Ni and Cu-catalyzed one pot synthesis of unsymmetrical 1,3-di(hetero)aryl-1: H -indazoles from hydrazine, o -chloro (hetero)benzophenones, and (hetero)aryl bromides

Article abstract of DOI:10.1039/c7ob00841d

The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in a one-pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation with (hetero)aryl bromides.

Full text of DOI:10.1039/c7ob00841d

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Takeharu Haino et al.
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DOI: 10.1039/C7OB00841D
Journal Name
ARTICLE
Ni and Cu-Catalyzed One Pot Synthesis of Unsymmetrical
,3-Di(hetero)aryl-1H-indazoles from Hydrazine, o-Chloro
hetero)benzophenones, and (Hetero)aryl Bromides
1
(
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
b
b
Carson Wiethan, Christopher M. Lavoie, Andrey Borzenko, Jillian S. K. Clark, Helio G.
a
b
DOI: 10.1039/x0xx00000x
Bonacorso* and Mark Stradiotto*
www.rsc.org/
The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-
hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in
(
a one-pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation with (hetero)aryl bromides.
Introduction
Building on this theme, we became interested in addressing
such synthetic challenges by developing new modular one-pot
1
H-Indazole derivatives have been shown to exhibit useful
routes to 1,3-di(hetero)aryl substituted 1H-indazoles as
outlined in Scheme 1, whereby hydrazones prepared in situ
from the condensation of parent hydrazine and ortho-
chloro(hetero)benzophenones could be C-N cross-coupled to
give 3-substituted-1H-indazoles, that in turn could be subjected
to N-arylation leading to 1,3-disubstituted 1H-indazoles. Given
the high cost and relative rarity of the platinum group metals,
pharmacological properties in a range of applications; the 1,3-
disubstituted 1H-indazole core structure in particular is found in
several commercialized pharmaceuticals, including but not
limited to granisetron (antiemetic) and benzydiamine
1
(
anaesthetic/analgesic). It is not surprising that there is
considerable interest in the establishment of new and/or
improved synthetic routes to substituted 1H-indazoles. In
moving beyond the diazotization or nitrosation of 2-alkyl
substituted anilines, which commonly require harsh reaction
7
our aim was to employ only base-metal catalysis; we were
particularly attracted to the use of nickel and/or copper9
8
catalysts, in light of their utility in C-N cross-coupling of
1-2
conditions,
recent focus has been directed toward the
(hetero)aryl electrophiles. Herein we disclose our success in this
development of alternative routes to substituted 1H-indazoles
that make use of relatively inexpensive and abundant starting
materials, and which can be conducted under comparatively
effort, whereby unsymmetrical 1,3-di(hetero)aryl-1H-indazoles
are assembled in a one-pot fashion via intramolecular (PAd-
10
DalPhos)Ni(o-tolyl)Cl -catalyzed C-N cross-coupling, followed
by (DMEDA)/CuI-catalyzed N-(hetero)arylation.
3
mild reaction conditions.
In this context, the cyclization of hydrazones derived from
ortho-(pseudo)haloaryl carbonyl compounds represents
a
conceptually attractive route to substituted 1H-indazoles.
While some reactions of this type have been shown to proceed
4
5
either uncatalyzed or base-catalyzed, in the case of
electronically unactivated (hetero)aryl hydrazones the
application of palladium, copper, or iron catalysts has proven
useful in enabling intramolecular C-N bond formation that
6
affords the 1H-indazole core. Notwithstanding such progress,
the vast majority of these transformations employ pre-formed
substituted/protected hydrazones, with no examples involving
substrates derived from ortho-chlorobenzophenones in
combination with parent hydrazine.
Scheme 1 Proposed one-pot, base metal-catalyzed route to 1,3-disubstituted 1H-
indazoles, and the catalysts employed successfully herein for these transformations (M
=
Ni; M’ = Cu).
a.Departamento de Química, Universidade Federal de Santa Maria, 97105-900
Santa Maria, Brazil. helio.bonacorso@ufsm.br
Department of Chemistry, Dalhousie University Halifax, NS, B3H 4R2 Canada.
Results and discussion
b.
mark.stradiotto@dal.ca
Electronic Supplementary Information (ESI) available: Copies of NMR spectra. See
DOI: 10.1039/x0xx00000x
Our initial efforts were directed toward the identification of an
effective nickel pre-catalyst for the intramolecular C-N cross-
c.
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ARTICLE
Journal Name
coupling of the hydrazone derived in situ from the condensation catalyzed intermolecular cross-coupling of 1aViewwAirttihcle Ofnrleinee
of parent hydrazine and ortho-chlorobenzophenone (1a), hydrazine is unlikely. Rather, a reactionDOscI:h1e0m.10e39s/uCc7hOBa0s08th41aDt
leading to 3-phenyl-1H-indazole (2a). From the outset we outlined in Scheme 1 appears to be operational, whereby fast
viewed transformations of this type as presenting a challenge, condensation affords the hydrazone, which in turn undergoes
given both the potential of nickel to effect undesired N-N bond nickel-catalyzed intramolecular C-N cross-coupling to afford the
cleavage of hydrazine derivatives,11 and the absence of reports target indazole.
documenting the nickel-catalyzed C-N cross-coupling of
(
hetero)benzophenone hydrazones with aryl chlorides.12
Encouraged by the catalytic utility of (PAd-DalPhos)Ni(o-
10
tolyl)Cl in ammonia monoarylation employing (hetero)aryl
chlorides, this pre-catalyst was selected for our preliminary
catalytic screen (Table 1). We were pleased to observe that this
PAd-DalPhos (L1)-derived pre-catalyst afforded high conversion
to the desired indazole 2a, (entry 1) under relatively mild
conditions (5 mol% Ni, 16 h, 60 °C). Whereas analogous
reactions conducted at 25 °C were unsuccessful (entry 2), the
application of a shorter reaction time was tolerated (entry 3).
Conversely, negligible conversion to 2a was achieved (24 h, 60 Scheme 2 Step-wise conversion of 1a into the hydrazone intermediate A,
followed by nickel-catalyzed ring-closure to afford 2a.
°
C) when using related pre-catalysts featuring either JosiPhos
13
14
CyPF-Cy (L2
) or DPPF (L3) (entries 4 and 5), or in the absence
The generality of this transformation leading to 3-
substituted-1H-indazoles was examined briefly (Table 2). A
series of substituted ortho-chloro(hetero) benzophenones
featuring electron-donating, electron-withdrawing and ortho-
substitution were employed successfully, leading to 2a-f (65-
of a nickel pre-catalyst (entry 6).
Table 1. Optimization studies for 3-phenyl-1H-indazole (2a) formation.a
8
0% yield). Our efforts to extend this methodology to ortho-
chloro(hetero)acetophenone derivatives were unsuccessful,
likely owing in part to the instability of the putative aryl alkyl
hydrazone intermediate (analogous to A
, Scheme 2).15
Table 2. Synthesis of 3-(hetero)aryl-1H-indazoles.a
Entry
Ligand (L)
Time (h)
16
16
12
24
T (°C)
60
25
60
60
Conversion to 2ab
1
2
3
4
5
6
L1
L1
L1
L2
L3
>90
<10
90
<10
<10
24
24
60
60
no-precatalyst
not detected
a
Reaction conditions: 2-Chlorobenzophenone (2a) (0.2 mmol), hydrazine
monohydrochloride (0.24 mmol, 1.2 eq.), (L)Ni(o-tolyl)Cl (5 mol%), NaOtBu (0.48
b
mmol, 2.4 eq.), toluene (2 mL). Estimated on the basis of calibrated gas
chromatographic data.
In an effort to gain insight regarding the order of events
leading from 1a to 2a, the reaction between 1a and hydrazine
under catalytic conditions, but in the absence of the nickel pre-
catalyst, was examined by use of calibrated GC methods
a
(
Scheme 2). A substantial quantity of the anticipated hydrazone
intermediate was detected after only 5 minutes; after 0.5 h
clean conversion of 1a to was observed. Subsequent addition
Reaction conditions: ketone 1a-f (0.5 mmol), hydrazine monohydrochloride
0.6 mmol, 1.2 eq.), NaOtBu (1.2 mmol, 2.4 eq.), (PAd-DalPhos)Ni(o-tolyl)Cl (5
mol%), toluene (2 mL).
(
A
A
of (PAd-DalPhos)Ni(o-tolyl)Cl (5 mol%) and base (in keeping
with the stoichiometry of the catalytic reaction) resulted in the
formation of 2a (70%) after 6 h. Moreover, in monitoring the
progress of the catalytic reaction (as in Table 1, entry 1), the
Having established a successful nickel-catalyzed route to 3-
(
hetero)aryl-1H-indazoles (Tables 1 and 2), we then sought to
extend this protocol to a one-pot synthesis of unsymmetrical
,3-di(hetero)aryl-1H-indazoles as outlined generically in
Scheme 1; notably this would require hitherto unknown nickel-
catalyzed indazole C-N cross-coupling with a (hetero)aryl
1
build-up of
A is rapid, followed by the slow conversion to 2a.
Collectively, these qualitative observations suggest that nickel-
2
| J. Name., 2012, 00, 1-3
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ARTICLE
Table 3. One-pot synthesis of unsymmetrical 1,3-di(hetero)aryl-1H-
electrophile. To test the feasibility of this latter transformation,
the C-N cross-coupling of 2a with 2-bromothiophene (1.4 eq) in
the presence of (PAd-DalPhos)Ni(o-tolyl)Cl (5 mol%) and base
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a
indazoles.
DOI: 10.1039/C7OB00841D
3 4
(NaOtBu or K PO , 2.4 eq.) was explored (24 h, 60 °C or 110 °C).
Unfortunately, under all conditions tested, no appreciable
amount of the target N-arylated indazole (3c) was detected on
the basis of NMR spectroscopic or gas chromatographic analysis
(Scheme 3). With an aim toward employing an alternative base
metal catalyst for the indazole N-arylation step, we turned our
attention to the use of catalytic CuI/DMEDA under conditions
16
described by Buchwald and co-workers for the N-arylation of
azoles. Gratifyingly, high conversion to 3c was achieved under
the conditions outlined in Scheme 3. Subsequently, efforts were
made to employ CuI/DMEDA (10 and 20 mol%, respectively) for
the transformation of 1a into 2a. However, the use of
CuI/DMEDA in place of the nickel catalyst, either under the
conditions outlined in Table 2 (NaOtBu, 16 h, 60 °C) or using
3 4
K PO (24 h, 110 °C), proved ineffective for the synthesis of 2a.
Scheme 3 Screening of nickel and copper catalysis for the N-arylation of 2a
with 2-bromothiophene to give 3c (2.4 eq. base used throughout).
Collectively, these observations established nickel as being
optimal for the initial indazole ring-closure and copper as being
optimal for the subsequent indazole N-arylation within our
reactivity survey, thereby forming the basis for a one-pot, two-
step protocol for the assembly of unsymmetrical 1,3-
a
Reaction conditions: Step 1: ketone 1a-e (0.5 mmol), hydrazine
di(hetero)aryl-1H-indazoles (Table 3). In this regard, 3- monohydrochloride (0.6 mmol, 1.2 eq.), NaOtBu (1.2 mmol, 2.4 eq.), (PAd-
DalPhos)Ni(o-tolyl)Cl (5 mol%), toluene (2 mL). Step 2: (hetero)aryl bromide (0.7
mmol, 1.4 eq.), K PO (1.2 mmol, 2.4 eq.), CuI (10 mol%), DMEDA (20 mol%),
3 4
toluene (1 mL). Note that no workup was carried out between Steps 1 and 2.
(
hetero)aryl-1H-indazoles 2a-f derived from 1a-f were
generated in situ and subjected to CuI/DMEDA-catalyzed N-
arylation to afford a series of structurally diverse unsymmetrical
1
,3-di(hetero)aryl-1H-indazoles 3a-s. We were pleased to find
that electron-rich, electron-poor, and ortho-substituted
bromides, including heteroaryl variants (thiophenyl, pyridyl,
quinolyl, and appended triazole), were each successfully
employed in this one-pot protocol. The average overall isolated
Conclusions
In summary, we have developed the first nickel-catalyzed
cyclization of in situ-generated ortho-chlorobenzophenone
hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles,
and have demonstrated that the derived 1H-indazoles can be
transformed subsequently in a one-pot procedure into 1,3-
di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation
with (hetero)aryl bromides. This modular new route to 1,3-
di(hetero)aryl-1H-indazoles is attractive in that it makes use of
parent hydrazine monohydrochloride without prior
functionalization/protection, and circumvents the use of
platinum-group metal catalysis. Encouraged by these results,
we are currently exploring the extension of these reactivity
concepts to the assembly and functionalization of other sought-
after heterocyclic structures.
yield of
3 (63%, 19 examples; most of which are reported here
for the first time) is notable in that this value corresponds to
approximately 85% yield for each of the three one-pot steps
leading from
chloro(hetero)benzophenones; nickel-catalyzed ring-closure to
give 3-substitued-1H-indazoles ; and copper-catalyzed N-
arylation leading ).
1 to 3 (i.e., condensation of hydrazine and ortho-
2
3
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3
-(Thiophen-2-yl)-1H-indazole (2b): Eluted with 2V0i%ew AErtticOleAOcnlinine
Experimental Section
General considerations. Unless otherwise indicated, all
hexanes solution. Physical aspect: yellow soDliOdI.: Y10ie.1ld03: 96/7C7mOgB0–068741%D.
1
3
NMR: H (500 MHz, CDCl , 25 °C) δ = 10.41 (b, 1H), 8.06 (d, J = 8.2,
reactions were setup inside a nitrogen-filled inert atmosphere 1H), 7.69 (dd, J = 3.5, 0.8, 1H), 7.46 – 7.41 (m, 2H), 7.39 (dd, J = 5.1,
13
1
glovebox and worked up in air using benchtop procedures. 0.9, 1H), 7.28 – 7.25 (m, 1H), 7.20 (dd, J = 5.1, 3.6, 1H). C{ H} (125
3
Toluene was deoxygenated by sparging with nitrogen followed MHz, CDCl , 25 °C) δ = 141.6, 140.8, 135.8, 127.7, 127.2, 125.2, 124.9,
by passage through an mBraun double column solvent 121.6, 120.9, 120.5, 110.1. Data agree with literature.18
purification system packed with alumina and copper-Q5
3
-(4-Methoxyphenyl)-1H-indazole (2c): Eluted with 20% EtOAc in
reactant and storage over activated 4 Å molecular sieves.
Synthesis and characterization of the ketones 1b-f are provided
hexanes solution. Physical aspect: yellow solid. Yield: 82 mg – 73%.
NMR: H (300 MHz, CDCl
–
1
3
): δ = 11.61 (b, 1H), 8.03 – 7.96 (m, 3H), 7.38
in the Supporting Information. The pre-catalysts (
L
)Ni(o-tolyl)Cl
7.32 (m, 1H), 7.26-7.18 (m, 2H), 7.11 – 7.06 (m, 2H), 3.90 (s, 3H).
10
13b
14
(PAd-DalPhos, L1
;
JosiPhos CyPF-Cy, L2
;
or DPPF, L3 ) were 13
1
C{ H} (75 MHz, CDCl
3
): δ = 159.7, 145.7, 141.8, 128.9, 126.6, 126.2,
prepared by use of literature procedures. Otherwise, all
reagents including 1a were obtained from commercial sources
18
1
21.1, 121.1, 114.4, 110.3, 55.4 Data agree with literature.
and used without further purification. Column chromatography 3-(3-Methoxyphenyl)-1H-indazole (2d): Eluted with 20% EtOAc in
hexanes solution. Physical aspect: yellow solid. Yield: 73 mg – 65%.
was performed on silica gel (230−400 mesh). All NMR spectra
were acquired on a 300 or 500 MHz spectrometer with samples
1
3
NMR: H (300 MHz, CDCl ): δ = 10.05 (b, 1H), 8.05 (d, J = 8.2, 1H), 7.62
–
7.56 (m, 2H), 7.45 (t, J = 7.9, 1H), 7.40 – 7.36 (m, 2H), 7.26 – 7.21
dissolved in CDCl
accordingly. Data are reported as follows: Chemical shift (δ)
multiplicity, coupling constant, integration). Splitting patterns
3 6
or DMSO-d , and with signals referenced
13
1
(
m, 1H), 7.02 – 6.99 (m, 1H), 3.89 (s, 3H). C{ H} (75 MHz, CDCl
3
): δ =
1
1
60.1, 145.7, 141.8, 134.8, 130.0, 126.8, 121.4, 121.1, 120.2, 114.2,
12.9, 110.4, 55.3. Data agree with literature.
(
19
are indicated as follows: s = singlet, d = doublet, t = triplet, q =
quartet, qui = apparent quintet, dd = doublet of doublets, td =
3
-(2-Methoxyphenyl)-1H-indazole (2e): Eluted with 20% EtOAc in
triplet of doublets, m = multiplet, b = broad. All coupling hexanes solution. Physical aspect: yellow solid. Yield: 90 mg – 80%.
1
constants (J) are reported in Hertz (Hz). High resolution mass NMR: H (300 MHz, CDCl
3
): δ = 10.64 (b, 1H), 7.80 – 7.73 (m, 2H), 7.50
spectrometry data (HRMS) were obtained using ion trap (ESI) – 7.44 (m, 1H), 7.34 – 7.29 (m, 1H), 7.20 – 7.15 (m, 2H), 7.11 (d, J =
1
3
1
7
1
.8, 2H), 3.84 (s, 3H). C{ H} (75 MHz, CDCl
3
): δ = 157.4, 143.1, 141.4,
instruments operating in positive ion mode.
31.4, 129.7, 126.4, 122.2, 122.0, 120.9, 120.6, 111.4, 110.4, 55.5.
Data agree with literature.
20
General procedure for the synthesis of 3-(hetero)aryl-1H-indazoles
(
2a-f). Ketone (0.5 mmol), hydrazine monohydrochloride (0.6 mmol),
3
-(Naphthalen-1-yl)-1H-indazole (2f): Eluted with 10% EtOAc in
NaOtBu (1.2 mmol), (PAd-DalPhos)Ni(o-tolyl)Cl (5 mol%), and
toluene (2 mL) were added to a screw capped vial containing a
magnetic stir bar. The vial was sealed with a cap containing a PTFE
septum, placed in a temperature-controlled aluminum heating block
set at 60 °C, and magnetic stirring was initiated. After 16 h, product
workup was carried out; the crude reaction mixture was filtered over
a silica plug, followed by rinsing of the plug with EtOAc (60 mL). The
combined eluent was collected, concentrated on the rotary
evaporator, and the crude product thus obtained was purified by use
of column chromatography.
hexanes solution. Physical aspect: yellow solid. Yield: 87 mg – 71%.
NMR: H (500 MHz, CDCl
1
3
): δ = 12.25 (b, 1H), 8.32 – 8.31 (m, 1H), 8.01
–
7.98 (m, 2H), 7.79 – 7.67 (m, 2H), 7.57 – 7.52 m, 2H), 7.48 – 7.39
13
1
(
m, 2H), 7.21 (t, J = 6.7, 1H), 6.93 – 6.92 (m, 1H). C{ H} (125 MHz,
CDCl ): δ = 143.4, 134.1, 131.9, 131.3, 128.8, 128.2, 128.1, 126.7,
26.4, 126.3, 126.1, 125.4, 121.9, 121.3, 110.9. HRMS (ESI):
Na (M + Na) requires 267.0898 / Found: 267.0893.
3
1
C
17 12 2
H N
4-(3-Phenyl-1H-indazol-1-yl)benzonitrile (3a): Eluted with 10%
EtOAc in hexanes solution. Physical aspect: Yellow solid. Yield: 97 mg
–
–
7
1
1
+
1
66%. NMR: H (500 MHz, CDCl
3
, 25 °C) δ = 8.11 (d, J = 8.1, 1H), 8.04
General procedure for the one-pot synthesis of unsymmetrical 1,3-
di(hetero)aryl-1H-indazoles (3a-s). Products 2a-f were generated as
outlined above. However, instead of conducting product workup,
under inert atmosphere the reaction vial was opened and
8.00 (m, 4H), 7.87 – 7.83 (m, 3 H), 7.57 – 7.53 (m, 3H), 7.48 (tt, J =
13
1
.4, 1.5, 1H), 7.36 (t, J = 7.5, 1H). C{ H} (125 MHz, CDCl
47.9, 143.8, 140.0, 133.5, 132.4, 128.9, 128.8, 128.0, 127.9, 124.1,
22.9, 122.1, 122.0, 118.6, 110.7, 109.2. HRMS (ESI): C20 Na (M
Na) requires 318.1007 / Found: 318.0988. Data agree with
3
, 25 °C) δ =
13 3
H N
(
3 4
hetero)aryl bromide (0.7 mmol), K PO (1.2 mmol), CuI (10 mol%),
DMEDA (20 mol%), and toluene (1 mL) were added. The vial was re-
sealed with a cap containing a PTFE septum, placed in a temperature-
controlled aluminum heating block set at 110 °C, and magnetic
stirring was initiated. After 24 h, the crude reaction mixture was
filtered over a silica plug, followed by rinsing of the plug with EtOAc
2
1
literature.
1
-(4-Methoxyphenyl)-3-phenyl-1H-indazole (3b): Eluted with 5%
EtOAc in hexanes solution. Physical aspect: yellow solid. Yield: 105
1
mg – 70%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 8.08 – 8.01 (m, 3H),
(
60 mL). The combined eluent was collected, concentrated on the
7
7
2
1
C
.69 – 7.64 (m, 3H), 7.54 – 7.49 (m, 2H), 7.45 – 7.38 (m, 2H), 7.28 –
rotary evaporator, and the crude product thus obtained was purified
by use of column chromatography.
13
1
3
.23 (m, 1H), 7.09 – 7.03 (m, 2H), 3.87 (s, 3H). C { H} (75 MHz, CDCl ,
5 °C) δ = 158.5, 145.5, 140.6, 133.4, 133.3, 128.8, 128.1, 127.7,
26.9, 124.8, 122.7, 121.7, 121.5, 114.6, 110.5, 55.6. HRMS (ESI):
3
-Phenyl-1H-indazole (2a): Eluted with 20% EtOAc in hexanes
20
H
17
2
N O (M + H) requires 301.1341 / Found: 301.1338.
1
solution. Physical aspect: yellow solid. Yield: 75 mg – 77%. NMR: H
(
500 MHz, CDCl
3
): δ = 11.18 (b, 1H), 8.08 – 8.04 (m, 3H), 7.58 (t, J =
3
-Phenyl-1-(thiophen-2-yl)-1H-indazole (3c): Eluted with 2% EtOAc
7
.5, 2H), 7.49 – 7.46 (m, 1H), 7.43 – 7.37 (m, 2H), 7.29 – 7.25 (m, 1H);
in hexanes solution. Physical aspect: yellow solid. Yield: 73 mg – 53%.
NMR: H (300 MHz, CDCl
8
1
3
1
3
C{ H} (125 MHz, CDCl ): δ = 145.8, 141.7, 133.6, 128.9, 128.2, 127.7,
1
3
, 25 °C) δ = 8.07 (dt, J = 8.1, 0.9, 1H), 8.05 –
17
1
26.8, 121.4, 121.1, 121.0, 110.2. Data agree with literature.
.01 (m, 2H), 7.79 (dt, J = 8.5, 0.8, 1H), 7.57 – 7.42 (m, 4H), 7.34 –
4
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Org aP nl ei ca s &e dB oi o nmo ot la ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
ARTICLE
7
.29 (m, 2H), 7.19 (dd, J = 5.5, 1.4, 1H), 7.09 (dd, J = 5.5, 3.7, 1H). 136.8, 134.9, 129.9, 128.0, 127.7, 125.9, 125.6, 124.1,Vi1ew22A.r9tic,le1O2n2l.in6e,
1
3
1
C{ H} (75 MHz, CDCl
3
, 25 °C) δ = 146.6, 142.4, 140.9, 132.7, 128.8, 121.6, 110.3. HRMS (ESI): C16
H
11 3
N SNa (M +DNOaI): 1r0e.q10u3ir9e/sC37O00B.000587411D/
1
28.5, 127.9, 127.6, 126.0, 123.0, 122.3, 121.6, 121.1, 117.3, 110.7 Found: 300.0569.
12 2
HRMS (ESI): C17H N
SNa (M + Na) requires 299.0619 / Found:
2
99.0606.
1-(Pyridin-2-yl)-3-(thiophen-2-yl)-1H-indazole (3j): Eluted with 15%
EtOAc in hexanes solution. Physical aspect: yellow solid. Yield: 79 mg
1
3
-Phenyl-1-(pyridin-3-yl)-1H-indazole (3d): Eluted with 10% EtOAc – 57%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 8.92 (dt, J = 8.6, 0.9, 1H),
in hexanes solution. Physical aspect: yellow solid. Yield: 84 mg – 62%. 8.53 (ddd, J = 4.9, 1.8, 0.8, 1H), 8.15 (dt, J = 8.4, 0.9, 1H), 8.09 (dt, J =
1
NMR: H (500 MHz, DMSO-d
6
, 25 °C) δ = 9.13 (s, 1H), 8.65 (d, J = 4.3, 8.1, 1.0, 1H), 7.86 – 7.80 (m, 1H), 7.78 (dd, J = 3.6, 1.1, 1H), 7.59 –
1
H), 8.32 – 8.30 (m, 1H), 8.20 (d, J = 8.2, 1H), 8.08 – 8.06 (m, 2H), 7.96 7.53 (m, 1H), 7.44 (dd, 5.1, 1.1, 1H), 7.39 – 7.34 (m, 1H), 7.22 (dd, J
13
1
(
3
d, J = 8.5, 1H), 7.67 (dd, J = 8.2, 4.7, 1H), 7.61 – 7.58 (m, 3H), 7.50 (t, = 7.1, 3.6, 1H), 7.15 (ddd, J = 7.3, 4.9, 1.0, 1H). C{ H} (75 MHz, CDCl ,
J = 7.4, 1H), 7.41 (t, J = 7.5, 1H). C{ H} (125 MHz, DMSO-d
13
1
6
, 25 °C) δ 25 °C) δ = 154.1, 147.6, 142.0, 140.2, 138.2, 135.3, 128.1, 127.7,
=
1
147.5, 145.9, 143.3, 139.8, 136.1, 132.1, 129.6, 128.9, 128.6, 127.9, 126.0, 125.8, 123.4, 123.0, 120.7, 119.8, 115.7, 113.7. HRMS (ESI):
27.3, 124.3, 122.7, 122.4, 121.4, 110.7. HRMS (ESI): C18
H
14
N
3
(M +
C
16
H
11
3
N SNa (M + Na) requires 300.0571 / Found: 300.0562.
H) requires 272.1188 / Found: 272.1182.
3-(3-(Thiophen-2-yl)-1H-indazol-1-yl)quinoline (3k): Eluted with
4
-(3-Phenyl-1H-indazol-1-yl)isoquinoline (3e): Eluted with 10% 15% EtOAc in hexanes solution. Physical aspect: white solid. Yield:
1
EtOAc in hexanes solution. Physical aspect: yellow solid. Yield: 109 105 mg – 64%. NMR: H (300 MHz, CDCl
mg – 68%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 9.46 (d, J = 2.3,
1
3
, 25 °C) δ = 9.39 (s, 1H), 8.82 (s, 1H), 8.49 (d, J = 2.4, 1H), 8.22 (d, J = 8.3, 1H), 8.17 (dt, J = 8.2, 1.0,
1
–
H), 8.19 – 8.09 (m, 4H), 7.88 – 7.85 (m, 1H), 7.75 – 7.68 (m, 2H), 7.59 1H), 7.94 (dd, J = 8.1, 1.2, 1H), 7.84 (dt, J = 8.5, 0.8 1H), 7.80 – 7.74
13
1
7.54 (m, 2H), 7.49 – 7.41 (m, 2H), 7.38 – 7.32 (m, 2H). C{ H} (75 (m, 2H), 7.67 – 7.62 (m, 1H), 7.58 – 7.52 (m, 1H), 7.45 (dd, J = 5.1, 1.1,
13
1
3 3
MHz, CDCl , 25 °C) δ = 152.9, 146.9, 142.8, 140.9, 133.0, 132.5, 131.4, 1H), 7.41 – 7.36 (m, 1H), 7.23 (dd, J = 5.1, 3.6). C{ H} (75 MHz, CDCl ,
1
1
/
31.0, 129.4, 128.8, 128.4, 128.0, 127.8, 127.7, 127.3, 122.8, 122.4, 25 °C) δ = 146.4, 145.9, 142.4, 140.5, 134.9, 133.6, 129.5, 129.4,
22.1, 121.6, 110.3. HRMS (ESI): C22
H
16
N
3
(M + H) requires 322.1344 128.1, 127.9, 127.8 (two signals), 127.7, 127.3, 126.0, 125.7, 123.0,
122.7, 121.7, 110.3. HRMS (ESI): C20 S (M + H) requires 328.0908
Found: 328.0892.
Found: 322.1334.
14 3
H N
/
3-(3-Phenyl-1H-indazol-1-yl)quinoline (3f): Eluted with 15% EtOAc in
hexanes solution. Physical aspect: off-white solid. Yield: 98 mg – 61%. 4-(3-(Thiophen-2-yl)-1H-indazol-1-yl)isoquinoline (3l): Eluted with
1
NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 9.50 (d, J = 2.4, 1H), 8.50 (d, J = 15% EtOAc in hexanes solution. Physical aspect: off-white solid. Yield:
1
2
7
7
°
1
.4, 1H), 8.21 (d, J = 8.5, 1H), 8.13 (d, J = 8.2, 1H), 8.09 – 8.05 (m, 2H), 122 mg – 75%. NMR: H (300 MHz, CDCl
.93 (dd, J = 8.1, 1.0, 1H), 7.87 (d, J = 8.5, 1H), 7.79 – 7.74 (m, 1H), (s, 1H), 8.19 (d, J = 8.0, 1H), 8.14 – 8.10 (m, 1H), 7.84 – 7.78 (m, 2H),
.66 – 7.45 (m, 5H), 7.39 – 7.33 (m, 1H). C{ H} (75 MHz, CDCl , 25 7.74 – 7.68 (m, 2H), 7.47 – 7.41 (m, 2H), 7.38 – 7.31 (m, 2H), 7.23 (dd,
3
3
, 25 °C) δ = 9.38 (s, 1H), 8.79
13
1
13
1
C) δ = 147.4, 146.5, 146.1, 140.6, 133.7, 132.8, 129.5, 129.4, 128.9, J = 5.1, 3.6, 1H). C{ H} (75 MHz, CDCl
28.6, 127.9, 127.8, 127.8, 127.6, 127.1, 123.5, 122.5, 121.9, 110.3. 141.0, 135.3, 132.6, 131.5, 130.8, 129.4, 128.1, 127.8, 127.7, 127.6,
HRMS (ESI): C22 (M + H) requires 322.1344 / Found: 322.1341.
125.7, 125.4, 122.8, 122.4, 121.9, 121.3, 110.4. HRMS (ESI):
S (M + H) requires 328.0908 / Found: 328.0896.
3
, 25 °C) δ = 153.0, 142.7, 142.0,
16 3
H N
20 14 3
C H N
2
-(3-Phenyl-1H-indazol-1-yl)quinoline (3g): Eluted with 4% EtOAc in
hexanes solution. Physical aspect: white solid. Yield: 112 mg – 70%. 4-(3-(Thiophen-2-yl)-1H-indazol-1-yl)benzonitrile (3m): Eluted with
1
NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 9.30 (d, J = 8.5, 1H), 8.44 (d, J = 15% EtOAc in hexanes solution. Physical aspect: yellow solid. Yield:
1
8
7
7
.9, 1H), 8.27 (d, J = 8.9, 1H), 8.15 (d, J = 8.4, 1H), 8.12 – 8.07 (m, 3H), 80 mg – 53%. NMR: H (300 MHz, CDCl
.84 (dd, J = 8.1, 1.2, 1H), 7.78 – 7.72 (m, 1H), 7.67 – 7.62 (m, 1H), 0.9, 1H), 8.0 – 7.96 (m, 2H), 7.85 – 7.81 (m, 3H), 7.76 (dd. J = 3.6, 1.1,
.61 – 7.55 (m, 2H), 7.53 – 7.46 (m, 2H), 7.43 – 7.37 (m, 1H). C{ H} 1H), 7.57 – 7.52 (m, 1H), 7.45 (dd, J = 5.1, 1.1, 1H), 7.41 – 7.36 (m,
75 MHz, CDCl
3
, 25 °C) δ = 8.14 (dt. J = 8.1,
13
1
13
1
(
3
, 25 °C) δ = 153.0, 147.4, 146.7, 140.5, 138.2, 132.9, 1H), 7.22 (dd, J = 5.1, 3.6, 1H). C{ H} (75 MHz, CDCl
3
, 25 °C) δ =
1
1
3
29.9, 128.8, 128.7, 128.3, 128.0, 128.0, 127.6, 126.1, 125.3, 124.3, 143.5, 142.8, 139.9, 134.6, 133.5, 128.3, 127.8, 126.3, 125.9, 123.5,
23.2, 121.0, 116.4, 113.7. HRMS (ESI): C22
H
16
N
3
(M + H) requires 123.1, 122.0, 121.9, 118.5, 110.8, 109.3. HRMS (ESI): C18
11 3
H N SNa (M
22.1344 / Found 322.1329.
+ Na) requires 324.0571 / Found: 324.0554.
3-Phenyl-1-(2-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)phenyl)-1H-
3-(3-(4-Methoxyphenyl)-1H-indazol-1-yl)quinolone (3n): Eluted
indazole (3h): Eluted with 15% EtOAc in hexanes solution. Physical with 15% EtOAc in hexanes solution. Physical aspect: yellow solid.
1
1
aspect: off-white solid. Yield: 103 mg – 48%. NMR: H (300 MHz, Yield: 135 mg – 77%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 9.50 (d, J =
CDCl , 25 °C) δ = 8.14 (dt, J = 8.2, 0.8, 1H), 8.07 – 8.03 (m, 2H), 7.76 2.5, 1H), 8.49 (d, J = 2.3, 1H), 8.21 (d, J = 8.4, 1H), 8.10 (d, J = 8.2, 1H),
3
(
s, 1H), 7.68 – 7.64 (m, 2H), 7.61 – 7.28 (m, 13H), 5.62 (s, 2H). 13C{ H} 8.03 – 7.99 (m, 2H), 7.92 (dd, J = 8.1, 0.9, 1H), 7.86 (d, J = 8.5, 1H),
1
(
75 MHz, CDCl , 25 °C) δ = 147.7, 146.5, 142.1, 137.5, 132.9, 132.3, 7.78 – 7.73 (m, 1H), 7.66 – 7.60 (m, 1H), 7.55 – 7.50 (m, 1H), 7.37 –
3
13
1
1
1
C
31.1, 130.5, 129.7, 129.3, 129.0, 128.7, 128.6, 128.0, 127.6, 126.9, 7.31 (m, 1H), 7.12 – 7.07 (m, 2H), 3.90 (s, 3H). C{ H} (75 MHz, CDCl
25.6, 122.3, 122.2, 121.6, 120.3, 110.2, 50.0. HRMS (ESI): 25 °C) δ = 160.1, 147.3, 146.4, 146.1, 140.5, 133.8, 129.5, 129.3,
Na (M + Na) requires 450.1695 / Found 450.1678.
129.1, 128.0, 127.8, 127.7, 127.6, 126.8, 125.4, 123.5, 122.3, 122.0,
14.4, 110.2, 55.4. HRMS (ESI): C23 O (M + H) requires 352.1450
3
,
28 21 5
H N
1
18 3
H N
1
-(Pyridin-3-yl)-3-(thiophen-2-yl)-1H-indazole (3i): Eluted with 15% / Found: 352.1451.
EtOAc in hexanes solution. Physical aspect: yellow solid. Yield: 86 mg
1
–
3
7
1
62%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 9.15 (s, 1H), 8.64 (d, J = 3-(4-Methoxyphenyl)-1-(thiophen-2-yl)-1H-indazole (3o): Eluted
.4, 1H), 8.15 (d, J = 8.1, 2H), 7.80 – 7.76 (m, 2H), 7.56 – 7.51 (m, 2H), with 4% EtOAc in hexanes solution. Physical aspect: yellow solid.
1
.45 (dd, J = 5.1, 1.1, 1H), 7.39 – 7.34 (m, 1H), 7.24 (dd, J = 5.1, 3.6, Yield: 110 mg – 72%. NMR: H (300 MHz, CDCl
3
, 25 °C) δ = 8.06 – 7.97
13
1
3
H). C{ H} (75 MHz, CDCl , 25 °C) δ = 147.5, 143.7, 142.3, 140.2, (m, 3H), 7.78 (d, J = 8.4, 1H), 7.50 (t, J = 7.5, 1H), 7.33 – 7.28 (m, 2H),
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 6 of 8
ARTICLE
Journal Name
1
7
.18, (d, J = 5.1, 1H), 7.09 – 7.07 (m, 3H), 3.90 (s, 3H). 13C{ H} (75 MHz, H. Cerecetto, A. Gerpe, M. Gonzalez, V. J. Aran, C. O. de Ocariz,
View Article Online
DOI: 10.1039/C7OB00841D
CDCl
25.2, 122.9, 122.1, 121.6, 120.8, 116.9, 114.3, 110.6, 55.3. HRMS
ESI): C18 OSNa (M + Na) requires 329.0725 / Found 329.0715.
3
, 25 °C) δ = 159.9, 146.3, 142.5, 140.7, 129.0, 127.5, 125.9,
Mini-Rev. Med. Chem. 2005, 5, 869-878; (d) A. Thangadurai, M.
1
(
Minu, S. Wakode, S. Agrawal, B. Narasimhan, Med. Chem. Res.
14 2
H N
2
012, 21, 1509-1523; (e) D. D. Gaikwad, A. D. Chapolikar, C. G.
Devkate, K. D. Warad, A. P. Tayade, R. P. Pawar, A. J. Domb, Eur.
J. Med. Chem. 2015, 90, 707-731.
3
-(4-Methoxyphenyl)-1-(2-((4-phenyl-1H-1,2,3-triazol-1-yl) methyl)
phenyl)-1H-indazole (3p): Eluted with 15% EtOAc in hexanes
solution. Physical aspect: off-white solid. Yield: 117 mg – 51%. NMR:
1
2. (a) P. Jacobson, L. Huber, Ber. Dtsch. Chem. Ges. 1908, 41,
H), 7.75 (s, 1H), 7.67 (d, J = 7.2, 2H), 7.60 – 7.28 (m, 10H), 7.08 (d, J 660-671; (b) C. Ruchardt, V. Hassmann, Liebigs Ann. Chem.
, 25 °C) δ 1980, 908-927; (c) T. Yoshida, N. Matsuura, K. Yamamoto, M.
160.0, 147.7, 146.3, 142.0, 137.6, 132.2, 131.1, 130.5, 129.6, 129.1, Doi, K. Shimada, T. Morie, S. Kato, Heterocycles 1996, 43, 2701-
3
H (300 MHz, CDCl , 25 °C) δ = 8.11 (d, J = 8.1, 1H), 7.99 (d, J = 8.7,
2
=
=
1
1
8.7, 2H), 5.62 (s, 2H), 3.90 (s, 3H). 13C{ H} (75 MHz, CDCl
1
3
28.8, 128.6, 127.9, 127.5, 126.8, 125.6, 125.4, 122.1 (two signals),
21.6, 120.4, 114.4, 110.2, 55.4, 50.1. HRMS (ESI): C29 ONa (M +
2
2
712; (d) F. Crestey, V. Collot, S. Stiebing, S. Rault, Tetrahedron
006, 62, 7772-7775.
23 5
H N
Na) requires 480.1800 / Found 480.1793.
3
. For selected recent examples involving uncatalyzed aryne
3
-(3-methoxyphenyl)-1-(thiophen-2-yl)-1H-indazole (3q): Eluted
cycloaddition or employing arylamino oxime synthons, see: (a)
T. Jin, Y. Yamamoto, Angew. Chem. Int. Ed. 2007, 46, 3323-3325;
with 4% EtOAc in hexanes solution. Physical aspect: yellow solid.
Yield: 107 mg – 70%. NMR: H (500 MHz, CDCl
8
7
1
3
, 25 °C) δ = 8.09 (d, J =
(b) B. C. Wray, J. P. Stambuli, Org. Lett. 2010, 12, 4576-4579; (c)
.2, 1H), 7.78 (d, J = 8.5, 1H), 7.65 (d, J = 7.6, 1H), 7.63 – 7.62 (m, 1H),
.52 – 7.49 (m, 1H), 7.47 (t, J = 7.9, 1H), 7.33 – 7.30 (m, 2H), 7.19 (dd, C. Spiteri, S. Keeling, J. E. Moses, Org. Lett. 2010, 12, 3368-3371.
J = 5.5, 1.3, 1H), 7.09 (dd, J = 5.5, 3.7, 1H), 7.04 – 7.02 (m, 1H), 3.93
1
3
1
(
1
1
s, 3H). C{ H} (125 MHz, CDCl
3
, 25 °C) δ = 159.9, 146.4, 142.3, 140.9, 4. For selected examples, see: (a) G. M. Shutske, R. C. Allen, M.
33.9, 129.8, 127.6, 125.9, 123.0, 122.3, 121.6, 121.1, 120.3, 117.3,
14.4, 113.1, 110.7, 55.3. HRMS (ESI): C18H N OSNa (M + Na)
14 2
requires 329.0725 / Found 329.0718.
F. Forsch, L. L. Setescak, J. C. Wilker, J. Med. Chem. 1983, 26,
307-1311; (b) B. R. Henke, C. J. Aquino, L. S. Birkemo, D. K.
1
Croom, R. W. Dougherty, G. N. Ervin, M. K. Grizzle, G. C. Hirst,
M. K. James, M. F. Johnson, K. L. Queen, R. G. Sherrill, E. E. Sugg,
E. M. Suh, J. W. Szewczyk, R. J. Unwalla, J. Yingling, T. M. Willson,
J. Med. Chem. 1997, 40, 2706-2725; (c) S. Caron, E. Vazquez,
Synthesis 1999, 588-592; (d) V. Leroy, G. E. Lee, J. Lin, S. H.
Herman, T. B. Lee, Org. Process Res. Dev. 2001, 5, 179-183; (e)
4
-(3-(2-Methoxyphenyl)-1H-indazol-1-yl)benzonitrile (3r): Eluted
with 10% EtOAc in hexanes solution. Physical aspect: White solid.
Yield: 70 mg – 43%. NMR: H (300 MHz, CDCl
H), 7.85 – 7.79 (m, 4H), 7.68 (dd, J = 7.5, 1.7, 1H), 7.54 – 7.45 (m,
1
3
): δ = 8.03 – 7.98 (m.
2
2
13
1
H), 7.31 – 7.26 (m, 1H), 7.15 – 7.09 (m, 2H), 3.88 (s, 3H). C{ H} (75
MHz, CDCl
3
): δ = 157.4, 146.8, 143.8, 139.3, 133.4, 131.5, 130.5, J. R. J. Cui, G. L. Araldi, J. E. Reiner, K. M. Reddy, S. J. Kemp, J. Z.
1
1
3
27.7, 125.5, 123.4, 122.1, 121.8, 121.2, 120.9, 118.6, 111.3, 110.3, Ho, D. V. Siev, L. Mamedova, T. S. Gibson, J. A. Gaudette, N. K.
09.9, 108.8, 55.5. HRMS (ESI): C21
15 3
H N ONa (M + Na) requires
Minami, S. M. Anderson, A. E. Bradbury, T. G. Nolan, J. E.
Semple, Bioorg. Med. Chem. Lett. 2002, 12, 2925-2930; (f) J.
Witherington, V. Bordas, A. Gaiba, A. Naylor, A. D. Rawlings, B.
P. Slingsby, D. G. Smith, A. K. Takle, R. W. Ward, Bioorg. Med.
Chem. Lett. 2003, 13, 3059-3062; (g) T. J. Watson, T. A. Ayers, N.
Shah, D. Wenstrup, M. Webster, D. Freund, S. Horgan, J. P.
48.1113 / Found 348.1099.
3
1
1
8
7
-(Naphthalen-1-yl)-1-(thiophen-2-yl)-1H-indazole (3s): Eluted with
0% EtOAc in hexanes solution. Physical aspect: yellow solid. Yield:
1
3
15 mg – 71%. NMR: H (500 MHz, CDCl ): δ = 8.33 – 8.30 (m, 1H),
.00 – 7.94 (m, 2H), 7.89 – 7.83 (m, 2H), 7.71 (dt, J = 8.1, 1.0, 1H), Carey, Org. Process Res. Dev. 2003, 7, 521-532; (h) K. Lukin, M.
.65 – 7.60 (m, 1H), 7.57 – 7.52 (m, 2H), 7.50 – 7.47 (m, 1H), 7.36 (dd, C. Hsu, D. Fernando, M. R. Leanna, J. Org. Chem. 2006, 71, 8166-
J = 3.7, 1.4, 1H), 7.29 – 7.24 (m, 1H), 7.20 (dd, J = 5.5, 1.4, 1H), 7.11 8172.
dd, J = 5.5, 3.7, 1H). 13C{ H} (125 MHz, CDCl
1
(
3
): δ = 146.6, 142.6, 140.2,
1
1
C
34.0, 131.8, 130.3, 129.2, 128.4, 128.3, 127.8, 126.5, 126.2, 126.0,
26.0, 125.3, 124.9, 122.1, 121.9, 120.8, 116.9, 110.6. HRMS (ESI):
SNa (M + Na) requires 349.0775 / Found: 349.0765.
5
. I. Thome, C. Besson, T. Kleine, C. Bolm, Angew. Chem. Int.
Ed. 2013, 52, 7509-7513.
21 14 2
H N
6
. For selected representative examples including variations on
this reaction theme, see: (a) J. J. Song, N. K. Yee, Org. Lett. 2000
,
Acknowledgements
2
2
, 519-521; (b) J. J. Song, N. K. Yee, Tetrahedron Lett. 2001, 42,
937-2940; (c) K. Inamoto, M. Katsuno, T. Yoshino, I. Suzuki, K.
We are appreciative of the generous financial support of this
work from the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and the Natural Sciences and
Engineering Research Council of Canada (NSERC Canada).
Hiroya, T. Sakamoto, Chem. Lett. 2004, 33, 1026-1027; (d) D. K.
O'Dell, K. M. Nicholas, Heterocycles 2004, 63, 373-382; (e) C. S.
Cho, D. K. Lim, N. H. Heo, T.-J. Kim, S. C. Shim, Chem. Commun.
2
004, 104-105; (f) A. Y. Lebedev, A. S. Khartulyari, A. Z.
Voskoboynikov, J. Org. Chem. 2005, 70, 596-602; (g) C. Pabba,
H. J. Wang, S. R. Mulligan, Z. J. Chen, T. M. Stark, B. T. Gregg,
Notes and references
1
. (a) G. A. Bistocchi, G. Demeo, M. Pedini, A. Ricci, H. Brouilhet, Tetrahedron Lett. 2005, 46, 7553-7557; (h) K. Inamoto, M.
S. Boucherie, M. Rabaud, P. Jacquignon, Farmaco Ed. Sci. 1981
,
Katsuno, T. Yoshino, Y. Arai, K. Hiroya, T. Sakamoto,
3
6, 315-333; (b) W. Stadlbauer, Sci. Synth. 2002, 12, 227-324; (c) Tetrahedron 2007, 63, 2695-2711; (i) K. Inamoto, T. Saito, M.
6
| J. Name., 2012, 00, 1-3
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Org aP nl ei ca s &e dB oi o nmo ot la ed cj uu sl at rm Ca hr ge imn si stry
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Organic & Biomolecular Chemistry
Page 8 of 8
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DOI: 10.1039/C7OB00841D
O
R
.
4
N H HCl
2
R
N
N
Cl
(Hetero)aryl Br
Ni
Cu
(Hetero)aryl
R = (Hetero)aryl
A new nickel-catalyzed cyclization of ortho-chlorobenzophenone hydrazones, to afford 3-
hetero)aryl-1H-indazoles, is developed and applied in a one-pot synthesis of 1,3-di(hetero)aryl-
H-indazoles.
(
1