yl) -phenyl-NH-1,2,3-triazole) that was formed from the nitrile was detectable. The isolated yield of the tetrazole is 19% and 25% in
the batch and continuous-flow reaction respectively.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Therefore, minimized water was added into the solvent to
and nitromethane, the protocol that nitroalkenes as substrate
resolve this problem, and more optimization were proceeded as
listed in table 2. The synthesis of 4-phenyl-1,2,3-1H-triazole was
still chosen as the model reaction, and the reaction could be
performed at higher temperature in a microreactor to enhance the
efficiency of synthesis by shortening the reaction time. These
results showed that the reaction in the microreactor was more
efficient than in the sealed tube. When the reaction was
performed at 120 °C and a retention time of 1.65 min, 75% yield
of 1b was obtained (table 2, entry1). Increasing the temperature
from 120 °C to 200 °C, the yield improved by 10% at the same
retention time. To extend the reaction time slightly gave the
excellent yield of triazole, which was 93% at 200 oC for 3.3 min
(table 2, entry 4). To our delight, the reaction in the continuous-
flow microreactor have better chemoselectivity than in the sealed
tube, which because the cycloaddition of nitroalkene with azide
benefits from high temperature as mentioned in the literature.20a
That may be deduced from the high cycloaddition’ activation
energy, so the higher reaction temperature provides the better
selectivity.
seems to be arduous. Encouraged by the recent reports,22g we
attempted to perform the condensation and the cycloaddition in
“one pot” procedure to produce NH-1,2,3-triazoles from the
simple and accessible materials. That meant a more step-
economical method for the synthesis of N-unsubstituted 4-aryl-
1H-1,2,3-triazoles, as the separation of the intermediates is
avoidable. We conducted the three-component reaction of
nitroalkane, aldehydes and sodium azide with acetic acid as the
catalyst. The model reaction of benzaldehyde, nitromethane and
sodium azide was carried out under different reaction conditions.
Scheme1. The scale-up capabilities of the continuous-flow
process
0.3mmol
70mmol
0.2mmol
93%
81%
95%
Ref. 22b
TsOH as catalyst
Ref. 22c
The scope of functionalities. Under the optimized
experimental conditions, a range of nitroolefins were used to
investigate the scope of the methodology both in batch and the
continuous flow equipment. As shown in table 3, the nitroolefins
with electron-donating or electron-withdrawing group on aryl
ring all reacted smoothly with sodium azide to afford the
corresponding products in good to excellent yields. Especially,
the nitroolefins bearing isopropyl, methoxyl and chloro atom
gave excellent yields (table 3, entries 1, 2, 5, 8, 9). The strong
electron-withdrawing substituents on the aryl ring are
disadvantageous for the reaction, and the corresponding products
were acquired in moderate yields (table 3, entries 10 and 11). As
[3+2] cycloaddition was catalyzed by acid, the reaction of
nitroolefin bearing basic amino group was so slow that only a
Amberlyst as
catalyst
10mmol
0.3mmol
10mmol
86%
93%
93%
This work
Acetic acid as
catalyst
The best results was obtained when the reaction was carried
o
o
out at 140 C for 80 min in the presence of 8 equivalent acetic
small amount of 12b and 13b was formed at 60 C for 1 hour.
o
acid and 1 equivalent ammonium acetate, and the yield was up to
97% (table 4, entry 1). The lower reaction temperature did not
give a desired yield of triazole (table 4, entry 2). Furthermore,
the lack of either glacial acetic acid or ammonium acetate led to
the decrease of the yield (Table 4, entry 3, 4).
Raising the temperature to 140 C and extending the reaction
time to 3 h gave the satisfactory results. As expected, the
reactions in continuous flow microreactor possessed better
selectivity than in batch for most substrates. For example, TLC
monitoring showed several by-products in the reactions of 7a in
batch, but only few of them were detectable in the continuous-
flow protocol. Besides, both of 12b and 13b obtained good
yields in such a short retention time.
Under the optimized reaction conditions, a range of aldehydes
were used to investigate the tolerance of the reaction. For
aromatic aldehydes, the desired triazoles were obtained in good
to excellent yields after isolated by silica gel chromatography
(Table 4, entries 1, 5~11). Obviously, the influence of the
functional group for the reaction was matched with the stepwise
synthesis. The aromatic aldehydes bearing halogen atom,
methoxy and alkyl group had a positive impact on the reaction,
but the substrates with strongly electron-withdrawing group,
such as NO2, gave relatively low yields (Table 4, entry 10).
Besides, because some nitroolefins are not easy to acquire, one-
pot procedure to directly obtain the 4-aryl-1H-1,2,3-triazoles is
favorable.
The scaled-up study for the synthesis of triazoles. To
investigate the scale-up capabilities of the continuous process
beyond laboratory scale, a gramscale reaction was performed
(Scheme 1). The flow process was run continuously at the flow
rate of 0.5 mL/min, and 73 mL of reaction liquid contained 10
mmol of β-nitrostyrene was collected in 146 minutes and gave
1.35g of 1b. The yield was 93%. We compare our results with
other reported methods on gram scale (scheme 1). When the
reaction was catalyzed by p-toluenesulfonic, the yield of
gramscale preparation (70 mmol) of 4-phenyl-NH-1,2,3-triazole
22b
dropped by 12% comparing with the 0.3 mmol-scale reaction,
For continuous flow microreactor, we developed an "in-tube
retention time gradient" (IT-RTG) technology, which is used for
obtaining more data with less experimental operations. When the
reaction mixture was at steady-state, the instantaneous switch of
flow rate may lead to a gradient distribution of the retention time
when the reaction solution were retained in the reaction channel.
In this study, when the solution steadily flew through a 3.0 mL
reaction channel at 1 mL/min, the flow rate was switched
instantaneously to 0.1 mL / min at a certain time. As a result, the
reaction solution remained in the channel was time-gradient
distributed. The retention time of the reaction liquid at the
and yield decreased by 9% as well when the same reaction
catalyzed by Amberlyst-15 was amplified to 10 mmol scale from
0.2 mmol-scale.22c From the reported results above, we can
deduce that the amplification effect is very serious in this
reaction, especially in batch. The continuous-flow manner can
easily solve the problem because the chemical reaction has been
in a steady state during the reaction. Without any losing of yield
we amplified the reaction to 10 mmol scale from 0.3 mmol.
The synthesis of triazoles from a one-pot procedure.
Because nitroolefins was artificially synthesized from aldehydes

5
channel exit was 3 min, while at the entrance was 30 min and in
89% for 1c and 85% for 4c. With the extension of reaction
time, the yields increased and reached steady-state after 12 min.
ACCEPTED MANUSCRIPT
the channel was gradient-distributed from 3 to 30 min according
to their distances to the exit. Every 0.1 mL solution were
collected for detecting, and 30 samples with different reaction
times were obtained in one experiment, while the reagent
consumption was only several milliliters. We utilized the IT-
RTG technology to monitor the one-pot synthesis of 1,2,3-
triazole, the results were presented in Fig.1 ultimately.
DSC experiments. The cyclization of β-nitrostyrene with
NaN3 is usually an exothermic reaction. As these two kinds of
reagents are dangerous under heating, the differential scanning
calorimetry (DSC) measurements were carried out for the
reactions
of
2,5-dimethoxy-nitro-styrene
and
2,5-
dimethoxybenzaldehyde (one pot reaction). The samples were
heated in a sealed crucible from 25 C to 200 C at a ramp of 10
oC/min. The results are shown in Figure 2.
o
o
Table 4. The synthesis of 4-aryl-NH-1,2,3-triazole through a
three-component reaction a
Entry
R
Product
Yield (%) b
1
phenyl (1c)
1b
1b
1b
1b
2b
3b
4b
8b
9b
11b
97
72c
73d
84e
89
90
68
88
92
70
84
2
phenyl (1c)
3
phenyl (1c)
4
phenyl (1c)
5
4-chlorophenyl（2c）
4-bromophenyl（3c）
3-hydroxphenyl (4c)
2,5-dimethoxyphenyl (5c)
4-isopropylphenyl（6c）
3-nitrophenyl (7c)
6
7
Fig.2 DSC results for the reactions. A: 2,5-dimethoxy-β-
nitrostyrene reacts with NaN3 to afford 1,2,3-triazole. B: 2,5-
dimethoxybenzaldehyde reacts with NaN3 and CH3NO2 to
afford 1,2,3-triazole.
8
9
10
11
In the cyclization of 2,5-dimethoxyꢀ β-nitrostyrene with
NaN3, the reaction rate is quite slow when the temperature is
4-(dimethylamino)phenyl(8c) 12b
o
below 100 C. The reaction dramatically speeds up from about
a Reaction conditions: aldehydes (1 mmol), nitroalkanes (2 mmol), sodium
azide (2 mmol), CH3COOH (8 equiv.), CH3COONH4 (1 equiv.), DMF (6 ml)
at 140 oC for 80 min. b Isolated yield. c the reaction was performed at 60 oC
for 80 min; d in the absence of CH3COONH4; e in the absence of CH3COOH
120 oC, and the exothermic peak appears at 149.66 oC (A). In the
one-pot reaction that forms the same product, there are two
exothermic peaks, one is at 113.13 and the other is at 173.43 C
o
(B). We suspect that the two peaks indicate the two steps of the
reaction, and there are complex side reactions.20a
% (B)
% (A)
94
92
90
88
86
84
Conclusion
We demonstrated that acetic acid was an effective catalyst for
the synthesis of 4-aryl-NH-1,2,3-triazoles from nitroalkenes and
sodium azide, and continuous-flow technology offered
outstanding safety and efficiency. When the reaction was
conducted in a high-temperature/high-pressure system, most
target products were obtained in a very short period of time with
excellent yield. Moreover, the continuous-flow reaction could be
directly amplified without any loss of yield. On the other hand,
the one-pot three-component reaction of aldehydes, nitromethane
and NaN3 was proved to be a convenient protocol for the same
synthesis. The scalable synthesis in the manner of continuous-
flow appears to be well appropriate to produce safely industrial-
scale 4-aryl-NH-1,2,3-triazoles.
0
5
10
15
20
25
30
Time(min)
Experimental Section
Fig.1 Monitoring of the synthesis of 1,2,3-triazole with IT-
RTG technology. A: the reaction of benzaldehyde (1c) B: the
reaction of 4-isopropylbenzaldehyde (4c)
Typical procedure for the synthesis of 1,2,3-triazole in
batch: formation of 4-phenyl-NH-1,2,3-triazoles (1a): A
mixture of 0.3 mmol ꢀ β-nitrostyrene, 0.6 mmol NaN3 , 0.75
mmol HOAc and 2 mL DMF was stirred in a sealed tube at 60 oC
for 1h. On completion of the reaction (detected by TLC), the
reaction liquid was cooled to room temperature, quenched with
Both benzaldehyde (A) and 4-isopropylbenzaldehyde (B)
o
were carried out in the continuous flow microreactor at 190 C
with the IT-RTG operation. In a short time (3 min), the reactions
reached high yield (according to HPLC detection), which were

6
Tetrahedron
H2O (10 mL) and extracted with EtOAc (3×10 mL). The
HRMS Calcd. (ESI) m/z for C9H10N3O2: [M+H]+ 192.0768,
ACCEPTED MANUSCRIPT
organic phase was dried with hydrous Na2SO4 and evaporated in
vacuum. The residue was purified by flash column
chromatography on silica gel (SiO2, hexanes/EtOAc) to afford
the 4-phenyl-NH-1,2,3-triazole 1a as a white solid in 93% yield.
found 192.0773
2-methoxy-6-(1H-1,2,3-triazol-5-yl)phenol (7b), Yellow
solid. m.p. 173-174 oC; 1H NMR (400 MHz, DMSO-D6) ꢀ 8.17
(s, 1H), 7.42 (dd, J = 7.8, 1.3 Hz, 1H), 6.95 – 6.88 (m, 1H), 6.84
(d, J = 7.9 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz, DMSO-
D6) ꢀ 148.60, 144.47, 142.53, 128.28, 119.51, 119.21, 117.46,
111.46, 56.38. HRMS Calcd. (ESI) m/z for C9H10N3O2: [M+H]+
192.0768, found 192.0765
Description of the continuous-flow microreactor. The
reaction channel was a stainless steel tube with inner diameter of
0.03 inches and the effective length of 3.6 meters, so the inner
volume of the reactor was 1.65 mL. The channel was enwound to
the aluminum block that was electrically heated to the desired
reaction temperatures and wrapped with asbestos cloth on the
outside. The reaction mixture was pumped to get through the
reactor pipe by a LC-9A pump, and a 54 bar back-pressure
regulator was equipped at the end of the reaction tube. The
retention time was controlled by the flow rate. All joints are
standard HPLC components which can endure 50 MPa pressure,
so the self-made continuous-flow microreactor possesses
outstanding safety performance in operation.
5-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole (8b), Yellow
solid. m.p. 118-119 oC; H NMR (600 MHz, DMSO-D6) ꢀ 8.19
1
(s, 1H), 7.58 (s, 1H), 7.06 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 8.9
Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H). 13C NMR (151 MHz, DMSO-
D6) ꢀ 153.77, 150.59, 140.90, 129.37, 120.21, 114.53, 113.50,
112.83, 56.46, 55.95. HRMS Calcd. (ESI) m/z for C10H12N3O2:
[M+H]+ 206.0924, found 206.0920
5-(4-isopropylphenyl)-1H-1,2,3-triazole (9b), White solid.
o
1
m.p. 145-150 C; H NMR (400 MHz, DMSO-D6) ꢀ 8.20 (s,
1H), 7.92 – 7.43 (m, 2H), 7.30 (d, J = 8.3 Hz, 2H), 2.89 (hept, J
= 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz,
DMSO-D6) ꢀ 148.58, 145.27, 128.83, 127.27, 126.05, 33.74,
24.32. MS (ESI) m/z for C11H14N3: 188 ([M+H]+)
Typical procedure for the synthesis of 1,2,3-triazole in
continuous-flow microreactor: formation of 4-phenyl-NH-
1,2,3-triazoles (1a): A mixture of 1a (3.0 mmol), NaN3 (2.0
equiv., cation! The sodium azide is dangerous and it must be
operated in a hood), acetic acid (2.5 equiv.) with DMF (20 mL)
and H2O (1 mL) was pumped into the reactor with the
temperature of 200oC under the flow rate of 0.5 mL/min, then
was collected steadily. The yield was calculated from a sample
that was collected in 5 minutes and was handled with a general
work-up procedure described above. 93% of 1b was obtained as
a white solid.
5-phenyl-1H-1,2,3-triazole (1b) White solid. m.p. 140-143 oC;
1H NMR (400 MHz, DMSO-D6) ꢀ 8.28 (s, 1H), 7.91-7.80 (m,
2H), 7.51-7.39 (m, 2H), 7.37-7.23 (m, 1H). 13C NMR (101 MHz,
DMSO-D6) ꢀ 145.41, 131.30, 129.38, 128.25, 127.66, 125.97.
MS (ESI) m/z for C8H8N3: 146 ([M+H]+)
4-(1H-1,2,3-triazol-5-yl)benzonitrile (10b), Yellow solid.
m.p. 170-172 oC; 1H NMR (600 MHz, DMSO-D6) ꢀ 15.41 (s,
1H), 8.59 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.95 (d, J = 8.3 Hz,
2H). 13C NMR (101 MHz, DMSO-D6) ꢀ 133.21, 125.87, 119.83.
MS (ESI) m/z for C9H7N4: 171 ([M+H]+)
4-(3-nitrophenyl)-1H-1,2,3-triazole (11b), Yellow solid. m.p.
o
1
201-204 C; H NMR (400 MHz, DMSO-D6) ꢀ 8.28 (s, 1H),
7.76-7.07 (m, 3H), 6.79 (d, J = 7.1 Hz, 1H). 13C NMR (101
MHz, DMSO-D6) ꢀ 158.31, 130.49, 116.99, 115.70, 112.84. MS
(ESI) m/z for C8H7N4O2: 191 ([M+H]+)
N,N-dimethyl-4-(1H-1,2,3-triazol-5-yl)aniline (12b) Yellow
1
solid. m.p. 162-164 oC; H NMR (600 MHz, DMSO-D6) ꢀ 8.02
5-(4-chlorophenyl)-1H-1,2,3-triazole (2b), White solid. m.p.
155-157 oC; 1H NMR (400 MHz, DMSO-D6) ꢀ 15.22 (s, 1H),
8.40 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H).
13C NMR (101 MHz, DMSO-D6) ꢀ 133.06, 129.49, 127.76. MS
(ESI) m/z for C8H7ClN3: 180 ([M+H]+)
(s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 2.89
(s, 6H). 13C NMR (151 MHz, DMSO-D6) ꢀ 150.63, 126.95,
118.56, 112.88. MS (ESI) m/z for C10H12N4Na: 221 ([M+Na]+)
N,N-diethyl-4-(1H-1,2,3-triazol-5-yl)aniline (13b), Yellow
1
solid. m.p. 105-113 oC; H NMR (400 MHz, DMSO-D6) ꢀ 8.01
5-(4-bromophenyl)-1H-1,2,3-triazole (3b), White solid. m.p.
170-171oC; 1H NMR (600 MHz, DMSO-D6) ꢀ 15.23 (s, 1H),
8.41 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H).
13C NMR (151 MHz, DMSO-D6) ꢀ 143.90, 132.26, 132.10,
127.65, 120.00. HRMS Calcd (ESI) m/z for C8H7BrN3: [M+H]+
223.9823, found: 223.9818
(s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.35
(q, J = 7.0 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H). 13C NMR (101
MHz, DMSO-D6) ꢀ 147.70, 145.10, 127.29, 126.86, 117.37,
112.05, 44.17, 12.96. MS (ESI) m/z for C12H17N4: 217 ([M+H]+)
4-(1H-1,2,3-triazol-5-yl)phenol (14b), White solid. m.p. 213-
214oC; 1H NMR (400 MHz, DMSO-D6) ꢀ 10.61 (s, 1H), 9.80 (s,
1H), 7.77 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H). 13C NMR
(101 MHz, DMSO-D6) ꢀ 191.46, 163.85, 132.62, 128.95,
116.37. MS (ESI) m/z for C8H8N3O: 162 ([M+H]+)
3-(1H-1,2,3-triazol-5-yl)phenol (4b), White solid. m.p. 205-
208 oC; 1H NMR (400 MHz, DMSO-D6) ꢀ 8.30 (s, 1H), 7.37-
7.26 (m, 3H), 6.82 (d, J = 6.6 Hz, 1H). 13C NMR (101 MHz,
DMSO-D6) ꢀ 158.31, 131.97, 130.51, 117.01, 115.73, 112.85.
MS (ESI) m/z for C8H8N3O: 162 ([M+H]+)
Acknowledgements
5-(2,4-dichlorophenyl)-1H-1,2,3-triazole (5b), White solid.
1
m.p. 178-179 oC; H NMR (600 MHz, DMSO-D6) ꢀ 16.03-14.47
This work was financially supported by National Natural
Science Foundation of China (21235004, 21175080) and the
Ministry of Science and Technology (2013ZX09507005).
(s, 1H), 8.73-8.15 (m, 1H), 8.13-7.80 (m, 1H), 7.75 (s, 1H), 7.55
(dd, J = 8.4, 1.9 Hz, 1H). 13C NMR (151 MHz, DMSO-D6) ꢀ
133.78, 132.21, 131.79, 130.20, 128.89, 128.32. MS (ESI) m/z
for C8H6N2Cl2: 214 ([M+H]+)
References and notes
2-methoxy-4-(1H-1,2,3-triazol-5-yl)phenol (6b), White solid.
m.p. 165-171 oC; 1H NMR (400 MHz, DMSO-D6) ꢀ 9.64 (s, 1H),
7.33 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 (d, J = 1.7 Hz, 1H), 6.81 (d, J
= 8.1 Hz, 1H), 3.79 (s, 3H). 13C NMR (101 MHz, DMSO-D6) ꢀ
190.33, 158.71, 149.67, 127.89, 126.20, 116.31, 110.37, 55.80.
1. (a) Rossetti I, Compagnoni M. Chem. Eng. J. 2016; 296: 56;
(b) Wegner J, Ceylan S,Kirschning A. Adv. Synth. Catal. 2012;
354: 17;
(c) Plouffe P, Macchi A, Roberge DM. Org. Process Res. Dev.
2014; 18: 1286;
(d) Wiles C, Watts P. Green Chem. 2012; 14: 38;

7
(e) Wiles C, Watts P. Chem. Commun. 2011; 47: 6512.
2. (a) Ducry L, Roberge DM. 2005; 117: 8186;
(b) Qiao L, Lu Y, Liu BH, Girault HH. J. Am. Chem. Soc. 2011;
133: 19823.
Janson CA, Ryan MD, Zhang GF, Johanson KO, Kirkpatrick
ACCEPTED MANUSCRIPT
RB, Ho TF, Fisher PW, Mattern MR, Johnson RK, Hansbury MJ,
Winkler JD, Ward KW, Veber DF, Thompson SK. J. Med. Chem.
2005; 48: 5644;
3. (a) Bakker JJW, Zieverink MMP, Reintjens RWEG, Kapteijn F,
Moulijn JA, Kreutzer MT. ChemCatChem 2011; 3: 1155;
(b) Gutmann B, Roduit J-P, Roberge D, Kappe CO. 2011; 17:
13146;
(b) Roehrig UF, Awad L, Grosdidier A, Larrieu P, Stroobant V,
Colau D, Cerundolo V, Simpson AJG, Vogel P, Van den Eynde
BJ, Zoete V, Michielin O. J. Med. Chem. 2010; 53: 1172.
22. (a) Habib PM, Raju BR, Kavala V, Kuo C-W, Yao C-F.
Tetrahedron 2009; 65: 5799;
(c) Cantillo D, Damm M, Dallinger D, Bauser M, Berger M,
Kappe CO. Org. Process Res. Dev. 2014; 18: 1360;
(d) Hornung CH, Hallmark B, Mackley MR, Baxendale IR, Ley
SV. Adv. Synth. Catal. 2010; 352: 1736.
(b) Quan X-J, Ren Z-H, Wang Y-Y, Guan Z-H. Org. Lett. 2014;
16: 5728;
(c) Zhang H, Dong D-Q, Wang Z-L. Synthesis 2016; 48: 131;
(d) Wang T, Hu X-C, Huang X-J, Li X-S, Xie J-W. J. Braz.
Chem. Soc 2012; 23: 1119;
(e) Chen Y, Nie G, Zhang Q, Ma S, Li H, Hu Q. Org. Lett. 2015;
17: 1118;
(f) Hu QQ, Liu Y, Deng XC, Li YJ, Chen YF. Adv. Synth. Catal.
2016; 358: 1689;
4. (a) Liu XY, Jensen KF. Green Chemistry 2013; 15: 1538;
(b) Gutmann B, Elsner P, Roberge D, Kappe CO. ACS Catal.
2013; 3: 2669.
5. (a) Riva E, Gagliardi S, Martinelli M, Passarella D, Vigo D,
Rencurosi A. Tetrahedron 2010; 66: 3242;
(b) Deng QL, Shen RW, Zhao ZM, Yan MM, Zhang LX. Chem.
Eng. J. 2015; 262: 1168;
(c) He Z, Jamison TF. Angew. Chem. Int. Edit. 2014; 53: 3353.
6. (a) Chen M, Buchwald SL. Angew. Chem. Int. Edit. 2013; 52:
4247;
(g) Wu LY, Wang XH, Chen YX, Huang QL, Lin Q, Wu MS.
Synlett 2016; 27: 437.
23. (a) Brandt JC, Wirth T. Beilstein J. Org. Chem 2009; 5: 30;
(b) Sahoo HR, Kralj JG, Jensen KF. Angew. Chem. Int. Edit.
2007; 46: 5704-5708.
24. (a) Gutmann B, Roduit J-P, Roberge D, Kappe CO. Angew.
Chem. Int. Edit. 2010; 49: 7101;
(b) Palde PB, Jamison TF. Angew. Chem. Int. Edit. 2011: 50:
3525.
25. Roberson CE, Austin CM. Anal. Chem. 1957; 29: 854.
(b) Otvos SB, Mandity IM, Kiss L, Fulop F. Chem.-Asian J.
2013; 8: 800;
(c) Martin RE, Lenz M, Alzieu T, Aebi JD, Forzy L. Tetrahedron
Lett. 2013; 54: 6703;
(d) DeAngelis A, Wang DH, Buchwald SL. Angew. Chem. Int.
Edit. 2013; 52: 3434.
7. (a) Tsubogo T, Ishiwata T, Kobayashi S. Angew. Chem. Int. Edit.
2013; 52: 6590;
(b) Pommella A, Tomaiuolo G, Chartoire A, Caserta S, Toscano
G, Nolan SP, Guido S. Chem. Eng. J. 2013; 223: 578.
8. (a) Movsisyan M, Delbeke EIP, Berton JKET, Battilocchio C, Ley
SV, Stevens CV. Chemical Society Reviews 2016; 45: 4892;
(b) Oger N, Le Grognec E, Felpin F-X. Organic Chemistry
Frontiers 2015; 2: 590;
(c) Deadman BJ, Collins SG, Maguire AR. Chem.-Eur. J. 2015;
21: 2298.
9. Hu C-T, Shaughnessy KH, Hartman RL. React. Chem. Eng. 2016;
1: 65.
10. Chen C-Y, Lee P-H, Lin Y-Y, Yu W-T, Hu W-P, Hsu C-C, Lin
Y-T, Chang L-S, Hsiao C-T, Wang J-J, Chung M-I. Bioorg. Med.
Chem. Lett. 2013; 23: 6854.
11. Alvarez R, Velazquez S, Sanfelix A, Aquaro S, Declercq E, Perno
CF, Karlsson A, Balzarini J, Camarasa MJ. J. Med. Chem. 1994;
37: 4185.
12. Fung-Tomc JC, Huczko E, Minassian B, Bonner DP. Antimicrob.
Agents Chemother. 1998; 42: 313.
13. Palhagen S, Canger R, Henriksen O, van Parys JA, Riviere ME,
Karolchyk MA. Epilepsy Research. 2001; 43: 115.
14. Sugawara A, Sunazuka T, Hirose T, Nagai K, Yamaguchi Y,
Hanaki H, Sharpless KB, Omura S. Bioorg. Med. Chem. Lett.
2007; 17: 6340.
15. (a) Kappe CO, Van der Eycken E. Chem. Soc. Rev. 2010; 39:
1280;
(b) Jin T, Kamijo S, Yamamoto Y. Eur. J. Org. Chem. 2004;
3789;
(c) Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302.
16. (a) Bai H-W, Cai Z-J, Wang S-Y, Ji S-J. Org. Lett. 2015; 17:
2898;
(b) Huisgen R. Angew. Chem. Int. Edit. 1963; 2: 565;
(c) Huisgen R. Angew. Chem. Int. Edit. 1963; 2: 633.
17. (a) Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Edit.
2001; 40: 2004;
(b) Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew.
Chem. Int. Edit. 2002; 41: 2596;
(c) Tornoe CW, Christensen C, Meldal M. J. Org. Chem. 2002;
67: 3057.
18. Otvos SB, Fulop F. Catal. Sci, Technol. 2015; 5: 4926.
19. (a) Gursel IV, Aldiansyah F, Wang Q, Noel T, Hessel V. Chem.
Eng. J. 2015; 270: 468;
(b) Sun H-b, Li D, Xie W, Deng X. Heterocycles 2016; 92: 423;
(c) Gu JJ, Fang Z, Yang Z, Li X, Zhu N, Wan L, Wei P, Guo K.
Rsc Advances 2016; 6: 89073.
20. (a) Quiclet-Sire B, Zard SZ. Synthesis 2005; 3319;
(b) Amantini D, Fringuelli F, Piermatti O, Pizzo F, Zunino E,
Vaccaro L. The Journal of Organic Chemistry 2005; 70: 6526.
21. (a) Kallander LS, Lu Q, Chen WF, Tomaszek T, Yang G, Tew D,
Meek TD, Hofmann GA, Schulz-Pritchard CK, Smith WW,

ACCEPTED MANUSCRIPT
Supporting Information for:
A Flow Strategy for the Rapid, Safe and Scalable Synthesis of N-H
1,2,3-Triazoles via Acetic Acid Mediated Cycloaddition Between
Nitroalkene and NaN3
Dong Li,‡ Lei Liu, ‡ Yu Tian, Yongjian Ai, Zhike Tang, Hong-bin Sun *, Gang
Zhang **
1. Department of Chemistry, Northeastern University, Shenyang
110819, P. R. China,
Table of Content
1. Table S1. Optimization in batch
2. Table S2. The detailed exploration for the amounts of acetic
acid (equiv.) between 2.0 and 5.0.
3. The estimation of residual NaN3
4. The GC-MS results for batch and continuous-flow reaction
5. The typical procedure of a three-component reaction;
6. Characterization data of products
7. Copies of 1H and 13C NMR spectrums
1

ACCEPTED MANUSCRIPT
Table S1. Conditions optimization of the cyclization of nitrostyrene with
NaN3 to afford 1,2,3-triazole in batcha
Entry
1
catalyst
HCOOH
solvent
DMF
yieldꢀ%ꢁ
78
2
TsOH
DMF
0
3
CuCl2
DMF
76
4
FeCl3
DMF
75
5
BiCl3
DMF
70
6
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
Urotropine
Tri-n-butylamine
-
DMF
93
7
CH3OH
H2O
30
8
trace
trace
trace
trace
90b
78c
9
CH2Cl2
CH3COCH3
toluene
CH3OH
DMF
10
11
12
13
14
15
16
17
DMF
86d
DMF
42
DMF
39
DMF
40
Tri-n-butylamine
+TsOH
18
DMF
72e
aReaction conditions: 1a (0.3 mmol), NaN3 (2.0 equiv), catalyst (2.5 equiv.) and
solvent (2 mL) were heated at 60 oC for 60 minutes. b 6.0 eqive. NaN3 and 120 oC;
c1.6 eq. NaN3 was used. d 1.8 eq. NaN3 was used. e 2.5 equiv. TsOH and 1 equiv.
Tri-n-butylamine.
We can find that less NaN3 lead to decrease of yield (entry 13, 14), and pure bases
2

ACCEPTED MANUSCRIPT
have no catalytic activity (entry 15, 16). However, the co-existence of acid and base
may promote the cyclization (entry 18). Of the tested solvent, only methanol can
afford separable product, and by modifying the reaction conditions, the reaction in
methanol can provide acceptable yield of triazole. Unfortunately, the required dosage
of NaN3 is too much. (entry 12)
Table S2. The detailed exploration for the amounts of acetic acid (equiv.)
between 2.0 and 5.0
Amount of acetic acid
Entry
Yield (%)
(equiv.)
2.3
1
2
3
4
5
6
7
8
90
92
93
92
89
85
80
77
2.4
2.5
2.6
2.7
3.0
4.0
5.0
With the increase of amount of acetic acid, the yield of product rise in the first
stage, and then decrease. And the optimal dosage of acetic acid was determined for
2.5 equiv.
3

ACCEPTED MANUSCRIPT
The estimation of residual NaN3
Generally, the residual sodium azide has to be destroyed in the reactions that
excess sodium azide is used. However, we do not worry about this question in our
protocol. The nitrous acid that generates from the cascade elimination of the
cyclization of nitroalkene and NaN3 can destroy the excess sodium azide in the
present of excess acetic acid. We estimated the azide ion in two reactions (the
formation of 1b and 6b).
We took an internationally recognized method to detect azide, namely Fe(III)
colorimetry at 465 nm wavenumber. As the composition of the reaction liquid is
complicated and we can’t contain all influence factors in the blank solution, the data
we get can only reflect the general trend. Firstly, we confirmed that DMF and tiny
amount of ethyl acetate have no effect on the detection method by preparing the
same concentration of aqueous solution of sodium azide. Then, we made a series of
standard solution of sodium azide containing a certain amount of chromogenic agent
and established the standard calibration of azide concentration and absorbance.
Finally, we diluted the aqueous phase of the reaction extract to a certain volume and
detected the azide concentration to calculate the consumption and the remaining
amount of azide.
Detailed process for 6b
N
HN
N
H3CO
HO
NO2
H3CO
HO
NaN3
+
m
0.7g
195
0.45g
65
M
n
0.0036 mol
1
0.0069 mol
1.92
:
4

ACCEPTED MANUSCRIPT
-
the standard curve of N3
0.3
0.25
0.2
A = 0.0044ρ + 0.0011
R² = 0.9995
0.15
0.1
0.05
0
0
10
20
30
40
50
60
70
Firstlyꢂwe diluted the aqueous phase of the reaction extract to 46.8g. Then, we
took 500 mg of diluent out and diluted to 0.025L containing a certain amount of
chromogenic agent. Later, we conducted the UV-VIS detection at 465 nm
wavenumber.
M(N3-)/500mg =ρ* V =ρ* 0.02500
M(N3-)total = M(N3-)/500mg *46.8g / 0.5g
Consumption (%) = (0.45-M(N3-)total)/0.45
T(ꢃC)
A
140
0.7024
159.39
0.02500
3.98mg
0.373g
17
160
0.6211
140.91
0.02500
3.52mg
0.330g
27
170
0.5076
115.11
0.02500
2.88mg
0.270g
40
190
0.2961
67.05
0.02500
1.68mg
0.157g
65
200
0.1939
43.82
0.02500
1.10mg
0.103g
77
ρ(mg/L)
Volume(L)
-
M(N3 )/500mg
-
M(N3 )total
Consumption(%)
Table S3. The estimation of residual NaN3 in the synthesis of 1b and 6b
Removal of excess NaN3 (%)
Tꢀꢄꢁ
140
For 1b
87
For 6b
17
160
86
27
170
86
40
190
86
65
200
87
77
5

ACCEPTED MANUSCRIPT
In the reaction that formats 1b, the removal of NaN3 is nearly 90% under various
reaction temperature. This is close to the yield of 1b. There is one mole of nitrous
acid generates accompany with triazole, and according to eq. (1) that indicates the
consumption of NaN3 requires one equivalence of HNO2, the results of NaN3
determination is reliable to the yield of triazole.. As this reaction that forms 1b is fast,
there is no difference in various temperature. To further confirm the results, we
checked a slow reaction that was the synthesis of 6b, and we found that as the
temperature raised, the consumption of azide gradually increased. When the
o
-
temperature rises to 210 C, the consumption of N3 achieved to 77%. In our
reactions, when the temperature was 200 oC, there was 80% of 6b was obtained. It is
obvious that the produced HNO2 destroyed the excess sodiun azide.
The GC-MS results for batch and continuous-flow reaction with benzaldehyde
as a substrate
Oven Temp. Program
Rate
-
Temperature(°C)
40.0
Hold Time(min)
5.00
6.00
300.0
20.00
6

ACCEPTED MANUSCRIPT
No.1 and No.2 are the result of the batch and the continuous-flow reaction,
respectively. Due to the hot fluid was collected with plastic tube, some plasticizer
dissolved in the reaction liquid. Some oligomer are undetectable in the GC-MS. The
peak at 26.617 is assigned to the triazole. The peak at 29.269 represents for unknown
by-product. The substance appeared at 46.521 min is the product of Michael addition
that nitroolefin with acetic acid. The peak at 48.313 is assigned to the
triphenylbenzene. The peak at 49.423 represents for triphenylbenzene contains one
nitro.
The typical procedure for the synthesis of triazole via the three-component
reaction
The mixed of aldehydes (1mmol), nitroalkanes (2 mmol), sodium azide (2 mmol),
CH3COOH (8 equiv.) and CH3COONH4 (1 equiv.) were stirred in DMF (6 mL) at
o
140 C for 80 min. After completion of the reaction (detected by TLC), the reaction
mixture was cooled to room temperature, then quenched with H2O (30 mL) and
extracted with EtOAc (3×30 mL). The organic layers was dried over anhydrous
Na2SO4 and evaporated in vacuum. The residue was purified by flash column
chromatography on silica gel (SiO2, hexane/EtOAc) to afford the
4-phenyl-NH-1,2,3-triazole 1a as a white solid in 97% yield. Other of
4-aryl-NH-1,2,3-triazoles were prepared by the similar procedure.
Characterization data of products
1b
o
1
5-phenyl-1H-1,2,3-triazole (1b)1 White solid. m.p. 140-143 C; H NMR (400
MHz, DMSO-D6) δ 8.28 (s, 1H), 7.91-7.80 (m, 2H), 7.51-7.39 (m, 2H), 7.37-7.23
(m, 1H). 13C NMR (101 MHz, DMSO-D6) δ 145.41, 131.30, 129.38, 128.25,
127.66, 125.97. MS (ESI) m/z for C8H8N3: 146 ([M+H]+)
2b
7

ACCEPTED MANUSCRIPT
o
5-(4-chlorophenyl)-1H-1,2,3-triazole (2b),1 White solid. m.p. 155-157 C; 1H
NMR (400 MHz, DMSO-D6) δ 15.22 (s, 1H), 8.40 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H),
7.53 (d, J = 8.6 Hz, 2H). 13C NMR (101 MHz, DMSO-D6) δ 133.06, 129.49, 127.76.
MS (ESI) m/z for C8H7ClN3: 180 ([M+H]+)
3b
5-(4-bromophenyl)-1H-1,2,3-triazole (3b),1 White solid. m.p. 170-171oC; 1H
NMR (600 MHz, DMSO-D6) δ 15.23 (s, 1H), 8.41 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H),
7.66 (d, J = 8.4 Hz, 2H). 13C NMR (151 MHz, DMSO-D6) δ 143.90, 132.26, 132.10,
127.65, 120.00. HRMS Calcd (ESI) m/z for C8H7BrN3: [M+H]+ 223.9823, found:
223.9818
4b
3-(1H-1,2,3-triazol-5-yl)phenol (4b),2 White solid. m.p. 205-208 oC; 1H NMR (400
13
MHz, DMSO-D6) δ 8.30 (s, 1H), 7.37-7.26 (m, 3H), 6.82 (d, J = 6.6 Hz, 1H). C
NMR (101 MHz, DMSO-D6) δ 158.31, 131.97, 130.51, 117.01, 115.73, 112.85. MS
(ESI) m/z for C8H8N3O: 162 ([M+H]+)
5b
8

ACCEPTED MANUSCRIPT
1
5-(2,4-dichlorophenyl)-1H-1,2,3-triazole (5b),1 White solid. m.p. 178-179 oC; H
NMR (600 MHz, DMSO-D6) δ 16.03-14.47 (s, 1H), 8.73-8.15 (m, 1H), 8.13-7.80
(m, 1H), 7.75 (s, 1H), 7.55 (dd, J = 8.4, 1.9 Hz, 1H). 13C NMR (151 MHz,
DMSO-D6) δ 133.78, 132.21, 131.79, 130.20, 128.89, 128.32. MS (ESI) m/z for
C8H6N2Cl2: 214 ([M+H]+)
6b
2-methoxy-4-(1H-1,2,3-triazol-5-yl)phenol (6b), White solid. m.p. 165-171 oC; 1H
NMR (400 MHz, DMSO-D6) δ 9.64 (s, 1H), 7.33 (dd, J = 8.1, 1.8 Hz, 1H), 7.27 (d,
J = 1.7 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.79 (s, 3H). 13C NMR (101 MHz,
DMSO-D6) δ 190.33, 158.71, 149.67, 127.89, 126.20, 116.31, 110.37, 55.80. HRMS
Calcd. (ESI) m/z for C9H10N3O2: [M+H]+ 192.0768, found 192.0773
7b
2-methoxy-6-(1H-1,2,3-triazol-5-yl)phenol (7b), Yellow solid. m.p. 173-174 oC;
1H NMR (400 MHz, DMSO-D6) δ 8.17 (s, 1H), 7.42 (dd, J = 7.8, 1.3 Hz, 1H), 6.95
– 6.88 (m, 1H), 6.84 (d, J = 7.9 Hz, 1H), 3.82 (s, 3H). 13C NMR (101 MHz,
DMSO-D6) δ 148.60, 144.47, 142.53, 128.28, 119.51, 119.21, 117.46, 111.46,
56.38. HRMS Calcd. (ESI) m/z for C9H10N3O2: [M+H]+ 192.0768, found 192.0765
9

ACCEPTED MANUSCRIPT
8b
5-(2,5-dimethoxyphenyl)-1H-1,2,3-triazole (8b), Yellow solid. m.p. 118-119 oC;
1H NMR (600 MHz, DMSO-D6) δ 8.19 (s, 1H), 7.58 (s, 1H), 7.06 (d, J = 9.0 Hz,
13
1H), 6.90 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H), 3.77 (s, 3H). C NMR (151 MHz,
DMSO-D6) δ 153.77, 150.59, 140.90, 129.37, 120.21, 114.53, 113.50, 112.83,
56.46, 55.95. HRMS Calcd. (ESI) m/z for C10H12N3O2: [M+H]+ 206.0924, found
206.0920
9b
1
5-(4-isopropylphenyl)-1H-1,2,3-triazole (9b),3 White solid. m.p. 145-150 oC; H
NMR (400 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.92 – 7.43 (m, 2H), 7.30 (d, J = 8.3
Hz, 2H), 2.89 (hept, J = 6.9 Hz, 1H), 1.21 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz,
DMSO-D6) δ 148.58, 145.27, 128.83, 127.27, 126.05, 33.74, 24.32. MS (ESI) m/z
for C11H14N3: 188 ([M+H]+)
10b
10

ACCEPTED MANUSCRIPT
o
1
4-(1H-1,2,3-triazol-5-yl)benzonitrile (10b),1 Yellow solid. m.p. 170-172 C; H
NMR (600 MHz, DMSO-D6) δ 15.41 (s, 1H), 8.59 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H),
7.95 (d, J = 8.3 Hz, 2H). 13C NMR (101 MHz, DMSO-D6) δ 133.21, 125.87, 119.83.
MS (ESI) m/z for C9H7N4: 171 ([M+H]+)
11b
o
1
4-(3-nitrophenyl)-1H-1,2,3-triazole (11b),1 Yellow solid. m.p. 201-204 C; H
NMR (400 MHz, DMSO-D6) δ 8.28 (s, 1H), 7.76-7.07 (m, 3H), 6.79 (d, J = 7.1 Hz,
13
1H). C NMR (101 MHz, DMSO-D6) δ 158.31, 130.49, 116.99, 115.70, 112.84.
MS (ESI) m/z for C8H7N4O2: 191 ([M+H]+)
12b
N,N-dimethyl-4-(1H-1,2,3-triazol-5-yl)aniline (12b)4 Yellow solid. m.p. 162-164
oC; 1H NMR (600 MHz, DMSO-D6) δ 8.02 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 6.73
(d, J = 8.6 Hz, 2H), 2.89 (s, 6H). 13C NMR (151 MHz, DMSO-D6) δ 150.63, 126.95,
118.56, 112.88. MS (ESI) m/z for C10H12N4Na: 221 ([M+Na]+)
13b
11

ACCEPTED MANUSCRIPT
N,N-diethyl-4-(1H-1,2,3-triazol-5-yl)aniline (13b), Yellow solid. m.p. 105-113 oC;
1H NMR (400 MHz, DMSO-D6) δ 8.01 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 6.71 (d, J
13
= 8.8 Hz, 2H), 3.35 (q, J = 7.0 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H). C NMR (101
MHz, DMSO-D6) δ 147.70, 145.10, 127.29, 126.86, 117.37, 112.05, 44.17, 12.96.
MS (ESI) m/z for C12H17N4: 217 ([M+H]+)
14b
o
1
4-(1H-1,2,3-triazol-5-yl)phenol (14b),2 White solid. m.p. 213-214 C; H NMR
(400 MHz, DMSO-D6) δ 10.61 (s, 1H), 9.80 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 6.94
13
(d, J = 8.4 Hz, 2H). C NMR (101 MHz, DMSO-D6) δ 191.46, 163.85, 132.62,
128.95, 116.37. MS (ESI) m/z for C8H8N3O: 162 ([M+H+)
12

ACCEPTED MANUSCRIPT
Copies of 1H and 13C NMR spectrums
13

ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
20

ACCEPTED MANUSCRIPT
21