Pd- and Cu-catalyzed C-H arylation of indazoles

Article abstract of DOI:10.1016/j.tet.2012.05.091

The palladium- and copper-catalyzed C-H arylation reactions of 1H- and 2H-indazoles with haloarenes are described. A PdCl₂/phen/Ag ₂CO₃/K₃PO₄ catalytic system is effective for the C-H arylation of 1H- and 2H-indazoles with haloarenes, whereas a less expensive CuI/phen/LiOt-Bu catalytic system is applicable to the C-H coupling of substituted 2H-indazoles and iodoarenes. The utility of newly developed catalyst was demonstrated in the rapid synthesis of YC-1 (an antitumor agent) and YD-3 (platelet anti-aggregating agent). These new reactions represent important direct functionalization tools of indazoles, well-known bioisosteres of pharmaceutically important indole core.

Full text of DOI:10.1016/j.tet.2012.05.091

Tetrahedron 68 (2012) 7605e7612
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd- and Cu-catalyzed CeH arylation of indazoles
y
y
*
*
Keika Hattori , Kazuya Yamaguchi , Junichiro Yamaguchi , Kenichiro Itami
Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The palladium- and copper-catalyzed CeH arylation reactions of 1H- and 2H-indazoles with haloarenes
are described. A PdCl2/phen/Ag2CO3/K3PO4 catalytic system is effective for the CeH arylation of 1H- and
2H-indazoles with haloarenes, whereas a less expensive CuI/phen/LiOt-Bu catalytic system is applicable
to the CeH coupling of substituted 2H-indazoles and iodoarenes. The utility of newly developed catalyst
was demonstrated in the rapid synthesis of YC-1 (an antitumor agent) and YD-3 (platelet
anti-aggregating agent). These new reactions represent important direct functionalization tools of
indazoles, well-known bioisosteres of pharmaceutically important indole core.
Received 11 March 2012
Accepted 22 May 2012
Available online 4 June 2012
Keywords:
Indazole
Catalysis
CeH arylation
Heterobiaryl
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
bioisosteres in medicinal chemistry. In an attempt to expand
existing knowledge in the chemical manipulation of various het-
Heteroaromatics are one of the most important structural motifs
in medicinal chemistry.1 To develop a successful pharmaceutical, it
is necessary to ensure the biological activity, stability, and safety of
a given compound. Once a lead heteroaromatic compound is
identified, it is typically used as a starting point for chemical
modification to enhance its positive parameters and to suppress its
negative effects. One way to modify a lead heteroaromatic com-
pound with subtlety is to append functional groups to the existing
ring system. Methods to create a library of related medicinal
compounds in a time-efficient manner are always in high demand,
and therefore countless methods for the functionalization of het-
eroaromatics have been developed. Another way to refashion a lead
compound is to convert a heteroaromatic compound into its bio-
isostere.2 For example, indazoles are the well-known bioisosteres
of indole, a privileged structure in pharmaceutically relevant
molecules.3
eroarene bioisosteres, we set out to develop the direct CeH aryla-
tion of indazoles.
Recently, the CeH functionalization of heteroaromatics through
transition metal catalysis has received significant attention as it
allows us to transform CeH bonds into other functional groups in
one step, thus saving time and costs of operation.4 While a number
of indole CeH functionalization reactions (particularly CeH aryla-
tion) have been developed by many research groups including our
own,5 the CeH functionalization of its bioisostere, indazoles, is still
very rare (Scheme 1). There is a necessity to develop a ‘chemical
toolbox’ that enables the rapid functionalization of heteroarene
Scheme 1. CeH arylation of 1H- and 2H-indazoles, which are indole bioisosteres.
There are two indazole isomers, 1H-indazole and 2H-indazole
depending on the position of N-substituent (Scheme 1). Of these
two isomers, the CeH arylation of 1H-indazoles has not yet been
reported.6 As for the CeH arylation of 2H-indazoles, there are two
available methods reported by Lautens and Greaney using
* Corresponding authors. E-mail address: itami.kenichiro@a.mbox.nagoya-u.ac.jp
(K. Itami).
y
Both authors contributed equally to this work.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.091

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K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
palladium catalysts.7 Our study aimed at developing reliable CeH
arylation methods for indazoles, we identified two effective cata-
lytic systems based on palladium and copper. These results are
reported in this paper. The key findings include (1) the accom-
plishment of the CeH arylation of 2H-indazoles with iodoarenes by
the Daugulis’ copper-based catalyst; (2) the development of new
palladium-based catalytic system for the CeH arylation of 1H- and
2H-indazoles with haloarenes; and (3) the application of palladium
catalysis to rapid synthesis of biologically active compounds.
Table 1
Effect of aryl coupling partners in the CeH arylation of 2-phenyl-2H-indazole (1a)a
Entry
2
3 (Yield, %)b
2. Results and discussion
1
2
X¼I (2a)
X¼Br
3aa (58)
3aa (4)
2.1. Copper-catalyzed CeH arylation of 2H-indazoles
2.1.1. Discovery of copper-catalyzed CeH arylation. We began our
studies by attempting to perform the CeH arylation of 2-substituted
2H-indazoles using inexpensive catalysts such as copper or
nickel.8,9 We thus screened some representative catalysts and
conditions that have previously been used for the CeH arylations of
heteroarenes (Scheme 2). The reaction of 2-phenyl-2H-indazole
(1a) and an aryl reagent was used as a model reaction in this
screening process. Although our copper-based oxidative CeH ary-
lation protocol (conditions A)8b and nickel-based protocol (condi-
tions B)9h were totally ineffective, we found that the Daugulis’
copper-based system promoted the reaction (conditions C).8d For
example, treatment of 1a (1.0 equiv) with iodobenzene (2a;
2.0 equiv) in the presence of CuI (10 mol %), 1,10-phenanthroline
(phen; 10 mol %), and LiOt-Bu (2.0 equiv) in DMF at 110 ꢀC for 15 h
afforded 2,3-diphenyl-2H-indazole (3aa) in 58% yield (Scheme 2).
3
R¼2-Me (2b)
3ab (66)
4
5
R¼3-Me (2c)
R¼4-Me (2d)
3ac (37)
3ad (62)
6
R¼Cl (2e)
3ae (46)
7
8
R¼OMe (2f)
R¼CF3 (2g)
3af (56)
3ag (52)
9
2h
3ah (40)
a
Conditions: 1a (0.4 mmol), 2ae2h (0.8 mmol), CuI (0.04 mmol; 10 mol %), phen
(0.04 mmol; 10 mol %), LiOt-Bu (0.8 mmol; 2.0 equiv), DMF (0.5 mL), 110 ꢀC, 15 h.
b
Isolated yields.
when compared to the reaction of 2-phenyl-2H-indazole (1a to
3aa). Methoxy and fluorine groups on 2-ary-2H-lindazole (1c and
1d) were tolerated to give products 3ca and 3da in moderate yields.
2.2. Palladium-catalyzed CeH arylation of 1H-indazoles
2.2.1. Discovery of new palladium catalyst. We were able to dem-
onstrate that the Daugulis’ copper-based catalytic system is
Scheme 2. Discovery of a copper-catalyzed CeH arylation of 2H-indazoles.
Table 2
Effect of indazole substituents in the CeH arylation of 2H-indazoles
2.1.2. Substrate scope. We next examined the scope and limitation
of the copper-catalyzed CeH arylation of 2-substituted 2H-inda-
zoles with various aryl halides (Table 1). Whereas the use of iodo-
benzene gave product 3aa in 58% isolated yield (entry 1), the use of
bromobenzene resulted in a lower yield (entry 2). The use of ortho-
substituted phenyl iodide 2b furnished the desired coupling prod-
uct in good yield (entry 3), as did meta- and para-substituted phenyl
iodides (2c and 2d; entries 4 and 5). Aryl iodides bearing electron-
withdrawing groups (2e and 2g), as well as those that bear electron-
donating groups (2f), coupled smoothly with 1a to provide the
corresponding arylindazoles 3 in moderate yields (entries 6e8).
Notably, sterically hindered aryl iodide 2h was also an acceptable
coupling partner for the CeH arylation of 2H-indazoles (entry 9).
This robust CuI/phen/LiOt-Bu catalytic system can also be ap-
plied to the CeH arylation of a variety of 2H-indazoles with iodo-
benzene (2a) (Table 2). Reaction of 2-alkylated 2H-indazoles such as
1b afforded the corresponding coupling product 3ba in higher yield

K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
7607
applicable to the CeH arylation of various 2-substituted 2H-inda-
zoles with aryl iodides. As a next challenge, we decided to explore
the hitherto unreported CeH arylation of 1H-indazoles. Initially, 1-
phenyl-1H-indazole (4a) was treated with iodobenzene (2a) under
the influence of CuI/phen/LiOt-Bu catalytic system (Scheme 3).
However, the reaction did not yield the desired product 5aa. In-
stead the reaction produced triphenylamine derivative 8 in 53%
yield as the main product. This unexpected product 8 might be
formed by the sequence consisting of (i) deprotonation of 4a by
strong base LiOt-Bu, (ii) ring-opening reaction of lithiated indazole
6 to afford nitrile 7,10 and (iii) Cu-catalyzed N-arylation reaction of 7
with iodobenzene (2a). To prevent this ring-opening reaction
manifold, we next investigated an electrophilic palladium catalytic
system without using a strong base.
Interestingly, the use of 1,10-phenanthroline (phen) as a ligand
resulted in much better yield (45% GC yield; entry 3), and the re-
action also proceeded at lower temperature (165 ꢀC) without mi-
crowave irradiation (entry 4). The extra addition of K3PO4 was also
effective for the reaction (55% GC yield; entry 5). We finally found
that the yield of 5aa could be increased to 81% GC yield (60% iso-
lated yield; entry 6) by increasing the amount of iodobenzene (2a)
to 2.0 equiv relative to 4a.
2.2.2. Substrate scope of 1H-indazole arylation. We were pleased to
find that the CeH arylation of 1-phenyl-1H-indazole (4a) with
iodobenzene (2a) was effectively promoted by PdCl2 (10 mol %),
phen (10 mol %), Ag2CO3 (1.5 equiv), and K3PO4 (2.0 equiv) in DMAc
at 165 ꢀC for 12 h to give 5aa in 60% isolated yield (Table 4, entry 1).
With this novel procedure in hand, the scope of applicable hal-
oarenes was next examined (Table 4). When bromobenzene was
used instead of iodobenzene as a coupling partner, the yield of 5aa
was decreased (11% yield; entry 2). The use of methyl-substituted
iodobenzenes (2be2d) successfully gave the resulting coupling
products in good yields (entries 3e5). Furthermore, the reactions
using iodoarenes bearing chloro (2e), methoxy (2f), and tri-
fluoromethyl (2g) groups as well as 3-iodopyridine (2h) proceeded
well to afford the corresponding coupling products in moderate
yields (entries 6e9).
Table 4
Scope of haloarenes in the CeH arylation of 1-phenyl-1H-indazole (4a)a
Scheme 3. Unexpected reaction of 1-phenyl-1H-indazole (4a) when using CuI/phen/
LiOt-Bu.
We previously disclosed that a PdCl2/2,20-bipyridyl (bipy)/
Ag2CO3 catalytic system is effective for the CeH arylation of thio-
phenes and thiazoles with iodoarenes.11 Thus, we began by ap-
plying these reaction conditions to the CeH arylation of 1-phenyl-
1H-indazole (4a) with iodobenzene (2a) (Table 3). However, the
standard conditions only gave the coupling product 5aa in trace
amounts (entry 1). By increasing the reaction temperature to
200 ꢀC under microwave irradiation in N,N-dimethylacetamide
(DMAc), the yield of 5aa improved to 15% GC yield (entry 2).
Entry
2
5 (Yield, %)b
1
2
X¼I (2a)
X¼Br
5aa (60)
5aa (11)
3
R¼2-Me (2b)
5ab (65)
Table 3
4
5
R¼3-Me (2c)
R¼4-Me (2d)
5ac (72)
5ad (80)
Effects of ligand, additive, solvent, temperature, and reaction stoichiometry on the
CeH arylation of 1-phenyl-1H-indazole (4a) with iodobenzene (2a)a
6
R¼Cl (2e)
5ae (51)
7
8
R¼OMe (2f)
R¼CF3 (2g)
5af (54)
5ag (71)
Entry
Ligand
Additive
Solvent
Temp (ꢀC)
5aa Yield, %c
1
2
3
4
bipy
bipy
phen
phen
phen
phen
d
Dioxane
DMAc
DMAc
DMAc
DMAc
DMAc
120
200b
200b
165
165
165
<1
15
45
52
d
d
9
2h
5ah (50)
d
5
K3PO4
K3PO4
55
6d
81 (60)e
a
Conditions: 4a (0.2 mmol), 2ae2h (0.4 mmol), PdCl2 (0.02 mmol; 10 mol %),
phen (0.02 mmol; 10 mol %), Ag2CO3 (0.3 mmol; 1.5 equiv), K3PO4 (0.4 mmol;
2.0 equiv), DMAc (0.8 mL), 165 ꢀC, 12 h.
a
Conditions: 4a (0.2 mmol), 2a (0.3 mmol), PdCl2 (0.02 mmol; 10 mol %), ligand
(0.02 mmol; 10 mol %), Ag2CO3 (0.3 mmol), additive (0.4 mmol), solvent (0.8 mL),
165 ꢀC, 12 h.
b
Isolated yields.
b
Reactions were conducted under microwave irradiation for 90 min.
GC yield.
Compound 2a (0.4 mmol) was used.
Isolated yield.
c
d
Substituents other than a phenyl group on 1H-indazole were
also investigated (Table 5). Gratifyingly, the reactions of methyl-,
e

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K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
Table 5
Effect of indazole substituents in the CeH arylation of 1H-indazoles
Scheme 5. CeH arylation of unsubstituted indazole.
benzyl-, and [2-(trimethylsilyl)ethoxy]methyl (SEM)-substituted
1H-indazoles (4be4d) with iodobenzene (2a) took place smoothly
to deliver the corresponding coupling products in moderate to
good yields.
2.4. Application to the synthesis of biologically active
compounds
2.3. CeH arylation of 2H-indazoles under PdCl2/phen/Ag2CO3/
K3PO4 catalytic system
2.4.1. Arylindazoles as biologically active compounds. Biologically
active compounds containing arylated indazole scaffolds have been
reported, and representative compounds are shown in Scheme 6.12
In the series of 3-aryl-1H-indazoles, the potent antitumor agent YC-
1 (10), nigellidine (11), and platelet anti-aggregation agent YD-3
(12) are known. Meanwhile, liver X receptor agonist 13 and anti-
angiogenic agent 14 have been reported as bioactive 3-aryl-2H-
indazoles. Among various routes accessing these bioactive 3-aryl-
2H-indazoles, there is only one report using CeH arylation of
indazoles.7b Therefore, we applied our developed arylation meth-
odology to the synthesis of YC-1 (10) and YD-3 (12).
Notably, the newly developed palladium-based catalytic system
turned out to be effective also for the CeH arylation of 2H-indazoles
(Scheme 4). For example, under the influence of PdCl2/phen/
Ag2CO3/K3PO4, 2-phenyl-2H-indazole (1a) reacted with 2a to give
2,3-diphenyl-2H-indazole (3aa) in 87% yield. Similarly, the reaction
of 2-benzyl-2H-indazole (1e) with 2a afforded 2-benzyl-3-phenyl-
2H-indazole (3ea) in 68% yield. Thus, the PdCl2/phen/Ag2CO3/K3PO4
system can be considered as a general catalytic protocol for the
indazole CeH arylation reaction.
Scheme 4. CeH arylation of 2H-indazoles with iodobenzene (2a) under palladium
catalysis.
We then became curious to see what would be the outcome of
CeH arylation when an indazole bearing a free NH (i.e., unsub-
stituted indazole; we draw it here as its 1H-indazole form, see
Scheme 5) is used in our catalytic system. We found that both
palladium- and copper-based CeH arylation conditions (for 2-
substituted 2H-indazoles and 1-substituted 1H-indazoles) were
not effective. This problem was overcome by developing the fol-
lowing three-step sequence: (i) benzylation of NH-free indazole,
resulting in a mixture of benzylated 1H- and 2H-indazoles (4c/
1c¼2:1); (ii) palladium-catalyzed CeH arylation of the mixture of
4c and 1c, resulting in the C3-arylation of both compounds (5ca/
3ea¼2:1); (iii) debenzylation of the mixture of 5ca and 3ea with
KOt-Bu in DMSO under air.12 Using this method, N-unsubstituted 3-
aryl-1H-indazole (9) can be obtained from unsubstituted indazole
in 65% yield with only one purification.
Scheme 6. Biologically active compounds containing the 3-arylindazole framework.
2.4.2. Syntheses of YC-1 and YD-3 via CeH arylation. Our synthesis
of YD-3 (12) and YC-1 (10) commenced with 1-benzyl-2H-indazole
(4c), which was prepared by the benzylation of indazole (Scheme
7). This was then coupled with aryl halides 15 and 16 by the
PdCl2/phen/Ag2CO3/K3PO4 catalyst. The CeH coupling of 4c and

K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
7609
ethyl 4-iodobenzoate (15) delivered YD-3 (12) in 64% yield. The
coupling of 4c and methyl 5-bromofuran-2-carboxylate (16) affor-
ded the resulting coupling product in 36% yield (77% based on re-
covered starting material). The follow-up reduction of the ester by
LiAlH4 yielded YC-1 (10) in 82% yield.
developed chromatogram was analyzed by UV lamp (254 nm).
Flash column chromatography was performed with E. Merck silica
gel 60 (230e400 mesh). Preparative thin-layer chromatography
(PTLC) was performed using Wakogel B5-F silica coated plates
(0.75 mm) prepared in our laboratory. Preparative high perfor-
mance liquid chromatography (preparative HPLC) was performed
with a Biotage IsoleraÒ, one equipped with Biotage SNAP Cartridge
KP-C18-HS columns using acetonitrile/water as an eluent. Gas
chromatography (GC) analysis was conducted on a Shimadzu GC-
2010 instrument equipped with an HP-5 column (30 mꢁ0.25 mm,
Hewlett-Packard). GCeMS analysis was conducted on a Shimadzu
GCMS-QP2010 instrument equipped with an HP-5 column
(30 mꢁ0.25 mm, Hewlett-Packard). LCeMS analysis was conducted
on Agilent Technologies 1200 series. High-resolution mass spectra
(HRMS) were obtained from a JMS-T100TD instrument (DART).
Nuclear magnetic resonance (NMR) spectra were recorded on JEOL
JMN-GSX-270 (1H 270 MHz) spectrometer, a JEOL JMN-A-400 (1H
400 MHz) spectrometer, and JEOL JMN-ECS400-B (1H 400 MHz)
spectrometer. Chemical shifts for 1H NMR are expressed in parts per
million (ppm) relative to tetramethylsilane ( 0.0 ppm) or residual
d
peak of DMSO ( 2.50 ppm) and CD2Cl2 (d 5.32 ppm). Chemical
d
shifts for 13C NMR are expressed in parts per million relative to
CDCl3 (d 77.0 ppm), CD2Cl2 (d 53.8 ppm) or DMSO (d 39.5 ppm).
Data are reported as follows: chemical shift, multiplicity (s¼singlet,
d¼doublet, dd¼doublet of doublets, dt¼doublet of triplet,
t¼triplet, q¼quartet, m¼multiplet, br¼broad signal), coupling
constant (Hz), and integration.
Scheme 7. Rapid syntheses of YD-3 (12) and YC-1 (10) through CeH arylation.
3. Conclusion
4.2. General procedure of copper-catalyzed CeH arylation of
2-substituted 2H-indazoles with iodoarenes
In summary, we reported the palladium- and copper-catalyzed
CeH arylation of 1H- and 2H-indazoles with haloarenes. A PdCl2/
phen/Ag2CO3/K3PO4 catalytic system is effective for the CeH
arylation of 1H- and 2H-indazoles with haloarenes, whereas a less
expensive CuI/phen/LiOt-Bu catalytic system is applicable to the
CeH coupling of substituted 2H-indazoles and iodoarenes. The
utility of newly developed catalyst was demonstrated in the rapid
synthesis of YC-1 (an antitumor agent) and YD-3 (platelet
anti-aggregating agent). These new reactions not only represent
important direct functionalization tools of indazoles, well-known
bioisosteres of pharmaceutically important indole core, but also
showcase the power of CeH functionalization to rapidly
access arylated heteroaromatics. In order to continue establishing
more methods for the ‘chemical toolbox’ of heteroaromatic bio-
isostere synthesis, further investigations are ongoing in our
laboratory.
A 10-mL glass vessel equipped with J. YoungÒ O-ring tap con-
taining a magnetic stirring bar was flame-dried under vacuum and
filled with argon after cooling to room temperature. To this tube
were added 2-substituted 2H-indazole (1: 0.40 mmol), CuI (7.6 mg,
0.04 mmol), 1,10-phenanthroline (7.2 mg, 0.04 mmol), LiOt-Bu
(64 mg, 0.80 mmol), and haloarene (2: 0.80 mmol), followed by
DMF (0.5 mL) under a stream of argon. The tube was sealed with O-
ring tap, and then heated at 110 ꢀC for 15 h in an eight-well reaction
block with stirring. After cooling the reaction mixture to room
temperature, the mixture was passed through a short pad of CeliteÒ
(EtOAc). The filtrate was concentrated and the residue was sub-
jected to preparative HPLC (acetonitrile/water as an eluent) to af-
ford the arylated product 3.
4.3. Compound data of coupling products 3
4. Experimental section
4.1. General
4.3.1. 2,3-Diphenyl-2H-indazole (3aa).19 Compound 3aa (63 mg,
58%) was isolated as a white solid. 1H NMR (CDCl3, 400 MHz)
d
7.81
(d, J¼8.8 Hz, 1H), 7.71 (d, J¼8.6 Hz, 1H), 7.46e7.31 (m, 11H),
7.15e7.10 (m, 1H); 13C NMR (CDCl3, 100 MHz)
148.92, 140.15,
d
Unless otherwise noted, all materials including dry solvents
were obtained from commercial suppliers and used as received. 1-
Phenyl-1H-indazole,13 2-phenyl-2H-indazole,14 2-methyl-2H-
indazole,15 1-benzyl-1H-indazole,16 1-SEM-1H-indazole,17 2-(4-
methoxyphenyl)-2H-indazole,14 and 5-fluoro-2-(p-tolyl)-2H-inda-
zole18 were synthesized according to procedures reported in the
literature. All coupling reactions were performed in 10-mL glass
Schlenk tubes equipped with J. YoungÒ O-ring tap and heated in an
eight-well reaction block (heaterþmagnetic stirrer). Other re-
actions were performed with dry solvents under an atmosphere of
argon in flame-dried glassware with standard vacuum-line tech-
niques. All work-up and purification procedures were carried out
with reagent-grade solvents in air.
135.32, 129.82, 129.61, 128.92,128.70, 128.24,128.19,126.93, 125.95,
122.45, 121.67, 120.46, 117.69; HRMS calcd for C19H15N2 [MþH]þ:
271.1235, found: 271.1235.
4.3.2. 2-Phenyl-3-(o-tolyl)-2H-indazole (3ab).7b Compound 3ab
(75 mg, 66%) was isolated as awhite solid.1H NMR (CDCl3, 400 MHz)
d
7.82 (d, J¼8.6 Hz, 1H), 7.45e7.39 (m, 3H), 7.37e7.21 (m, 8H),
7.10e7.05 (m, 1H), 1.93 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
148.75,
140.33, 137.68, 135.14, 131.04, 130.56, 129.53, 129.17, 128.80, 127.79,
126.89, 125.97, 124.67, 122.50, 122.01, 120.62, 117.61, 19.81; HRMS
calcd for C20H17N2 [MþH]þ: 285.1392, found: 285.1392.
4.3.3. 2-Phenyl-3-(m-tolyl)-2H-indazole (3ac). Compound 3ac
Analytical thin-layer chromatography (TLC) was performed us-
ing E. Merck silica gel 60 F254 precoated plates (0.25 mm). The
(42 mg, 37%) was isolated as awhite solid.1H NMR (CDCl3, 400 MHz)
d
7.80 (d, J¼8.8 Hz, 1H), 7.72 (d, J¼8.6 Hz, 1H), 7.47e7.32 (m, 6H),

7610
K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
7.27e7.07 (m, 5H), 2.34 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
148.93,
400 MHz)
d
7.76 (dd, J¼9.3, 4.8 Hz, 1H), 7.41e7.24 (m, 8H), 7.19e7.11
158.95 (d,
140.25, 138.44, 135.55, 130.18, 129.76, 129.07, 128.89, 128.58, 128.16,
126.92, 126.83, 125.96, 122.33, 121.68, 120.60, 117.68, 21.40; HRMS
calcd for C20H17N2 [MþH]þ: 285.1392, found: 285.1393.
(m, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
J¼224 Hz), 146.25, 138.39, 137.64, 135.44 (d, J¼8.6 Hz), 129.71,
129.60, 129.46, 128.82, 128.33, 125.60, 121.01 (d, J¼11.4 Hz), 119.83
(d, J¼9.5 Hz), 118.41 (d, J¼29.6 Hz), 102.87 (d, J¼25.7 Hz), 21.14;
HRMS calcd for C20H16FN2 [MþH]þ: 303.1298, found: 303.1303.
4.3.4. 2-Phenyl-3-(p-tolyl)-2H-indazole (3ad).7b Compound 3ad
(71 mg, 62%) was isolated as a white solid. 1H NMR (CDCl3,
400 MHz)
(m, 6H), 7.27e7.23 (m, 2H), 7.20e7.18 (m, 2H), 7.14e7.11 (m, 1H),
2.38 (s, 3H); 13C NMR (CDCl3, 100 MHz)
148.96, 140.32, 138.27,
135.54, 129.51, 129.47, 128.93, 128.15, 126.91, 126.00, 122.27, 121.64,
120.61, 117.68, 21.31; HRMS calcd for C20H17N2 [MþH]þ: 285.1392,
found: 285.1388.
d
7.79 (d, J¼8.6 Hz, 1H), 7.70 (d, J¼9.5 Hz, 1H), 7.46e7.34
4.3.12. 2-Benzyl-3-phenyl-2H-indazole (3ea). Following the typical
procedure (see Section 4.5), the crude product was purified by
preparative thin-layer chromatography (hexane/EtOAc¼5:1) to
give 3ea (39 mg, 68%) as a white solid. 1H NMR (CDCl3, 400 MHz)
d
d
7.76 (d, J¼8.2 Hz, 1H), 7.59 (d, J¼8.6 Hz, 1H), 7.53e7.40 (m, 5H),
7.36e7.21 (m, 4H), 7.12e7.03 (m, 3H), 5.64 (s, 2H); 13C NMR (CDCl3,
100 MHz) 148.34, 136.90, 136.47, 129.70, 128.97, 128.87, 128.68,
d
4.3.5. 3-(4-Chlorophenyl)-2-phenyl-2H-indazole (3ae).7b Compou-
nd 3ae (56 mg, 46%) was isolated as a white solid. 1H NMR (CDCl3,
127.69, 126.88, 126.38, 121.88, 120.34, 117.46, 54.35; HRMS calcd for
C20H17N2 [MþH]þ: 285.1392, found: 285.1391.
400 MHz)
(m, 8H), 7.30e7.24 (m, 2H), 7.17e7.12 (m, 1H); 13C NMR (CDCl3,
100 MHz) 148.93, 139.90, 134.37, 133.99, 130.77, 129.08, 129.05,
d
7.80 (d, J¼8.8 Hz, 1H), 7.66 (d, J¼8.6 Hz, 1H), 7.44e7.33
4.4. 2-(Diphenylamino)benzonitrile (8)
d
128.42, 128.29, 127.03, 125.94, 122.79, 121.64, 120.05, 117.83; HRMS
Following the general procedure (see Section 4.2), the crude
product was purified by preparative thin-layer chromatography
(hexane/EtOAc¼10:1) to give 8 (57 mg, 53%) as a white solid. 1H
calcd for C19H14ClN2 [MþH]þ: 305.0846, found: 305.0849.
4.3.6. 3-(4-Methoxyphenyl)-2-phenyl-2H-indazole (3af). Compound
3af (67 mg, 56%) was isolated as a white solid. 1H NMR (CDCl3,
NMR (CDCl3, 400 MHz)
d
7.57 (d, J¼7.7 Hz,1H), 7.46 (t, J¼7.1 Hz,1H),
7.31e7.24 (m, 4H), 7.20e7.01 (m, 8H); 13C NMR (100 MHz, CDCl3)
400 MHz)
8H), 7.14e7.10 (m, 1H), 6.95e6.90 (m, 2H), 3.83 (s, 3H); 13C NMR
(CDCl3, 100 MHz) 159.54, 148.91, 140.28, 135.34, 130.91, 128.94,
d
7.79(d, J¼8.7 Hz,1H), 7.69(d, J¼8.5 Hz,1H), 7.48e7.25(m,
d 150.70, 147.12, 134.73, 133.70, 129.40, 127.37, 123.98, 123.82,
123.71, 117.02, 109.50; HRMS calcd for C19H15N2 [MþH]þ: 271.1235,
d
found: 271.1234.
128.11, 126.89, 125.97, 122.16, 122.12, 121.55, 120.57, 117.64, 114.25,
55.24; HRMS calcd for C20H17N2O [MþH]þ: 301.1341, found: 301.1341.
4.5. General procedure of palladium-catalyzed CeH arylation
of 1-substituted 1H-indazoles with iodoarenes
4.3.7. 2-Phenyl-3-(4-(trifluoromethyl)phenyl)-2H-indazole (3ag).
Compound 3ag (70 mg, 52%) was isolated as a white solid. 1H NMR
To a flame-dried 20-mL screw cap vessel containing a magnetic
stirring bar were added 1-substituted 1H-indazole (1: 0.20 mmol),
iodoarene (2: 0.40 mmol), PdCl2 (3.5 mg, 0.02 mmol), 1,10-
(CDCl3, 400 MHz)
d
7.83 (d, J¼8.8 Hz,1H), 7.70 (d, J¼8.4 Hz,1H), 7.65
(d, J¼8.2 Hz, 2H), 7.51e7.36 (m, 8H), 7.22e7.17 (m, 1H); 13C NMR
(CDCl3, 100 MHz)
d
149.03, 139.84, 133.60, 133.51, 130.09 (q,
phenanthroline
(3.6 mg,
0.02 mmol),
Ag2CO3
(82.7 mg,
J¼32.6 Hz), 129.81, 129.25, 128.68, 127.17, 126.02, 125.74 (q,
J¼3.8 Hz),123.88 (q, J¼274 Hz),123.27,121.89,119.89, 118.03; HRMS
calcd for C20H17F3N2 [MþH]þ: 339.1109, found: 339.1108.
0.30 mmol), K3PO4 (84.9 mg, 0.40 mmol), and DMAc (0.8 mL). The
mixture was stirred at 165 ꢀC for 12 h. After cooling the reaction
mixture to room temperature, the mixture was passed through
a pad of short silica gel (EtOAc) and the filtrate was evaporated
under reduced pressure. The residue was purified by preparative
thin-layer chromatography to give the arylated product 5.
4.3.8. 3-(2,6-Dimethylphenyl)-2-phenyl-2H-indazole (3ah). Comp-
ound 3ah (48 mg, 40%) was isolated as a white solid. 1H NMR
(CDCl3, 400 MHz)
7.38e7.24 (m, 6H), 7.14e7.03 (m, 3H), 1.94 (s, 6H); 13C NMR (CDCl3,
100 MHz) 148.86, 140.38, 138.38, 134.25, 129.32, 129.20, 128.82,
d
7.82 (d, J¼8.8 Hz, 1H), 7.44e7.40 (m, 2H),
4.6. Compound data of coupling products 5
d
127.77, 127.68, 126.91, 123.91, 122.15, 121.93, 120.53, 117.83, 20.25;
4.6.1. 1,3-Diphenyl-1H-indazole (5aa).21 Following the general
procedure, the crude product was purified by preparative thin-
layer chromatography (hexane/EtOAc¼10:1) to give 5aa (33 mg,
HRMS calcd for C21H19N2 [MþH]þ: 299.1548, found: 299.1553.
4.3.9. 2-Methyl-3-phenyl-2H-indazole (3ba).7b Compound 3ba
60%) as a white solid. 1H NMR (CDCl3, 400 MHz)
d
8.09 (d, J¼8.2 Hz,
(58 mg, 70%) was isolated as a colorless oil. 1H NMR (CDCl3,
1H), 8.05 (d, J¼7.7 Hz, 2H), 7.83e7.77 (m, 3H), 7.59e7.50 (m, 4H),
400 MHz)
d
7.71 (d, J¼8.7 Hz, 1H), 7.58e7.44 (m, 6H), 7.32e7.28 (m,
7.49e7.35 (m, 3H), 7.32e7.27 (m, 1H); 13C NMR (CDCl3, 100 MHz)
1H), 7.09e7.04 (m, 1H), 4.16 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
146.08,140.31,140.11,133.20,129.44,128.82,128.26,127.77,127.10,
d
147.97,135.92,129.62,129.48,128.91,128.61,126.16,121.70,121.09,
126.67, 123.11, 123.00, 121.90, 121.59, 110.67; HRMS calcd for
120.04, 116.90, 38.44; HRMS calcd for C15H13N2 [MþH]þ: 209.1079,
C19H15N2 [MþH]þ: 271.1235, found: 271.1236.
found: 209.1076.
4.6.2. 1-Phenyl-3-(o-tolyl)-1H-indazole (5ab). Following the gen-
eral procedure, the crude product was purified by preparative thin-
layer chromatography (hexane/EtOAc¼10:1) to give 5ab (37 mg,
4.3.10. 2-(4-Methoxyphenyl)-3-phenyl-2H-indazole (3ca).20 Comp-
ound 3ca (50 mg, 42%) was isolated as a white solid. 1H NMR
(CDCl3, 400 MHz)
7.42e7.32 (m, 8H), 7.16e7.10 (m, 1H), 6.88 (d, J¼8.8 Hz, 2H), 3.82 (s,
3H); 13C NMR (CDCl3, 100 MHz)
159.29, 148.76, 135.21, 133.31,
d
7.79 (d, J¼8.6 Hz, 1H), 7.71 (d, J¼8.4 Hz, 1H),
65%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz)
d 7.86e7.77 (m,
3H), 7.72 (d, J¼8.2 Hz, 1H), 7.62e7.51 (m, 3H), 7.49e7.43 (m, 1H),
d
7.40e7.20 (m, 5H), 2.48 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
146.91,
129.95, 129.63, 128.71, 128.16, 127.12, 126.78, 122.31, 121.54, 120.43,
117.60, 114.09, 55.45; HRMS calcd for C20H17N2O [MþH]þ: 301.1341,
found: 301.1341.
140.24, 139.43, 137.41, 131.84, 130.84, 130.48, 129.39, 128.37, 127.10,
126.40, 125.72, 124.57, 122.64, 121.70, 121.59, 110.51, 20.68; HRMS
calcd for C20H17N2 [MþH]þ: 285.1392, found: 285.1392.
4.3.11. 5-Fluoro-3-phenyl-2-(p-tolyl)-2H-indazole
(3da). Compo-
4.6.3. 1-Phenyl-3-(m-tolyl)-1H-indazole (5ac). Following the gen-
eral procedure, the crude product was purified by preparative thin-
und 3da (58 mg, 48%) was isolated as a white solid. 1H NMR (CDCl3,

K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
7611
layer chromatography (hexane/EtOAc¼10:1) to give 5ac (41 mg,
72%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz)
8.08 (d,
a white solid. 1H NMR (CDCl3, 400 MHz)
d
8.03 (d, J¼8.6 Hz), 7.96 (d,
d
J¼7.3 Hz, 2H), 7.54e7.47 (m, 2H), 7.46e7.37 (m, 3H), 7.25e7.18 (m,
J¼8.2 Hz, 1H), 7.89e7.75 (m, 5H), 7.59e7.52 (m, 2H), 7.49e7.34 (m,
1H), 4.14 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 143.69, 141.40,133.66,
3H), 7.31e7.23 (m, 2H), 2.47 (s, 3H); 13C NMR (CDCl3, 100 MHz)
128.77, 127.78, 127.34, 126.23, 121.58, 121.32, 120.88, 109.17, 35.52;
d
146.24,140.28,140.11,138.51,133.05,129.43,129.08,128.69,128.39,
HRMS calcd for C14H13N2 [MþH]þ: 209.1079, found: 209.1076.
127.06, 126.64, 124.90, 123.15, 123.01, 121.83, 121.66, 110.62, 21.56;
HRMS calcd for C20H17N2 [MþH]þ: 285.1392, found: 285.1390.
4.6.10. 1-Benzyl-3-phenyl-1H-indazole (5ca).23 Following the gen-
eral procedure, the crude product was purified by preparative thin-
layer chromatography (hexane/EtOAc¼8:1) to give 5ca (50 mg,
4.6.4. 1-Phenyl-3-(p-tolyl)-1H-indazole (5ad). Following the gen-
eral procedure, the crude product was purified by preparative thin-
layer chromatography (hexane/EtOAc¼10:1) to give 5ad (45 mg,
88%) as a white solid. 1H NMR (CDCl3, 400 MHz)
d
8.03 (d, J¼8.2 Hz,
1H), 8.01e7.93 (m, 2H), 7.51 (t, J¼7.7 Hz, 2H), 7.43e7.13 (m, 9H),
80%) as a white solid. 1H NMR (CDCl3, 400 MHz)
d
8.08 (d, J¼8.2 Hz,
5.66 (s, 2H); 13C NMR (CDCl3, 100 MHz)
d
144.16, 141.04, 136.87,
1H), 7.94 (d, J¼8.2 Hz, 2H), 7.83e7.76 (m, 3H), 7.59e7.52 (m, 2H),
7.48e7.43 (m, 1H), 7.40e7.32 (m, 3H), 7.31e7.25 (m, 1H), 2.45 (s,
133.64, 128.78, 128.69, 127.87, 127.68, 127.52, 127.12, 126.36, 122.09,
121.41, 121.09, 109.63, 53.06; HRMS calcd for C20H17N2 [MþH]þ:
285.1392, found: 285.1394.
3H); 13C NMR (CDCl3, 100 MHz)
d 146.15, 140.27, 140.16, 138.13,
130.32, 129.53, 129.43, 127.63, 127.03, 126.58, 123.15, 122.98, 121.77,
121.66, 110.62, 21.38; HRMS calcd for C20H17N2 [MþH]þ: 285.1392,
found: 285.1394.
4.6.11. 3-Phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole
(5da). Following the general procedure, the crude product was
purified by preparative thin-layer chromatography (hexane/
EtOAc¼10:1) to give 5da (30 mg, 46%) as a colorless oil. 1H NMR
4.6.5. 3-(4-Chlorophenyl)-1-phenyl-1H-indazole (5ae). Following
the general procedure, the crude product was purified by pre-
parative thin-layer chromatography (hexane/EtOAc¼10:1) to give
5ae (31 mg, 51%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz)
(CDCl3, 400 MHz)
d
8.02 (d, J¼8.2 Hz, 1H), 7.99e7.94 (m, 2H), 7.62
(d, J¼8.6 Hz, 1H), 7.55e7.39 (m, 4H), 7.30e7.24 (m, 1H), 5.80 (s, 2H),
3.67e3.60 (m, 2H), 0.95e0.88 (m, 2H), ꢂ0.06 (s, 9H); 13C NMR
d
8.04 (d, J¼8.2 Hz, 1H), 7.99 (d, J¼8.2 Hz, 2H), 7.79 (d, J¼7.7 Hz, 3H),
(CDCl3, 100 MHz) d 144.85, 141.26, 133.37, 128.79, 128.10, 127.61,
7.61e7.23 (m, 7H); 13C NMR (CDCl3, 100 MHz)
d
144.88, 140.38,
126.72, 122.58, 121.66, 121.34, 109.95, 77.75, 66.42, 17.75, ꢂ1.47;
139.97, 134.15, 131.75, 129.50, 129.05, 128.90, 127.23, 126.87, 123.06,
122.89, 122.15, 121.29, 110.81; HRMS calcd for C19H14ClN2 [MþH]þ:
305.0846, found: 305.0848.
HRMS calcd for C19H25N2OSi [MþH]þ: 325.1736, found: 325.1734.
4.7. Synthesis of 3-phenyl-1H-indazole (9)
4.6.6. 3-(4-Methoxyphenyl)-1-phenyl-1H-indazole (5af).22 Follow-
ing the general procedure, the crude product was purified by pre-
parative thin-layer chromatography (hexane/EtOAc¼10:1) to give
To a solution of 1H-indazole (24 mg, 0.20 mmol) in DMSO (2 mL)
was added NaH (60% in oil, 9 mg, 0.21 mmol). After the mixture was
stirred at room temperature for 20 min, benzyl chloride (24 mL,
0.21 mmol) was added, and the resultant mixture was stirred at
room temperature for 2 h. The mixture was poured into water and
extracted with EtOAc. The organic layer was washed with water,
brine, dried over anhydrous Na2SO4, and evaporated under reduced
pressure to give the benzylated product as a mixture of 4c and 1e.
The crude mixture was subjected to the CeH arylation with iodo-
benzene under PdCl2/phen/Ag2CO3/K3PO4 catalyst (see Section 4.5).
The reaction mixture was passed through a pad of short silica gel
(EtOAc) and the filtrate was washed with water, brine, dried over
anhydrous Na2SO4, and evaporated under reduced pressure to give
the mixture of 5ca and 3ea. Then to a solution of the crude in DMSO
(2 mL) was added KOt-Bu (157 mg, 1.40 mmol) and stirred at room
temperature for 3 h under air. The mixture was poured into water,
and then extracted with EtOAc. The organic layer was washed with
water, brine, dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The residue was purified by preparative thin-
layer chromatography (hexane/EtOAc¼2:1) to give 9 (25 mg, 65%
from 1H-indazole) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz)
5af (33 mg, 54%) as a white solid. 1H NMR (CDCl3, 400 MHz)
d 8.05
(d, J¼8.6 Hz, 1H), 8.01e7.95 (m, 2H), 7.82e7.95 (m, 3H), 7.58e7.51
(m, 2H), 7.47e7.42 (m, 1H), 7.39e7.33 (m, 1H), 7.30e7.24 (m, 1H),
7.10e7.04 (m, 2H), 3.88 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 159.75,
145.92, 140.23, 140.16, 129.41, 128.97, 127.02, 126.50, 125.80, 123.07,
122.90, 121.70, 121.61, 114.27, 110.60, 55.35; HRMS calcd for
C20H17N2O [MþH]þ: 301.1341, found: 301.1344.
4.6.7. 1-Phenyl-3-(4-(trifluoromethyl)phenyl)-1H-indazole
(5ag). Following the general procedure, the crude product was
purified by preparative thin-layer chromatography (hexane/
EtOAc¼10:1) to give 5ag (48 mg, 71%) as a white solid. 1H NMR
(CDCl3, 400 MHz)
d
8.18 (d, J¼8.2 Hz, 2H), 8.07 (d, J¼8.2 Hz, 1H),
7.82e7.76 (m, 5H), 7.57 (t, J¼7.8 Hz, 2H), 7.43e7.38 (m, 1H), 7.41 (t,
J¼10.6 Hz, 1H), 7.33 (t, J¼7.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d
144.45, 140.44, 139.83, 136.79, 136.79, 128.99 (q, J¼32.4 Hz),
129.53, 127.78, 127.33, 127.06, 125.74 (q, J¼3.8 Hz), 124.23 (q,
J¼271.8 Hz), 123.12, 122.90, 122.43, 121.14, 110.92; HRMS calcd for
C20H14F3N2 [MþH]þ: 339.1109, found: 339.1109.
d
10.75 (br s, 1H), 8.08e7.95 (m, 3H), 7.57e7.35 (m, 5H), 7.26e7.19
(m, 1H); 13C NMR (CDCl3, 100 MHz)
d
145.83, 141.66, 133.54, 128.88,
4.6.8. 1-Phenyl-3-(pyridin-3-yl)-1H-indazole (5ah). Following the
general procedure, the crude product was purified by preparative
thin-layer chromatography (hexane/EtOAc¼1:1) to give 5ah
128.15, 127.63, 126.81, 121.40, 121.17, 121.01, 110.06; HRMS calcd for
C13H21N2 [MþH]þ: 195.0922, found: 195.0923.
(27 mg, 50%) as a white solid. 1H NMR (CD2Cl2, 400 MHz)
d 9.29 (d,
J¼2.3 Hz, 1H), 8.66 (dd, J¼4.5, 1.4 Hz, 1H), 8.37e8.31 (m, 1H), 8.09
4.8. Synthesis of YD-3 (12)24
(d, J¼8.2 Hz, 1H), 7.86e7.77 (m, 3H), 7.64e7.55 (m, 2H), 7.54e7.39
(m, 3H), 7.38e7.30 (m, 1H); 13C NMR (CD2Cl2, 100 MHz)
d
149.67,
Following the general procedure (see Section 4.5), the crude
product was purified by preparative thin-layer chromatography
(hexane/EtOAc¼10:1) to give YD-3 (12: 46 mg, 64%) as a white
148.96, 143.34, 140.71, 140.36, 134.91, 129.90, 129.71, 127.75, 127.31,
124.09, 123.31, 123.27, 122.77, 121.45, 111.28; HRMS calcd for
C18H14N3 [MþH]þ: 272.1188, found: 272.1187.
solid. 1H NMR (DMSO-d6, 400 MHz)
d 8.21e8.14 (m, 3H), 8.11 (d,
J¼8.2 Hz, 1H), 7.82 (d, J¼8.2 Hz, 1H), 7.52e7.44 (m, 1H), 7.38e7.22
4.6.9. 1-Methyl-3-phenyl-1H-indazole (5ba). Following the general
procedure, the crude product was purified by preparative thin-layer
chromatography (hexane/EtOAc¼10:1) to give 5ba (26 mg, 62%) as
(m, 6H), 5.78 (s, 2H), 4.36 (q, J¼7.3 Hz, 2H), 1.36 (q, J¼7.3 Hz, 3H);
13C NMR (DMSO-d6, 100 MHz)
d 165.51, 141.44, 140.98, 137.65,
137.20, 129.81, 128.77, 128.62, 127.61, 127.37, 126.73, 126.66, 121.94,

7612
K. Hattori et al. / Tetrahedron 68 (2012) 7605e7612
Med. Chem. 1990, 33, 1771; (c) Bermudez, J.; King, F. D.; Sanger, G. J. Bioorg. Med.
Chem. Lett. 1992, 2, 1509; (d) Amir, M.; Dhar, N.; Tiwari, S. K. Indian J. Chem. 1997,
36B, 96; (e) Breteche, A.; Duflos, M.; Dassonville, A.; Nourrisson, M.-R.; Brelet,
J.; Le Baut, G.; Grimaud, N.; Petit, J.-Y. J. Enzyme Inhib. Med. Chem. 2002, 17, 415;
(f) Zhang, D.; Kohlman, D.; Krushinski, J.; Liang, S.; Ying, B.-P.; Reilly, J. E.; Dinn,
S. R.; Wainscott, D. B.; Nutter, S.; Gough, W.; Nelson, D. L. G.; Schaus, J. M.; Xu,
Y.-C. Bioorg. Med. Chem. Lett. 2004, 14, 6011.
4. (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (b) Campeau,
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35; (c) Satoh, T.; Miura,
M. Chem. Lett. 2007, 36, 200; (d) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013; (e)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792; (f)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094; (g) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
5. Selected recent examples in the catalytic CeH arylation of indoles: (a) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172; (b) Stuart, D.; Villemure, E.; Fagnou, K.
J. Am. Chem. Soc. 2007, 129, 12072; (c) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li,
Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473; (d) Phipps, R. J.; Grimster, N.
P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172; (e) Join, B.; Yamamoto, T.;
Itami, K. Angew. Chem., Int. Ed. 2009, 48, 3644; (f) Yamaguchi, A. D.; Mandal, D.;
Yamaguchi, J.; Itami, K. Chem. Lett. 2011, 40, 555; (g) Wang, Z.; Li, K.; Zhao, D.;
Lan, J.; You, J. Angew. Chem., Int. Ed. 2011, 50, 5365; (h) Mandal, D.; Yamaguchi,
A. D.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2011, 133, 19660.
121.00, 120.92, 110.59, 60.76, 52.05, 14.20; HRMS calcd for
C23H21N2O2 [MþH]þ: 357.1603, found: 357.1604.
4.9. Synthesis of YC-1 (10)23
To a flame-dried microwave vessel in K3PO4 (85 mg, 0.40 mmol)
were added 4c (42 mg, 0.20 mmol), 16 (41 mg, 0.40 mmol), PdCl2
(3.5 mg, 0.02 mmol), 1,10-phenanthroline (3.6 mg, 0.02 mmol),
Ag2CO3 (28 mg, 0.1 mmol), and DMAc (0.8 mL). The mixture was
heated at 200 ꢀC for 5 min under microwave irradiation. To the
reaction mixture were added 16 (41 mg, 0.40 mmol) and Ag2CO3
(28 mg, 0.1 mmol), then heated at 200 ꢀC for 5 min. Then 16 (41 mg,
0.40 mmol) and Ag2CO3 (28 mg, 0.1 mmol) were added and heated
at 200 ꢀC for 5 min again. After cooling the mixture to room tem-
perature, the mixture was passed through a pad of short silica gel
(EtOAc) and the filtrate was evaporated under reduced pressure.
The residue was semipurified by preparative thin-layer chroma-
tography (hexane/EtOAc¼3:1) to give the corresponding coupling
product (24 mg, 36%; 77% brsm) as a white solid and recovered
6. Very recently, Knochel and co-workers reported the arylation of indazoles
utilizing
a Negishi cross-coupling reaction: Unsinn, A.; Knochel, P. Chem.
Commun. 2012, 2680.
7. (a) Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 9164; (b) Ohnmacht, S. A.;
Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12, 224.
starting material 4c (21 mg, 49%). 1H NMR (CDCl3, 400 MHz)
(d, J¼8.5 Hz, 1H), 7.41e7.19 (m, 9H), 7.01 (d, J¼3.6 Hz, 1H), 5.65 (s,
2H), 3.95 (s, 3H); 13C NMR (CDCl3, 100 MHz)
159.18, 152.93,
d 8.26
8. Representative reports in the CeH arylation of heteroarenes using Cu catalysts:
(a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404; (b) Ban, I.; Sudo, T.;
Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 3607; (c) Yoshizumi, T.; Tsurugi, H.;
Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598; (d) Do, H.-Q.; Khan, R. M.
K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
9. Representative reports in the CeH arylation of heteroarenes using Ni catalysts:
(a) Canivet, J.; Yamaguchi, J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733; (b)
Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737; (c) Ko-
bayashi, O.; Uraguchi, D.; Yamanaka, T. Org. Lett. 2009, 11, 2679; (d) Tobisu, M.;
Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070; (e) Hachiya, H.; Hir-
ano, K.; Satoh, T.; Miura, M. ChemCatChem 2010, 2, 1403; (f) Hachiya, H.; Hir-
ano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2010, 49, 2202; (g)
Yamamoto, T.; Muto, K.; Komiyama, M.; Canivet, J.; Yamaguchi, J.; Itami, K.
Chem.dEur. J. 2011, 17, 10113; (h) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem.
Soc. 2012, 134, 169.
10. (a) Bunnell, A.; O’Yang, C.; Petrica, A.; Soth, M. J. Synth. Commun. 2006, 36, 285;
(b) Perez, J. D.; Yranzo, G. I.; Ferraris, M. A.; Elguero, J.; Claramunt, R. M.; Sanz,
D. Bull. Soc. Chim. Fr. 1991, 4, 592; (c) Welch, W. M.; Hanau, C. E.; Whalen, W. M.
Synthesis 1992, 937.
11. (a) Yanagisawa, S.; Ueda, K.; Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009,
131, 14622; (b) Yanagisawa, S.; Itami, K. Tetrahedron 2011, 67, 4425; (c)
Meyer, C.; Neue, B.; Schepmann, D.; Yanagisawa, S.; Yamaguchi, J.;
d
143.56, 140.50, 136.28, 135.29, 128.75, 127.87, 127.08, 127.04, 122.10,
121.97, 121.72, 119.79, 109.62, 108.07, 53.39, 51.86; HRMS calcd for
C20H17N2O3 [MþH]þ: 333.1239, found: 333.1239.
To
a solution of the resulting coupling product (24 mg,
0.07 mmol) in THF (5 mL) was added LiAlH4 (5.4 mg, 0.15 mmol)
and stirred at room temperature for 2 h. Then Na2SO4$10H2O
(55 mg) was added and stirred at room temperature for 30 min. The
mixture was passed through a pad of CeliteÒ and the filtrate was
concentrated under reduced pressure. The residue was purified by
preparative thin-layer chromatography (hexane/EtOAc¼1:1) to
give YC-1 (10: 18 mg, 82%) as a white solid. 1H NMR (CDCl3,
400 MHz)
J¼3.2 Hz, 1H), 6.48 (d, J¼3.2 Hz, 1H), 5.66 (s, 2H), 4.75 (d, J¼5.0 Hz,
2H), 2.05e1.90 (m, 1H); 13C NMR (CDCl3, 100 MHz)
153.85, 148.65,
d
8.06 (d, J¼8.2 Hz, 1H), 7.45e7.17 (m, 8H), 6.88 (d,
d
140.51, 136.57, 136.16, 128.71, 127.77, 127.04, 126.86, 121.51, 121.42,
121.33, 109.70, 109.63, 107.90, 57.64, 53.20; HRMS calcd for
C19H17N2O2 [MþH]þ: 305.1290, found: 305.1291.
€
€
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Acknowledgements
This work was supported by the Funding Program for Next
Generation World-Leading Researchers from JSPS (220GR049 to
K.I.) and the Grant-in-Aid for Scientific Research on Innovative
Areas ‘Molecular Activation Directed toward Straightforward Syn-
thesis’ (23105517 to J.Y.) from MEXT.
13. Antilla, J. A.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578.
14. Cadogan, J. I. G.; Mackie, R. K. Org. Synth. 1968, 48, 113.
Supplementary data
15. Cheung, M.; Boloor, A.; Stafford, J. A. J. Org. Chem. 2003, 68, 4093.
16. Slade, J. D.; Pelz, F. N.; Bodnar, W.; Lampe, W. J.; Watson, S. P. J. Org. Chem. 2009,
74, 6331.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.05.091.
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