A ligand-free copper-catalyzed strategy to the N-arylation of indazole using aryl bromides

Article abstract of DOI:10.1080/00397911.2021.1883062

A simple and efficient strategy for the C–N cross-coupling of indazole with a variety of substituted aryl bromides is reported. Under the optimized conditions, a broad scope of N-arylated products were obtained in good to excellent yields (up to 87%) under the ligand-free conditions.

Full text of DOI:10.1080/00397911.2021.1883062

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A ligand-free copper-catalyzed strategy to the N-
arylation of indazole using aryl bromides
Di-Xiang Bai, Rachel Sin-Ee Lim, Hui-Fen Ng & Yong-Chua Teo
To cite this article: Di-Xiang Bai, Rachel Sin-Ee Lim, Hui-Fen Ng & Yong-Chua Teo (2021) A
ligand-free copper-catalyzed strategy to the N-arylation of indazole using aryl bromides, Synthetic
Communications, 51:9, 1398-1405, DOI: 10.1080/00397911.2021.1883062
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2021, VOL. 51, NO. 9, 1398–1405
https://doi.org/10.1080/00397911.2021.1883062
A ligand-free copper-catalyzed strategy to the N-arylation
of indazole using aryl bromides
Di-Xiang Bai, Rachel Sin-Ee Lim, Hui-Fen Ng, and Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological
University, Singapore
ABSTRACT
ARTICLE HISTORY
Received 22 October 2020
A simple and efficient strategy for the C–N cross-coupling of inda-
zole with a variety of substituted aryl bromides is reported. Under
the optimized conditions, a broad scope of N-arylated products were
obtained in good to excellent yields (up to 87%) under the ligand-
free conditions.
KEYWORDS
Indazole; copper (I) iodide;
aryl bromides; ligand-free;
N-arylation
GRAPHICAL ABSTRACT
Introduction
Nitrogen-containing heterocycles serve as an important class of synthesized compounds
found in various natural products and biologically active pharmaceuticals.[1] In particu-
lar, N-arylindazole exhibits useful biological responses as anti-inflammatories and anti-
cancer compound.[2]
Ullmann-type coupling has attracted great interest among the synthetic community as it
offers numerous application options such as N-, O-, C-aryl bond formations.[3] Moreover,
copper catalysis offers more advantages due to its lower cost[4] and ability to work well for
the arylation of several nucleophiles.[5] However, this classical copper-catalyzed coupling
has its limitations, for example, high reaction temperature, highly polar solvents and high
catalyst loadings.[6] In this context, some of the limitations can be overcome by the use of
suitable mono- or bidentate ligands such as diamines,[7] 1,10-phenanthroline,[8] amino
acids,[9] and nitrogen containing ligands[10] to enhance the reactivity of the copper cata-
lysts, broaden the substrate scope and also to achieve a milder reaction condition.
However, the use of ligands has its disadvantages such as additional cost, and a need for
special synthesis under inert conditions in some instances.
CONTACT Yong-Chua Teo
yongchua.teo@nie.edu.sg
Natural Sciences and Science Education, National Institute
of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Henceforth, the development of ligand free catalytic system for N-arylation of azoles
is of great significance since it offers a more cost effective and strategy. Correa and
Bolm reported the N-arylation of sulfoximines and nitrogen heterocycles with aryl hal-
ides using a ligand free Cu2O catalytic system.[11]
Xu reported a reusable catalytic system for N-arylation of a variety of nitrogen-
containing heterocycles with aryl and heteroaryl halides using Cu2O.[12] However, the
substrate scope for aryl bromides is limited to imidazole in the presence of a strong
KOH base. Rossi demonstrated a CuOAc-mediated C–N coupling reactions of indoles
and carbazole with aryl iodides under ligand-free and base-free conditions.[13] Chan
developed a successful protocol for the coupling of nitrogen heterocycles with aryl
iodides under ligand-free conditions using Cu(I) halide salts with NaOH as base and
Bu4NBr as the phase transfer catalyst.[14] Sperotto also reported an efficient protocol for
the coupling of various nitrogen nucleophiles with aryl halides under copper-catalyzed
ligand-free condition.[15] Similarly, the protocol reported efficient coupling of imidazole
with limited aryl bromides scope as the electrophilic reagents at 160 ꢀC.
The majority of these ligand-free catalytic systems developed utilize mostly aryl
iodides as the electrophilic coupling partners to ensure efficiency of the catalytic sys-
tems. The use of aryl bromides remained limited due to the lower reactivities of such
reagents under the ligand-free reaction conditions. However, aryl bromides offer added
advantages compared to the iodide counterparts due to its lower toxicity and costs. To
the best of our knowledge, cross coupling reaction of indazoles with substituted aryl
bromides under ligand-free conditions has not been reported. Henceforth, as part of
our efforts to develop more practical and cost effective cross-coupling technologies, we
envisaged the application of the ligand-free systems established in our research group[16]
for the N-arylation of indazoles using aryl bromides as the electrophilic partners.
Results and discussion
In our initial study, indazole and bromobenzene were chosen as model substrates for
the copper-catalyzed N-arylation reaction. Under the ligand-free conditions with CuI as
the catalyst, the reaction gave a favorable yield of 66% of the product (Table 1, entry 1).
In order to optimize the reaction, the efficiency of various copper sources for the aryla-
tion reaction was investigated (entries 1–5). Among them, CuBr and CuCl gave modest
yields, (entries 2 and 3) affording the products in 64% and 61%, respectively. However,
the use of Cu2O was not efficient which gave the product in a poor yield of 19% (entry
4), while Cu as catalyst afforded the product in a moderate yield of 42% (entry 5).
Next, the solvent effect of commonly used organic solvents as reaction medium was
explored. In this study, DMF proved to be the best solvent that gave rise to a yield of
66%. However, the findings also demonstrated that DMSO is another suitable solvent,
giving a yield of 65% (Table 1, entry 7). Further experiments revealed that K3PO4 is the
ideal choice as the base for the coupling reaction as Na2CO3, K2CO3 and Cs2CO3
resulted in lower yields (entries 10–12). A scale up reaction using 1 g of indazole with 3
equiv of bromobenzene under the optimized condition was attempted which gave the
N-arylated product in a good yield of 71%.

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D.-X. BAI ET AL.
Table 1. Optimization studies of ligand-free copper-catalyzed cross coupling of indazole and
bromobenzene[a].
Entry
Catalyst
Base
Solvent
Yield[b] (%)
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
Cu2O
Cu
CuI
CuI
CuI
CuI
CuI
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Na2CO3
K2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
t-Butanol
DMSO
Dioxane
Toluene
DMF
DMF
DMF
66
64
61
19
42
55
65
48
39
9
10
11
12
Trace
56
63
CuI
[a]Unless otherwise shown, the reaction was carried out with indazole (1.5 mmol), bromobenzene (2.25 mmol), K3PO4
(3.0 mmol), Cu source (20 mol%) in DMF (0.75 ml) at 130 oC for 18 h.
[b]Isolated yield after column chromatography.
In summary, the optimized conditions for our ligand-free copper-catalyzed cross-cou-
pling reaction was achieved using a combination of CuI (20mol%), K3PO4 (2 equiv) in
DMF at 130 ꢀC for 18hours.
To examine the generality of this protocol, a variety of ortho-, meta-, and para-substi-
tuted bromobenzenes were coupled with indazole under the optimized condition. In
general, good to excellent yields were obtained for cross-coupling of sterically unhin-
dered bromobenzenes.
The findings concur that ortho-substituted bromobenzene was not suitable electro-
philic partners due to steric hindrance effect except for 2-F and 2-CF3 substituted bro-
mobenzene (Table 2, entries 2 and 3). No significant electronic effects were observed
for both meta- and para-substituted bromobenzene (entries 4–11) except for OMe sub-
stituent which gave trace amount of products. However, reactions attempted using 2-,
3- and 4-bromopyridines as electrophilic partners were not successful as these substrates
gave only trace amount of the products.
In order to expand the scope of this ligand-free CuI catalytic system, the cross-
coupling reactions between a series of nitrogen heterocycles and bromobenzene were
carried out. (Table 3, entries 1–5). Notably, pyrazole gave the best yield of 95% under
the cross coupling reaction with bromobenzene (entry 1). Moderate yields were
obtained in the case of 7-azaindazole and indole (entries 4 and 5) as coupling partners.
However, the reaction using pyrrole was not encouraging as only trace amount of the
product was obtained. Next, we broaden the scope of the nucleophilic partners to
include representative sulfonamides and amides. In this case, sulfonamides proved to be
efficient reagents under the reaction conditions, affording the corresponding N-arylated

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Table 2. CuI-catalyzed N-arylation of indazole with substituted aryl bromides.[a].
Entry
1
ArX
Product
Yield [b] (%)
3a
66
2
3b
3c
57
37
75
3
4
3d
3e
3f
5
6
69
78
7
3g
3h
68
73
8
9
3i
3j
79
87
10
11
3k
60%
[a]Unless otherwise shown, the reaction was carried out with indazole (1.5 mmol), bromobenzene (4.5 mmol), K3PO4
(3.0 mmol), CuI (20 mol%) in DMF (0.75 ml) at 130 ꢀC for 18 h.
[b]Isolated yield after column chromatography.

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D.-X. BAI ET AL.
Table 3. CuI-catalyzed N-arylation of substituted N-containing nucleophiles with bromobenzene.[b].
Entry
Amine
Product
Yield[b] (%)
1
4a
95
2
4b
4c
56
71
3
4
4d
4e
40
43
5
6
4f
62
75
7
8
4g
4h
4i
49
32
9
[a]Unless otherwise shown, the reaction was carried out with substituted N-heterocycle (1.5 mmol), bromobenzene
(4.5 mmol), K3PO4 (3.0 mmol), CuI (20 mol%) in DMF (0.75 ml) at 130 ꢀC for 18 h.
[b]Isolated yield after column chromatography.
products in good yields (entries 6 and 7). However, the use of benzamide and pyrrolidi-
none gave the products in lower yields of 49% and 32%, respectively.
Experimental
General procedure for N-arylation of indazole
A mixture of CuI (Sigma-Aldrich, 99.99% purity, 0.3 mmol), K3PO4 (3.0 mmol) and
indazole (1.5 mmol) was dissolved in (0.75 ml) dimethylformamide (DMF). Following,

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the bromobenzene (2.25 mmol) was added to the reaction vial. The reaction vial was
then sealed tightly with a screw cap and the reaction was allowed to stir at room tem-
perature for 5 minutes. The reaction mixture was stirred under air in a closed system at
130 ꢀC for 18 h in an oil bath, following the reaction mixture was then cooled to room
temperature with dichloromethane (DCM). The resulting solution was directly filtered
through a pad of Celite and washed with dichloromethane for a few times. The com-
bined organic extracts were dried with anhydrous Na2SO4 and removed by filtration.
Subsequently, the crude product was purified by silica-gel column chromatography to
afford the N-arylated product. The purity, identity and structure of the final product
1
was confirmed by H, 13C NMR spectroscopic analysis and elemental analysis.
1-Phenyl-1-indazole (3a)
223.5 mg (77%) of the coupled product was obtained as a yellow oil.
1H NMR (400 MHz, CDCl3): d8.21 (s, 1H), d7.81(d, J ¼ 6.8 Hz, 1H), d7.74–7.78 (m,
3H), d7.55 (t, J ¼ 7.8 Hz, 2H), d7.44 (t, J ¼ 7.6 Hz, 1H), d7.37 (t, J ¼ 7.2 Hz, 1H),
d7.22–7.26 (m, 1H)
13C NMR (100 MHz, CDCl3): 140.2, 138.7, 135.4, 129.4, 127.1, 126.6, 125.3, 122.7,
121.5, 121.3, 110.4
Anal. Calculated for C13H10N2: C, 80.39; H, 5.19; N, 14.42. Found: C, 79.96 H, 5.17;
N, 14.19
All spectral data correspond to those given in the literature.[16(b)]
Conclusion
In summary, we have developed a simple, versatile and viable ligand-free CuI-catalyzed
cross coupling protocol for the arylation of various nitrogen heterocycles with different
substituted aryl bromides. In most instances, this protocol generates the N-heterocyclic
products in moderate to good yields. The economical and simple reaction conditions
offer ease of transfer to industrial scale operations.
1
Supporting Information: Full experimental detail, H and 13C NMR spectra and elem-
ental analysis. This material can be found via the “Supplementary Content” section of
this article’s webpage.’
Funding
We would like to thank the National Institute of Education [RI 5/17 TYC], Nanyang
Technological University for their generous financial support.
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