Rhodium(III)-Catalyzed Oxidative Annulation of Ketoximes with Sulfonamide: A Direct Approach to Indazoles

Article abstract of DOI:10.1021/acs.orglett.8b03488

A rhodium(III)-catalyzed intermolecular C-H amination of ketoxime and iodobenzene diacetate-enabled N-N bond formation in the synthesis of indazoles has been developed. A variety of functional groups were well tolerated, providing the corresponding produc

Full text of DOI:10.1021/acs.orglett.8b03488

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium(III)-Catalyzed Oxidative Annulation of Ketoximes with
Sulfonamide: A Direct Approach to Indazoles
Ning Wang, Lingling Liu, Wentao Xu, Mengye Zhang, Zhibin Huang,* Daqing Shi,*
and Yingsheng Zhao*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow Unversity, 199
Renai Street, Suzhou, Jiangsu 215123, China
S
* Supporting Information
ABSTRACT: A rhodium(III)-catalyzed intermolecular C−H
amination of ketoxime and iodobenzene diacetate-enabled N−
N bond formation in the synthesis of indazoles has been
developed. A variety of functional groups were well tolerated,
providing the corresponding products in moderate to good
yields. Moreover, the nitro-substituted ketoximes are well
compatible in this reaction, leading to the corresponding products in moderate to good yields.
ransition-metal-catalyzed C−H functionalization reac-
Scheme 1. Intermolecular Synthesis of 1H-Indazoles
T
tions have been successfully developed, which greatly
enriched the route to construct vital synthetic skeletons in
chemistry. In particular, this approach provides a highly
efficient approach to directly realize the bioactive compounds
in high atom efficiency.1
Indazoles are usually the key scaffolds of a range of
pharmaceuticals, bioactive compounds, and natural products
(Figure 1).2 Therefore, it is very attractive to obtain the
anthranils to directly generate the indazoles (Scheme 1a).11
Several other research groups such as those of You (Scheme
1c),12 Kim,13 Iiao,14 Zhu, and Xi15 have extensively worked in
this field, thus providing different methods for synthesizing
indazole derivatives from azoxybenzenes, azobenzenes, arylpyr-
idines, or hydrazones. The group of Lee reported an efficient
approach to synthesize the 2-aryl-2H-benzotriazoles from
azobenzenes via sequential Rh-catalyzed amination and
oxidantion in one pot. It was proposed that PhI(OAc)2 was
the key factor in realizing the oxidative cyclization reaction.17
Although these developments have greatly enriched the route
to indazole synthesis, it is still uncommon to directly
synthesize indazoles by employing simple ketoximes as the
substrates. Due to the exceeding importance of indazoles and
the limitations of the reported methods, the development of
new methods using readily available substrates would be very
attractive in synthetic chemistry. Herein, we report the
Figure 1. Representative drugs containing the indazole skeleton.
indazoles from ubiquitous compounds. Traditionally, indazoles
have been synthesized via the condensation/cyclization of aryl
ketones with hydrazines3 or by cross-coupling/cyclization of o-
halophenylacetylenes with hydrazines.4 Recently, the tran-
sition-metal-catalyzed C−H functionalization strategy has
provided an atom- and step-economy approach to the indazole
derivatives. For instance, a redox-neutral coupling of
azobenzenes with aryl aldehydes via Rh(III) or Co(III)
catalysts for the synthesis of indazoles has been disclosed by
the research group of Ellman (Scheme 1b).5 Simultaneously,
Glorius and co-workers reported a Rh(III)7-catalyzed oxidative
annulation of arylimidates with organo azides to form the 1H-
indazoles (Scheme 1a).8 Subsequently, a copper-catalyzed
tandem C−N/N−N bond formation in the synthesis of 1H-
Indazoles was disclosed by the research group of Zhu (Scheme
1a).9 Later, Li and co-workers developed an efficient Co(III)/
Cu(II)10-catalyzed oxidative annulation of imidates with
Received: November 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
synthesis of indazoles by directly coupling ketoximes with
sulfonamides using rhodium(III) as a catalyst and iodobenzene
diacetate as an oxidant. Moreover, the nitro-substituted
ketoximes are all well compatible, leading to the corresponding
products in moderate to good yields.
Scheme 2. Substrate Scope of Ketoximes
The nitro group is a versatile functionality which can be
easily converted into amino, halogen, and hydroxyl groups.16
However, only a few reports on the transition-metal-catalyzed
C−H functionalization to synthesize indazoles with the nitro
functional group have been reported. Hence, we herein tried to
address this issue through the further study of C−H
functionalization reactions. At the beginning of our study,
the 4-nitroacetophenone oxime (1a) and 4-toluenesulfonamide
(2a) were selected as substrates for the optimization studies.
Gratifyingly, the substrates 1a and 2a could be transformed
into the indazole product 3a in 39% yield through heating in
the presence of [Cp*RhCl2]2, AgSbF6, and PhI(OAc)2 in
ethanol at 90 °C for 24 h (Table 1, entry 2). Next, a variety of
a
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1 (0.2 mmol), 2b (0.6 mmol), [Cp*RhCl2]2
(2.5 mol %), PhI(OAc)2 (0.6 mmol), AgSbF6 (10 mol %) in TFE(1.5
b
c
mL) at 90 °C for 24 h. Isolated yields are given. 1 (0.2 mmol), 2
(0.6 mmol), [Cp*RhCl2]2 (2.5 mol %), PhI(OAc)2 (0.6 mmol),
AgSbF6 (10 mol %), KOAc (20 mol %) in TFE (1.5 mL) at 90 °C for
24 h. 1 (0.2 mmol), 2c (0.6 mmol), [Cp*RhCl2]2 (2.5 mol %),
PhI(OAc)2 (0.6 mmol), AgSbF6 (10 mol %), KOAc (50 mol %) in
b
entry
additive
oxidant
solvent
MeOH
EtOH
t-Amyl−OH
HFIP
TFE
TFE
TFE
TFE
TFE
yield (%)
d
1
2
3
4
5
6
7
8
9
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
K2S2O8
35
39
31
76
TFE(1.5 mL) at 90 °C for 24 h. 2c: 4-methoxybenzenesulfonamide.
oxime only afforded the product 3c in moderate yield, along
with the starting material being recovered. In this case, the
lower yield was ascribed to steric effects. The disubstituted
acetophenone oxime derivatives were all compatible in this
transformation, affording the corresponding products in good
yields (3d−g). In addition, the crystal structure of 3f further
established the structure of the product. Further study revealed
that both p-ester- (2h) and cyano-substituted (2i) acetophe-
none oximes all reacted smoothly, providing the corresponding
products in moderate yields. However, the acetophenone
oxime was unreactive, leading to less than 15% yield of 3j,
accompanied by the recovery of the starting material. Although
the underlying reason is unclear, we inferred that the 4-
toluenesulfonamide was less reactive for this transformation.
Therefore, a variety of amides were further screened to address
the predicament of the narrow substrate scope (Scheme 3).
The results of this study clearly demonstrated that the
phenylsulfonamides substituted with electron-withdrawing
functional groups provided better yields of the products. For
instance, 4-nitrobenzenesulfonamide provided the indazole
product 3j in 52% yield. Benzamide and trifluoroacetamide
afforded the desired products in less than 10% yields, while
trifluoromethanesulfonamide generated the product 3j in 51%
yield. We next explored various substituted acetophenone
oximes with 4-nitrobenzenesulfonamide under the standard
reaction conditions, and the results are presented in Scheme 4.
Propiophenone, n-butyrophenone, cyclopropyl phenyl ketone,
and diphenylketone were all well tolerated, providing the
corresponding products in good yields. The lower yield of 3o
and 3w might be attributed to the de composition of the
substrates (1o and 1w) in the reaction. The acetophenone
oximes substituted with functional groups such as F, Br, I, and
CF3 all reacted well, leading to the corresponding products in
good yields (3q−v). It is worth noting that the iodide
79
NR
trace
trace
65
NaIO4
Cu(OAc)2
PhI(OAc)2
PhI(OAc)2
c
10
AgSbF6
TFE
trace
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol), 2a (0.6
mmol), [Cp*RhCl2]2 (2.5 mol %), PhI(OAc)2 (0.6 mmol), AgSbF6
b
(10 mol %) in TFE (1.5 mL) at 90 °C for 24 h. Isolated yields are
c
given. Without [Cp*RhCl2]2.
solvents was explored; it was observed that the desired product
3a can be obtained only when alcohol was used as the solvent
(Table 1, entries 1−5). On the other hand, solvents such as
1,2-dichloroethane (DCE), toluene, 1,4-dioxane, and DMF did
not afford the product 3a, and the starting material was
recovered (see Supporting Information).
Delightfully, a satisfactory yield of 3a was obtained when
trifluoroethanol was used as the solvent (Table 1, entry 5).
Subsequently, several other oxidants such as K2S2O8, NaIO4,
and Cu(OAc)2 were screened, among which none gave the
products in good yields (Table 1, entries 6−8). Furthermore,
only 65% yield of 3a was obtained when AgSbF6 was not used
in the reaction (Table 1, entry 9). A control reaction revealed
that the rhodium(III) catalyst is indispensable for this oxidative
annulation reaction (Table 1, entry 10). It is worth noting that
the intermolecular amination reaction was not observed under
these reaction conditions. With the optimized reaction
conditions in hand, we next investigated the functional group
tolerance on ketoximes, and the data are presented in Scheme
2. The nitro-substituted acetophenone oxime derivatives all
performed well, leading to the corresponding indazoles in
moderate to good yields (3a−g). The 2-nitrobenzaldehyde
B
DOI: 10.1021/acs.orglett.8b03488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Amide Effect
Scheme 5. Applications of the Reaction
Scheme 6. Kinetic Isotopic Effect
a
Reaction conditions, unless otherwise noted: 1 (0.2 mmol), 2a (0.6
mmol), [Cp*RhCl2]2 (2.5 mol %), PhI(OAc)2 (0.6 mmol), AgSbF6
b
(10 mol %) in TFE (1.5 mL) at 90 °C for 24 h. Isolated yields are
c
given. 1 (0.2 mmol), 2b (0.6 mmol), [Cp*RhCl2]2 (2.5 mol %),
PhI(OAc)2 (0.6 mmol), AgSbF6 (10 mol %) in TFE (1.5 mL) at 90
d
°C for 24 h. 1 (0.2 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2.5 mol
%), PhI(OAc)2 (0.6 mmol), AgSbF6 (10 mol %), KOAC (20 mol %)
in TFE (1.5 mL) at 90 °C for 24 h.
Second, when iodonium (6) was used instead of 4-
toluenesulfonamide, the corresponding product 3a was
obtained in 61% yield (Scheme 7a). This result indicates
a
Scheme 4. Substrate Scope of Ketoximes
Scheme 7. Preliminary Mechanistic Study
that 6 may be generated in the reaction, followed by its
reaction with the rhodium complex. Finally, when the substrate
7 was subjected to the standard reaction conditions, the
desired product 3a was isolated in 51% yield, accompanied by
the product 8 in 45% yield (Scheme 7b). Interestingly, when 7
was treated with rhodium(III) catalyst and AgSbF6, without
iodobenzene diacetate, the product 3a was not obtained, while
1a was completely recovered (Scheme 7c). On the other hand,
the product 3a could be attained in 57% yield, along with the
product 8 in 47% yield, when iodobenzene diacetate was used
as the oxidant (Scheme 7d).17 Altogether, these results
indicated that the intermolecular amination occurred first
followed by N−N bond formation with iodobenzene diacetate
as the oxidant. The obtained product 8 may explain the reason
why only alcohol as the solvent could provide the C−N/N−N
bond formation product.
a
Reaction conditions, unless otherwise noted: 1 (0.2 mmol), 2 (0.6
mmol), [Cp*RhCl2]2 (2.5 mol %), PhI(OAc)2 (0.6 mmol), AgSbF6
b
(10 mol %) in TFE (1.5 mL) at 90 °C for 24 h. Isolated yields are
given.
functional group might provide a convenient means to install
other functional groups through known protocols.
To further demonstrate the synthetic utility of this method,
the methoxy group on the indazole was first removed under
mild reaction conditions (see the Supporting Information).
Furthermore, the product 5 can be easily prepared and may be
used as a key precursor to synthesize ionidamise (Scheme 5a).
The reaction could also be easily scaled up to grams with
slightly reduced yields (Scheme 5b).
To explore the pathway of this rhodium(III)-catalyzed
annulation of ketoximes with arylsulfonamide, several parallel
reactions were carried out to elucidate the role of each reagent.
First, a kinetic isotopic effect (PH/PD = 1.6) was observed
from the intermolecular completion experiment (Scheme 6).
Based on these results and previous reports, a plausible
catalytic cycle was proposed in Scheme 8. The cationic
[Cp*RhIII] complex I would be generated in the presence of
AgSbF6 in the reaction, which would coordinate with ketoxime,
followed by the C−H activation, leading to the complex II.
C
DOI: 10.1021/acs.orglett.8b03488
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 8. Proposed Mechanism
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Natural
Science Foundation of China (Nos. 21772139, 21572149), the
Prospective Study Program of Jiangsu (Nos. 17KJA150006,
BY2015039-08), Jiangsu Province Natural Science Found for
Distinguished Young Scholars (No. BK20180041), and the
Project of Scientific and Technologic Infrasracture of SuZhou
(No. SZS2018201708).
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The iodonium 6 which was formed in situ in the reaction can
oxidize the complex II, providing the complex III, followed by
the migratory insertion, generating the complex IV. The
intermolecular amination product would be formed and release
the active complex I. Subsequently, the product 3a reacted
with iodobenzene diacetate to give the final product.
In conclusion, we have developed a practical approach for
the synthesis of indazoles via the rhodium(III)-catalyzed
intermolecular C−H amination of ketoxime and iodobenzene
diacetate-enabled N−N bond formation. Moreover, the well-
known nitro-substituted ketoximes were all well compatible,
leading to the corresponding products in good to excellent
yields.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
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1
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Accession Codes
CCDC 1875850 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, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zbhuang@suda.edu.cn.
*E-mail: dqshi@suda.edu.cn.
*E-mail: yszhao@suda.edu.cn.
ORCID
Yingsheng Zhao: 0000-0002-6142-7839
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b03488
Org. Lett. XXXX, XXX, XXX−XXX