Kemp-type elimination of 1-arylsulfonyl-3-iodo-1H-indazoles

Article abstract of DOI:10.1080/00397911.2021.1939053

An intriguing ring-opening reaction of 1-arylsulfonyl-3-iodo-1H-indazoles, which can afford the corresponding ortho-(arylsulfonylamino)benzonitriles under base catalysis, was obtained unexpectedly. Herein, the optimal reaction conditions were explored and

Full text of DOI:10.1080/00397911.2021.1939053

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Kemp-type elimination of 1-arylsulfonyl-3-iodo-1H-
indazoles
Jiawei Zhang, Kaimin Kong, Xiangjun Li & Qian Zhang
To cite this article: Jiawei Zhang, Kaimin Kong, Xiangjun Li & Qian Zhang (2021) Kemp-type
elimination of 1-arylsulfonyl-3-iodo-1H-indazoles, Synthetic Communications, 51:15, 2365-2376,
DOI: 10.1080/00397911.2021.1939053
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 15, 2365–2376
https://doi.org/10.1080/00397911.2021.1939053
Kemp-type elimination of 1-arylsulfonyl-3-iodo-
1H-indazoles
Jiawei Zhang, Kaimin Kong, Xiangjun Li, and Qian Zhang
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 5 January 2021
An intriguing ring-opening reaction of 1-arylsulfonyl-3-iodo-1H-inda-
zoles, which can afford the corresponding ortho-(arylsulfonylamino)-
benzonitriles under base catalysis, was obtained unexpectedly.
Herein, the optimal reaction conditions were explored and the
results showed that high temperature and aprotic polar solvent are
favorable to the ring-opening reaction. Most of the substrates
studied can provide the corresponding ring-opening products in
moderate to good yields after stirring in DMSO with K2CO3 at 120ꢀC
for 18 h, suggesting the excellent compatibility of functional groups
and the broad substrate scope of this reaction. Furthermore, the
control experiments implied that 1-arylsulfonyl-3-iodoindazoles go
through an E2 elimination mechanism similar to Kemp elimination.
KEYWORDS
Kemp elimination; 1-
substituted 3-iodo-1H-
indazoles; ring opening;
ortho-(arylsulfonylamino)-
benzonitriles; E2 elimination
GRAPHICAL ABSTRACT
Introduction
Kemp and coworkers found that benzo[d]isoxazoles can undergo an irreversible ring
opening under hydroxide or amine catalysis to generate ortho-hydroxybenzonitriles
(Scheme 1).[1] The Kemp elimination reaction has recently been used widely as a bench-
mark in the computational design of enzymes,[2–13] providing new mechanistic insights
into protein science,[14–16] on account of some advantages of this reaction, such as the
simplicity of its one-step E2 mechanism, the fact that it is not catalyzed by any natural
enzyme, the easy synthesis of the reactants and the ease of following its kinetics.[17]
In addition, Kemp elimination can provide benzonitriles via a cyanide-free route,
with which a wide range of compounds can be synthesized in one pot.[18,19] This
CONTACT Qian Zhang
zhangqian511@shmu.edu.cn
Department of Medicinal Chemistry, School of Pharmacy,
Fudan University. No. 826 Zhangheng Road, Shanghai, 201203, China.
Supplemental data for this article can be accessed on the publisher’s website
ß 2021 Taylor & Francis Group, LLC

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J. ZHANG ET AL.
(A) Typical Kemp Elimination:
(B) Ring opening of 1-Sulfonyl-1H-indazoles:
Scheme 1. Kemp elimination and the ring opening of 1-sulfonyl-1H-indazoles.
Scheme 2. The unexpected product of 1-tosyl-3-iodo-7-nitro-1H-indazole (1) under the conditions of
the Stille reaction.
synthetic method is environmentally friendly and very useful in the synthesis of physio-
logical and pharmacological compounds.[20–22]
Recently, ring-opening reactions of 1-substituted indazoles were reported by a few
research groups. In the presence of strong bases such as LDA or t-BuOK, 1-substituted
indazoles can undergo Kemp-like elimination to provide ortho-(substituted amino)ben-
zonitriles.[23–26] In 2018, Meng Tang’s group reported in detail the elimination of 1-sul-
fonyl-1H-indazoles (Scheme 1).[27] Similarly, ortho-aminobenzonitriles are useful
building blocks in organic chemistry,[28] since they can undergo Thorpe-Ziegler reaction
to synthesize a variety of pharmaceutical intermediates, such as the antimalarial alka-
loids quindolinone and cryptolepinone.[28–30]
Indazole is a very important heterocyclic pharmacophore in drug discovery and
appears widely in many physiologically and pharmacologically active molecules.[31–35]
For example, Axitinib[36] has been used in kidney-cell cancer treatment and investigated
for treatment in pancreatic[37] and thyroid[38] cancer as a second-generation inhibitor
selectively against vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2,
VEGFR-3). Granisetron is a 5HT-3 selective antagonist used as an antiemetic and anti-
nauseant,[33,39] and benzydamine hydrochloride is applied for treatment analgesic and
anti-inflammatory as a COX inhibitor.[40,41]
In our previous research, a class of novel 1H-indole-4,7-diones was designed and syn-
thesized as indoleamine 2,3-dioxygenase (IDO1) inhibitors.[42] Therefore, we attempted

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Table 1. Screening of reaction conditionsa.
Entry
(CH3)4Sn
3 equiv.
PdCl2 (pddf)
K2CO3
Temp. (ꢀC)
Yieldb
1
2c
3
4
5
6
7
0.1 equiv.
3 equiv.
/
3 equiv.
3 equiv.
3 equiv.
3 equiv.
3 equiv.
120
120
120
120
120
90
66%
22%
62%
60%
54%
51%
Trace
d
/
/
/
/
/
0.1 equiv.
3 equiv.
/
/
/
/
/
60
aReaction conditions: 1a (0.25 mmol) and DMF (2.0 mL) in a round-bottomed flask at the designated temperature, 18 h;
c
bIsolated yield after purification by chromatography on silica gel; Reaction time of 96 h; dWithout this reagent.
to construct indazole analogues of these inhibitors to explore their structure–activity
relationships (SAR). First, 1-tosyl-3-iodo-7-nitro-1H-indazole (1) was prepared via iod-
ination[43] and p-toluenesulfonyl (tosyl) protection[41] from 7-nitro-1H-indazole (see
Supporting Information). Subsequently, we tried to introduce a methyl group at the 3-
position of 1 via coupling reaction[44–46] and then to oxidize the methyl group to form
an aldehyde. After 1 was stirred with tetramethylstannane, K2CO3 and PdCl2(pddf) in
DMF according to the classical conditions of the Stille coupling reaction,[47] the reaction
afforded not the expected product, 1-tosyl-3-methyl-7-nitro-1H-indazole (2i), but a
compound resulting from ring opening, namely 2-(tosylamino)-3-nitrobenzonitrile (2)
1
(Scheme 2) . The structure of this unexpected product was identified by H NMR, 13C
NMR, and HRMS.
At this point, we switched our efforts to clarify this unexpected reaction, including
the optimal conditions, the scope of the reaction, and the possible mechanism.
Furthermore, the structures of two compounds (1e and 2e) were confirmed via single-
crystal X-ray diffraction.
Results and discussion
1-Tosyl-3-iodo-1H-indazole (1a) was synthesized as a model substrate, with which the
necessity and effectiveness of the reagents and the reaction temperature of the ring-
opening reaction were investigated and described in Table 1. After heating with
(CH3)4Sn (3 equiv.), PdCl2(pddf) (0.1 equiv.) and K2CO3 (3 equiv.) in DMF at 120 ꢀC
for 18 h, 1a was converted into 2-(tosylamino)benzonitrile (2a) in an isolated yield of
66% (Entry 1). When the reaction was conducted without any of the reagents, the yield
of 2a was dramatically decreased (Entry 2) compared with entry 1. However, when only
the base was added, the conversion of the reaction was comparable (Entry 3) to entry 1.
Neither tetramethylstannane nor PdCl2(pddf) with the base could improve the yield
(Entries 4 and 5), which suggests that only the base was necessary for this reaction.

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J. ZHANG ET AL.
Table 2. Screening of solvents for the ring-opening reactiona.
Entry
Solvent
2ab
3ab
1
2
3
4
5
6
7
8
9
DMF
DMF/H2O (1/1)
DMSO
DMSO (dried)
DMAc
62%
Trace
83%
92%
33%
Trace
Trace
Trace
Trace
Trace
96%
14%
Trace
10%
Trace
Trace
Trace
Trace
HMPA
Toluene
Paraxylene
1,2-Dimethoxyethane
aReaction conditions: 1a (0.25 mmol), K2CO3 (0.75 mmol), and solvent (2.0 mL) in a round-bottomed flask at 120 ꢀC for
18 h; bIsolated yield after purification by chromatography on silica gel.
As for the effect of temperature, the reaction afforded the ring-opening compound
(2a) in 51% yield at 90 ꢀC (Entry 6). However, when the temperature was decreased to
60 ꢀC, no product was isolated (Entry 7). Therefore, temperature is another critical par-
ameter in the ring-opening reaction of 3-iodo-1-tosyl-1H-indazole (1a).
Then, a variety of high-boiling solvents was screened under the above conditions
with 3 equivalents of K2CO3 at 120 ꢀC. As shown in Table 2, a strong aprotic polar
solvent is favorable for this reaction. Using dried DMSO, the reaction afforded 2a in an
isolated yield of 92% (Entry 4). When water was also present in the reaction system, the
hydrolysis product of 1a, 3-iodo indazole (3a), could be detected along with the ring-
opening product (2a), both of which were separated and purified via column chroma-
tography. The tosyl removal product from hydrolysis (3a) became the major product
when the solvent was DMF/H2O in a 1/1 ratio (Entry 2). With weak polar or non-polar
solvents such as HMPA, toluene, 1,4-xylene or 1,2-dimethoxyethane, both products are
present only in trace amounts (Entries 6–9).
With the optimized conditions established, the scope of the substrates was investi-
gated. A series of 3-iodo-1H-indazoles with different substituents on the benzene ring
(1a–d) and different aryl sulfonyl groups on the 1-N atom (1e–m) were prepared (see
Supporting Information). All substrates with 1-aromatic sulfonyl groups underwent the
ring-opening reaction and provided the corresponding products (2a–m) in moderate to
good yields, except 2i (Entry 10, Table 3), implying that the electronic property and the
steric hindrance of the indazole ring substituents have small effects on the reaction
yield. The yields of indazoles bearing an ester group (1b and 1c) were relatively low due
to the partial hydrolysis of esters (Entry 3 and 4).
Owing to the high electronegativity of the fluorine atom (Scheme 3), 1-(p-flurophe-
nylsulfonyl)-3-iodo-1H-indazole (1i) afforded a condensation product (4) of the
ring- opening product (2i) with the unreacted substrate; the intermediate ring-opening
product was not isolated. In the same way, the substrate with 1-(p-nitrophenylsulfonyl)

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Table 3. The ring-opening reaction of substituted 3-iodo-1H-indazolesa.
Entry
Products
R1
R2
Yieldb
1
2
3
4
5
6
7
8
2
2a
2b
2c
2d
2e
2f
2g
2h
2i
7-NO2
H
5-COOCH3
4-COOCH3, 6-Br
Tosyl
Tosyl
Tosyl
Tosyl
Tosyl
91%
83%
41%
39%
81%
90%
86%
88%
91%
Tracec
31%c
95%
74%
80%
6-Br
H
H
H
H
H
H
H
H
Phenylsulfonyl
m-Cl-phenylsulfonyl
p-Cl-phenylsulfonyl
p-Br-phenylsulfonyl
p-F-phenylsulfonyl
p-NO2-phenylsulfonyl
p-OMe-phenylsulfonyl
Pyridine-3-ylsulfonyl
Naphthalen-2-ylsulfonyl
9
10
11
12
13
14
2j
2k
2l
2m
H
aReaction conditions: 1a–m (0.25 mmol), K2CO3 (0.75 mmol), and DMSO (2.0 mL) in a round-bottomed flask at 120 ꢀC for
c
18 h; bIsolated yield after purification by chromatography on silica gel; Compound 4 was separated.
Scheme 3. The main product of 1-p-flurophenylsulfonyl-3-iodoindazole (1i) stirred in DMSO at 120 ꢀC
with K2CO3.
(1j) provided both products, the ring-opening one and its successive condensa-
tion product (4).
Furthermore, single crystals of 1-phenylsulfony-3-iodo-1H-indazole (1e) and its ring-
opening product 2-(phenylsulfonylamino)benzonitrile (2e) were cultivated. As described
in Figure 1 and Supplementary Tables S1–S6, the molecular structures of these two
compounds were unambiguously confirmed by single-crystal X-ray diffraction analysis.
To gain further understanding of this unexpected reaction, we carried out several
control experiments (Scheme 4). First, 1-tosyl-3-chloro-1H-indazole (1n) and 1-tosyl-3-
bromo-1H-indazole (1o) were prepared and heated in DMSO at 120 ꢀC with K2CO3 for
18 h. However, these two substrates are stable under these conditions and can be recov-
ered quantitatively rather than undergoing the ring-opening reaction. Furthermore,
3-iodo-1H-indazole (3a), the hydrolysis product of 1a, was subjected to the same condi-
tions. Also, in this case, the unchanged starting material was isolated. Changing the

2370
J. ZHANG ET AL.
Figure 1. X-ray structures of 1-phenylsulfonyl-3-iodo-1H-indazole (1e) and 2-(phenylsulfonylamino)-
benzonitrile (2e).
Reactions of substituted 1H-indazoles (3a and 1n-q) under the optimized conditions:
(A)
Radical Capture Experiments:
(B)
Scheme 4. Control experiments. The reaction was performed under optimized conditions.

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Scheme 5. A plausible mechanism of the ring opening of 1-arylsulfonyl-3-iodo-1H-indazoles as a
Kemp-type elimination.
substituents of the 1-N atom of 3-iodoindazole to 1-methylsulfonyl (1p) or 1-actyl (1q)
afforded the hydrolysis product (3a) quantitatively, rather than the ring-opening prod-
ucts, after they were stirred and heated in DMSO with the base for 12 h. The result was
the same with dried DMSO as solvent. These facts suggest that the presence of bulkier
and more strongly electron-withdrawing substituents at the 1-N atom is a pivotal factor
in this type of reaction. Atoms with weak electronegativity at the 3-position, such as I
or H, can promote the reaction, possibly by losing cations or radicals.
Second, varying amounts of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO: 1, 2, and 3
equiv.) were added to the mixture to explore whether the mechanism involves the action of
a free radical. As shown in Scheme 4B, the addition of TEMPO did not affect the product or
the yield of this reaction, and no captured products were detected from the reaction system,
suggesting that the ring-opening reaction does not go through a free radical mechanism.
According to the primary mechanistic studies above and the fact that aprotic polar
solvents are favored for this reaction, we consider this unexpected ring-opening reaction
to occur via an ionic mechanism. As described in Scheme 5, we speculated that the ring
opening of 1-arylsulfonyl-3-iodo-1H-indazoles occurs via a Kemp-type elimination.
Conclusion
We discovered a Kemp-type reaction of 1-arylsulfonyl-3-iodo-1H-indazoles that enables
ring opening in a simple way, including a moderate base, elevated temperatures and an
aprotic polar solvent. In this reaction, a diverse array of functionalities is tolerated, and
a variety of ortho-aminobenzonitriles can be obtained in good to excellent yields via a
cyanide-free route. This reaction could also be applied in the design of enzymes to cata-
lyze iodine cation transfer.
Experimental
All commercially available solvents and reagents were used without further purification.
1H NMR spectra were recorded with Varian Inova-400M spectrometer and 13C NMR
spectra were recorded with Bruker Ascend 600 spectrometer equipped with CryoProbe
Prodigy BBO at room temperature. ESI-MS spectra were taken on Agilent G1946D.
HR-MS spectra were determined on Bruker APEX III 7.0 Tesla FTMS. Crystallographic
data were collected on Bruker SMART1000 single-crystal X-ray diffractometer at room
temperature. TLC was performed on the glass-backed silica gel sheets (silica gel 60 Å
GF254). Column chromatography was performed on silica gel (300–400 mesh,
Huanghai Chemical Ltd.). Chemical shifts (d) are reported in parts per million (ppm)

2372
J. ZHANG ET AL.
and coupling constants (J) are reported in Hertz (Hz). The following abbreviations are
used for spin multiplicity: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
dd ¼ double doublet, and br ¼ broad.
General procedure for preparation of 3 and 3a–c
To a round-bottomed flask, indazole (1 mmol) and DMSO (5 mL) were added, following
KOH (3 equiv.) and I2 (3 equiv.) were sequentially added. The mixture was stirred at
room temperature about 4 h until the reaction was completed as monitored by TLC
analysis. After completed, the reaction was quenched by excess sodium bisulfite, and a
precipitate was formed. The precipitate was filtered off with suction and washed with
water (3 ꢁ 30 mL). The solid was left to dry at 30 ꢀC in a vacuum oven overnight to
afford the desired product 3 and 3a–c.
3-Iodo-1H-indazole (3a): Yield: 91%. white solid, m.p.: 154–155 ꢀC. 1H NMR
(DMSO-d6, 400 MHz) d 13.51 (s, 1H, H-1), 7.55 (d, J ¼ 8.5 Hz, 1H, H-7), 7.44–7.42 (m,
2H, H-4, H-6), 7.20 (t, J ¼ 7.1 Hz, 1H, H-5). ESI-MS m/z 245 [M þ Hþ].
General procedure for preparation of 1 and 1a–q
To a solution of 3-iodo-1H-indazole (0.5 mmol) in acetonitrile (10 mL), certain sulfonyl
chloride/acyl chloride (2 equiv.), and KOH (3 equiv.) were added. The mixture was
stirred at room temperature for 8 h and diluted with water. The aqueous phase was
extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4
and concentrated in vacuum. The resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 10:1) to give the desired products.
3-Iodo-1-(phenylsulfonyl)-1H-indazole (1e): Yield: 89%. White solid, m.p.:
160–162 ꢀC. 1H-NMR (CDCl3, 400 MHz) d 8.18 (d, J ¼ 8.5 Hz, 1H, H-7), 8.01 (d,
J ¼ 8.5 Hz, 2H, H-20, H-60), 7.68–7.56 (m, 2H, H-4, H-6), 7.48 (t, J ¼ 8.0 Hz, 3H, H ꢂ30,
H-40, H-50), 7.40 (t, J ¼ 8.0 Hz, 1H, H-5). ESI-MS m/z 385 [M þ Hþ]. CCDC 1984775
contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
General procedure for preparation of compounds 2, 2a–h, and 2j–m
A mixture of 1 (0.25 mmol) and K2CO3 (3 equiv.) in DMSO (5 mL) was stirred at
120 ꢀC for 10 h under a nitrogen atmosphere. After quenching with water, the product
was extracted with EtOAc and the organic layer was washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
Purification by column chromatography on silica gel (hexane/ethyl acetate, 4:1) afforded
the products.
N-(Phenylsulfonyl)-2-aminobenzonitrile (2e): Yield: 90%. White solid, m.p.:
1
173–174 ꢀC. H NMR (DMSO-d6, 400 MHz) d 10.59 (s, 1H, -NH-), 7.79 (dd, J ¼ 7.7,
1.1 Hz, 1H, H-6), 7.72–7.64 (m, 3H, H-20, H-40, H-60), 7.61–7.54 (m, 3H, H-30, H-50, H-
4), 7.37–7.39 (m, 1H, H-5), 7.02 (d, J ¼ 8.1 Hz, 1H, H-3). 13C NMR (DMSO-d6;
150 MHz) d 139.29, 138.43, 133.86, 133.07, 129.21, 126.97, 126.59, 126.14, 116.34,

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109.64. ESI-MS m/z 259 [M þ Hþ]. HR-MS (ESI) m/z calcd. for C13H10N2O2S
[M þ Naþ]: 281.0355; found: 281.0354. CCDC 1984788 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge via www.
ccdc.cam.ac.uk/data_request/cif.
1
Full experimental detail, H and 13C NMR spectra, HPLC traces. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
The authors thank Alicia Glatfelter, PhD, from Liwen Bianji, Edanz Editing China (www.liwen-
bianji.cn/ac) for editing the English text of a draft of this manuscript.
Funding
This work was financially supported by Shanghai Committee of Science and Technology of
China [Nos. 15431902900 and 19431901800].
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