Cu(I)/KOH-Promoted Condensation between o-Arylenediamines and Nitroarenes to Access 2-Aryl-2H-Benzotriazoles

Article abstract of DOI:10.1002/adsc.202000397

Reported is the condensation between o-arylenediamines and nitroarenes enabled by a cooperative action of acid and base, providing a direct entry to 2-aryl-2H-benzotriazoles. The potential practicability of this methodology was demonstrated by 100 mmol-scale reactions and the synthesis of serotonin/dopamine receptor ligand and human growth hormone. (Figure presented.).

Full text of DOI:10.1002/adsc.202000397

Title: Cu(I)/KOH-Promoted Condensation between o-Arylenediamines
and Nitroarenes to Access 2-Aryl-2H-Benzotriazoles
Authors: Chen-Yuan Li, Wenxia Gao, Xiaobo Huang, Yun-Bing Zhou,
Miaochang Liu, and Huayue Wu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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.202000397
Link to VoR: https://doi.org/10.1002/adsc.202000397

10.1002/adsc.202000397
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Cu(I)/KOH-Promoted Condensation between o-
Arylenediamines and Nitroarenes to Access 2-Aryl-2H-
Benzotriazoles
Hong-Chen Li,a Wen-Xia Gao,a Xiao-Bo Huang,a Yun-Bing Zhou,a Miao-Chang Liu a*
and Hua-Yue Wua
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, People’s Republic of China.
E-mail: mcl@wzu.edu.cn
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. Reported is the condensation between o-
arylenediamines and nitroarenes enabled by a cooperative
action of acid and base, providing a direct entry to 2-aryl-
2H-benzotriazoles. The potential practicability of this
methodology was demonstrated by 100 mmol-scale
reactions and the synthesis of serotonin/dopamine receptor
ligand and human growth hormone.
Keywords: Condensation; Nitroarenes; Cyclization;
Benzotriazoles; O-Arylenediamines
Benzotriazoles,
representing
an
important
heterocyclic core with a unique fused five-membered
ring, find wide applications in many fields such as
pharmaceuticals,[1] functionalized materials,[2] and
organic synthesis.[3] Significantly, 2-aryl-2H-
benzotriazoles are key motifs due to their important
roles in many pharmaceuticals, organic electronic
materials and UV stabilizers (Figure 1).[4]
Scheme 1. The Routes to 2-Aryl-2H-benzotriazoles.
regard, several strategies to achieve regioselective
synthesis of 2-aryl-2H-benzotriazoles have been
established (Scheme 1). Typical methods relied on
the
utilization
of
ortho-prefunctionalized
azobenzenes with an intrinsic nitro, amino or azido
group (Path A).[6] These ortho-prefunctionalized
azobenzenes could regioselectively deliver 2-aryl-
2H-benzotriazoles via reduction of nitro-substituted
azobenzenes, oxidative coupling of amino-substituted
azobenzenes or thermal decomposition of azido-
substituted azobenzenes respectively. The second
strategy to access 2-aryl-2H-benzotriazoles involved
Cu-catalyzed cyclization of 2-haloaryltriazenes with
NaN3 as a nitrogen source (Path B).[7] Starting from
more easily accessible raw stock, previous metal-
catalyzed ortho C-H activation of non-
prefunctionalized azobenzenes was described
previously for the regioselective synthesis of 2-aryl-
2H-benzotriazoles. For example, Lee’s group
Figure 1. Important 2-aryl-2H-benzotriazole scaffolds.
However, low site selectivity in N2-arylation[5] of
benzotriazoles reduces the utility of this approach for
the formation of 2-aryl-2H-benzotriazoles. In this
disclosed
a
selective route to 2-aryl-2H-
benzotriazoles in two steps involving Rh/Ag-
1
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10.1002/adsc.202000397
Advanced Synthesis & Catalysis
catalyzed amidation of non-prefunctionalized
azobenzenes with TsN3 and oxidation with PhI(OAc)2
(Path C).[8] Other successful examples[9,10] included
the development of transition-metal-catalyzed
synthesis of 2‑ aryl-2H-benzotriazoles from non-
prefunctionalized azobenzenes using either TMSN3 or
AgNO3 as the nitrogen source (Path D and Path E),
but their substrate scope was mostly limited to
symmetrical azobenzenes due to the challenging site-
selective C-H functionalization. Therefore, the issues
associated with existing methods such as the poor
accessibility of the starting materials, narrow
substrate scope and use of precious metals and
dangerous and expensive nitrogen sources, continue
to fuel research into the development of a simple
method for the regioselective synthesis of 2-aryl-2H-
benzotriazoles.
extra addition of sacrificial oxidizing reagents or
nitrogen source (Figure 2b). The existing
condensation between o-diaminobenzene and
nitrobenzene[11] gave very low yield (< 15%)
probably due to the low reactivity of the nitro group.
Therefore, we intended to develop a suitable acid-
base synergistic system, in which a strong base
increases nucleophilicity of o-diaminobenzene
through proton capture while a Lewis acid increases
the electrophilicity of the nitro group by
coordination-polarization, thus allowing the efficient
condensation between o-arylenediamines and
nitroarenes.
The feasibility of the proposed process was
investigated by selecting o-diaminobenzene (1a) and
p-Cl-nitrobenzene (2d) as model substrates (Table 1).
Initially, the model reaction was performed in THF
under N2 atmosphere at 110 °C in the presence of t-
BuONa and Cu(OAc)2. To our delight, the
combination of Cu(OAc)2 with t-BuONa successfully
facilitated this transformation, delivering the desired
product 3ad in 30% yield (entry 1). The survey of Cu
salts (entries 2-6) showed that CuSCN was the best
choice as the catalyst, which could be attributed to its
good compatibility with a strong base and the role of
SCN- as a good ligand. It was found that the basicity
of the bases had dramatic effects on the reaction
efficiency. For example, the employment of strong
bases such as KOH and NaOH provided the
corresponding product in 81% and 28% yields
respectively (entries 10 and 11) while using a
relatively weak base failed to promote the reaction
(entries 7-9). In addition to the basicity, other factors
including solubility, ionization, aggregation, and
metal ion size may be responsible for this difference
in yields.[12] Control experiments demonstrated the
Table 1. Optimization of Reaction Conditions.a
entry
1
2
3
4
5
6
7
8
Cu salt
Cu(OAc)2 t-BuONa
Cu2O
CuCl2
CuCl
base
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
yield(%)
30
25
27
31
39
48
0
0
0
81
28
0
0
0
0
0
0
0
0
83
0
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
Cs2CO3
Na3PO4
Na2CO3
KOH
NaOH
-
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
CuI
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
-
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
9
10
11
12
13
14
15
16
17
18
19
20b
21c
THF
Table 2. Scope of Nitroarenes.a
DMSO
DMF
1,4-dioxane
CH3CN
toluene
i-PrOH
THF
THF
a
Reaction conditions: 1a (0.5 mmol), 2d (0.9 mmol), Cu
salt (0.05 mmol), base (1.0 mmol), solvent (2 mL), 24 h,
c
110 °C, N2 atmosphere, isolated yield. b At 90 °C. Under
air or O2 atmosphere.
From the retrosynthetic analysis, 2-aryl-2H-
benzotriazoles can be constructed from o-
arylenediamines and aromatic amines in one single
step via oxidative N-N bond coupling. In
consideration of the consumption of stoichiometric
oxidant, an attractive alternative to aromatic amines
can be nitroarenes which fulfill a triple role of
oxidant, nitrogen source and aryl reagent. Hence, we
envisaged that the condensation between o-
arylenediamines and nitroarenes would enable the
direct synthesis of 2-aryl-2H-benzotriazoles without
a
Reaction conditions: 1a (0.5 mmol), 2 (0.9 mmol),
CuSCN (0.05 mmol), KOH (1.0 mmol), THF (2 mL),
90 °C, 24 h, N2, isolated yields. b KOH (2.0 mmol).
2
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10.1002/adsc.202000397
Advanced Synthesis & Catalysis
necessity of a strong base and Cu salt (entries 12 and
13). Further screening on the solvents showed that the
use of other solvents shut down completely this
reaction, indicating a high solvent dependence
(entries 14-19). We attribute their failures to the poor
solubility and ionization of KOH in these solvents.
Reducing the reaction temperature to 90 °C proved to
be slightly beneficial to reaction efficiency (entry 20).
Interestingly, this reaction failed to give the desired
product under air or O2 atmosphere (entry 21).
Therefore, the conditions used in entry 20 proved to
be optimal.
Having established optimal reaction conditions, we
examined the scope of nitroarenes (Table 2). To our
delight, the reaction conditions proved to be
compatible with a broad range of substitutions on the
aromatic ring. For instance, halogen substituents
including I (2b), Br (2c), Cl (2d-2f) and F (2g), were
amenable to the standard reaction conditions, thus
facilitating further derivatization. Nitroarenes
containing either electron-donating or electron-
withdrawing groups all reacted well with o-
arylenediamine 1a, delivering the desired products in
moderate yields (3ah-3ap). It turned out that
substituents at meta position (2l and 2p) on the ring
led to better yields in comparison with those at the
ortho (2m) and para positions (2k and 2o).
Unfortunately, neither m-dinitrobenzene nor 2-
nitrothiophene underwent condensation with o-
arylenediamine to afford the desired products (3aq
and 3ar). The transformation was further effective for
electron-neutral the substrates, as demonstrated by
the installation of phenyl and alkynyl groups,
providing the corresponding products in moderate to
good yields (3as-3au). The use of 4 equiv of KOH
was required for complete consumption of substrates
(2b, 2f, 2g, 2k, 2m, 2o and 2p). Low yields were
obtained in some cases because a large amount of
azobenzene as the main byproduct accompanied the
formation of the desired products.
The possibility to extend this protocol to
differently substituted o-arylenediamines was also
investigated in the reaction with nitrobenzene (2a)
(Table 3). A wide range of halogenated o-
arylenediamines were amenable to this methodology,
offering the corresponding products in moderate
yields (3ba-3ja). The presence of two halogen
substituents on the phenyl ring (1g-1j) was not
problematic. Both electron-rich and -deficient o-
arylenediamines (1k-1n) were accommodated by the
standard reaction conditions. Nevertheless, in the
case of nitro-substituted o-arylenediamine, no
formation of the desired product (3oa) was observed.
Notably, it was found that our protocol was also
efficient for the preparation of 2-phenyl-2H-
[1,2,3]triazolo[4,5-c]pyridine
(3pa).
Polycyclic
triazole 3qa was also accessed in a usable yield via
the condensation between naphthalene-2,3-diamine
(1q) and nitrobenzene (2a). Furthermore, this
synergistic catalysis system successfully enabled the
condensation of o-arylenediamine containing a
phenyl or phenylethynyl group with nitrobenzene,
giving rise to the desired products in 71% (3ra) and
64% (3sa) yields respectively.
Table 3. Scope of o-Arylenediamines.a
Scheme 2. Scale-up Reactions and Synthesis of
Serotonin/Dopamine Receptor Ligand and Human Growth
Hormone.
To demonstrate the potential practicability of this
methodology, we conducted the reaction of 1a and 2a
on a 100 mmol scale with an increased substrate
concentration, delivering the desired product 3aa in a
yield comparable to that of the small-scale reaction
(Scheme 2a). Similar results were observed for the
100 mmol scale reaction of 1a and 2d. Additionally,
the utility of the protocol was significantly enhanced
by its application to the preparation of
serotonin/dopamine receptor ligand (3aw) and human
growth hormone (3bd). The total synthesis of 3aw
aReaction conditions: 1 (0.5 mmol), 2a (0.9 mmol),
CuSCN (0.05 mmol), KOH (1.0 mmol), THF (2 mL),
90 °C, 24 h, N2, isolated yields. bKOH (2.0 mmol).
3
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10.1002/adsc.202000397
Advanced Synthesis & Catalysis
achieved in a 53% overall yield, involved a three-step
sequence in which our method served as a key step
(Scheme 2b). Remarkably, the Cu/base-mediated
condensation between o-arylenediamines and
nitroarenes was successfully coupled with Cu/base-
promoted C-N bond coupling, enabling the overall
process to be promoted by one copper and base, and
thus providing straightforward access to 3bd in a
single step (Scheme 2c).
diaminobenzene, while Cu+ interacts with the nitro
group to polarize the N-O bond, and thus increasing
the positive charge density on the nitrogen atom. As a
result, the polarized nitro group is more susceptible to
be attacked by the negatively charged o-
diaminobenzene to produce intermediate A, which is
dehydrated to form azoxybenzene 5aa. Next, 5aa
undergoes an intramolecular cyclization to provide
intermediate B, followed by deprotonation/
isomerization to form the desired product 3aa finally.
Scheme 4. Proposed Mechanism.
In conclusion, we have disclosed a condensation
between o-arylenediamines and nitroarenes enabled
by the cooperative action of acid and base, providing
a facile entry to 2-aryl-2H-benzotriazoles. The
protocol features wide substrate scope, high atom
economy and no need for oxidizing reagents or noble
metal. Especially, the use of o-arylenediamines and
nitroarenes as feedstock materials substantially
streamlines synthetic efforts on the selective
construction of 2-aryl-2H-benzotriazoles while
bypassing substrate preparation and activation steps.
The potential practicability of this methodology was
further demonstrated by the 100 mmol-scale reactions
as well as the synthesis of serotonin/dopamine
receptor ligand and human growth hormone.
Scheme 3. Some Control Experiments. Standard
conditions: CuSCN (0.05 mmol), KOH (1.0 mmol), THF
(2 mL), 90 °C, 24 h, N2, isolated yields.
To gain some insights into the condensation
between o-arylenediamines and nitroarenes, we
performed several control experiments (Scheme 3).
The addition of TEMPO to the reaction between 1a
and 2a showed negligible influence on the yield of
product 3aa, ruling out a radical process (Scheme 2a).
To obtain the reaction intermediates, we conducted
the model reaction for a shorter reaction time at a
reduced reaction temperature (Scheme 3b).
Interestingly, in addition to the desired product 3ad,
cross azo and azoxy compounds (4ad and 5ad) were
also detected by GC-MS. To further confirm the
Experimental Section
General procedure for condensation between o-
arylenediamines and nitroarenes
intermediate,
azobenzene
we
prepared
and
amino-substituted
amino-substituted
4aa[13]
A 25 mL Schlenk tube equipped with a stir bar was
charged with o-arylenediamines (0.5 mmol), CuSCN (10
mol%) and KOH (2.0 equiv), nitroarenes (0.9 mmol). The
tube was fitted with a rubber septum, and then it was
evacuated and refilled with nitrogen three times. Under
nitrogen, THF (2 mL) was added in turn to the Schlenk
tube through the rubber septum using syringes, and then
the rubber septum was replaced by a Teflon screwcap
under nitrogen flow. The reaction mixture was stirred at
90 ℃ for 24 h. After cooling down, the reaction mixture
was diluted with 10 mL of ethyl ether, filtered through a
pad of silica gel and concentrated under reduced pressure.
The residue was then purified by flash chromatography on
silica gel to provide the corresponding product.
azoxybenzene 5aa[14] according to previous synthetic
approaches. The treatment of 4aa with standard
conditions gave only 7% yield of 3aa (Scheme 3c).
Nevertheless, the reaction of 5aa under standard
conditions delivered 3aa in 84% yield, which was
comparable with the scenario where the reaction
between 1a and 2a was performed under standard
conditions (Scheme 3d). These results suggested that
the reaction process involved an amino-substituted
azoxybenzene intermediate rather than an azobenzene
intermediate.
Therefore,
the
formation
of
azobenzenes might account for the low yields
obtained in some cases.
On the basis of these results, a possible mechanism
for the condensation between o-arylenediamine (1a)
and nitroarene (2a) was proposed (Scheme 4). At the
Acknowledgements
beginning, KOH captures
a
proton from o-
4
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10.1002/adsc.202000397
Advanced Synthesis & Catalysis
We are grateful for financial support from the National Natural
Science Foundation of China (21901187 and 21372177).
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5
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10.1002/adsc.202000397
Advanced Synthesis & Catalysis
COMMUNICATION
Cu(I)/KOH-Promoted Condensation between o-
Arylenediamines and Nitroarenes to Access 2-
Aryl-2H-Benzotriazoles
Adv. Synth. Catal. Year, Volume, Page – Page
Hong-Chen Li,a Wen-Xia Gao,a Xiao-Bo Huang,a
Yun-Bing Zhou,a Miao-Chang Liu a* and Hua-Yue
Wua
6
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