Palladium-catalyzed C–H acetoxylation of 2-arylindazoles

Article abstract of DOI:10.1016/j.tet.2021.132277

A Pd(II)-catalyzed acetoxylation of 2H-indazoles with phenyliodine (III) diacetate (PIDA) has been successfully developed. Notably, pharmacophore 2H-indazole was utilized as an inherent directing group to access ortho-acetoxylated arylindazoles in moderate to high yields. The representative acetoxylated indazole could further undergo hydrolysis to afford the corresponding hydroxylated product.

Full text of DOI:10.1016/j.tet.2021.132277

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed CeH acetoxylation of 2-arylindazoles
Xu-Yan Wang, Yigao Li, Linlin Shi, Xinju Zhu*, Xin-Qi Hao, Mao-Ping Song**
College of Chemistry, Zhengzhou University, No. 100 of Science Road, Zhengzhou, Henan, 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd(II)-catalyzed acetoxylation of 2H-indazoles with phenyliodine (III) diacetate (PIDA) has been suc-
cessfully developed. Notably, pharmacophore 2H-indazole was utilized as an inherent directing group to
access ortho-acetoxylated arylindazoles in moderate to high yields. The representative acetoxylated
indazole could further undergo hydrolysis to afford the corresponding hydroxylated product.
© 2021 Published by Elsevier Ltd.
Received 21 March 2021
Received in revised form
18 May 2021
Accepted 31 May 2021
Available online xxx
Keywords:
Pd-catalyzed
2H-indazole
PIDA
Acetoxylation
1. Introduction
Despite the above elegant work, methodologies for ortho carbon-
heteroatom bonds formation were rarely explored (Scheme 1c)
Indazole is an important class of nitrogen-containing hetero-
cycles due to their wide existence in many therapeutic agents, some
of which have been commercialized, such as GK activator Pflizer,
PARA inhibitor Niraparib, and VEGF inhibitor Pazopanib (Fig. 1) [1].
Meanwhile, indazole derivatives have been discovered as potential
fluorophores for in vivo mitochondria imaging with superior pho-
tostability and low cytotoxicity [2]. Consequently, the synthesis and
functionalization of an indazole scaffold have attracted much
attention [3]. In particular, C3 functionalization of 2H-indazoles to
construct CeC [4], CeN [5], CeS [6] and CeP [7] bonds are well
developed. With tremendous progress in chelation-assisted CeH
functionalization [8], indazole-directed ortho CeH functionaliza-
tion has also emerged as a promising strategy to regioselectively
afford the target molecules without prefunctionalization [9e12].
Following this principle, Rh(III)-catalyzed CeH annulation of 2-
arylindazoles with internal alkynes [9a], maleimides (Scheme 1a)
[12]. To the best of our knowledge, transition-metal-catalyzed CeO
bond formation to give the corresponding indazole derivatives has
not been reported.
Acetoxy compounds are ubiquitous in varieties of natural
products, pharmaceutical molecules, and synthetic intermediates
[13]. Since the pioneering work of Sanford's group [14], the groups
of Yu [15], Dong [16], and others [17] have contributed to Pd(II)-
catalyzed CeH acetoxylation to access structurally diverse esters
[18]. Meanwhile, other transition-metals, such as Rh [19], Ru [20],
Co [21], Ni [22] and Cu [23], have also been successfully employed.
Our group have been interested in transition-metal-catalyzed CeH
functionalization. Recently, we have realized Co(II)-catalyzed CeH
alkoxylation [24a] and Cu(II)-mediated aryloxylation [24b] of am-
ides assisted by an N,O-bidentate directing group. Meanwhile,
Rh(III)-catalyzed ortho CeH cyanation (Scheme 1d) [25a] and
acylmethylation [25b] of indazoles have also been investigated. As
the continuous of our previous work [24e26], we herein reported a
palladium-catalyzed ortho CeH acetoxylation of 2-arylindazoles
using PIDA as both an acetoxy source and oxidant (Scheme 1e).
[9b], a-diazo carbonyl compounds [9c], and aza-bicyclic olefins was
developed to provide indazolo[2,3-a]quinolones and 2H-indazo-
lylbenzocarbazoles [10]. Recently, Hajra et al. have also reported
Rh(III)-catalyzed (hydro)arylation of indazoles with maleimides
[11a], N-sulfonylformaldimines, or aldehydes (Scheme 1b) [11b].
2. Results and discussion
We commenced our investigation with 2-phenyl-2H-indazole
1a (0.1 mmol) and PIDA (0.2 mmol) in the presence of Pd(OAc)2
(5 mol%) in AcOH (1 mL). To our delight, ortho acetoxylated product
2a was achieved in 27% yield at 100 ꢀC for 6 h (Table 1, entry 1).
* Corresponding author.
** Corresponding author.
E-mail addresses: zhuxinju@zzu.edu.cn (X. Zhu), mpsong@zzu.edu.cn
(M.-P. Song).
https://doi.org/10.1016/j.tet.2021.132277
0040-4020/© 2021 Published by Elsevier Ltd.
Please cite this article as: X.-Y. Wang, Y. Li, L. Shi et al., Palladium-catalyzed CeH acetoxylation of 2-arylindazoles, Tetrahedron, https://doi.org/
10.1016/j.tet.2021.132277

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X.-Y. Wang, Y. Li, L. Shi et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Optimization of reaction conditionsa.
Entry
Catalyst
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(CH3CN)2Cl2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AcOH
AcOH/DCE (1/1)
AcOH/MeCN (1/1)
AcOH/1,4-Dioxane (1/1)
AcOH/Toluene (1/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
AcOH/1,4-Dioxane (10/1)
27
38
17
41
29
47
trace
31
41
58
69
78
73
9
10b
11b,c
12b,c,d
13b,c,d,e
Fig. 1. Indazole containing chemotherapeutics.
a
Reaction conditions: 1a (0.1 mmol), PIDA (2 equiv), Pd(OAc)2 (5 mol%), solvent
(1 mL), in sealed tube, under air, 100 ꢀC, 6 h. Isolated yield.
b
Pd(OAc)2 (10 mol%).
3 h.
90 ꢀC.
In open flask. PIDA ¼ PhI(OAc)2.
c
d
e
With the optimized conditions in hand (Table 1, entry 12), the
substrate scope of 2-arylindazoles was examined for this catalytic
transformation (Table 2). 2-Arylindazoles bearing electron
t
electron-donating groups, such as methyl, methoxy, and butyl, at
the para-position proceeded smoothly to afford the expected
products 2b-d in 47e74% yields. When electron-withdrawing
group (Cl) was introduced, a substantial decreased reactivity was
observed to give acetoxylated products 2e in 22% yield. A possible
reason could be that the presence of electron-withdrawing group
might render the benzene ring highly electron-deficient and hinder
the electrophilic palladation [27]. For meta-substituted 2-
arylindazoles, regioselective acetoxylation occurs at the sterically
less hindered position to give the target products 2fꢁj in 45e88%
yields. Substituents locating at the ortho position were found to be
detrimental to the reaction efficiency due to the difficulty in for-
mation of cyclometalated intermediate. Nevertheless, ortho-Me
and ortho-OMe substituted 2-arylindazoles were well tolerated to
generate products 2k and 2l in 64% and 82% yields, respectively.
Encouraged by the above results, the effects of substituents on
the arene ring of 2-arylindazoles was further investigated (Table 3).
In general, both electron-donating (Me and OMe) and electron-
withdrawing (F, Cl, and Br) groups at the C5 or C6 position was
compatible under the optimized conditions to give products 3a-j in
34e78% yields. Compared with halogen groups, methoxy-
substituted substrates led to slightly decreased yields for 3a and
3f, which is also the case in 2-(2H- [1,3]dioxolo[4,5-f]indazol-2-yl)
phenyl acetate to furnish product 3j in 47% yield. On the other hand,
disubstituted indazoles was also employed to provide the ace-
toxylated products 3kꢁm in 50e78% yields. Finally, 1-
phenylpyrazole and 1-phenyl-1H-indazole were also proved to be
suitable substrates to afford products 3n and 3o in 69% and 60%
yields, respectively.
Scheme 1. Indazole-directed CeH bond activation.
According to the previous report [14,16,17,19], a mixture solvent
was employed (Table 1, entries 2e5), which indicates that AcOH/
1,4-dioxance (1/1, v/v) was the best choice to afford 2a in 41% yield
(Table 1, entry 4). Subsequently, the solvent ratio was systemati-
cally modulated (Table S2), and the reaction efficiency was
increased in 47% yield in AcOH/1,4-dioxance (10/1, v/v) (Table 1,
entry 6). Next, various oxidants (Table S3) and Pd salts (Table 1,
entries 7e9) were also screened, which all gave inferior results.
When the catalyst loading of Pd(OAc)2 was increased to 10 mol%,
product 2a was further improved in 58% yield (Table 1, entry 10).
Finally, the reaction time and temperature were also investigated
(Table S6), which provide the desired product 2a in 78% yield at
90 ꢀC for 3 h (Table 1, entry 12). When the reaction was carried out
in open flask, the yield was slightly diminished (Table 1, entry 13).
The structure of 2a was further confirmed by X-ray crystallography
analysis (see the Supporting information).
A gram-sacle production experiment was conduct to demon-
strate the synthetic potential of Pd-catalyzed acetoxylation reac-
tion. When 2-phenyl-2H-indazole 1a (1.16 g 6 mmol) was carried
out under the optimized conditions, the target product 2a was
2

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Tetrahedron xxx (xxxx) xxx
Table 2
Substrate scope of aryl ring substituted 2-arylindazolesa.
obtained in 65% yield (Scheme 2a). Meanwhile, the acetyl group
could be successfully removed using K2CO3 in methanol at room
temperature to give the hydroxylated product 4 in 90% yield.
To gain insights into the reaction mechanism, control experi-
ments, H/D exchange experiments, and kinetic isotope effect (KIE)
were conducted (Scheme 3). Without the PhI(OAc)2, no desired
product was formed, while although the yield of the reaction was
quite low, the reaction could proceed in the absence of AcOH. This
result suggested that the acetoxy might derive from PhI(OAc)2.
Based on the previous work reported by Yu [15a], we assume that
AcOH would facilitate the generation of PdꢁOAc the palladacycle B
(Scheme 4), thereby producing acetoxylation product. Next, H/D
exchange experiments were.
regeneration of active Pd(II) catalyst to fulfill the catalytic cycle.
3. Conclusions
In conclusion, we have developed a palladium-catalyzed ortho-
selective acetoxylation of 2-arylindazoles using an inexpensive
PIDA as the acetoxy source. A broad range of substrates was
employed to give the desired product in moderate to high yields
with good regioselectivity. Meanwhile, a gram-sacle preparation of
acetoxylated indazole was successfully achieved, which could
further be transformed to the corresponding hydroxyl derivative.
The KIE experiments indicate that the cleavage of the CeH bond is
probably the rate-determining step.
conducted in the absence of PhI(OAc)2. No detectable incorpo-
ration of deuterium into 1a and insertion of hydrogen into 1a-d5
were observed by 1H NMR spectra, showing that cleavage of the
CeH bond might be an irreversible process. Finally, the parallel KIE
of 3.89 was observed from two side-by-side reactions using 2-
arylindazole (1a) and 2-aryl-[d5]indazole (1a-d5). And in the reac-
tion of 1a and 1a-d5 with PhI(OAc)2, the competitive KIE of 4.26 was
also obtained. Both results revealed that the cleavage of the CeH
bond might be involved in the rate-determining step.
Based on above results and previous literature, a plausible re-
action mechanism was proposed (Scheme 4). Firstly, Pd(II) salt
chelates with the N-atom of 2-arylindazole 1a to form a five-
membered palladacycle A via CeH activation. Next, oxidation of
palladacycle A by PIDA in the presence of AcOH forms the palla-
dacycle B. Finally, the ortho-acetoxylated product 2a is obtained by
a reductive elimination of intermediate B, accompanied with
4. Experimental section
4.1. General information
Unless otherwise mentioned, all materials were commercially
obtained and used without further purification, and all procedures
were performed under ambient air. 2H-Indazoles are known
compounds and synthesized according to previous references [28].
Melting points were measured by a XT4A melting point apparatus
without correction. Flash column chromatography was performed
using 200e300 mesh silica gel. Analytical and preparative thin-
layer chromatography (TLC) plates coated with commercial silica
gel GF254 were used to monitor the reactions and purify products.
1H, 13C and 19F NMR spectra were recorded at 600, 151, and
565 MHz, respectively, on Bruker DPX instruments using TMS as an
3

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X.-Y. Wang, Y. Li, L. Shi et al.
Tetrahedron xxx (xxxx) xxx
Table 3
Substrate scope of indazole ring substituted 2-arylindazolesa.
diffractometer with graphite-mono-chromated Mo Ka radiation.
4.2. General procedure for acetoxylation 2 or 3
To a 35 mL oven-dried sealed tube were added 2H-indazole 1
(0.1 mmol), PhI(OAc)2 (64.4 mg, 0.2 mmol), and Pd(OAc)2 (2.3 mg,
10 mol%) in a mixed solvent of AcOH/1,4-dioxane (10:1) (1 mL)
under open air conditions. The tube was sealed and placed in a
preheated oil bath at 90 ꢀC for 3 h. After the reaction was
completed, the reaction mixture was cooled to room temperature
and concentrated under vacuo. The crude mixture was purified by
preparative TLC to give the desired products 2 or 3.
Scheme 2. Gram-scale production and removal of acetyl group.
4.3. Characterization of acetoxylation 2 and 3
internal standard. Data are reported as follows: chemical shift (
d
4.3.1. 2-(2H-Indazol-2-yl)phenyl acetate (2a)
ppm), multiplicity (s single, doublet, triplet,
¼
d
¼
t
¼
Purified by analytical TLC on silica gel with petroleum ether
(PE)/ethyl acetate (EA) ¼ 8/1 as an eluent with Rf ¼ 0.31, faint
yellow solid (19.6 mg, 78%), mp ¼ 86e87 ꢀC. 1H NMR (600 MHz,
m ¼ multiplet), integration, and coupling constants (J) in hertz (Hz).
HRMS were determined on a Q-Tof micro MS/MS system ESI
spectrometer. The structure of products 2a (Deposition Number:
2,053,676) was further confirmed by X-ray diffraction collected on a
CDCl3)
d
8.23 (s,1H), 7.79 (d, J ¼ 8.8 Hz,1H), 7.72 (dd, J ¼ 13.0, 8.2 Hz,
2H), 7.47 (t, J ¼ 7.7 Hz, 1H), 7.40 (t, J ¼ 7.7 Hz, 1H), 7.33 (t, J ¼ 7.7 Hz,
4