A Metal- and Azide-free Oxidative Coupling Reaction for the Synthesis of [1,2,3]Triazolo[1,5-a]quinolines and their Application to Construct C?C and C-P Bonds, 2-Cyclopropylquinolines and Imidazo[1,5-a]quinolines

Article abstract of DOI:10.1002/adsc.202001052

An iodine-promoted one-pot cascade oxidative annulation reaction has been developed for the synthesis of [1,2,3]triazolo[1,5-a]quinolines from methyl azaarenes and N-tosylhydrazines. The reaction has a broad substrate scope and can be easily scaled up to gram-scale. 1,2,3-Triazoles are an important skeletal structure for the construction of C?C and C?P bonds, 2-cyclopropylquinolines and imidazo[1,5-a]quinolines, for which different synthetic applications were explored. (Figure presented.).

Full text of DOI:10.1002/adsc.202001052

Title: A Metal- and Azide-free Oxidative Coupling Reaction for the
Synthesis of [1,2,3]Triazolo[1,5-a]quinolines and their Application
to Construct C-C and C-P Bonds, 2-Cyclopropylquinolines and
Imidazo[1,5-a]quinolines
Authors: Zhi-Hao Shang, Zhen-Xiao Zhang, Wei-Zhao Weng, Yu-Fei
Wang, Tian-Wei Cheng, Qiu-Yi Zhang, Li-Qun Song, Tian-Qi
Shao, Kai-Xuan Liu, and Yan-ping Zhu
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001052
Link to VoR: https://doi.org/10.1002/adsc.202001052

10.1002/adsc.202001052
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
A Metal- and Azide-free Oxidative Coupling Reaction for the
Synthesis of [1,2,3]Triazolo[1,5-a]quinolines and their
Application to Construct C-C and C-P Bonds, 2-
Cyclopropylquinolines and Imidazo[1,5-a]quinolines
Zhi-Hao Shang+, Zhen-Xiao Zhang+, Wei-Zhao Weng+, Yu-Fei Wang+, Tian-Wei
Cheng+, Qiu-Yi Zhang, Li-Qun Song, Tian-Qi Shao, Kai-Xuan Liu, Yan-Ping Zhu*
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education,
Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,
Yantai University, Shandong, Yantai 264005, P. R. China.
E-mail: chemzyp@foxmail.com
+
These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An iodine-promoted one-pot cascade oxidative synthetic applications were explored.
annulation reaction has been developed for the synthesis of
[1,2,3]triazolo[1,5-a]quinolines from methyl azaarenes and
N-tosylhydrazines. The reaction has a broad substrate scope
and can be easily scaled up to gram-scale. 1,2,3-Triazoles are
an important skeletal structure for the construction of C-C and
C-P bonds, 2-cyclopropylquinolines and imidazo[1,5-
a]quinolines, for which different
Keywords: Metal- and azide-free; [1,2,3]Triazolo[1,5-
a]quinolines; Oxidative functionalization; Synthetic
application.
The traditional method to synthesize 1,2,3-triazoles
is through the 1,3-dipolar cycloaddition of azides and
alkynes, also described as the Huisgen reaction.[4]
However, the low efficiency and poor regioselectivity
of this approach greatly limit its widespread
application. The development of the copper(I)-
catalyzed azide–alkyne cycloaddition reaction
(CuAAC) to obtain disubstituted 1,2,3-triazoles has
represented a remarkable advance in triazole synthesis,
and it has become a premier example of “click
chemistry” reaction.[5] Recently, stable and reactive N-
tosylhydrazines reagents have been widely used in
azide-free 1,2,3-triazoles synthesis. For example,
Zhang and co-workers successfully constructed 1,2,3-
triazoles from N-tosylhydrazines and amines through
a copper-mediated reaction (Scheme 1a).[6] Moreover,
a metal- and azide-free strategy for the synthesis of
1,2,3-triazoles has been reported by Wan’s group,
using molecular iodine as the only catalyst and
offering a new perspective for the synthesis of fused
1,2,3-triazoles (Scheme 1b).[7]
Introduction
Triazole moieties have gained special attention as
important five-membered heterocycles due to their
widespread applications in chemistry, biology, and
materials science.[1] More specifically, 1,2,3-triazole
derivatives are utilized in chemical biology research
and drug discovery.[2] In particular, fused 1,2,3-
triazoles are important skeletal structures with a broad
spectrum of biological properties, such as anti-
carcinogenic, anti-photoaging, and anti-diabetic
activity (Figue 1).[3]
Classical protocols for the synthesis of fused 1,2,3-
triazoles mainly rely on the metal-catalyzed
intramolecular 1,3-dipolar cycloaddition of azides
with alkynes and the metal-catalyzed intramolecular
C−C coupling reaction of triazoles with aryl halides
(Scheme 1c).[8] In addition, novel methods for the
synthesis of fused 1,2,3-triazoles have been reported to
Figure 1. Some fused 1,2,3-triazole derivatives with
biological activities.
1
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
avoid the use of explosive and toxic organic materials
such as sodium azides and azide derivatives.[9] In 2014,
the Nagasawa group developed an efficient method for
the preparation of [1,2,3]triazolo[1,5-a]pyridines
through copper(II)-catalyzed oxidative N-N bond
formation using 2-pyridine ketone hydrazones
(Scheme 1d).[10] However, a metal catalyst is still
unavoidable and the starting materials need to be
(Table 1). The desired product 3aa was obtained with
a 50% yield in the presence of I2 (1.5 equiv.) and
K2CO3 (2.0 equiv.) at 100°C in DMSO under air
(Table 1, entry 1). Next, a series of bases were
screened for this reaction, such as Cs2CO3, Na2CO3,
NaHCO3, NaOH, and K3PO4-3H2O (Table 1, entries 2-
6). It was found that K3PO4-3H2O was the most
effective additive and increased the product yield to
62% (Table 1, entry 6). The yield was as high as 75%
when the dose of I2 was increased to 150–300 mol %
(Table 1, entries 7–9). Further optimization of the
reaction temperature revealed that 110°C was optimal
for the reaction (Table 1, entries 10-13). After
optimization of the dosage of K3PO4-3H2O (Table 1,
entries 14-16), the desired product (3aa) was obtained
in an 83% yield using 3.0 equivalents of K3PO4-3H2O
(Table 1, entry 14).
firstly
fabricated.
Recently,
the
elegant
electrochemical dehydrogenative cyclization of
hydrazones of 2-acylpyridines for the synthesis of
[1,2,3]triazolo[1,5-a]pyridines was reported by Xu’s
group (Scheme 1d).[11] This strategy was conducted
under mild conditions without oxidation reagents and
transition-metal catalysts.
Table 1. Optimization Studies for the Preparation of 3aaa.
I2
(equiv.)
1.5
Temp.
(°C)
100
100
100
100
100
100
100
100
100
80
Base
Yield
(%)b
50
Entry
(equiv.)
1
2
K2CO3 (2.0)
1.5
Cs2CO3 (2.0)
54
3
1.5
Na2CO3 (2.0)
48
4
1.5
NaOH (2.0)
43
5
1.5
NaHCO3 (2.0)
54
6
1.5
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (2.0)
K3PO4-3H2O (3.0)
K3PO4-3H2O (4.0)
K3PO4-3H2O (5.0)
62
7
2.0
69
75 (73)c
8
2.5
9
3.0
72
10
11
12
13
14
15
16
2.5
54
2.5
90
63
Scheme 1. Strategies for the synthesis of fused 1,2,3-
triazoles.
2.5
110
120
110
110
110
78
2.5
75
2.5
83
2.5
79
1,2,3-Triazoles play an important role as key
intermediates in organic synthesis.[12] They are
regarded as “masked” diazo compounds and are
widely utilized in cross-coupling reactions for C-C , C-
X and C-P bonds formation.[13] Hence, it is essential to
develop an effective method for the synthesis of fused
1,2,3-triazoles under metal- and azide-free conditions
from simple substrates. Inspired by the preceding
works,[14] we hypothesized that I2 might oxidize the sp3
C-H bond of 2-methyl-azaheteroarenes, which
followed by annulation with N-tosylhydrazines, would
deliver fused 1,2,3-triazoles. The key steps involve
molecular iodine as the activator for the tandem
formation of the C-N bond followed by a formal [3+2]
cycloaddition to afford the desired fused 1,2,3-
triazoles (Scheme 1e).
2.5
78
a)
Reaction conditions: 2-methyl quinoline 1a (0.3 mmol)
and I2 were heated in DMSO (3 mL) for 4-6 h, followed by
TsNHNH2 (0.36 mmol) and additive were added for another
5 h. b) Isolated yields. c) K3PO4 was used.
A series of 2-methyl quinoline derivatives were
examined to assess the generality of this method and
to evaluate the electronic influence of the aromatic
ring substituents. As shown in Scheme 2, while the
quinoline rings bearing electron-donating groups (e.g.,
7-Me, 6,8-Me2, 5-OMe, 7-OMe 7-OEt), the
corresponding products 3ba-3fa were obtained in
moderate to good yields (54-78%). The electron-
withdrawing groups, such as F, Cl, Br, CO2Me, CO2Et,
and CO2CH(CH3)2, could slightly increase the
reactivity (73-80%, 3ga-3na). Furthermore, the 4-
phenyl substituted substrate (1o) also reacted with
TsNHNH2 (2) to give satisfying results (68%, 3oa).
Moreover, two heteroatom containing substrates, 2-
Results and Discussion
According to the description above, 2-methyl
quinoline (1a) and TsNHNH2 (2a) were used as the
model substrates for the optimization of the conditions
methylquinoxaline
(1p)
and
2-methyl-1,8-
2
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
naphthyridine (1q) reacted with TsNHNH2 (2) to
generate the desired products 3pa and 3qa in 82% and
55% yields, respectively. Last, 1-methylisoquinoline
1r gave the corresponding products 3ra in 54% yield.
However, 2-methyl pyridine (2s), 2-methyl-4-ethyl
pyridine (2t), and 2,6-dimethyl pyridine (2u) were not
suitable for the reaction, probably due to the difficulty
of methyl pyridines to generate the intermediate
pyridine-2-carbaldehyde.
Scheme 3. Substrate scope of substituted sulfonylhydrazide
derivatives. Reaction conditions: 1a (0.3 mmol), I2 (0.75
o
mmol) in DMSO (3 mL) at 110 C for 4-6 h, then 2 (0.36
mmol) and K3PO4-3H2O(0.9 mmol) were added and, stirred
at 110 oC until the disappearance of 2 (monitored by TLC).
Isolated yields provided.
which aromatic rings are substituted with diverse
groups, were synthesized using Co(II)-based
metalloradical activation for cyclopropanation.
Notably, the di-substituted olefin substrates were also
compatible with the reaction (5ah-5ai). Following the
success of the formation of 2-cyclopropylquinolines
from [1,2,3]triazolo[1,5-a]quinolines and alkene, the
possibility of performing a one-pot transformation of
methyl azaarenes, alkene, and N-tosylhydrazine was
explored.
Specifically,
the
2-(2-
phenylcyclopropyl)quinoline (5aa) could be obtained
Scheme 2. Substrate scope of substituted 2-methyl
quinolines and derivatives. Reaction conditions: 1 (0.3
in good yield via a one-pot tandem method.
o
mmol), I2 (0.75 mmol) in DMSO (3 mL) at 110 C for 4-6
h, then 2a (0.36 mmol) and K3PO4-3H2O (0.9 mmol) were
o
added and stirred at 110 C until the disappearance of 2a
(monitored by TLC). Isolated yields provided. N.r. = no
reaction.
Next, a series of acylhydrazine derivatives were
examined (Scheme 3). It was found that various
sulfonylhydrazide and acylhydrazine substrates were
all suitable for the reaction to afford the same product
3aa. Aromatic sulfonylhydrazides, such as
benzenesulfonohydrazide 2b and naphthalene-2-
sulfonohydrazide 2c, successfully reacted with 2-
methyl quinoline to deliver the product in a good yield.
Aliphatic ethanesulfonohydrazide 2d could only
afford the product in a moderate yield. Additionally,
aromatic, aliphatic, or conjugated acylhydrazines
substrates 2e-2i only gave the end product in a low
yield.
Considering the unique reactivity of 1,2,3-triazole
moieties
for
various
efficient
synthetic
transformations,[15] the potential application of the
[1,2,3]triazolo[1,5-a]quinolines was investigated. First,
a concise route for the formal synthesis of 2-
cyclopropylquinoline derivatives via the Cobalt(II)
tetraphenylporphyrin (Co(TPP)) catalyzed cyclization
of 1,2,3-triazoles with alkenes is provided in Scheme
4. A series of 2-cyclopropylquinoline derivatives, in
Scheme 4. Synthesis of 2-cyclopropylquinoline derivatives.
Reaction conditions: 3 (0.2 mmol), Co(TPP) (5 mol%) and
o
4 (0.4 mmol) in benzene (2 mL) at 130 C under argon
atmosphere for 12h. Isolated yields provided. dr =
diastereomeric ratio.
3
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
To further explore the application of 1,2,3-
triazolo[1,5-a]quinolines, the construction of
imidazoquinoline through denitrogenative
Scheme 7. It was found that 2-methylquinoline (1a)
was converted into quinoline-2-carbaldehyde (1ab) in
an 88 % yield in the presence of I2 and DMSO at 110
oC for 4 h, whereas this conversion could not proceed
without I2 (Scheme 7a). 2-(Iodomethyl)quinoline
(1aa) was detected in a 30% yield as the
transformation proceeded for 30 min, while quinolin-
2-carboxaldehyde (1ab) was detected in a 42% yield.
Furthermore, 2-(iodomethyl) quinoline (1aa) reacted
with TsNHNH2 (2) to obtain the product (3aa) in good
yield with or without I2 (Scheme 7b). The reaction of
quinolin-2-carboxaldehyde (1ab) with TsNHNH2 (2)
also proceeded smoothly with an excellent yield
(Scheme 7c). These results demonstrate that
transannulation of quinolinetriazoles with nitriles
using BF3·Et2O as catalyst was analyzed (Scheme 5).
Different acyclic and aromatic 1-substituted
imidazo[1,5-a]quinolines were obtained from the
corresponding alkyl and aryl substituted nitriles in
high yields (7aa-7ag). In addition, quinolinetriazoles
can be utilized as robust building blocks to access α-
secondary quinoline via a denitrogenative C−C or C-P
cross-coupling reaction. The reaction of 1,2,3-
triazolo[1,5-a]quinolines (3) with phenylboronic acid
could smoothly produce the 2-benzylquinoline
derivatives (8) in good yields (70-78%). Moreover,
1,2,3-triazolo[1,5-a]quinolines (3) were successfully
applied to the synthesis of 2-picolylphosphoryl
quinoline-2-carbaldehyde
(1ab)
and
2-
(iodomethyl)quinoline (1aa) may be
key
intermediates in the transformation. Subsequently, the
reaction between quinolin-2-carboxaldehyde (1ab)
and TsNHNH2 (2) in EtOH with reflux was examined
to dismiss the possibility of the transformation from
1ab to 3aa (Scheme 7d). The reaction could afford
product 1ac, which could further transform into
product 3aa under standard conditions or without I2
(Scheme 7e). These results indicated that 1ac also
played an important role in the reaction as the potential
intermediate.
derivatives (9) through
a
copper-catalyzed
denitrogenative C-P coupling reaction with
diphenylphosphine oxide. These results demonstrated
that quinolinetriazole could be applied for structural
modification by the incorporation of quinoline units.
Scheme 5. Transformations of [1,2,3]triazolo[1,5-
a]quinolines. Isolated yields provided.
In order to show the potential application of this
synthetic route, the reaction was performed on a gram
scale with 20 mmol of starting material 1a (2.864 g),
giving the desired product 3aa (2.402 g) in a 71% yield
(Scheme 6). This promising result presents the
possibility for large-scale applications.
Scheme 7. Control Experiments.
Based on the results and previous literature reports,
a plausible mechanism was proposed as shown in
Scheme 8 (with 3aa as an example). Initially, 2-
methylpyridine (1a) undergoes an iodination reaction
with I2 to afford the intermediate 2-
(iodomethyl)quinoline (1aa). Subsequently, 2-
(iodomethyl)quinoline (1aa) is oxidized by DMSO to
generate quinoline-2-carbaldehyde (1ab) via
a
Kornblum oxidation. Next, the condensation reaction
between quinoline-2-carbaldehyde (1ab) and
TsNHNH2 (2) leads to the intermediate 1ac, which is
responsible for the annulation and oxidation process
that results in product 3aa.
Scheme 6. Scale-up of the reaction.
To gain further insight into the reaction mechanism,
control experiments were performed as illustrated in
4
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
2-neck 25 mL pressure vial was charged with
[1,2,3]triazolo[1,5-a]quinolines (3) (1.0 equiv.), nitriles (6)
(2 equiv.), BF3·Et2O (25 mol%), dichlorobenzene (DCB)
(0.2 mL) and dichloroethane (DCE) (0.25 mL). The vial was
sealed and the resulting mixture was stirred at 140 °C for 12
h under an air atmosphere. After the reaction completed
(monitored by TLC), solvent was removed under reduced
pressure and then added 50 mL water to the mixture, then
extracted with EtOAc 3 times (3 × 50 mL). The combined
organic phase was washed with brine solution, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
to yield the corresponding product 7.
Scheme 8. Plausible mechanism.
Conclusion
General procedure for the preparation of 2-
benzylquinoline Compounds (8): A 2-neck 25 mL
pressure vial was charged with [1,2,3]triazolo[1,5-
a]quinolines (3) (1.0 equiv.), phenylboronic acid (3 equiv.),
K2CO3 (3 equiv.) and dioxane (1.5 mL). The vial was sealed
and the resulting mixture was stirred at 150 °C for 24 h
under an argon atmosphere. After the reaction completed
(monitored by TLC), solvent was removed under reduced
pressure and then added 50 mL water to the mixture, then
extracted with EtOAc 3 times (3 × 50 mL). The combined
organic phase was washed with brine solution, dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
to yield the corresponding product 8.
A novel and efficient molecular iodine-mediated
coupling cyclization reaction for the synthesis of
[1,2,3]triazolo[1,5-a]quinolines
from
methyl
azaarenes and N-tosylhydrazines was developed. This
method features meta- and azide-free conditions and
has a broad substrate scope and high functional group
tolerance. The protocol provides easy access to
diversely
functionalized
[1,2,3]triazolo[1,5-
a]quinoline derivatives and easy scale-up. Moreover,
several synthetic applications of this methodology
were explored to construct C-C and C-P bonds, 2-
cyclopropylquinolines and imidazo[1,5-a]quinolines.
Future research directions include the exploration of
the further application of the reaction.
General procedure for the preparation of 2-
picolylphosphoryl Compounds (9): A 2-neck 25 mL
pressure vial was charged with [1,2,3]triazolo[1,5-
a]quinolines (3) (1.0 equiv.), diphenylphosphine oxide (1.5
equiv.), Cu(OAc)2 (50 mol %) and dioxane (1.5 mL). The
vial was sealed and the resulting mixture was stirred at
100 °C for 24 h under an argon atmosphere. After the
reaction completed (monitored by TLC), solvent was
removed under reduced pressure and then added 50 mL
water to the mixture, then extracted with EtOAc 3 times (3
× 50 mL). The combined organic phase was washed with
brine solution, dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel to yield the
corresponding product 9.
Experimental Section
General procedure for
the preparation of
[1,2,3]triazolo[1,5-a]quinolines Compounds (3): A 25 mL
pressure vial was charged with 2-methylquinoline (1) (1.0
equiv.) and I2 (2.5 equiv.) in DMSO (3.0 mL). The vial was
sealed and the resulting mixture was stirred at 110 °C for 4-
6 h under an air atmosphere, after disappearance of the
reactant (monitored by TLC), then TsNHNH2 (2a) (1.2
equiv.) and K3PO4-3H2O (3.0 equiv.) were added at 110 oC
for another 5 h. After the reaction completed, and added 50
mL water to the mixture, then extracted with EtOAc 3 times
(3 × 50 mL). The extract was washed with 10% Na2S2O3
solution (w/w), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to Acknowledgements
yield the corresponding product 3.
The authors are grateful to the National Natural Science
Foundation of China (21702091), Science and Technology
Innovation Development Plan of Yantai (2020MSGY114) and
Yantai “Double Hundred Plan”. The authors also thank Talent
Induction Program for Youth Innovation Teams in Colleges and
Universities of Shandong Province. The Graduate Innovation
Foundation of Yantai University (YDZD2035) is gratefully
acknowledged (for Z.-H. Shang). The College Students Innovation
and Entrepreneurship Training Program (S202011066007) are
gratefully acknowledged (for K.-X., Liu, L.-Q. Song, T.-Q. Shao).
General procedure for the preparation of 2-
cyclopropylquinoline Compounds (5): A 2-neck 25 mL
pressure vial was charged with [1,2,3]triazolo[1,5-
a]quinolines (3) (1.0 equiv.), Co(TPP) (5 mol%), styrenes
(4) (2.0 equiv.), and benzene (2.0 mL) under an argon
atmosphere. The vial was sealed and the resulting mixture
was stirred at 130 °C for 12 h. After the reaction completed
(monitored by TLC), benzene was removed under reduced
pressure and chromatographic separation with silica gel to
yield the corresponding product 5.
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5
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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10.1002/adsc.202001052
Advanced Synthesis & Catalysis
FULL PAPER
A Metal- and Azide-free Oxidative Coupling
Reaction for the Synthesis of [1,2,3]Triazolo[1,5-
a]quinolines and their Application to Construct C-
C and C-P Bonds, 2-Cyclopropylquinolines and
Imidazo[1,5-a]quinolines
Adv. Synth. Catal. Year, Volume, Page – Page
Zhi-Hao Shang , Zhen-Xiao Zhang , Wei-Zhao
Weng , Yu-Fei Wang , Tian-Wei Cheng , Qiu-Yi
Zhang, Li-Qun Song, Tian-Qi Shao, Kai-Xuan Liu
and Yan-Ping Zhu*
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