Tandem synthesis of highly functionalized 1,2,3-benzotriazines from isocyanides, aniline and dialkyl azadicarboxylate via Cu-catalyzed intramolecular C[sbnd]H activation reactions

Article abstract of DOI:10.1016/j.tetlet.2020.151649

A class of substituted 1,2,3-benzotriazines are obtained in tandem mode reaction by means of Cu-catalyzed intramolecular C[sbnd]H activation of aniline, isocyanides and dialkyl azadicarboxylate in acetonitrile at room temperature in good yields. The speed

Full text of DOI:10.1016/j.tetlet.2020.151649

Journal Pre-proofs
Tandem synthesis of highly functionalized 1,2,3-benzotriazines from isocya-
nides, aniline and dialkyl azadicarboxylate via Cu-catalyzed intramolecular C-
H activation reactions
Manijeh Nematpour, Anna Sedaghat, Hossein Fasihi Dastjerdi, Sayyed Abbas
Tabatabai
PII:
S0040-4039(20)30066-6
DOI:
https://doi.org/10.1016/j.tetlet.2020.151649
TETL 151649
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
23 December 2019
17 January 2020
Please cite this article as: Nematpour, M., Sedaghat, A., Fasihi Dastjerdi, H., Abbas Tabatabai, S., Tandem synthesis
of highly functionalized 1,2,3-benzotriazines from isocyanides, aniline and dialkyl azadicarboxylate via Cu-
catalyzed intramolecular C-H activation reactions, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151649
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Tandem synthesis of highly functionalized
1,2,3-benzotriazines from isocyanides, aniline
and dialkyl azadicarboxylate via Cu-
catalyzed intramolecular C-H activation
reactions
Leave this area blank for abstract info.
Manijeh Nematpour a, Anna Sedaghat a, Hossein Fasihi Dastjerdi b and Sayyed Abbas Tabatabai a,*
O
OR2
NH2
N N
R2O
R3
O
MeCN, r.t,
10 min
NR1
N
R3
CO2R2
CO2R2
R1NC, CuI (10 mol %), KOt-Bu (2.0 mmol)
H
CO2R2
CO2R2
R3
N
N
L-proline (20 mol %), MeCN, r.t, 6 h
N
N
N
H
H
R1 = Ph, tBu, Cyclohexyl
R2 = Me, iPr
R3 = H, Me, NO2, Br, OMe
yields: 76-90%
(10 exampels)
isocyanides, aniline and dialkyl
azadicarboxylate via Cu-catalyzed
intramolecular C-H activation reactions
Tetrahedron Letters
journal homepage: www.elsevier.com
Manijeh Nematpour a, Anna Sedaghat a, Hossein
Fasihi Dastjerdi b and Sayyed Abbas Tabatabai a, *
a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid
Beheshti University of Medical Sciences, Tehran, Iran.
b Student Research Committee, (Department and Faculty of pharmacy),
Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Tandem synthesis of highly
functionalized 1,2,3-benzotriazines from
Triazines are heterocyclic compounds with three nitrogen
atoms that form benzotriazines by bonding to benzene ring [1].
The two possible isomers of benzotriazine (1,2,3-benzotriazines
and 1,2,4-benzotriazines) are of great importance in
pharmaceutical chemistry and pesticides because of their wide
spectrum of action [2]. For example, azinphos-ethyl and
azinphos-methyl are commonly used in agriculture as acaricides
(see Figure 1) [1]. 1,2,3-Benzotriazine compounds have attracted
considerable attention due to potential pharmacological
properties, such as diuretic, sedative, anti-arthritis, analgesic,
antineoplastic, hypoxia-selective cytotoxicity, fungicide and anti-
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A class of substituted 1,2,3-benzotriazines
are obtained in tandem mode reaction by
means of Cu-catalyzed intramolecular C-H
activation of aniline, isocyanides and
dialkyl azadicarboxylate in acetonitrile at
room temperature in good yields. The
speed and ease of carrying out this three-
component reaction under mild one-pot
conditions with available materials,
without using column chromatography,
make it a method of choice to synthesize
Available online
Keywords:
1, 2, 3-benzotriazines
C-H Activation
Cu-catalyzed
substituted
derivatives.
1,2,3-benzotriazines
isocyanides
2009 Elsevier Ltd. All rights reserved.

3
tuberculosis activities in the field of drug design and bioorganic
chemistry [3-10]. Some of 1,2,3-benzotriazines are considered as
the HBp-3 area (hydrogen bond point area) on well-known
GABAA receptor in the benzodiazepine site [11]. Additionally,
these compounds exhibit inhibitory activity against the VEGFR-2
kinase and the proliferation of human microvascular endothelial
cells (MVECs) [12].*
Metal-catalyzed isocyanide-based multicomponent reactions
have previously been reported. The intramolecular
heterofunctionalization of sp2 C–H bond in the aromatic ring is
perfect strategy achieving complex fused-ring heterocycles,
especially for those containing nitrogen with higher atom
efficiency, and easy synthetic approach [18-21].
Our research team have been discovered
a
novel
Numbers of method have been reported for the synthesis of
these scaffolds that mainly require toxic reagents, costly
multicomponent reactions (MCRs) to prepare new heterocyclic
compounds by Cu(I)-catalyzed C-H activation [22-25].
Continuing our previous work and taking into account the
importance of the 1,2,3-benzotriazine scaffold, we developed a
three-component, tandem reaction of isocyanides, aniline and
dialkyl azadicarboxylate in MeCN at room temperature using the
catalyst activation reaction catalyzed by Cu (see Scheme 1). The
developed method was run under mild conditions, with simple
processing and purification, available low-cost starting reagents
and catalysts, and more purified products.
catalysts, harsh conditions and difficult multi-step processes
[13-17]. Therefore, the further development of novel high
performance methods for the synthesis of 1,2,3-benzotriazine is
still valuable.
O
O
P
O
O
P
N
N
S
O
N
N
S
O
O
O
N
N
This study included the synthesis of substituted 1,2,3-
benzotriazine derivatives using
a
copper-catalyzed C-H
activation reactions. The reaction conditions were optimized
based on a preliminary experiment in which structurally diverse
aniline 2a (1.0 mmol), dialkyl azadicarboxylate 1a (1.0 mmol)
and isocyanides 4a (1.5 mmol) were reacted in the presence of a
copper catalyst. The optimization results are presented in Table 1.
Various catalysts, bases and solvents were used to maximize
yield. A relatively good yield was obtained from different tested
catalysts, bases and solvents when the reaction was carried out in
acetonitrile (MeCN), at room temperature and in the presence of
Cu(I) iodide (10 mol%) as a catalyst, L-proline (20 mol%) as a
ligand and KOt-Bu (2.0 mmol) as the base.
azinphos-methyl
azinphos-ethyl
Figure 1. acaricide with benzotriazine structure
———
* Corresponding author at: Department of Pharmaceutical Chemistry,
School of Pharmacy, Shahid Beheshti University of Medical
Sciences, Tehran, Iran.
E-mail: sa_tabatabai@sbmu.ac.ir (S.A Tabatabai).
O
OR2
NH2
N N
R2O
R3
O
2
1
MeCN, r.t,
10 min
NR1
CO2R2
CO2R2
R3
CO2R2
CO2R2
H
R3
N
N
N
N
CuI (10 mol %), KOt-Bu (2.0 mmol)
R1NC
+
N
N
H
L-proline (20 mol %), MeCN, r.t, 6 h
H
4
5
3
Scheme 1. Synthesis of various 1,2,3-benzotriazine derivatives
Table 1 Optimization of reaction conditions for the formation of product 5a from 1.5 mmol of isocyanides, 1.0 mmol of diethyl
azadicarboxylate, 1.0 mmol of aniline, 10 mol % of copper salt as the catalyst and 2.0 mmol of the base, 20 mol % of L-proline
at room temperature
Entry
Catalyst
CuI
Solvent
MeCN
MeCN
DMF
DMF
THF
Base
Yield (%)a
1b
2
3
4
5
6
7
KOt-Bu
NaOH
Cs2CO3
KOt-Bu
KOt-Bu
K2CO3
KOH
83
62
69
72
78
41
34
CuI
CuI
CuI
CuI
CuCl
CuCl
THF
THF

4
Tetrahedron
8
CuCl
THF
KOt-Bu
68
69
38
35
60
37
21
30
22
20
12
9
CuBr
MeCN
DMF
DMF
THF
KOt-Bu
KOH
10
11
12
13
14
15
16
17
18
CuBr
CuBr
NaOH
CuBr
KOt-Bu
KOt-Bu
Cs2CO3
KOt-Bu
K2CO3
Cs2CO3
KOt-Bu
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuSO4
CuSO4
CuSO4
MeCN
DMF
THF
THF
MeCN
THF
a
Reaction time 6 h
b
5 mol% catalyst, reaction time was 11 h
O
OEt
H
NH2
N N
EtO
O
1
2
CO2Et
CO2Et
N
N
N
H
RNC
3
4
O
O
oxidative addition
R
N
H
O
N
Cu
KOt-Bu
C
CuI
CO2H
N
O
N
H
CO2Et
H
N
N
H
Cu
A
N
H
B
CO2Et
reductive elimination
NR
CO2Et
N
N
N
CO2Et
H
5
Scheme 2 Possible formation mechanism of compounds 5
NR1
R3
CO2R2
CO2R2
Table 2 Synthesis of various 1,2,3-benzotriazine derivatives
N
N
N
H
5
Compound R1
R2
R3
Yield of 5 (%)

5
5a
5b
5c
5d
5e
5f
Ph
Et
H
83
85
79
90
81
80
78
82
76
77
t-Bu
Ph
Et
Br
Acknowledgments
Et
Me
NO2
H
t-Bu
t-Bu
Cy
Et
This work was supported by the Research Council of
Shahid Beheshti University of Medical Sciences.
Et
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
H
References and notes
5g
5h
5i
Cy
Me
H
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t-Bu
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OMe
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Finally, ten analogs of 1,2,3-benzotriazine derivatives were
synthesized according to the synthetic route shown in Table 1,
from CuI as the catalyst, KOt-Bu as the base, L-proline as the
ligand, isocyanides (aliphatic and aromatic), dialkyl
azadicarboxylate, and anilines with a various of substituents
(electron-withdrawing or electron-donating) on the aromatic
rings (see Table 2).
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As shown in scheme 2, it appears that the reaction of CuI with
L-proline gives a five-membered chelate A. Oxidative addition of
the chelated Cu (I) with the NH moiety of nucleophilic adduct 3
(generated from dialkyl azadicarboxylate 1 and aniline 2) affords
the isocyanide stabilized intermediate B that may coordinate to
Cu. Reductive elimination of B allowed to obtain product 5,
leaving chelate A and the catalyst.
All structures were verified using Infrared, 1H-NMR, 13C-
1
NMR, and Mass spectroscopy methods. For example, the H-
NMR spectrum of compound 5a exhibited one singlet for NH
group (δ = 6.00 ppm) together with a cluster of characteristic
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signals in the aromatic zone for the aromatic C-H bonds. The 13
C
NMR spectrum of compound 5a showed 17 signals in
accordance with the proposed structure. The NMR spectra of
other analogues were similar to spectra 5a. The signal of
molecular ion 5a was shown at m/z = 368 and the fragmentation
pattern corresponded to the favored structure.
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Conclusion
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Sonochem. 2019, 50, 1.
In summary, this article presented a simple, effective synthesis
method in which a new, one-pot, three-component protocol via
intramolecular C-H activation reaction of isocyanides, aniline
and dialkyl azadicarboxylate, catalyzed by copper(I) iodide in
MeCN at room temperature with good yields to synthesize 1,2,3-
benzotriazine derivatives is described . The most important
points of our proposed method were mild conditions, high yields,
low temperature, ease of purification and finally time and cost
effective procedure
Supplementary Material
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