Suzuki-type cross-coupling reaction of unprotected 3-iodoindazoles with pinacol vinyl boronate: An expeditive C-3 vinylation of indazoles under microwave irradiation

Article abstract of DOI:10.3390/molecules23082051

Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel, were synthesized through this method, which proceeds in moderate to excellent yields starting from C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates allowing access to biologically active molecules.

Full text of DOI:10.3390/molecules23082051

molecules
Communication
Suzuki-Type Cross-Coupling Reaction of Unprotected
-Iodoindazoles with Pinacol Vinyl Boronate:
3
An Expeditive C-3 Vinylation of Indazoles under
Microwave Irradiation
1
1
2
Gonzalo Vera , Benjamín Diethelm , Claudio A. Terraza
1
,3, ID
and Gonzalo Recabarren-Gajardo
*
1
Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile,
Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile; glvera@uc.cl (G.V.);
bmdiethelm@uc.cl (B.D.)
Departamento de Química Orgánica, Facultad de Química, Pontificia Universidad Católica de Chile,
Casilla 306, Avda. Vicuña Mackenna 4860, Macul 7820436, Santiago, Chile; cterraza@uc.cl
Centro Interdisciplinario de Neurociencias, Pontificia Universidad Católica de Chile,
Marcoleta 391, Santiago 8330024, Santiago, Chile
2
3
*
Correspondence: grecabarren@uc.cl; Tel.: +56-223-541-418
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 7 July 2018; Accepted: 14 August 2018; Published: 16 August 2018
Abstract: Herein we report an expeditive C-3 vinylation of unprotected 3-iodoindazoles under
microwave irradiation. Ten C-5 substituted 3-vinylindazole derivatives, nine of them novel,
were synthesized through this method, which proceeds in moderate to excellent yields starting from
C-5 substituted 3-iodoindazole derivatives. In all cases, the C-3 vinylated derivative was the only
isolated product. This methodology allows access to 3-vinylated indazoles selectively and directly
without the need of N-protection. 3-Vinylindazoles could be interesting synthetic intermediates
allowing access to biologically active molecules.
Keywords: vinylation; Suzuki cross-coupling; 3-iodoindazole; 3-vinylindazole; microwave synthesis
1
. Introduction
The indazole ring is a heterocycle which, being an isostere of the indole ring, exhibits a very
interesting medicinal chemistry potential. Having shown a broad variety of biological activities,
this heterocycle could lead to the development of several pharmaceutical products [ ]. Interestingly,
the indazole nucleus is scarcely found in Nature, and to date, only three natural products containing
this unit have been isolated: nigellicine [ ], nigeglanine [ ], and nigellidine [ ]. For these reasons,
the development of synthetic methodologies aimed at this aromatic moiety is an active area of research.
Our research group has been conducting efforts to develop novel 5-HT receptor antagonists [ ].
1
2
3
4
5–7
6
In this sense, we are very interested in preparing 5-HT receptor ligands based on the indazole
6
nucleus, where a key intermediate in the envisaged synthetic route of these serotonergic ligands
is 3-vinylindazole. The synthesis of this parent compound has been reported in some works,
the first of them carrying out its preparation from synthetically complex precursors. In the 70s
Igeta et al. obtained 3-vinylindazole through both thermal and basic decomposition of 1-(pyridazino
[
1,6-b]indazol-9(4aH)-yl)ethan-1-one with poor to moderate yields [8,9]. Another work from Tsuchiya’s
group reported the synthesis of 3-vinyl indazole through a rearrangement of 3H-diazepines by
thermo- or photo-stimulation in outstanding yields (95% and 90% respectively) [10]. Furthermore,
Petrillo et al. described the preparation of 3-vinylindazole from o-allylphenylazosulfides in basic media
with excellent yield [11] (Scheme 1).
Molecules 2018, 23, 2051; doi:10.3390/molecules23082051
www.mdpi.com/journal/molecules

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Scheme 1. First reported syntheses of 3-vinylindazole: (
work [10] and (C) report of the Petrillo group [11].
A) Igeta’s work [8]; (B) Tsuchiya group’s
However, despite the excellent reported yields, none of these works have dealt with obtaining
C-5-substituted 3-vinylindazole derivatives. On the other hand, cross-coupling reactions have been
widely studied as a way to perform palladium or nickel catalyzed vinylation reactions with aryl halide
(
or pseudohalide) substrates [12–14]. Nevertheless, despite the vast number of developed transition
metal-catalyzed cross-coupling reactions, only a small fraction of these accommodate the attachment
of a simple vinyl unit, with an aryl halide being used as the substrate an overwhelming number of
times more than the heteroaryl halides [12]. On the other hand, in an outstanding work by Buchwald
et al. the authors describe the arylation and heteroarylation of unprotected, nitrogen-rich heterocycles
through a Suzuki cross-coupling reaction [15]. However, in this work the authors do not investigate the
vinylation reaction over these substrates. In this sense, some reports have used cross-coupling reactions
to functionalize the indazole ring as an attractive alternative to cyclization reactions. The most notable
works in this area have been performed by Collot et al. [16–22]. In one of such works, the authors report
the synthesis of a C-3 methyl acrylate-substituted indazole ring through a Heck cross-coupling reaction
in order to easily obtain azatryptamines [18]. However, in the case of our compounds the presence of
the ester function does not allow the easy preparation of our scaffold. More recently, the preparation
of some 3-vinylindazole derivatives using cross-coupling reactions has been reported [23–26]. In one
of them, the parent 3-vinylindazole was prepared in 60% yield from 3-bromo-1H-indazole via Stille
coupling, the main drawback being the toxicity of the tin compounds used [23]. In another work
by Sampson et al. the authors managed to prepare one 6-functionalized 3-vinylindazole with very
good yield, but in a long time of reaction, via Suzuki cross-coupling in the context of the discovery of
Polo-Like kinase 4 inhibitors as antitumoral agents [24]. In another example, the authors achieved the
synthesis of 3-vinyl-1H-indazol-5-carboxylic acid methyl ester from the corresponding N-unprotected
◦
3
-iodoindazole via Suzuki cross-coupling under microwave irradiation at 160 C in 40% yield [25].
Finally, in a patent by Li et al. the authors managed to prepare a highly functionalized 3-vinylindazole
derivative in 39% yield using three equivalents of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane and
10 mol% of catalyst under conventional heating in a very long time of reaction [26]. Additionally,
amongst the cross-couplings reactions, the Suzuki-Miyaura coupling is arguably the most important
C-C-coupling method employed due to its broad substrate scope, high level of functional group
tolerance, and, with modern catalysts, high turnover rates [15,27]. Considering all this gathered
background, we set ourselves the goal of evaluating the vinylation reaction directly on the indazole
nucleus through a Suzuki cross-coupling reaction and explore the influence of the electronic properties
of the C-5 substituent on the indazole nucleus on the course of the reaction. Consequently, the following
reaction sequence was proposed (Scheme 2).

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Scheme 2. Synthetic pathway to prepare 5-R-3-vinylindazole derivatives.
. Results and Discussions
.1. Synthesis of Starting Materials
2
2
According to Scheme 2, the first step in the envisaged pathway involved the preparation of the
3
-iodinated derivatives of several C-5 substituted commercial indazoles in a N,N-dimethyl-formamide
(
N,N-DMF) solution under standard basic conditions [16, ,28]. Thus, the corresponding
18
5
-R-3-iodoindazole derivatives were obtained in excellent yields ranging from 87% to 100% (Scheme 3).
An exception was 5-amino-3-iodoindazole; due to the high insolubility of the substrate in the reaction
solvent, the product was obtained through a three-step sequence with a moderate final yield (49%).
Said sequence involved: N-Boc protection of the aniline functionality (90%), iodination at C-3 (54%)
and quantitative N-deprotection. Attempts to improve the yield of this iodination were infructuous.
Scheme 3. Iodination reaction of commercial indazole.
As a previous step to the vinylation reaction assay, N -protection of 3-iodoindazole derivatives
1
with di-4-butyl dicarbonate (Boc O) under ultrasound irradiation in basic media at room temperature
2
was performed. The N -Boc-3-iodoindazole products were quantitatively obtained in less than 5 min
1
(Scheme 4).
Scheme 4. N -protection of 3-iodoindazole derivatives using ultrasound irradiation.
1
This experiment was carried out in accordance with works that report that the 3-arylation of
indazole requires the previous N -protection of the NH group due to the competing N -arylation
1
1
reaction [16,29]. It is noteworthy to mention that the previously reported N-protection procedures
apply ultrasound irradiation on aliphatic or aromatic amine substrates [30], which are inherently more
basic than N-heterocyclic rings. On the other hand, experimental procedures that employ indazole as

Molecules 2018, 23, 2051
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a substrate for N-protection use standard basic conditions, namely DMAP/Et N in acetonitrile [18,31].
3
Thus, to our knowledge, this is the first report that employs ultrasound energy to N-protect the
indazole nucleus.
2
.2. Optimisation
Once N-protection had been carried out, the obtained N -protected-3-iodoindazole (2a) was
1
employed in the vinylation reaction assay with pinacol vinyl boronate under microwave irradiation,
using Pd(PPh ) as a catalyst in basic media, replicating conditions described by Hopkins [29] (Table 1).
3
4
The first attempt led to the intended product in a moderate yield of 60%, with the concomitant and
expected loss of the Boc protecting group [32,33] (entry 1).
Table 1. Optimization of the reaction conditions.
◦
Yield a (%)
Entry
Reactant
Reaction Conditions
Pd(PPh3)4/Na2CO3
Pd(PPh3)4/Na2CO3
x
2
2
2
2
2
2
1
3
2
2
Time/Temp ( C)
1
2
3
4
5
6
7
8
9
2a
1a
1a
1a
1a
1a
1a
1a
1a
1a
40 min/120
40 min/120
40 min/120
40 min/120
40 min/120
40 min/120
40 min/120
40 min/120
40 min/180
60 min/120
60
75
20
34
50
20
48
59
68
34
Pd(OAc)2/XantPhos, K3PO4
Pd(OAc)2, Na2CO3
Pd(PPh3)2Cl2/PPh3, Na2CO3
NiCl2(dppe)/dppe, K3PO4
Pd(PPh3)4/Na2CO3
Pd(PPh3)4/Na2CO3
Pd(PPh3)4/Na2CO3
Pd(PPh3)4/Na2CO3
1
0
Reaction conditions: 5 mol % of catalyst, aqueous base, 1,4-dioxane,
purified products.
µ
W. a Yield corresponding to the
Afterwards, in an attempt to increase the yield of the reaction and to verify whether the vinylation
reaction exhibits a similar behaviour to the arylation reaction previously described in the literature,
the described vinylation reaction was tested employing non-N-protected 3-iodoindazole (1a) as
a substrate under the same experimental conditions. Interestingly, under these conditions the yield of
3
-vinylindazole increased to 75% (entry 2). Next, in order to explore whether the catalyst system could
influence the course of the reaction or the ratio of the products, we also performed a vinylation reaction
assay under microwave irradiation employing 3-iodoindazole (1a) and replicating previous conditions
(namely, presence of aqueous base, 1,4-dioxane as solvent, and two equivalents of pinacol vinyl
boronate) using different catalysts (entry 3–6) (Table 1). All the employed catalytic systems led to the
C-3-vinylation of 3-iodoindazole 1a without the need of N-protection. Nevertheless, only PdCl (PPh )
2
3 2
led to the complete conversion of the 3-iodoindazole substrate 1a, yielding a 50% of 3-vinylindazole 3a
entry 5). In all other cases, a significant amount of unreacted 3-iodoindazole 1a was recovered, carrying
(
to a poor reaction yield. Thus, use of the Pd(OAc) /XantPhos system led to a greater substrate recovery
2
percentage than product yield (32% vs. 20% for 1a and 3a respectively) (entry 3, Table 1). On the other
hand, Pd(OAc) afforded similar yields for both the vinylation product and the substrate (34% of 3a vs.
2
35% of 1a) but nevertheless the product yield was poor (entry 4, Table 1). Likewise, the nickel-based
catalyst showed no improvement on the yield of the vinylation reaction; although it was possible to
obtain the final reaction product, it was in a very low yield, and an important amount of the iodinated
precursor was recovered (44% vs. 20% for 1a and 3a respectively) (entry 6, Table 1). Therefore,

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even though the obtainment of the product, using various catalytic systems, reveals the versatility
and tolerability of the vinylation reaction in face of a lack of N-protection, the results achieved were
poorer than those obtained when Pd(PPh ) was employed as a catalyst. In order to determine the
3
4
optimum equivalents of Suzuki coupling partner for the vinylation reaction we proceeded to assay
the reaction of compound 1a with one or three equivalents of pinacol vinyl boronate (entries 7 and
8
4
). When one equivalent of the coupling partner was employed, 3-vinyl indazole was obtained in
8% yield, recovering 33% of 3-iodoindazole (entry 7). Alternatively, when we used three equivalents
of the boron compound, 59% of 3-vinylindazole, without traces of 3-iodo-indazole, was obtained
(
entry 8). As an additional exploration of the reaction conditions, we carried out two more changes in
◦
the reaction’s parameters. First, we assayed the precursor (1a) increasing the temperature to 180 C
while keeping all other conditions unchanged. Under this temperature the C-3 vinylation product was
◦
the only isolated compound, but a slightly lower yield was observed than at 120 C (68%, entry 9 vs.
7
◦
5%, entry 2). We also carried out the vinylation of 1a at 120 C in a longer reaction time, resulting in
a poorer product yield (34%, entry 8 vs. 75%, entry 2). Overall, the best conditions for the vinylation
reaction were those initially employed in this work, that is, two equivalents of the boron coupling
◦
partner, tetrakis triphenylphosphine palladium (0) as catalyst and microwave irradiation at 120 C
for 40 min (Table 1). Under these experimental conditions, the vinylation reaction proceeds with
quantitative conversion of the reactant yielding 3-vinylindazole (3a) after chromatographic purification
in a very good yield (entry 2, Table 1).
2
.3. Scope
In order to evaluate the scope of these conditions, the vinylation reaction was tested on several
N-unprotected 5-R-3-iodoindazoles encompassing a wide variety of both electron-withdrawing and
electron-donating substituents (entries 2, 4 and 6–12, Table 2).
Table 2. Results of the vinylation reaction of several 5-R-3-iodoindazole derivatives.
0
Yield a (%)
Entry
Reactant
2b
1b
2c
R
NO2
NO2
Br
R
Heating
µW
µW
µW
µW
µW
µW
µW
µW
µW
µW
µW
µW
Product
3b
3b
3c
b
1
2
3
4
5
6
7
8
9
Boc
H
Boc
H
Boc
H
H
H
H
H
H
13
87
c
43
1c
Br
3c
60
d
2d
1d
1e
1f
1g
1h
1i
1j
OCH3
OCH3
F
Cl
CH3
CN
NHBoc
NH2
H
NO2
OCH3
F
3d
3d
3e
46
58
47
60
49
61
55
3f
3g
3h
3i
3j
3a
3b
3d
3e
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
e
H
H
H
36 (55)
1a
conventional
conventional
conventional
conventional
conventional
44
21
75
0
1b
1d
1e
H
H
1g
CH3
3g
17
◦
Reaction conditions: pinacol vinyl boronate (2 eq), Pd(PPh
3
)
4
(5–6 mol %), Na
2
CO
3
(2N), 1,4-dioxane,
µW, 120 C,
◦
a
4
0 min (entries 1–12). Conventional heating, 101 C, 3 h (entries 13–17). Yields corresponding to the purified products.
-iodo-5-nitro-1H-indazole was obtained as the major product in 86% yield. 5-bromo-3-vinyl-N-protected derivative
was isolated as only coproduct in 5% yield. N-boc-3-vinyl-5-methoxy-1H-indazole was obtained as coproduct in 26%
b
c
3
d
e
yield. 55% yield for 5-amino-3-vinylindazole 3j corresponds to that obtained by deprotection of 3i.

Molecules 2018, 23, 2051
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In all cases, the isolated product was the C-3-vinyl derivative, while no other competing product
was detected. The obtained yields range from moderate to excellent (see Table 2). Despite the
variability in electronic effects of the C-5 substituents, no correlation was observed either in the
course of the reaction or in the yield of the reaction products, except for the opposing cases of the
nitro (electron-withdrawing) (entry 2) and amino (electron-donating) (entry 12) groups (Table 2).
Additionally, a few other N-protected derivatives was assayed in order to shed light on the unexpected
behavior of this vinylation (entries 1, 3 and 5). In this sense, 3-iodo-5-nitroindazole, a more reactive
substrate towards Suzuki cross coupling, was assayed with N-Boc protection under the optimized
experimental conditions (entry 1). Surprisingly, the vinylation product was formed in a very poor
yield (13%) with 3-iodo-5-nitro-1H-indazole being isolated as a co-product of the reaction in an 86%
yield as consequence of N-deprotection reaction. However, by conducting a more exhaustive search
of the literature, we find that a similar observation for the nitro analogue was previously reported
Guillaumet et al. where the Suzuki arylation coupling of N-Boc 3-iodo-7-nitroindazole fails to give
the C-3 arylation product, but the unprotected 3-iodo-7-nitro-1H-indazole is isolated in 95% [32].
Conversely, when unprotected 3-iodo-5-nitroindazole (1b) was employed, the vinylation product was
obtained in excellent yield (87%) (entry 2). It seems to be that the nitro indazole derivatives are highly
reactive towards N-deprotection. This is not surprising since the powerful electron withdrawing nitro
group is at the right place for stabilisation of the anion generated by the Boc deprotection. One tentative
explanation is that the N-deprotection for this analogue is so favored that occurs before the vinylation
reaction and the side products generated by the cleavage of the Boc group poison the Pd-catalytic
system [34]. However, more experiments to corroborate this hypothesis would be necessary [35].
Additionally, we used the N-Boc protected 5-bromo derivative (2c) (entry 3), and its unprotected
counterpart (1c) (entry 4), both under the same conditions, obtaining the C-3-vinylation product in
4
3% and 60% yield respectively. Noteworthy that in the experiment with the N-Boc protected 5-bromo
derivative (2c), we achieved to isolate a 5% of the 5-bromo-3-vinyl-N-protected derivative as only
coproduct of the reaction, without observation of the C-5 vinylation product. Finally, as an additional
proof of the reaction behavior, we performed the vinylation reaction with N-Boc protected 5-methoxy
derivative (2d) (entry 5), and its unprotected counterpart (1d) (entry 6). The first example (entry 5)
led to the isolation of the C-3-vinylation product in 46% yield and an additional 26% yield of the
N-protected C-3-vinylation compound. The reaction with the unprotected precursor (entry 6) conduct
to the preparation of the N-unprotected C-3 vinylation product in a 58% yield, corroborating the results
obtained with the three previous examples (Table 1). Interestingly, compared to nitro compound,
in the examples with 5-bromo and 5-methoxy derivatives the N-deprotection reaction possibly occurs
after the vinylation reaction. Considering the absence of a strong electron-withdrawing group in
these latter examples this hypothesis seems to be not very surprisingly. This is tentatively supported
by the recovery of the N-Boc vinylated products for the 5-Br and 5-OMe analogues, isolated in 5%
and 26% yield, respectively. The 5-OMe group being electron donating will be the most resistant to
N-deprotection and this is supported by the higher amount of recovered N-Boc vinylated product vs.
the 5-Br.
Next, with the aim of determining whether microwave heating was essential to the success of
the reaction, we also performed the vinylation reaction of the unprotected derivatives 3-iodoindazole
(1a), 5-nitro-3-iodoindazole (1b), 5-methoxy-3-iodoindazole (1d), 5-fluoro-3-iodoindazole (1e), and
5
-methyl-3-iodoindazole (1g) under conventional heating conditions (entries 13–17, Table 2). In most
cases, the reaction leads to the formation of the corresponding C-3 vinylation products (only fluoro
derivative led to recovery of precursor (63% yield) and no isolation of the vinylation product), but in
lower yields (except for 3g) and a longer reaction time than the procedure performed under microwave
heating. The case of 5-methoxy-3-iodoindazole 1g is particularly noteworthy, as the work of Hopkins
shows no arylation reaction of this 3-iodoindazole derivative under conventional heating (DME at
◦
◦
8
2
0 C) [29]. However, the present conditions led, with an increment in heating temperature of only
0 C, to the obtainment of the Suzuki cross-coupling product 3g in a very good (75%) yield.

Molecules 2018, 23, 2051
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The NMR analyses support the purity of the different synthesized compounds, the case of the
1
13
amine derivatives being an exception (see supplementary materials). Both the H- and C-NMR
spectra show a certain degree of impurities which could not be minimized despite the purification
efforts carried out. On the other hand, the analyses of mass spectrometry support the success of the
syntheses in all cases.
To the best of our knowledge, this is the first systematic study performing a vinylation
cross-coupling reaction on the C-5 substituted indazole derivatives without N-protection of the
indazole ring and without detection of the any other competing product.
3
. Materials and Methods
3
.1. General Information
All organic solvents used for the synthesis were of analytical grade. All reagents used were
purchased from Sigma-Aldrich (St. Louis, MO, USA), Merck (Darmstadt, Germany) or AK Scientific
Union City, CA, USA) and were used as received. Melting points were determined on a Stuart
(
Scientific SMP30 apparatus (Bibby Scientific Limited, Stone, UK) and are uncorrected. NMR spectra
1
were recorded on anAvance III HD 400 instrument (Bruker, Billerica, MA, USA) at 400 MHz for H
and 100 MHz for 13C-NMR spectra were recorded in DMSO-d unless otherwise indicated, using
6
the solvent signal as reference. The chemical shifts are expressed in ppm (δ scale) downfield from
tetramethylsilane (TMS), and coupling constants values (J) are given in Hertz. The IR spectra were
obtained on a Bruker Vector 22 spectrophotometer using KBr discs. High resolution mass spectra were
obtained on high resolution mass spectrometer Exactive™ Plus Orbitrap (ThermoFisher Scientific,
Bremen, Germany) using electron impact ionization. Column chromatography was performed on
Merck silica gel 60 (70–230 mesh). Thin layer chromatographic separations were performed on Merck
silica gel 60 (70–230 mesh) chromatofoils. Ultrasonic reactions were performed on an ultrasound
device Branson 2210R-MT Ultrasonic Cleaner (Marshall Scientific, Danbury, CT, USA). Suzuki cross
coupling reactions were performed on a microwave oven Monowave 300 (Anton Paar, Graz, Austria).
3
.2. Syntheses and Characterization Procedures
3
-Iodo-1H-indazole (1a). 3-Iodoindazoles were obtained by direct iodination of commercial indazoles by
the method previously described by Bocchi [28] with slight modifications. A solution of 1H-indazole
(
(
3 g, 25.4 mmol), iodine (12.7 g, 50.03 mmol) and potassium hydroxide (5.34 g, 95.25 mmol) in DMF
7 mL) was stirred for 3 h at room temperature. The reaction was quenched by dilution with saturated
solution of sodium bisulfite (150 mL) and a precipitated was formed. The precipitated was filtered
◦
over vacuum and washed with water (3
×
30 mL). The solid was left to dry at 30 C in a vacuum oven
◦
◦
overnight obtaining 6.17 g of a pale yellow solid. Yield: 100%; m.p.: 136–138 C (lit.: [36] 134–136 C);
−
1
1
IR (KBr)
H-7); 7.45–7.40 (2H, m, H-6 and H-4); 7.19 (1H, dd, J = 7.5 Hz, H-5). C-NMR
26.79; 121.23; 120.39; 110.51; 93.49; HRMS calculated for C H IN : 243.9497, Found: 243.9499.
ν (cm ): 3086 (NH); 424 (C-I). H-NMR δ (ppm): 13.50 (1H, s, H-1); 7.55 (1H, d, J = 8.6 Hz,
13
δ
(ppm): 140.41; 127.22;
1
7
5
2

Molecules 2018, 23, 2051
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3-Iodo-5-nitro-1H-indazole (1b). Prepared from 5-nitro-1H-indazole (3 g, 18.4 mmol), iodine (9.0 g,
3
5.46 mmol), potassium hydroxide (3.87 g, 69.00 mmol) and DMF (7 mL) to give 5.31 g of a pale
◦
◦
−1
ν (cm ): 3200 (NH); 1528 (NO2
yellow solid. Yield: 100%; m.p.: 216–217 C (lit.: [22] 214 C); IR (KBr)
asymmetrical); 1335 (NO symmetrical); 424 (C-I). H-NMR
J = 1.8 Hz, H-4); 8.23 (1H, dd, J = 9.2 and 2.1 Hz, H-6); 7.75 (1H, d, J = 9.2, H-7). C-NMR
1
δ
(ppm): 14.13 (1H, s, H-1); 8.30 (1H, d,
2
13
δ
(ppm):
1
2
42.99; 142.52; 126.77; 122.42; 118.57; 112.18; 97.67; HRMS calculated for C H IN O : 288.9348, Found:
88.9353.
7
4
3
2
5-Bromo-3-iodo-1H-indazole (1c). Prepared from 5-bromo-1H-indazole (1 g, 5.07 mmol), iodine (2.5 g,
9
.85 mmol), potassium hydroxide (1.07 g, 19.06 mmol) and DMF (4 mL) to give 1.63 g of a pale yellow
◦
◦
−1
solid. Yield: 100%; m.p.: 209–210 C (lit.: [22] 196 C); IR (KBr)
ν
(cm ): 3124 (NH); 424 (C-I and C-Br).
1
13
H-NMR
δ
(ppm): 13.69 (1H, s, H-1); 7.60 (1H, s, H-4); 7.57–7.50 (2H, m, H-6 and H-7). C-NMR
δ
(
ppm): 139.24; 129.98; 128.46; 122.59; 113.46; 112.74; 92.47; HRMS calculated for C H BrIN : 321.8603,
7 4 2
Found: 321.8617.
3-Iodo-5-methoxy-1H-indazole (1d). Prepared from 5-methoxy-1H-indazole (0.2 g, 1.35 mmol), iodine
(
0.7 g, 2.76 mmol), potassium hydroxide (284 mg, 5.06 mmol) and DMF (3 mL) to give 0.34 g of a
◦
◦
−1
ν (cm ): 3185 (NH);
pale brown solid. Yield: 90%; m.p.: 162–163 C (lit.: [22] 178–179 C); IR (KBr)
1
1
288 (C-O); 424 (C-I). H-NMR
δ
(ppm): 13.36 (1H, s, H-1); 7.46 (1H, d, J = 8.9 Hz, H-7); 7.08 (1H, d,
(ppm): 154.71; 136.16; 127.13; 119.51;
11.74; 99.24; 92.25; 55.45; HRMS calculated for C H IN O: 273.9603, Found: 273.9599.
J = 8.8 Hz, H-6); 6.76 (1H, s, H-4); 3.82 (3H, s, OCH3). 13C-NMR
δ
1
8
7
2
5-Fluoro-3-iodo-1H-indazole (1e). Prepared from 5-fluoro-1H-indazole (0.2 g, 1.47 mmol), iodine (0.75 g,
2
.95 mmol), potassium hydroxide (0.31 g, 5.52 mmol) and DMF (3 mL) to give 0.33 g of a pale brown
◦
◦
−1
solid. Yield: 87%; m.p.: 158–159 C (lit.: [37] 166 C); IR (KBr)
ν (cm ): 3171 (NH); 1165 (C-F); 424 (C-I).
δ (ppm): 13.61 (1H, s, H-1); 7.61 (1H, dd, J = 9.0 and 4.1 Hz, H-7); 7.32 (1H, td, J = 9.1 and
1
H-NMR

Molecules 2018, 23, 2051
9 of 19
2
.1 Hz, H-6); 7.17 (1H, dd, J = 8.7 and 1.7 Hz, H-4). 13C-NMR
δ
(ppm): 157.51 (d, J = 237.3 Hz); 137.56;
126.96 (d, J = 10.4 Hz); 116.84 (d, J = 27.5 Hz); 112.41 (d, J = 9.7 Hz); 104.44 (d, J = 24.2 Hz); 92.69 (d,
J = 5.8 Hz); HRMS calculated for C H FIN : 261.9403, Found: 261.9408.
7
4
2
5
-Chloro-3-iodo-1H-indazole (1f). Prepared from 5-chloro-1H-indazole (0.2 g, 1.31 mmol), iodine (0.65 g,
2
.56 mmol), potassium hydroxide (275 mg, 4.90 mmol) and DMF (3 mL) to give 0.33 g of a pale brown
◦
−1
1
solid. Yield: 90%; m.p.: 182–183 C; IR (KBr)
ν
(cm ): 3125 (NH); 710 (C-Cl); 424 (C-I). H-NMR
δ
13
(ppm): 13.69 (1H, s, H-1); 7.60 (1H, d, J = 8.7 Hz, H-7), 7.46–7.40 (2H, m, H-4 and H-6). C-NMR
δ
(
ppm): 139.10; 127.82; 127.64; 125.77; 119.48; 112.51; 92.64; HRMS calculated for C H ClIN : 277.9108,
7 4 2
Found: 277.9116.
3
2
-Iodo-5-methyl-1H-indazole (1g). Prepared from 5-methyl-1H-indazole (0.2 g, 1.51 mmol), iodine (0.75 g,
.95 mmol), potassium hydroxide (318 mg, 5.67 mmol) and DMF (3 mL) to give 0.36 g of a pale brown
◦
−1
1
solid. Yield: 93%; m.p.: 159–160 C; IR (KBr)
ν (cm ): 3186 (NH); 2916 (C-H); 424 (C-I). H-NMR
δ
(ppm): 13.37 (1H, s, H-1); 7.44 (1H, d, J = 8.2 Hz, H-7); 7.25 (1H, d, J = 8.1 Hz, H-6); 7.18 (1H, s,
H-4); 2.41 (3H, s, CH3). 13C-NMR
δ (ppm): 139.12; 130.43; 129.33; 127.10; 119.24; 110.31; 92.59; 20.91;
HRMS calculated for C H IN : 257.9654, Found: 257.9659.
8
7
2
3
-Iodo-1H-indazole-5-carbonitrile (1h). Prepared from 1H-indazole-5-carbonitrile (0.2 g, 1.4 mmol), iodine
(
0.7 g, 2.76 mmol), potassium hydroxide (295 mg, 5.26 mmol) and DMF (3 mL) to give 0.34 g of a white
◦
−1
1
solid. Yield: 91%; m.p.: 206–207 C; IR (KBr)
(
ν
(cm ): 3340 (NH); 2283 (CN); 424 (C-I). H-NMR
δ
13
ppm): 13.99 (1H, s, H-1); 8.04 (1H, s, H-7); 7.73 (2H, s, H-4 and H-6). C-NMR
δ
(ppm): 141.53; 129.27;
1
27.39; 126.73; 119.30; 112.25; 103.73; 95.36. HRMS calculated for C H IN : 268.9450, Found: 268.9455.
8 4 3

Molecules 2018, 23, 2051
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tert-Butyl (3-iodo-1H-indazol-5-yl)carbamate (1i). Prepared from tert-butyl(1-H-indazol-5-yl)carbamate
(
(
0.35 g, 1.5 mmol), iodine (0.75 g, 2.95 mmol), potassium hydroxide (316 mg, 5.63 mmol) and DMF
3 mL). The brown solid obtained was purificated by column chromatography on silica gel using
n-hexane/ethyl acetate 1:1 v/v to obtain 0.29 g of pure product as brown crystalline plates. Yield: 54%;
◦
−1
1
m.p.: 181–182 C; IR (KBr) ν (cm ): 3348 (NH); 1750 (C=O); 1157 (C-O); 424 (C-I). H-NMR δ (ppm):
3.35 (1H, s, H-1); 9.40 (1H, s, H-5); 7.70 (1H, s, H-4); 7.44 (1H, d, J = 8.9 Hz, H-8); 7.38 (1H, d, J = 8.9 Hz,
H-7); 1.50 (9H, s, H-6). 13C-NMR
(ppm): 153.05; 136.82; 133.63; 126.91; 120.89; 110.71; 107.38; 92.78;
9.04; 28.19; HRMS calculated for C H IN O : 359.0131, Found: 359.0128.
1
δ
7
12
14
3
2
3-Iodo-1H-indazol-5-amine (1j). To a solution of tert-butyl (3-iodo-1-H-indazol-5-yl)carbamate (0.2 g,
0
.56 mmol) (1i) and trifluoroacetic acid (5 mL, 65.34 mmol) in CH Cl (5 mL) was stirred vigorously
2
2
for 2 h at room temperature. After stirring, the reaction was neutralized to pH = 7 using NaOH 1M
and the organic layer was extracted with ethyl acetate (3 20 mL) The combined organic layers were
×
dried over anhydrous sodium sulfate and removal of the solvent under vacuum afforded a 144 mg of
◦
−1
pure product as a black solid. Yield: 100%; m.p.: 178–179 C; IR (KBr)
ν (cm ): 3375 (NH); 424 (C-I).
1
H-NMR
δ
(ppm): 13.07 (1H, s, H-1); 7.25 (1H, d, J = 8.8 Hz, H-7), 6.85 (1H, dd, J = 8.8 and 1.7 Hz, H-6);
.44 (1H, s, H-4); 5.01 (2H, br s, H-5). 13C-NMR
(ppm): 143.46; 134.79; 127.96; 119.39; 110.91; 99.83;
0.59; HRMS calculated for C H IN : 258.9606, Found: 258.9602.
6
9
δ
7
6
3
tert-Butyl 3-iodo-1H-indazole-1-carboxylate (2a). A mixture of 3-iodo-1H-indazole (0.2 g, 0.82 mmol),
di-tert-butyldicarbonate (0.2 g, 0.92 mmol) and triethylamine (1 mL) were put under ultrasonic
irradiation for 10 min. The resulted solution was neutralized using HCl 1M and then extracted
with dichloromethane (3
×
30 mL). The combined organic layers were dried with anhydrous sodium
sulfate and removal of the solvent under vacuum afforded a pure product as a pale yellow crystals.
◦
−1
ν (cm ): 1728 (C=O); 1150 (C-O); 424 (C-I). H-NMR (CDCl ) δ
3
1
Yield: 100%; m.p.: 93–95 C; IR (KBr)
ppm): 8.09 (1H, d, J = 8.5 Hz, H-7); 7.55 (1H, t, J = 7.8 Hz, H-4); 7.46 (1H, d, J = 7.9 Hz, H-6); 7.33 (1H,
t, J = 7.6 Hz, H-5); 1.71 (9H, s, CH3). 13C-NMR
(ppm): 148.35; 139.59; 130.17; 129.98; 124.21; 121.96;
14.56; 102.95; 85.48; 28.18; HRMS calculated for C H IN O : 344.0022, Found: 344.0016.
(
δ
1
12
13
2
2

Molecules 2018, 23, 2051
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tert-Butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (2b). Prepared from 3-iodo-5-nitro-1H-indazole (0.2 g,
0
.69 mmol), di-tert-butyldicarbonate (0.17 g, 0.78 mmol) and triethylamine (1 mL) to give 0.27 g
◦
−1
of a pale yellow solid. Yield: 100%; m.p.: 144–145 C; IR (KBr)
ν
(cm ): 1744 (C=O); 1528 (NO2
1
asymmetrical); 1381 and 1342 (NO symmetrical); 1258 (C-O); 617 (C-I). H-NMR
δ
(ppm): 8.49 (1H, br
(ppm): 147.11; 144.13;
41.57; 129.78; 124.83; 118.31; 115.39; 105.88; 86.23; 27.56; HRMS calculated for C H IN O : 388.9872,
2
13
s, H-4); 8.32 (1H, br s, H-7); 8.25 (1H, br s, H-6); 1.66 (9H, s, CH3). C-NMR
1
δ
12
12
3
4
Found: 388.9871.
tert-Butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (2c). Prepared from 5-bromo-3-iodo-1H-indazole
0.2 g, 0.62 mmol), di-tert-butyldicarbonate (0.15 g, 0.69 mmol) and triethylamine (1 mL) to give 0.27 g
(
◦
−1
of a pale yellow solid. Yield: 100%; m.p.: 152–153 C; IR (KBr)
4
7
ν (cm ): 1750 (C=O); 1157 (C-O);
1
24 (C-I and C-Br). H-NMR (CDCl )
δ
(ppm): 8.01 (1H, d, J = 8.8 Hz, H-7); 7.66 (1H, d, J = 9.2 Hz, H-6);
3
13
.64 (1H, s, H-4); 1.64 (9H, s, CH3). C-NMR
δ (ppm): 148.14; 138.67; 133.15; 131.89; 124.69; 117.56;
1
16.15; 101.11; 86.13; 28.23; HRMS calculated for C H BrIN O : 421.9127, Found: 421.9128.
12 12 2 2
tert-Butyl 3-iodo-5-methoxy-1H-indazole-1-carboxylate (2d). Prepared from 3-iodo-5-methoxy-1H-indazole
(
1
0.1 g, 0.365 mmol), di-tert-butyldicarbonate (0.08 g, 0.366 mmol) and triethylamine (1 mL) to give
◦
−1
19 mg of a pale yellow solid. Yield: 88%; m.p.: 130–131 C; IR (KBr)
ν
(cm ): 1740 (C=O); 1298
1
(
H C-O); 1157 (C-O); 424 (C-I). H-NMR (CDCl )
δ
(ppm): 8.01 (1H, d, J = 9.1 Hz, H-7); 7.22 (1H, dd, J
3
3
13
=
9.1 and 2.4 Hz, H-6); 6.82 (1H, d, J = 2.2 Hz, H-4); 3.93 (3H, s, OCH ); 1.74 (9H, s, CH ). C-NMR
3 3

Molecules 2018, 23, 2051
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δ
(ppm): 157.902; 148.32; 134.85; 130.95; 121.12; 115.58; 102.20; 101.71; 85.45; 55.86; 28.21; HRMS
calculated for C H IN O : 374.0127, Found: 374.0118.
13
15
2
3
3
-Vinyl-1H-indazole (3a). Method a: A mixture of 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of
vinyl boronic acid pinacol ester (0.27 mL, 1.62 mmol), tetrakis triphenylphosphine palladium (52 mg,
.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and 1,4-dioxane (7 mL), were placed
0
in a microwave glass tube and purged with nitrogen. The closed tube was placed under microwave
◦
irradiation to 120 C for 40 min. After irradiation was completed, the reaction was stopped by dilution
using 50 mL of brine. The organic layer was extracted with ethylacetate (3
organic layers were dried over anhydrous sodium sulfate. Removal of the solvent under vacuum
afforded a brown oil crude residue. The oil was purified by column chromatography on silica gel
×
45 mL) and the combined
(
hexane/ethylacetate 7:3) to yield 89 mg of white crystalline plates. Yield: 75%.
Method b Prepared from tert-butyl 3-iodo-1H-indazole-1-carboxylate (0.2 g, 0.58 mmol), 2 eq. of
vinyl boronic acid pinacol ester (0.27 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg,
.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave
:
0
method described above to obtain 50 mg of a crystalline plates: Yield: 60%.
Method c: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 1 equivalent of vinyl boronic acid
pinacol ester (0.14 mL, 0.823 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol),
an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method
described above to obtain 58 mg of a crystalline plates. Yield: 48%.
Method d: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 3 equivalents of vinyl boronic
acid pinacol ester (0.42 mL, 2.47 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol),
an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using the previously described
microwave method to obtain 70 mg of a crystalline plates. Yield: 59%.
Method e: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), palladium (II) acetate (5 mol%, 9 mg, 0.041 mmol), Xantphos
(
(
5 mol%, 24 mg, 0.041 mmol) an aqueous solution of potassium phosphate 1M (2 mL) and dioxane
7 mL) using microwave method described above to obtain 23 mg of a crystalline plates. Yield: 20%.
Method f: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), palladium (II) acetate (5 mol%, 9 mg, 0.041 mmol), an aqueous
solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above
to obtain 40 mg of a crystalline plates. Yield: 34%.
Method g: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), bis(triphenylphosphine)palladium (II) dichloride (5 mol%, 29 mg,
0.041 mmol), triphenylphosphine (5 mol%, 11 mg, 0.041 mmol), an aqueous solution of sodium
carbonate 2N (2 mL) and dioxane (7 mL) using microwave method described above to obtain 58 mg of
a crystalline plates. Yield: 49%.
Method h: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), [1,2-bis(diphenylphosphino)ethane]dichloro nickel (II) (5 mol%,
22 mg, 0.041 mmol), ethylenebis(diphenylphosphine) (5 mol%, 16 mg, 0.041 mmol), an aqueous
solution of potassium phosphate 1M (2 mL) and dioxane (7 mL) using microwave method described
above to obtain 24 mg of a crystalline plates. Yield: 20%.

Molecules 2018, 23, 2051
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Method i: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol),
an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method
◦
described above, but at a reaction temperature of 180 C, to obtain 80 mg of a crystalline plates.
Yield: 68%.
Method j: Prepared from 3-iodoindazole (0.2 g, 0.82 mmol), 2 equivalents of vinyl boronic acid
pinacol ester (0.28 mL, 1.62 mmol), tetrakistriphenylphosphine palladium (52 mg, 0.045 mmol),
an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using microwave method
described above, but with a reaction time of 60 min, to obtain 40 mg of a crystalline plates. Yield: 34%.
Method k: Prepared from 3-iodoindazole (0.1 g, 0.41 mmol), 2 eq. of vinyl boronic acid pinacol ester
(
0.1 mL, 0.81 mmol), tetrakistriphenylphosphine palladium (26 mg, 0.023 mmol), an aqueous solution
of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using method a described above, but employing
conventional heating, to obtain 26 mg of a crystalline plates: Yield: 44%.
◦
◦
−1
1
m.p.: 104–105 C (lit.: [11] 115.5–116.5 C); IR (KBr)
CDCl3) (ppm): 11.32 (1H, s, H-1); 7.95 (1H, d, J = 8.2 Hz, H-7); 7.48 (1H, d, J = 8.4 Hz, H-4); 7.40 (1H, t,
J = 7.6 Hz, H-6); 7.21 (1H, t, J = 7.5 Hz, H-5); 7.13 (1H, dd, Jtrans = 18.0 Hz and J = 11.5 Hz, H-1 );
ν (cm ): 3047 (NH); 1620 (C=C). H-NMR
(
δ
0
cis
0
0
13
6
.16 (1H, d, Jtrans = 18.0 Hz, H-3 ); 5.58 (1H, d, J = 11.4 Hz, H-2 ). C-NMR (CDCl3)
δ
(ppm): 144.18;
cis
1
41.59; 128.90; 127.03; 121.48; 121.14; 121.00; 117.18; 110.30; HRMS calculated for C H N : 144.0687,
9
8
2
Found: 144.0681.
5
2
-Nitro-3-vinyl-1H-indazole (3b). Method a: Prepared from 3-iodo-5-nitro-1H-indazole (0.2 g, 0.69 mmol),
equivalents of vinyl boronic acid pinacol ester (0.23 mL, 1.35 mmol), tetrakis- triphenylphospine
palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL),
to give 0.113 g of a pale brown solid. Yield: 87%.
Method b: Prepared from tert-butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (0.2 g, 0.514 mmol),
2
eq. of vinyl boronic acid pinacol ester (0.17 mL, 1.03 mmol), tetrakistriphenylphosphine palladium
(35 mg, 0.03 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using
microwave method described above to obtain 13 mg of a pale brown solid: Yield: 13%.
Method c: Prepared from 3-iodo-5-nitro-1H-indazole (0.18 g, 0.62 mmol), 2 equivalents of
vinyl boronic acid pinacol ester (0.21mL, 1.24 mmol), tetrakistriphenylphospine palladium (52 mg,
0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using method
a described above, but employing conventional heating, to give 24 mg of pale brown solid. Yield: 21%.
◦
−1
ν (cm ): 3179 (NH); 1620 (C=C); 1528 (NO asymmetrical); 1335 (NO
2 2
m.p.: 166–168 C; IR (KBr)
1
symmetrical). H-NMR
δ
(ppm): 13.75 (1H, s, H-1); 8.93 (1H, s, H-4); 8.20 (1H, d, J = 8.6 Hz, H-7);
0
7
J
.71 (1H, d, J = 9.2 Hz, H-6); 7.14 (1H, dd, Jtrans = 17.8 Hz and J =11.4 Hz, H-1 ); 6.19 (1H, d,
cis
0
0
13
trans = 17.8 Hz, H-3 ); 5.58 (1H, d, J = 11.4 Hz, H-2 ). C-NMR
δ
(ppm): 145.12; 142.97; 141.89; 127.65;
cis
1
21.14; 119.61; 118.21; 117.95; 111.31; HRMS calculated for C H N O : 189.0538, Found: 189.0535.
9 7 3 2

Molecules 2018, 23, 2051
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5-Bromo-3-vinyl-1H-indazole (3c). Method a: Prepared from 5-bromo-3-iodo-1H-indazole (0.2 g,
0.621 mmol), 2 equivalent of vinyl boronic acid pinacol ester (0.21 mL, 1.24 mmol), tetrakis-
triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2
mL) and dioxane (7 mL), to give 82 mg of a pale yellow solid. Yield: 60%.
Method b: Prepared from tert-butyl 5-bromo-3-iodo-1H-indazole-1-carboxylate (0.2 g, 0.47 mmol),
2
(
eq. of vinyl boronic acid pinacol ester (0.16 mL, 0.96 mmol), tetrakistriphenylphosphine palladium
28 mg, 0.024 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL) using
microwave method described above to obtain 45 mg of a pale yellow solid: Yield: 43%.
◦
−1
ν (cm ): 3112 (NH); 1689 (C=C); 424 (C-Br). H-NMR (CDCl ) δ
3
1
m.p.: 250–251 C; IR (KBr)
ppm): 11.68 (1H, s, H-1); 8.03 (1H, s, H-4); 7.44 (1H, d, J = 8.8 Hz, H-7); 7.32 (1H, d, J = 8.8 Hz, H-6);
(
0 0
.01 (1H, dd, Jtrans = 18.0 Hz and J = 11.5 Hz, H-1 ); 6.07 (1H, d, Jtrans = 18.0 Hz, H-3 ); 5.57 (1H, d,
cis
7
0
13
Jcis = 11.5 Hz, H-2 ). C-NMR (CDCl3)
δ
(ppm): 143.45;140.15; 130.21; 128.12; 123.48; 122.54; 117.83;
1
14.66; 111.77; HRMS calculated for C H BrN : 221.9793, Found: 221.9797.
9
7
2
5-Methoxy-3-vinyl-1H-indazole (3d). Method a: Prepared from 3-iodo-5-methoxy-1H-indazole (0.2 g,
0.73 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.24 mL, 1.43 mmol), tetrakis-
triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL)
and dioxane (7 mL), to give 74 mg of a pale yellow solid. Yield: 58%.
Method b: Prepared from tert-butyl 3-iodo-5-methoxy-1H-indazole-1-carboxylate (0.135 g,
0
.361 mmol), 2 eq. of vinyl boronic acid pinacol ester (0.12 mL, 0.72 mmol), tetrakistriphenylphosphine
palladium (21 mg, 0.018 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane
(7 mL) using microwave method described above to obtain 29 mg of a pale yellow solid. Yield: 46%.
Method c: Prepared from 3-iodo-5-methoxy-1H-indazole (0.2 g, 0.73 mmol), 2 equivalents of
vinyl boronic acid pinacol ester (0.24 mL, 1.43 mmol), tetrakistriphenylphosphine palladium (52 mg,
.045 mmol), an aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7.0 mL) using
0
method described above, but employing conventional heating, to obtain 96 mg of a pale yellow
solid. Yield: 75%.
◦
−1
1
m.p.: 88–89 C; IR (KBr)
1H, s, H-1); 7.44 (1H, d, J = 8.9 Hz, H-7); 7.33 (1H, s, H-4); 7.06–6.96 (2H, m, H-6 and H-1’); 6.02 (1H, d,
ν (cm ): 3155 (NH); 1635 (C=C); 1219 (C-O). H-NMR δ (ppm): 12.95
(
0
0
13
J
trans = 18.0 Hz, H-3 ); 5.41 (1H, d, J = 11.5 Hz, H-2 ); 3.82 (1H, s, OCH ). C-NMR
δ
(ppm): 154.50;
cis
3
1
1
41.71; 137.02; 129.38; 120.70; 118.05; 114.90; 111.47; 100.02; 55.50; HRMS calculated for C H N O:
74.0793, Found: 174.0788.
10
10
2

Molecules 2018, 23, 2051
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5-Fluoro-3-vinyl-1H-indazole (3e). Method a: Prepared from 5-fluoro-3-iodo-1H-indazole (0.2 g,
0.763 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis-
triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL)
and dioxane (7 mL), to give 58 mg of a pale yellow solid. Yield: 47%.
Method b: Prepared from 5-fluoro-3-iodo-1H-indazole (0.08 g, 0.305 mmol), 2 eq. of vinyl
boronic acid pinacol ester (0.075 mL, 0.61 mmol), tetrakistriphenylphosphine palladium (17 mg,
0
.015 mmol), an aqueous solution of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using
method a described above, but employing conventional heating, to obtain 50 mg of the precursor
-fluoro-3-iodo-1H-indazole: Yield of recovery: 63%.
5
◦
−1
ν (cm ): 3163 (NH); 1636 (C=C); 1118 (C-F). H-NMR (CDCl ) δ
3
1
m.p.: 104–105 C; IR (KBr)
(
7
J
ppm): 11.73 (1H, s, H-1); 7.52 (1H, dd, J = 8.9 and 1.7 Hz, H-4); 7.41 (1H, dd, J = 9.0 and 4.2 Hz, H-7);
0
.17 (1H, td, J = 8.9 and 2.0 Hz, H-6); 7.05 (1H, dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1 ); 6.05 (1H, d,
0
0
13
trans = 18.0 Hz, H-3 ); 5.56 (1H, d, J = 11.5 Hz, H-2 ). C-NMR (CDCl3)
δ
(ppm): 158.39 (d, J = 238.8
cis
Hz), 144.04 (d, J = 5.5 Hz), 138.52, 128.38, 121.01 (d, J = 10.0 Hz), 117.25, 111.49 (d, J = 9.7 Hz), 105.21
(
d, J = 24.1 Hz); HRMS calculated for C H FN : 162.0593, Found: 162.0590.
9 7 2
5-Chloro-3-vinyl-1H-indazole (3f). Prepared from 5-chloro-3-iodo-1H-indazole (0.2 g, 0.722 mmol),
2
equivalents of vinyl boronic acid pinacol ester (0.24 mL, 1.42 mmol), tetrakistriphenylphospine
palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL),
◦
−1
to give 77 mg of a yellow solid. Yield: 60%; m.p.: 131–132 C; IR (KBr)
(
ν (cm ): 3181 (NH); 1628
1
C=C); 649 (C-Cl). H-NMR δ (ppm): 13.28 (1H, s, H-1); 8.05 (1H, s, H-4); 7.56 (1H, d, J = 8.8 Hz, H-7);
.37 (1H, d, J = 8.7 Hz, H-6); 7.01 (1H, dd, Jtrans = 18.0 Hz and J = 11.5 Hz, H-1 ); 6.08 (1H, d, Jtrans
18.0 Hz, H-3 ); 5.46 (1H, d, J = 11.5 Hz, H-2 ). C-NMR
0
7
=
cis
0
0
13
δ (ppm): 142.00; 139.72; 128.57; 126.56;
cis
1
25.45, 121.23, 119.60, 116.29, 112.17; HRMS calculated for C H ClN : 178.0298, Found: 178.0296.
9 7 2
5-Methyl-3-vinyl-1H-indazole (3g). Method a: Prepared from 3-iodo-5-methyl-1H-indazole (0.2 g,
0.775 mmol), 2 equivalent of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis-

Molecules 2018, 23, 2051
16 of 19
triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL)
and dioxane (7 mL), to give 60 mg of a pale brown solid. Yield: 49%.
Method b: Prepared from 3-iodo-5-methyl-1H-indazole (0.095 g, 0.368 mmol), 2 equivalents of
vinyl boronic acid pinacol ester (0.090 mL, 0.736 mmol), tetrakistriphenylphosphine palladium (21 mg,
0.018 mmol), an aqueous solution of sodium carbonate 2N (1 mL) and dioxane (3.5 mL) using method
a described above, but employing conventional heating, to obtain 10 mg of a pale brown solid.
Yield: 17%.
◦
−1
1
m.p.: 88–89 C; IR (KBr)
ν
(cm ): 3179 (NH); 2916 (C-H); 1628 (C=C). H-NMR (CDCl )
δ
(ppm):
3
0
1
(
(
1.63 (1H, s, H-1); 7.72 (1H, s, H-4); 7.37 (1H, d, J = 8.5 Hz, H-7); 7.24–7.11 (2H, m, H-1 and H-6); 6.16
0 0
1H, d, Jtrans = 18.0 Hz, H-3 ); 5.57 (1H, d, J = 11.4 Hz, H-2 ); 2.50 (3H, s, CH ). C-NMR (CDCl3) δ
cis 3
13
ppm):143.28; 140.28; 130.84; 129.02; 128.96; 121.38; 119.96; 116.69; 110.12; 21.58; HRMS calculated for
C H N : 158.0844, Found: 158.0840.
10
10
2
5-Cyano-3-vinyl-1H-indazole (3h). Prepared from 5-cyano-3-iodo-1H-indazole (0.2 g, 0.743 mmol),
2
equivalents of vinyl boronic acid pinacol ester (0.25 mL, 1.48 mmol), tetrakistriphenylphospine
palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL) and dioxane (7 mL),
◦
−1
to give 77 mg of a white solid. Yield: 61%; m.p.: 156–157 C; IR (KBr)
ν (cm ): 3209 (NH); 2222 (CN);
1
1
612 (C=C). H-NMR
δ
(ppm): 13.59 (1H, s, H-1); 8.63 (1H, s, H-4), 7.68 (2H, s, H-7 and H-6); 7.04 (1H,
dd, Jtrans = 18.0 Hz and Jcis = 11.5 Hz, H-1 ), 6.21 (1H, d, J = 18.0 Hz, H-3 ), 5.53 (1H, d, J = 11.5 Hz,
0
0
0
13
H-2 ). C-NMR
δ (ppm): 143.56; 142.01; 128.38; 128.01; 127.43; 119.99; 119.82; 117.82; 111.98; 103.29;
HRMS calculated for C H N : 169.0640, Found: 169.0637.
10
7
3
tert-Butyl (3-vinyl-1H-indazol-5-yl)carbamate (3i). Prepared from tert-butyl (3-iodo-1-H-indazol-5-yl)
carbamate (0.2 g, 0.56 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.19 mL, 1.12 mmol),
tetrakistriphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate
◦
2
N (2 mL) and dioxane (7 mL), to give 80 mg of a White solid. Yield: 55%; m.p.: 189–190 C; IR
−
1
1
(
KBr)
ν
(cm ): 3356 (NH); 1700 (C=O); 1636 (C=C); 1165 (C-O). H-NMR
δ (ppm): 12.96 (1H, s, H-1);
9
.30 (1H, s, H-5); 8.13 (1H, s, H-4); 7.45–7.37 (2H, m, H-8 and H-7); 6.98 (1H, dd, Jtrans = 18.0 Hz and
0 0 0
= 11.4 Hz, H-1 ); 5.92 (1H, d, Jtrans = 18.0 Hz, H-3 ); 5.44 (1H, d, J = 11.4 Hz, H-2 ); 1.49 (9H, s, H-6).
cis
J
cis
3
1
C-NMR δ (ppm): 153.18; 141.83; 137.80; 133.36; 129.70; 120.33; 119.92; 114.88; 110.54; 107.98; 78.91;
2
8.22; HRMS calculated for C H N O : 259.1321, Found: 259.1330.
14 17 3 2

Molecules 2018, 23, 2051
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5-Amino-3-vinyl-1H-indazole (3j). Method a: Prepared from 5-amino-3-iodo-1H-indazole (1j, 0.2 g,
0.77 mmol), 2 equivalents of vinyl boronic acid pinacol ester (0.26 mL, 1.54 mmol), tetrakis-
triphenylphospine palladium (52 mg, 0.045 mmol), aqueous solution of sodium carbonate 2N (2 mL)
and dioxane (7 mL), to give 44 mg of a brown solid. Yield: 36%.
Method b: A solution of tert-butyl (3-vinyl-1H-indazol-5-yl) carbamate (3i, 145 mg, 0.4 mmol)
and trifluoroacetic acid (2 mL, 26.13 mmol) in CH Cl (2 mL) was stirred vigorously for 2 h at room
2
2
temperature. After stirring, the reaction was neutralized to pH = 7 using NaOH 1M and the organic
layer was extracted with ethyl acetate (3 20 mL) The combined organic layers were dried with
anhydrous sodium sulfate and removal of the solvent under vacuum afforded a 80 mg of pure product
×
◦
−1
1
as a brown solid. Yield: 100%; m.p.: 157–158 C; IR (KBr)
(ppm):12.64 (1H, s, H-1); 7.24 (1H, d, J = 8.7 Hz, H-7); 7.00 (1H, s, H-4); 6.91 (1H, dd, Jtrans = 18.0
ν (cm ): 3461 (NH); 1682 (C=O). H-NMR
δ
0
0
and Jcis = 11.5 Hz, H-1 ); 6.80 (1H, d, J = 8.8 Hz, H-6); 5.84 (1H, d, Jtrans = 18.0 Hz, H-3 ); 5.34 (1H, d,
Jcis = 11.5 Hz, H-2 ); 4.87 (2H, s, H5). C-NMR
0
13
δ
(ppm): 143.20; 140.39; 135.83; 130.33; 121.46; 118.02;
1
13.61; 110.81; 100.76; HRMS calculated for C H N : 159.0796, Found: 159.0792.
9
9
3
4
. Conclusions
We have prepared ten, nine of them novel, C-5 substituted 3-vinylindazole derivatives
through an easy, simple, fast and reproducible Suzuki cross-coupling reaction between unprotected
-iodoindazoles and pinacol vinyl boronate with yields ranging from moderate to excellent.
3
The vinylation reaction without N-protection herein presented shows tolerance concerning: (i) the
electronic properties of the C-5 substituent on the indazole nucleus, (ii) the use of conventional heating,
and (iii) the use of diverse catalytic systems. Despite such tolerance, the best conditions for this reaction
◦
were identified as: microwave irradiation, Pd(PPh ) as a catalyst, 120 C, and 40 min of reaction time.
3
4
In all reported cases the main isolated product was the C-3 vinyl derivative without detection of the
any other competing product. With this methodology in hand, vinylated indazoles may be directly
and selectively obtained without the need of N-protection.
1
Supplementary Materials: The Supplementary Materials are available online. Figure S1: H-NMR spectrum of
1
3
1
13
1
a
. Figure S2: C-NMR spectrum of 1a. Figure S3: H-NMR spectrum of 1b. Figure S4: C-NMR spectrum of 1b
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
1
13
1
Figure S5: H-NMR spectrum of 1c. Figure S6: C-NMR spectrum of 1c. Figure S7: H-NMR spectrum of 1d
Figure S8: C-NMR spectrum of 1d. Figure S9: H-NMR spectrum of 1e. Figure S10: C-NMR spectrum of 1e
Figure S11: H-NMR spectrum of 1f. Figure S12: C-NMR spectrum of 1f. Figure S13: H-NMR spectrum of 1g
Figure S14: C-NMR spectrum of 1g. Figure S15: H-NMR spectrum of 1h. Figure S16: C-NMR spectrum of 1h
Figure S17: H-NMR spectrum of 1i. Figure S18: C-NMR spectrum of 1i. Figure S19: H-NMR spectrum of 1j
Figure S20: C-NMR spectrum of 1j. Figure S21: H-NMR spectrum of 2a. Figure S22: C-NMR spectrum of 2a
Figure S23: H-NMR spectrum of 2b. Figure S24: C-NMR spectrum of 2b. Figure S25: H-NMR spectrum of 2c
Figure S26: C-NMR spectrum of 2c. Figure S27: H-NMR spectrum of 2d. Figure S28: C-NMR spectrum of 2d
Figure S29: H-NMR spectrum of 3a. Figure S30: C-NMR spectrum of 3a. Figure S31: H-NMR spectrum of 3b
Figure S32: C-NMR spectrum of 3b. Figure S33: H-NMR spectrum of 3c. Figure S34: C-NMR spectrum of 3c
Figure S35: H-NMR spectrum of 3d. Figure S36: C-NMR spectrum of 3d. Figure S37: H-NMR spectrum of 3e
Figure S38: C-NMR spectrum of 3e. Figure S39: H-NMR spectrum of 3f. Figure S40: C-NMR spectrum of 3f
Figure S41: H-NMR spectrum of 3g. Figure S42: C-NMR spectrum of 3g. Figure S43: H-NMR spectrum of 3h
Figure S44: C-NMR spectrum of 3h. Figure S45: H-NMR spectrum of 3i. Figure S46: C-NMR spectrum of 3i
Figure S47: H-NMR spectrum of 3j. Figure S48: C-NMR spectrum of 3j.
1
3
1
13
1
13
1
1
3
1
13
1
13
1
1
3
1
13
1
13
1
1
3
1
13
1
13
1
1
3
1
13
1
13
1
1
3
1
13
1
13
1
1
3
1
13
1
13

Molecules 2018, 23, 2051
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Author Contributions: G.R.-G. formulated the research idea, designed the synthetic route of compounds,
analyzed the data and wrote the manuscript; Compounds were synthesized and purified by G.V. and B.D.;
C.A.T. contributed with organic reagents and analytical tools, and participated in manuscript preparation.
Funding: This research was funded by DIPOG of the Chemistry Faculty-Pontificia Universidad Católica de Chile
grant number 3913-189-81 and 3913-529-81.
Acknowledgments: We also acknowledge the invaluable assistance of R. Tapia and R. Rojas by facilitating the
microwave equipment.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
2
3
4
5
.
.
.
.
.
Schmidt, A.; Beutler, A.; Snovvdovych, B. Recent advances in the chemistry of indazoles. Eur. J. Org. Chem.
008, 2008, 4073–4095. [CrossRef]
Attaurrahman; Malik, S.; He, C.H.; Clardy, J. Isolation and structure determination of nigellicine, a novel
alkaloid from the seeds of nigella-sativa. Tetrahedron Lett. 1985, 26, 2759–2762. [CrossRef]
Liu, Y.M.; Yang, J.S.; Liu, Q.H. A new alkaloid and its artificial derivative with an indazole ring from nigella
glandulifera. Chem. Pharm. Bull. 2004, 52, 454–455. [CrossRef] [PubMed]
Attaurrahman; Malik, S.; Hasan, S.S.; Choudhary, M.I.; Ni, C.Z.; Clardy, J. Nigellidine—A new indazole
alkaloid from the seeds of nigella-sativa. Tetrahedron Lett. 1995, 36, 1993–1996. [CrossRef]
Vera, G.; Lagos, C.F.; Almendras, S.; Hebel, D.; Flores, F.; Valle-Corvalán, G.; Pessoa-Mahana, C.;
2
Mella-Raipán, J.; Montecinos, R.; Recabarren-Gajardo, G. Extended N-arylsulfonylindoles as 5-HT receptor
6
antagonists: Design, synthesis & biological evaluation. Molecules 2016, 21, 1070. [CrossRef]
6
.
Mella, J.; Villegas, F.; Morales-Verdejo, C.; Lagos, C.F.; Recabarren-Gajardo, G. Structure-activity relationships
studies on weakly basic n-arylsulfonylindoles with an antagonistic profile in the 5-HT receptor. J. Mol. Struct.
6
2
017, 1139, 362–370. [CrossRef]
Diethelm, B.; Almendras, S.; Recabarren-Gajardo, G. 1-[1-(4-chlorobenzenesulfonyl)-1H-indole-3-yl]-3-
4-(pyridin-2-yl) piperazin-1-yl] propan-1-one. Molbank 2018, 2018, M991. [CrossRef]
7
8
9
1
1
1
1
1
.
.
.
[
Igeta, H.; Arai, H.; Hasegawa, H.; Tsuchiya, T. Studies on pyridazines. 24. Reaction of pyridazine N-oxides
and pyridazinium ylides with benzyne. Chem. Pharm. Bull. 1975, 23, 2791–2797. [CrossRef]
Hasegawa, H.; Arai, H.; Igeta, H. Studies on pyridazines. 26. Reaction of substituted N-acetyliminopy
ridazinium ylides with benzyne. Chem. Pharm. Bull. 1977, 25, 192–195. [CrossRef]
0. Tsuchiya, T.; Kurita, J. Studies on diazepines 4. 3H-1,2-benzodiazepines. Chem. Pharm. Bull. 1978, 26,
890–1895. [CrossRef]
1. Dellerba, C.; Novi, M.; Petrillo, G.; Tavani, C. A novel-approach to 1H-indazoles via arylazosulfides.
Tetrahedron 1994, 50, 3529–3536. [CrossRef]
1
2. Denmark, S.E.; Butler, C.R. Palladium-(and nickel-) catalyzed vinylation of aryl halides. Chem. Commun.
2
009, 1, 20–33. [CrossRef] [PubMed]
3. Shi, S.C.; Meng, G.R.; Szostak, M. Synthesis of biaryls through nickel-catalyzed Suzuki-Miyaura coupling of
amides by carbon-nitrogen bond cleavage. Angew. Chem. Int. Edit. 2016, 55, 6959–6963. [CrossRef] [PubMed]
4. Meng, G.R.; Szostak, M. General olefin synthesis by the palladium-catalyzed heck reaction of amides:
Sterically controlled chemoselective N-C activation. Angew. Chem. Int. Edit. 2015, 54, 14518–14522.
[CrossRef] [PubMed]
1
5. Dufert, M.A.; Billingsley, K.L.; Buchwald, S.L. Suzuki-miyaura cross-coupling of unprotected, nitrogen-rich
heterocycles: Substrate scope and mechanistic investigation. J. Am. Chem. Soc. 2013, 135, 12877–12885.
[CrossRef] [PubMed]
1
1
6. Collot, V.; Dallemagne, P.; Bovy, P.R.; Rault, S. Suzuki-type cross-coupling reaction of 3-iodoindazoles with
aryl boronic acids: A general and flexible route to 3-arylindazoles. Tetrahedron 1999, 55, 6917–6922. [CrossRef]
7. Arnautu, A.; Collot, V.; Ros, J.C.; Alayrac, C.; Witulski, B.; Rault, S. Sonogashira cross-coupling reaction of
3-iodoindazoles with various terminal alkynes: A mild and flexible strategy to design 2-aza tryptamines.
Tetrahedron Lett. 2002, 43, 2695–2697. [CrossRef]
1
8. Collot, V.; Varlet, D.; Rault, S. Heck cross-coupling reaction of 3-iodoindazoles with methyl acrylate: A mild
and flexible strategy to design 2-azatryptamines. Tetrahedron Lett. 2000, 41, 4363–4366. [CrossRef]

Molecules 2018, 23, 2051
19 of 19
1
9. Crestey, F.; Lohou, E.; Stiebing, S.; Collot, V.; Rault, S. Protected indazole boronic acid pinacolyl esters: Facile
syntheses and studies of reactivities in Suzuki-Miyaura cross-coupling and hydroxydeboronation reactions.
Synlett 2009, 2009, 615–619. [CrossRef]
2
0. Lam, B.V.; Berhault, Y.; Stiebing, S.; Fossey, C.; Cailly, T.; Collot, V.; Fabis, F. Iodoindazoles with selective
magnesiation at position 3: A route to highly functionalized indazoles. Chem.-Eur. J. 2016, 22, 4440–4446.
[CrossRef] [PubMed]
2
2
1. Collot, V.; Bovy, P.R.; Rault, S. First combined selective N- and C-arylations with boronic acids: Application
to the synthesis of 1,3-diarylindazoles. Tetrahedron Lett. 2000, 41, 9053–9057. [CrossRef]
2. Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Synthesis of new dehydro 2-azatryptophans and derivatives via
heck cross-coupling reactions of 3-iodoindazoles with methyl 2-(acetylamino) acrylate. Synth.-Stuttg. 2006
006, 3506–3514. [CrossRef]
,
2
2
2
3. Retich, C.; Brase, S. Asymmetric organocatalytic synthesis of bisindoles—Scope and derivatizations. Eur. J.
Org. Chem. 2018, 2018, 60–77. [CrossRef]
4. Sampson, P.B.; Liu, Y.; Patel, N.K.; Feher, M.; Forrest, B.; Li, S.W.; Edwards, L.; Laufer, R.; Lang, Y.H.; Ban, F.Q.;
et al. The discovery of polo-like kinase 4 inhibitors: Design and optimization of spiro [cyclopropane-1,3’
[
3H]indol]-2’ (1’ h)-ones as orally bioavailable antitumor agents. J. Med. Chem. 2015, 58, 130–146. [CrossRef]
[PubMed]
2
2
2
2
2
5. Carling, W.; Martos, J.; Kangasmetsa, J.; Wang, J.; Woodward, D. Compounds Acting at Multiple
Prostaglandin Receptors Giving a General Anti-Inflammatory Response. U.S. Patent 8,492,424, 23 July 2013.
6. Li, L.; Feng, J.; Long, Y.O.; Liu, Y.; Wu, T.; Ren, P.; Liu, Y. 2-Substituted Quinazoline Compounds Comprising
a Susbstituted Heterocyclic Group and Methods of Use Thereof. U.S. Patent 20170197945A1, 13 July 2017.
7. Miyaura, N.; Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev.
1
995, 95, 2457–2483. [CrossRef]
8. Bocchi, V.; Palla, G. High-yield selective bromination and iodination of indoles in N,N-dimethylformamide.
Synth.-Stuttg. 1982, 1982, 1096–1097. [CrossRef]
9. Salovich, J.M.; Lindsley, C.W.; Hopkins, C.R. Synthesis of 1,3-diarylsubstituted indazoles utilizing a Suzuki
cross-coupling/deprotection/N-arylation sequence. Tetrahedron Lett. 2010, 51, 3796–3799. [CrossRef]
[PubMed]
3
0. Amira, A.; K’tir, H.; Berredjem, M.; Aouf, N.E. A simple, rapid, and efficient N-boc protection of amines
under ultrasound irradiation and catalyst-free conditions. Monatsh. Chem. 2014, 145, 509–515. [CrossRef]
1. Swahn, B.M.; Huerta, F.; Kallin, E.; Malmstrom, J.; Weigelt, T.; Viklund, J.; Womack, P.; Xue, Y.F.; Ohberg, L.
Design and synthesis of 6-anilinoindazoles as selective inhibitors of c-jun N-terminal kinase-3. Bioorg. Med.
Chem. Lett. 2005, 15, 5095–5099. [CrossRef] [PubMed]
3
3
3
3
3
3
3
2. El Kazzouli, S.; Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. A mild and selective method
for the N-boc deprotection by sodium carbonate. Tetrahedron Lett. 2006, 47, 8575–8577. [CrossRef]
3. Mohapatra, D.K.; Durugkar, K.A. Efficient and selective cleavage of the tert-butoxycarbonyl (boc) group
under basic condition. Arkivoc 2005, 14, 20–28.
4. Smith, G.B.; Dezeny, G.C.; Hughes, D.L.; King, A.O.; Verhoeven, T.R. Mechanistic studies of the Suzuki
cross-coupling reaction. J. Org. Chem. 1994, 59, 8151–8156. [CrossRef]
5. Albers, P.; Pietsch, J.; Parker, S.F. Poisoning and deactivation of palladium catalysts. J. Mol. Catal. A-Chem.
2
001, 173, 275–286. [CrossRef]
6. Tang, R.J.; Milcent, T.; Crousse, B. Regioselective halogenation of arenes and heterocycles in
hexafluoroisopropanol. J. Org. Chem. 2018, 83, 930–938. [CrossRef] [PubMed]
7. Buchstaller, H.P.; Wilkinson, K.; Burek, K.; Nisar, Y. Synthesis of 3-indazolecarboxylic esters and amides via
pd-catalyzed carbonylation of 3-iodoindazoles. Synth.-Stuttg. 2011, 2011, 3089–3098. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).