A Copper-Catalyzed Tandem C–H ortho-Hydroxylation and N–N Bond-Formation Transformation: Expedited Synthesis of 1-(ortho-Hydroxyaryl)-1H-indazoles

Article abstract of DOI:10.1002/ejoc.201701149

A facile, one-pot synthesis of 1H-indazoles featuring a Cu-catalyzed C–H ortho-hydroxylation and N–N bond-formation sequence with the use of pure oxygen as the terminal oxidant was developed. The reaction of readily available 2-arylaminobenzonitriles with

Full text of DOI:10.1002/ejoc.201701149

DOI: 10.1002/ejoc.201701149
Communication
Domino Reactions
A Copper-Catalyzed Tandem C–H ortho-Hydroxylation and N–N
Bond-Formation Transformation: Expedited Synthesis of
1-(ortho-Hydroxyaryl)-1H-indazoles
Cheng-yi Chen,*[a] Fengxian He,[b] Guangrong Tang,*[b] Han Ding,[b] Zhaobin Wang,[b]
Dawei Li,[b] Lujiang Deng,[b] and Roger Faessler[a]
Abstract: A facile, one-pot synthesis of 1H-indazoles featuring lyzed hydroxylation at the ortho position of the aromatic ring
a Cu-catalyzed C–H ortho-hydroxylation and N–N bond-forma- followed by N–N bond formation in DMSO under a pure-oxy-
tion sequence with the use of pure oxygen as the terminal gen atmosphere afforded a wide variety of 1-(ortho-hydroxy-
oxidant was developed. The reaction of readily available 2-aryl- aryl)-1H-indazoles in good to excellent yields. This efficient
aminobenzonitriles with various organometallic reagents led to method does not require the utilization of noble-metal cata-
ortho-arylamino N–H ketimine species. Subsequent Cu-cata- lysts, elaborate directing groups, or privileged ligands.
Introduction
functionalization and ultimately decreases the overall efficiency
in the atom-economical reaction sequence. C–H functionaliza-
tion with the use of an inherent directing group for the prepara-
tion of target molecules would render this methodology far
more attractive.
Transition-metal-catalyzed C–H functionalization, which serves
as a straightforward and step-economical tool for the formation
of carbon–carbon and carbon–heteroatom bonds, has occupied
an important stage in organic synthesis. To overcome the diffi-
culties associated with functionalizing inert C–H bonds, these
reactions often have to rely on the utilization of noble ruth-
enium, rhodium, palladium, iridium, and platinum complexes in
conjunction with a stoichiometric amount of copper, silver, or
other strong oxidant.[1] Efforts in recent years were focused on
inexpensive, less-toxic, and abundant metals such as copper
salts for direct C–H functionalization, and a number of such
transformations were developed either under catalytic or stoi-
chiometric conditions.[2] Among the various reported oxidants,
molecular oxygen serves as an ideal candidate owing to its
atom-economical and environmentally benign characteristics.[3]
Efficient C–H functionalization, conversely, calls for the exten-
sive use of directing groups (DGs) in substrates to improve re-
gioselectivity.[1e,1j] Most directing groups used in C–H function-
alization are based on nitrogen-containing heterocycles such as
pyridine, pyrimidine, pyrazole, aminooxazoline, 8-aminoquin-
oline (AQ), picolinamide (PA), and 2-pyridinylisopropyl (PIP).[4]
The introduction of these auxiliaries and their subsequent re-
moval, however, defeats the original intention of direct C–H
Over the past decade, the selective hydroxylation of arenes
through the direct functionalization of C(sp2)–H bonds has at-
tracted considerable attention owing to the importance of
phenols. Following the pioneering work of Fujiwara and co-
workers,[5] a number of methods for Cu-catalyzed ortho-hydrox-
ylation with the use of different azaheterocycles as mono-
dentate or bidentate directing groups have been reported (Fig-
ure 1).[6] We herein report a new strategy for C–H functionaliza-
tion by using the ortho-aminoaryl N–H ketimine moiety as an
effective directing group for the Cu-catalyzed hydroxylation of
aryl groups followed by intramolecular N–N bond formation.
This synthetic methodology allows for expedited entry to a
wide variety of rarely accessible 1-(ortho-hydroxyaryl)indazoles
(Figure 1).
[a] Janssen Pharmaceutica, API Small Molecule Development,
Hochstrasse 201, 8200 Schaffhausen, Switzerland
E-mail: cchen117@its.jnj.com
[b] Porton (Shanghai) R&D Center,
1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241,
China
E-mail: arthur.tang@porton.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201701149.
Figure 1. Cu-catalyzed ortho-hydroxylation of a C(sp2)–H bond and subse-
quent N–N bond formation.
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Results and Discussion
was not realized until copper(II) trifluoromethanesulfonate
[Cu(OTf)2], Cu(NO3)2, and CuSO4 were tested (Table 1, entries 6–
8), albeit with modest selectivity. Very interestingly, CuO im-
proved the selectivity to 1:10, but desired indazole 3 bearing
an ortho-hydroxyaryl group was only isolated in 65 % yield. The
selectivity was further improved to 1:12.5 but with only a mar-
ginal improvement in the yield upon using Cu(acac)2 (acac =
acetylacetonate). Finally, we were delighted to find that both
the selectivity and the yield of the isolated product could be
increased if both the catalyst loading and the reaction tempera-
ture were decreased (Table 1, entry 11). Hence, we anticipated
that such operationally simple conditions could be readily ap-
plied to the direct ortho-hydroxylation of the C(sp2)–H bonds
of arene rings with subsequent N–N bond formation for the
facile synthesis of unique 1H-indazoles containing an ortho-
hydroxyaryl group.
We previously reported the facile synthesis of 1H-indazoles
through Cu-catalyzed N–N bond formation by employing oxy-
gen as the terminal oxidant.[7] In this synthetic protocol, ortho-
aminoaryl N–H ketimines were formed through the addition of
a Grignard or organolithium reagent to readily available ortho-
aminobenzonitriles. We envisioned that the ortho-aminoaryl
N–H ketimine moiety or the indazole moiety could potentially
serve as an effective directing group for the C–H functionaliza-
tion of the aromatic ring of the arylamino group under Cu-
catalyzed conditions. During preparative work to produce 20 g
of indazole 2 by using a Cu-catalyzed N–N bond-formation pro-
tocol, we were able to isolate a small amount of 1-(ortho-
hydroxyphenyl) 1H-indazole 3 as a byproduct (Table 1).[8] The
initial assumption was that this byproduct could be derived
from subsequent reaction of indazole 2. However, subjecting
isolated indazole 2 to the same reaction conditions did not
afford 1-(ortho-hydroxyphenyl)indazole 3. As such, we reasoned
that the hydroxy group was introduced to the molecule by Cu-
catalyzed C(sp2)–H hydroxylation and subsequent N–N bond
formation to give the indazole.[9] Furthermore, we reasoned
that the amino ketimine moiety served as an effective inherent
directing group for this unprecedented C(sp2)–H ortho-hydroxy-
lation of aryl groups.[10] Encouraged by this exciting result, we
envisioned that the optimal copper catalyst could be identified
through conventional salt screening.
We next explored the generality of the newly defined reac-
tion conditions for the synthesis of indazoles by employing
nitrile 4 as the starting material (Table 2). The addition of phen-
Table 2. Synthesis of ortho-hydroxyaryl-1H-indazoles from 2-phenylamino-
benzonitriles.[a]
Table 1. Copper-salt screening for C–H hydroxylation and N–N bond forma-
tion.[a]
Entry
Cu salt (mol-%)
Ratio of 2/3[b] (Yield [%] of 3)
1
2
Cu(OAc)2 (20)
CuI (40)
10.7:1
6.0:1
3
CuBr (40)
3.7:1
4
CuCl (40)
2.5:1
5
CuBr2 (40)
3.2:1
6
7
8
9
Cu(OTf)2 (40)
Cu(NO3)2 (40)
CuSO4 (40)
CuO (40)
Cu(acac)2 (40)
Cu(acac)2 (20)
1:2.0
1:2.8
1:3.3
1:10 (65)
1:12.5 (67)
1:15.9 (86)
10
11[c]
[a] All reactions except that in entry 11 were performed on a 0.5 g scale
under a pure-oxygen atmosphere in DMSO (9 mL) at 85 °C for 3 h. [b] The
ratios for 2/3 was measured by HPLC analysis; yield of isolated 3 based on
nitrile 4 is given in parentheses. [c] Entry 11 was performed on a 1 g scale
at 65 °C by using Cu(acac)2 (20 mol-%).
As shown in Table 1, a wide variety of readily available cop-
per salts was screened to improve the C–H hydroxylation and
N–N bond-formation cascade sequence. Copper salts such as
Cu(OAc)2, CuX (X = I, Br, Cl), and CuBr2 (Table 1, entries 1–5)
favored the formation of indazole 2. Reversed selectivity
[a] All reactions were performed on a 0.5 g scale under a pure-oxygen atmos-
phere in DMSO (9 mL) at 65 °C for 6–8 h, and the products were isolated by
silica-gel column chromatography. Yields of the isolated products are based
on 4. [b] Reaction was performed on a 10 g scale.
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ylmagnesium bromide to this nitrile afforded ortho-aminoaryl Me, and ortho-OMe groups all failed to give the desired hydrox-
N–H ketimine 5, which upon quenching and isolation was di- ylated indazoles.[11] This unexpected result could possibly be
rectly subjected to the Cu-catalyzed reaction to give 3 in 86 % interpreted by steric interaction of the ortho group with the
yield as shown in Table 1, entry 11. This same reaction was later adjacent ortho proton, which would decrease the accessibility
performed on a 10 g scale to afford 3 in 89 % yield, which of the C–H bond for hydroxylation. No C–H ortho -hydroxylation
demonstrated the practicality and simplicity of this newly de- occurred for substrate 14 bearing a nitro group.[12] However,
veloped synthetic protocol. As expected, other aryl groups we were delighted to find that the C–H hydroxylation occurred
could be readily introduced to the 3-position of the indazole, on the pyridine ring to give compound 17 in 51 % yield
as shown for products 6a–f (80–86 % yield on 500 mg scale). (Scheme 2).
The reaction also tolerated halide groups, as 6f was readily pre-
pared in 80 % yield. The reaction of the substrate containing a
heteroaromatic 2-thienyl group also proceeded efficiently to
give indazole 6g in 81 % yield. Installation of alkyl groups such
as methyl, ethyl, and cyclopropyl groups was uneventful and
afforded 6h–j in good yields.
Next, we extended the generality of the defined conditions
for the synthesis of indazoles from benzonitriles 7 bearing sub-
stituted arylamino groups (Table 3). The C–H hydroxylation re-
action tolerated a wide variety of substitution patterns of the
aromatic ring. C–H ortho-hydroxylation on the tolyl group oc-
curred smoothly to afford 9a, 9e, and 9g in 80–85 % yield. para-
Methoxy, para-bromo, and para-fluoro derivatives were also tol-
erated and underwent the reaction to afford products 9b–d. In
particular, para-fluoro derivative 9c was obtained in an excel-
lent yield of 90 %. Functionalization of the 3,5-difluroaryl group
was also feasible, and product 9f was obtained in 82 % yield.
Scheme 1. C–H hydroxylation of ortho-substituted aryl nitriles to 1H-ind-
azoles.
Table 3. Synthesis of ortho-hydroxyaryl 1H-indazoles from substituted 2-aryl-
benzonitriles.[a]
Scheme 2. C–H hydroxylation of electron-deficient aromatic and hetero-
aromatic rings.
We next probed the origin of the oxygen atom in the prod-
uct, as both DMSO[13] and O2 could deliver the hydroxy group
to the molecule. As such, a control experiment was performed
to determine the source of the hydroxy group. Upon perform-
ing the reaction under an argon atmosphere with 100 mol-
% Cu(acac)2 in DMSO, only the N–N bond-formation reaction
[a] All reactions were performed on a 0.5 g scale under a pure-oxygen atmos-
occurred to afford the desired 1H-indazole in 12 % yield at 65 °C
and in 30 % yield at 85 °C (see the Supporting Information).
The C–H hydroxylation reaction to form the 1-(ortho-hydroxy-
phenyl)-1H-indazole did not proceed, which suggested that the
oxygen atom in the OH group originated from dioxygen.
To gain more insight into the reaction mechanism, we also
phere in DMSO (9 mL) at 65 °C for 6–8 h, and the products were isolated by
silica-gel column chromatography. Yields of the isolated products are based
on 7.
The C–H ortho-hydroxylation reaction, however, did not pro-
ceed if the aryl group contained an ortho substituent
(Scheme 1). For example, substrates 10 bearing ortho-F, ortho- conducted isotope-labeling experiments.[14] As shown in
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Communication
Notes
Scheme 3, upon performing an intermolecular competition ex-
periment under the reaction conditions, a high secondary ki-
netic isotope effect (kH/kD = 1.32) was observed. Interestingly,
an inverse kinetic isotope effect (kH/kD = 0.77) was observed if
the intramolecular competition reaction was performed with
substrate 22. Though accurate interpretation of these isotope
effects is difficult, the results indicate that C–H bond breaking
is not involved in the rate-determining step. The inverse isotope
effect also suggests that the hybridization changes at the ortho
position during the C–H oxidation. Furthermore, the reaction
was not suppressed by the addition of a radical inhibitor, such
as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO), and thus, the
likelihood of a radical mechanism could be ruled out.
The authors declare no competing financial interest.
Acknowledgments
We would like to acknowledge Mrs. Huawei Ma at Porton
(Shanghai) R&D Center for analytical support. We also acknowl-
edge Dr. Dominik Gaertner of Janssen for helpful discussions
during the preparation of this manuscript.
Keywords: C–H activation · Copper · Domino reactions ·
Hydroxylation · Nitrogen heterocycles
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Conclusions
In conclusion, we developed a new and efficient method for
the construction of 1-(ortho-hydroxyaryl)-1H-indazoles on the
basis of a Cu-catalyzed C(sp2)–H hydroxylation and N–N bond-
formation sequence by using pure oxygen as the terminal
oxidant. We believe this to be the first example of a C–H func-
tionalization/N–N bond-formation cascade for the efficient pro-
duction of 1-(ortho-hydroxyaryl)-1H-indazoles. This protocol
takes advantage of readily accessible ketimine precursors as in-
herent directing groups to facilitate the C(sp2)–H hydroxylation
reaction. Importantly, both nitrogen atoms in the starting mate-
rial are conserved, and the phenol moiety is readily introduced
with only the formation of water as a byproduct. The method
demonstrated herein allows easy access to structurally diverse
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for the modular synthesis of 1H-indazole-containing medicinal
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Supporting Information (see footnote on the first page of this
article): Experimental details, characterization data, and NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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[11]
Only the corresponding indazoles were formed in low yields (30–50 %),
as detected by LC–MS.
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Received: August 16, 2017
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Domino Reactions
C.-y. Chen,* F. He, G. Tang,*
H. Ding, Z. Wang, D. Li, L. Deng,
R. Faessler ............................................. 1–6
A Copper-Catalyzed Tandem C–H
ortho-Hydroxylation and N–N Bond-
Formation Transformation: Expe-
dited Synthesis of 1-(ortho-Hydroxy-
aryl)-1H-indazoles
A Cu-catalyzed C(sp2)–H ortho-hydrox- oxidant. The ortho-arylamino N–H ket-
ylation and N–N bond-formation se- imine moiety serves as an effective di-
quence is described for the synthesis recting group for C(sp2)–H oxidation.
of 1-(ortho-hydroxyaryl)-1H-indazoles acac = acetylacetonate.
by using pure oxygen as the terminal
DOI: 10.1002/ejoc.201701149
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