Synthesis of 5-pentafluorosulfanyl indazoles

Article abstract of DOI:10.1016/j.tetlet.2017.10.031

An efficient method for the synthesis of 5-SF₅ substituted indazoles from commercially available 4-nitro-(pentafluorosulfanyl)benzene through vicarious nucleophilic substitution of hydrogen (VNS) reaction, reduction of nitro group and cyclizati

Full text of DOI:10.1016/j.tetlet.2017.10.031

Accepted Manuscript
Synthesis of 5-Pentafluorosulfanyl Indazoles
Tao Fan, Wei-Dong Meng, Yu-Lan Xiao, Xingang Zhang
PII:
S0040-4039(17)31312-6
https://doi.org/10.1016/j.tetlet.2017.10.031
TETL 49393
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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14 September 2017
9 October 2017
13 October 2017
Please cite this article as: Fan, T., Meng, W-D., Xiao, Y-L., Zhang, X., Synthesis of 5-Pentafluorosulfanyl Indazoles,
Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.031
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Synthesis of 5-Pentafluorosulfanyl Indazoles
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Tao Fan,a Wei-Dong Meng,a Yu-Lan Xiaob and Xingang Zhang*b
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China.
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy
of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China.

1
Tetrahedron Letters
journal homepage: www.els evier.com
Synthesis of 5-Pentafluorosulfanyl Indazoles
Tao Fan,a Wei-Dong Meng,a Yu-Lan Xiaob and Xingang Zhang*b
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, China.
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient method for the synthesis of 5-SF5 substituted indazoles from
commercially available 4-nitro-(pentafluorosulfanyl)benzene through vicarious
nucleophilic substitution of hydrogen (VNS) reaction, reduction of nitro group and
cyclization of resulting anilines were described. Transformations of 5-SF5-indazoles
led to a variety of SF5-substiuted heteroarenes that can serve as a versatile building
block for diversity-oriented organic synthesis.
Received in revised form
Accepted
Available online
Keywords:
Pentafluorosulfanylation
Pentafluorosulafnyl indazoles
Pentafluorosulfanyl heteroaromatics
VNS reaction
2013 Elsevier Ltd. All rights reserved.
The demand for discovering new pharmaceuticals,
agrochemicals and advanced functional materials has triggered
continuing endeavors in preparation of novel fluorinated
compounds.1 Recently, the pentafluorosulfanyl (SF5) group
containing molecules have received increasing attention because
of the unique properties of such a “super-trifluoromethyl” group,2
such as high lipophilicity, remarkable stability, large steric bulk,
and strong electron-withdrawing ability, which can dramatically
improve both the pharmacokinetic and pharmacodynamic
properties of biologically active molecules. For example,
incorporation of SF5 into the triazolopyrimidine led to the
discovery of the first dihydroorotate dehydrogenase (DHODH)
inhibitor I for the treatment of malaria with improved oral
bioavailability and metabolic stability (Figure 1).3 The improved
pharmacokinetic and pharmacodynamic of selective COX-2
inhibitor II, used for the treatment of inflammation and
associated pain, has also resulted from the introduction of SF5
into the benzopyrans (Figure 1).4 Despite of the important
applications of SF5-containing (hetero)aromatic compounds
[(Het)Ar-SF5] in medicinal chemistry, efficient methods for
preparation of such a valuable structural motif are very limited,5
which significantly impeded the use of (Het)Ar-SF5 as a potential
core-structure for drug discovery and development.
heteroarenes in medicinal chemistry.5b Recently, Dolbier7c and
Shibata7d reported the efficient synthesis of SF5-substituted
pyridines from pyridine disulfides, separately, however, the
synthesis of other HetAr-SF5 are not applicable to this method.
An alternative strategy to address this issue is based on the SF5-
containing building blocks. In this regard, other types of SF5-
substituted N-heteroarenes were prepared, including pyrazoles,8
pyrroles,9 indoles,10 quinolonines11, triazoles8b and isoxazoles12.
However, to the best of our knowledge, the synthesis of SF5-
substituted indazoles has not been reported yet.
Generally, there are two strategies to access (Het)Ar-SF5. One
is based on arene disulfides through direct oxidative fluorination6
Figure 1. Representative SF5-Containing Biologically Active Molecules.
or via
chloride/fluoride
pentafluorosulfanyl(hetero)arenes; the other is the utilization of
pentafluorosulanylated building blocks to prepare relatively more
complex molecules.5b Among these methods, the preparation of
SF5-containing heteroaromatic compounds has received
a
stepwise oxidative chlorotetrafluorination and
exchange7
to prepare simple
Indazoles is an important class of heteroarenes found in many
pharmaceuticals and agrochemicals.13 Conceptually, the
introduction of SF5 into indazoles would provide good
opportunities to discover interesting new bioactive molecules. In
2013, we have developed a cross-coupling reaction through
increasing attention due to the important application of
———
∗ Corresponding authors. e-mail address: xgzhang@mail.sioc.ac.cn
palladium-catalyzed
direct
arylation
of
nitro-

2
Tetrahedron
(pentafluorosulfanyl)benzenes.14 To continue our interests in
With the alkylated 4-(pentafluorosulfanyl)anilines in hand, the
cyclization of 5 to construct the 5-SF5-substituted indazoles were
investigated. The strong electron withdrawing group SF5 and
other versatile functional groups, such as ester, sulfonyl,
phosphonate and cyano, did not interfere with the reaction
efficiency. As shown in Table 1, treatment of 5a with acetic
anhydride and isoamyl nitrite in the presence of potassium
acetate afforded an excellent yield of product 1a (entry 1).16
Moderate to good yields of 1b and 1c were also obtained under
same reaction conditions (entries 2-3). While in the case of 1d,
68% yield of indazole without protection by acyl group was
provided (entry 4).
efficient preparation of pentafluorosulfanylated compounds,
herein, we report an efficient method to prepare 5-SF5 substituted
indazoles
from
readily
available
4-nitro-
(pentafluorosulfanyl)benzene. The resulting heteroaromatics can
serve as a versatile building block for various transformations.
We envisioned that the preparation of 5-SF5 substituted indazoles
1 could be derived from SF5-substituted anilines 5, which could
be readily prepared from 4-nitro-(pentafluorosulfanyl)benzene 2
through vicarious nucleophilic substitution of hydrogen (VNS)
reaction with electron-withdrawing groups substituted
chloromethane 3, followed by reduction of nitro group.
In order to demonstrate the versatility of these SF5-substituted
indazoles, several transformations of compound 1a were
conducted (Scheme 3). The acyl group could be selectively
removed with intact CO2tBu group by treatment of 1a with
DIBAL-H. While, the acyl and tert-butyl groups could be readily
deprotected in one pot when compound 1a was treated with TFA.
Reduction of indazole 6 with LiAlH4 led to alcohol 7, which was
oxidized by IBX to afford another versatile building block 8.
Since aldehyde is a good functional group for a wide range of
transformations, this method provides a good platform for
structural diversity synthesis. Alternatively, compound 7 could
also be directly obtained by reduction of 1a with LiAlH4.
NH2
R1
N
N
R2
NO2
F5S
R1
+
Cl
EWG
3
SF5
5
SF5
2
1
Scheme 1. Retrosynthesis of 5-SF5 Substituted Indazoles.
Accordingly, a variety of alkylated arenes by reaction of
(pentafluorosulfanyl)benzene 2 with nucleophiles, which was
generated in situ by treatment of compounds 3 with tBuOK, were
prepared through VNS reaction according to the literature15
(Scheme 2). Generally, high yields of compounds 4 were
obtained with exclusive alkyl substitution ortho to the nitro group.
However, in the case of 2-phenoxyacetonitrile 3d, a synthetic
reasonable yield (41%) was obtained. Hydrogenation of
compounds 4 with Raney nickel as a catalyst underwent
smoothly, providing anilines 5 with high efficiency.15 While, for
the compound 4d, 10% Pd/C was used and the reaction was
conducted under 10 atm H2 with 80% yield obtained.
Furthermore, the functionalization of 1a could be conducted
on the indazole skeleton. As shown in Scheme 3c, nitration of 1a
exclusively provided 7-nitro-substituted indazole 10, which was
further reduced under 1 atm H2 in the presence of 10% Pd/C to
afford amine 12 with high efficiency. Conversion of amine group
into iodide through two-step synthetic procedure also proceeded
smoothly. In light of the importance of amine group and aryl-
iodide in organic synthesis, these transformations provide a
useful tool for applications in medicinal chemistry.
a
)
Ac
H
H
N
N
N
DIBAL-H
LiAlH4
N
N
N
DCM, 0 oC - r.t.
THF, 0 o
C
F5S
F5S
F5S
CO2tBu
CO2tBu
OH
1a
7, 72%
6
, 87%
H
N
IBX
N
DMSO, r.t.
F5S
CHO
8
, 66%
Ac
H
N
H
N
N
b)
Scheme 2. Synthesis of Anilines
5.
TFA
LiAlH4
N
N
N
F5S
THF, 0 o
C
F5S
DCM, r.t.
F5S
CO2tBu
CO2H
OH
1a
9
, 93%
7
, 56%
Table 1. Synthesis of Pentafluorosulfanyl Indazoles 1 a
.
NO2
Ac
NO2
H
H
c)
N
N
MeOH, H2SO4
reflux
N
H2SO4, HNO3
r.t. to 60 o
N
N
N
F5S
F5
S
C
F5S
CO2
H
CO2tBu
CO2Me
10
, 83%
11
1a
, 52%
NH2
I
H
N
H
N
i) HCl, NaNO2, 0 o
ii) KI, 0 o
C
10% Pd/C
H2 (1 atm), MeOH, r.t.
N
N
Entry
5
R1
CO2tBu
PhSO2
P(O)(OEt)2
CN
R2
Yieldb (%)
F5S
C
F5S
CO2Me
CO2Me
13, 52%
12, 95%
1
2
5a
5b
5c
5d
C(O)CH3
C(O)CH3
C(O)CH3
H
1a, 94
1b, 56
1c, 81
1d, 68
Scheme 3. Transformations of 5-SF5 Substituted
Indazole 1a
3
4c
.
aReactions were carried out using
isoamyl nitrite (7.0 mmol) and AcOK (1.3 mmol) in toluene (5 mL).
5 (1.0 mmol), Ac2O (7.0 mmol),
In conclusion, we have developed an efficient method for the
synthesis of 5-SF5-indazoles from commercially available 4-
nitro-(pentafluorosulfanyl)benzene. Transformations of 5-SF5-
indazoles showed that this type of novel SF5-substiuted
bIsolated yields. Reaction was carried out with 5d (0.52 mmol), Ac2O
c
(3.64 mmol), isoamyl nitrite (3.64 mmol) and AcOK (0.68 mmol) in
toluene (5 mL).

3
Matsuzaki, K.; Saito, N.; Shibata, N. Chem. Commun. 2017, 53,
3850.
heteroarenes can serve as a versatile building block for diversity-
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applications in drug discovery and development.
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2141002), the Strategic Priority Research Program of the Chinese
Academy of Sciences (No. XDB20000000), and Shanghai Institute
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6.
7.

4
Tetrahedron
Highlights
ꢀ
ꢀ
ꢀ
Readily available starting material
Facile access to 5-pentafluorosulfanyl indazoles
Versatile building block for medicinal chemistry