One-pot, two-step synthesis of 7-methylene-1,5-piperazine-fused 1,2,3-triazoles

Article abstract of DOI:10.1080/00397911.2020.1843178

A facile, one-pot two-step synthesis of 7-methylene-1,5-piperazine-fused 1,2,3-triazole derivatives has been developed. The protocol employs an N-allylation of N-propargylated amines with 2,3-dibromopropene in the presence of K₂CO₃ in DMSO and a CuI-catalyzed [3 + 2] cycloaddition reaction of the synthetic N-(2-bromoallyl)-N-propargyl amines with sodium azide sequentially. Such a method provides methylene-substituted 1,2,3-triazole fused piperazines with some advantages such as simple operation, high efficiency and good product yield (80–91%) through readily available starting materials.

Full text of DOI:10.1080/00397911.2020.1843178

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One-pot, two-step synthesis of 7-methylene-1,5-
piperazine-fused 1,2,3-triazoles
Lu Kuang , Peng Ming , Chang-Feng Wan , Jun-Min Chen & Shou-Ri Sheng
To cite this article: Lu Kuang , Peng Ming , Chang-Feng Wan , Jun-Min Chen & Shou-Ri Sheng
(2020): One-pot, two-step synthesis of 7-methylene-1,5-piperazine-fused 1,2,3-triazoles, Synthetic
Communications, DOI: 10.1080/00397911.2020.1843178
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https://doi.org/10.1080/00397911.2020.1843178
One-pot, two-step synthesis of 7-methylene-1,5-piperazine-
fused 1,2,3-triazoles
Lu Kuanga, Peng Minga,b, Chang-Feng Wana, Jun-Min Chena, and Shou-Ri Shenga
aKey Laboratory of Functional Small Organic Molecule, Ministry of Education, Jiangxi Normal University,
b
Nanchang, P. R. China; Shenzhen Lifotronic Technology Company Limited, Shenzhen, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 28 April 2020
A facile, one-pot two-step synthesis of 7-methylene-1,5-piperazine-
fused 1,2,3-triazole derivatives has been developed. The protocol
employs an N-allylation of N-propargylated amines with 2,3-dibromo-
propene in the presence of K2CO3 in DMSO and a CuI-catalyzed
[3 þ 2] cycloaddition reaction of the synthetic N-(2-bromoallyl)-N-
propargyl amines with sodium azide sequentially. Such a method
provides methylene-substituted 1,2,3-triazole fused piperazines with
some advantages such as simple operation, high efficiency and good
product yield (80–91%) through readily available starting materials.
KEYWORDS
[3 þ 2] cycloaddition; 2,3-
dibromopropene; 7-
methylene-1,5-piperazine-
fused 1,2,3-triazoles; N-
propargylated amines; N-
allylation; one-
pot procedure
GRAPHICAL ABSTRACT
R2
R1
R1
K2CO3
R1
N
NaN3
Br
N
N
H
Br R2
+
N
Br
R2
N
N
DMSO
Introduction
1,2,3-Triazoles are a very important class of heterocyclic compounds, which are widely
applied in pharmaceuticals, agrochemicals, dyes, corrosion inhibitors, biochemicals, pol-
ymers, and functional materials.[1,2] Since Sharpless[3a] and Meldel[3b] groups independ-
ently discovered the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction,
“click chemistry” has received growing interest in the regioselective synthesis of 1,4-
disubstituted 1,2,3-triazoles. Following these pioneering works, many effective synthetic
methods for achieving this ring system have been developed for different purposes.[4]
At the same time, fused 1,2,3-triazoles have also attracted considerable interest due to
their diverse array of pharmaceutical functionalities such as antitumor, antiproliferative,
antivirus and glycosidase inhibitory activities.[5] Among the fused 1,2,3-triazoles family,
1,2,3-triazoles particularly condensed with heterocycles at the 1,5-positions exhibited
significant biological activities.[6,7] For instance, 1,2,3-triazolo[1,5-a]quinoxaline has
shown good affinity toward benzodiazepine and adenosine receptors.[6a,6b] Therefore,
CONTACT Chang-Feng Wan
wanfeng@jxnu.edu.cn; Shou-Ri Sheng
shengsr@jxnu.edu.cn
College of Chemistry
and Chemical Engineering, Jiangxi Normal University, Nanchang, P. R. China.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
L. KUANG ET AL.
Scheme 1. Synthetic routes to 7-methylene-1,5-piperazine-fused 1,2,3-triazoles.
searching convenient access to the fused 1,2,3-triazoles derivatives is highly appealing
work. In recent years, several synthetic routes to 1,2,3-triazoles fused at the 1,5-positions
with a piperazine framework have been described by alkyne-azide intramolecular “click”
reaction from different starting materials such as a-amino acid, primary amine and sul-
famidate derivatives.[8–17] Among them, Ning et al.,[15] have explored that the tandem
hydroazidation/alkyne-azide cycloaddition of diynes with TMS-N3 under Ag2CO3 cataly-
sis to the methylene-substituted triazolo[1,5-a]pyrazines (Scheme 1, Eq. (1)). The forma-
tion of several analogous 1,5-fused-1,2,3-triazole compounds by click reaction of vinyl
azides and propargyl bromides have also been investigated in this study. In addition,
1,3-dipolar cycloaddition followed by intramolecular 6-exodig cycloaddition of diprop-
2-ynylamines was used to construct the similar products (Scheme 1, Eq. (2)).[16] These
methods provided easy access to the desired fused 1,2,3-triazoles, but it needs more
toxic and expensive reagents, as well as vinyl azides, which are not easy to obtain. As
far as we know, there are few reports on triazolo [1,5-a] pyrazine derivatives containing
functional methylene groups. Herein, we report a one-pot, two-step procedure for the
construction of 7-methylene-1,5-piperazine-fused 1,2,3-triazoles by sequent N-allylation
and click reaction from N-propargylated amines, 2,3-dibromopropene and NaN3, as
shown in Scheme 1.
In order to find the most suitable one-pot reaction conditions, N-propargyl benzyl-
amine (1a), 2,3-dibromopropene and NaN3 were chosen as model substrates for the
preparation of 5-benzyl-7-methylene-4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-a]pyrazine
(3a). For this purpose, the formation of N-(2-bromoallyl)-N-propargyl benzylamine
(2a), the key step in the proposed route were firstly explored (Scheme 2), and the corre-
sponding experimental results were outlined in Table 1. As highlighted in Table 1, the
nature of the base played a crucial role in this process, exemplified by the observation

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SYNTHETIC COMMUNICATIONSV
3
CH2=CH(Br)CH2Br
N
N
NaN3
N
N
H
N
Br
N
1a
2a
3a
Scheme 2. Formation of 1,5-piperazine-fused 1,2,3-triazole derivative (3a).
Table 1. Screening of reaction conditions in the synthesis of 2aa.
b
Entry
Base
Solvent
Temperature (ꢀC)
Time (h)
Yield of 2a (%)
1
2
3
4
5
6
7
8
Et3N
DBU
CH3CN
CH3CN
CH3CN
CH3CN
DCE
Toluene
EtOH
Dioxane
DMF
DMSO
DMSO
DMSO
r.t.
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
80
80
6
6
6
6
6
6
6
6
6
6
5
5
0
0
70
75
0
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
51
42
80
85
90
90c
9
10
11
12
aReaction conditions: 1a (1.0 mmol), 2,3-dibromopropene (1.0 mmol), base (1.0 mmol) and solvent (10 mL). bIsolated
c
yield. K2CO3 (1.5 mmol) was used.
that 2a was not formed when triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) were employed (Table 1, entry 1 and 2). In contrast, inorganic bases such as ces-
ium carbonate and potassium carbonate could promote effectively the formation of 2a
in 70% and 75% yields (Table 1, entry 3 and 4), respectively. A screen of solvents
showed that the desired product 2a was not generated when the reaction was carried
out in 1,2-dichloroethane (DCE) or toluene (Table 1, entry 5 and 6), and 2a was formed
in low yields when ethanol and dioxane were used as solvents (Table 1, entry 7 and 8).
After a series of optimization, it was found that acetonitrile, N,N-dimethylformamide
(DMF) and dimethylsulfoxide (DMSO) could be used in this transformation, and
DMSO seemed to be the most suitable solvent for this transformation in comparison
with others. Moreover, increasing the reaction temperature to 80 ꢀC in DMSO could
not only increase the yield of 2a but also shorten the reaction time (Table 1, entry 11).
Further screening showed that increasing the amount of k2CO3 to 1.5 equivalent did
not result in an improved yield of 2a (Table 1, entry 12).
With 2a in hand, without isolating this compound, the reaction mixture was sub-
jected to intramolecular cycloaddition. After further study on the [3 þ 2] cycloaddition
with some copper (I) catalysts such as CuCl, CuBr and CuI, it was found that the
expected triazole derivative 3a, as only product was obtained in 86% yield in the pres-
ence of CuI (10 mol %) and K2CO3 at 65 ꢀC for 5 h, whereas the possible isomers of 3a,
5-benzyl-7-methyl-4,5-dihydro-[1,2,3]triazolo[1,5-a]pyrazine
was
not
observed.
Changing CuI loading from 10 mol % to 20 mol % did not alter the yield of 3a, while
using 10 mol % CuCl or CuBr gave 42% and 68% yields, respectively. In another experi-
ment, the same reaction was tested through thermal cycloaddition (90 ꢀC, 5 h), 3a was
formed in 75% yield with 2a being isolated, and no better results were obtained at an
elevated temperature of 120 ꢀC or prolonging the reaction time.

4
L. KUANG ET AL.
Table 2. Preparation of compounds (3a–3m) via one-pot two-step reaction.a
Entry
R1 (1)
R2
Products (3)
Yield (%)b
1
2
3
4
5
6
7
8
C6H5CH2 (1a)
C6H5CH2 (1a)
C6H5CH2 (1a)
C6H5CH2 (1a)
C6H5CH2 (1a)
H
C6H5
4-ClC6H4
4-CH3C6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
86
81
80
82
89
88
86
81
83
88
92
91
82
CH3
H
H
H
H
H
H
H
H
4-CH3OC6H4CH2 (1b)
4-CH3C6H4CH2 (1c)
2-ClC6H4CH2 (1d)
3-BrC6H4CH2 (1e)
C6H5 (1f)
4-CH3OC6H4 (1g)
4-CH3C6H4 (1h)
4-ClC6H4 (1i)
9
10
11
12
13
3j
3k
3l
3m
aReaction conditions: 1 (1.0 mmol), 2,3-dibromopropene (1.0 mmol), K2CO3 (1.0 mmol) and solvent (6 mL). bIsolated yield.
R2
R1
N
N
path 1
path 2
CuN
N
R2
N
R1
Br
R1
N
N
A
Br R2
N
N
R1
N
N3 R2
2
3
B
Scheme 3. Plausible reaction mechanism.
Finally, the optimized reaction conditions were extended to a variety of N-propargy-
lated amines (1a–1i), derived from benzyl amines and primary aromatic amines, and
the results were summarized in Table 2. As observed from Table 2, for all substrates,
the reaction could proceed smoothly and the corresponding 7-methylene-1,5-piperazine-
fused 1,2,3-triazoles (3a–3m) were obtained in good yields. No significant difference in
reactivity was found for the examined benzyl amines, including those containing 2-
chloro, 3-bromo, 4-methyl, and 4-methoxy groups (Table 2, entries 1–9). It is note-
worthy higher yields were obtained when R2 was methyl group rather than an aryl
group (Table 2, entries 2–5). Furthermore, a variety of arylamines substituted by 4-
methyl, 4-methoxy, 4-chloro on the benzene ring were also converted effectively to the
corresponding products (Table 2, entries 10–13).
On the basis of the above experimental results and the literature reports on the
copper(I)-catalyzed azide-alkyne click reactions,[18a,18b] two plausible mechanistic paths
(1 or 2) could be considered for the formation of products 3, as shown in Scheme 3.
Path 1 involves an initial formation of 1,2,3-triazole copper-intermediate A, followed by
intramolecular Ullmann-type coupling to give 4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5-
a]pyrazines (3). Path 2 takes place a copper-catalyzed Ullmann-type coupling to form
intermediate B firstly, and subsequent intramolecular azide-alkyne cycloaddition produ-
ces the final product 3.

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5
In summary, we have developed a simple and efficient, one-pot, two-step reaction for
the synthesis of 7-methylene-1,5-piperazine-fused 1,2,3-triazole derivatives from readily
available starting materials under mild conditions. Considering the potential broad bio-
activities in such fused bicyclic structures, this method might be practically useful.
Further investigation concerning the scope and synthetic application of the present
functional fused 1,2,3-triazoles is ongoing in our laboratory.
Experimental
N-Propargylated amines (1a–1i) were prepared in good yields by the reaction of primary
amines with propargyl bromides in the presence of anhydrous potassium carbonate in
DMF. The other reagents and solvents were purchased from commercial suppliers and
were used without further purifications. The reaction progress was detected by thin layer
chromatography (TLC) on GF254 silica gel analytical aluminum plates, and the products
were visualized by UV spectrophotometer. Column chromatography was performed using
silica gel 60 (250–400 mesh) with petroleum ether/ethyl acetate as eluent. Melting points
1
were measured with a Beijing-Taike X-4 apparatus without corrected. H NMR and 13C
NMR spectra were recorded in deuterated CDCl3 on an Avance-Bruker 400 MHz NMR
spectrometer, operating at 400 and 100 MHz, respectively. FTIR analyses were performed
with a Perkin-Elmer SP One FTIR spectrophotometer. Microanalyses were performed
with a Carlo Erba 1106 Elemental Analyzer.
General procedure for the preparation of 7-methylene-1,5-piperizine-fused
1,2,3-triazoles
A mixture of N-propargylated amine (1.0 mmol), K2CO3 (1.0 mmol) and 2,3-dibro-
mopropene (1.0 mmol) in DMSO (6 mL) was stirred at 90 ꢀC for 5–6 h until the
reaction was completed (determined by TLC). After cooling to room temperature,
CuI (19 mg, 0.1 mmol) was added to the mixture, and the mixture was then stirred
at 65 ꢀC for 5–6 h (TLC monitoring). After completion, water (15 mL) was added
and the aqueous phase was extracted with EtOAc (3 ꢁ 10 mL). The combined organic
phases were washed with water, dried over anhydrous sodium sulfate, and concen-
trated under vacuum. The residue was loaded onto a column and purified by col-
umn chromatography (silica gel, petroleum ether/ethyl acetate, 10:1) to afford the
final product.
Characterization data of all target compounds, copies of 1H NMR and 13C NMR spectra
of new compounds. This material can be found via the “Supplementary Content”.
Funding
We are grateful to the National Natural Science Foundation of China [No. 21762022], the
Research Program of Jiangxi Province Department of Education [No. GJJ160289, GJJ11380], the
Opening Foundation of National Research Center for Carbohydrate Synthesis [No. GJDTZX-KF-
201414] and the Opening Foundation of Key Laboratory of Functional Small Organic Molecule
of Ministry of Education [No. KLFS-KF-201411] for the financial support.

6
L. KUANG ET AL.
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