Synthesis of 2-alkenyl-2H-indazoles from 2-(2-carbonylmethyl)-2H-indazoles

Article abstract of DOI:10.3390/molecules21020238

A procedure has been developed for synthesis of 2-alkenyl-2H-indazoles starting from 2-(2-carbonylmethyl)-2H-indazoles, which are prepared by gallium/aluminium- and aluminium-mediated, direct, regioselective alkylation of indazoles with α-bromocarbonyl compounds. The structure of 3-(2H-indazol-2-yl)-2H-chromen-2-one was proven by X-ray crystallography. The styrene- and coumarin-2H-indazoles produced by using the newmethod were found to have interesting fluorescence properties.

Full text of DOI:10.3390/molecules21020238

molecules
Article
Synthesis of 2-Alkenyl-2H-indazoles from
2-(2-Carbonylmethyl)-2H-indazoles
Mei-Huey Lin *, Kung-Yu Liang, Chang-Hsien Tsai, Yu-Chun Chen, Hung-Chang Hsiao,
Yi-Syuan Li, Chung-Hao Chen and Hau-Chun Wu
Department of Chemistry, National Changhua University of Education, Changhua 50007, Taiwan;
k7731379@livemail.tw (K.-Y.L.); blueangela39@gmail.com (C.-H.T.); stu01250008@gmail.com (Y.-C.C.);
j2261102002@hotmail.com (H.-C.H.); jere035330@hotmail.com (Y.-S.L.);
zx25610548zx25610548@yahoo.com.tw (C.-H.C.); smile3156@gmail.com (H.-C.W.)
* Correspondence: mhlin@cc.ncue.edu.tw; Tel.: +886-4723-2105 (ext. 3543)
Academic Editor: Derek J. McPhee
Received: 27 January 2016 ; Accepted: 15 February 2016 ; Published: 19 February 2016
Abstract: A procedure has been developed for synthesis of 2-alkenyl-2H-indazoles starting from
2-(2-carbonylmethyl)-2H-indazoles, which are prepared by gallium/aluminium- and aluminium-mediated,
direct, regioselective alkylation of indazoles with
α-bromocarbonyl compounds. The structure of
3-(2H-indazol-2-yl)-2H-chromen-2-one was proven by X-ray crystallography. The styrene- and coumarin-
2H-indazoles produced by using the new method were found to have interesting fluorescence properties.
Keywords: indazoles; coumarin; regioselective alkylation; styrene; fluorescence
1. Introduction
Owing to their unique binding affinities to key enzymes and proteins involved metabolic
processes, nitrogen-containing heterocyclic compounds have drawn intensive attention in the area
of drug discovery [1–4]. Among these substances, indazoles display a broad range of interesting
biological properties that have been used advantageously in the design of new drugs. Consequently,
methods for the synthesis of indazole derivatives are in high demand. Special interest has been given
to the development of procedures for regioselective introduction of functionality on the two nitrogen
atoms of indazoles [5–8]. This task is simplified somewhat by the fact that the reactivities of the
two nitrogen atoms in indazoles are dramatically different. In general, N-1 substituted indazoles
are thermodynamically favored products of these processes. However, finding new methods for
regioselective synthesis of 2H-indazoles remains a significant challenge in the field of nitrogen
heterocycles. While reasonable progress has been made in devising techniques to prepare 2-alkyl- and
2-aryl-2H-indazoles [9–16], fewer advances have been made in developing methods for the preparation
of 2-alkenyl-2H-indazoles. Thus, a need exists to design operationally simple methods to access the
privileged 2-alkenyl-2H-indazole pharmacophore.
Of the methods described thus far, copper-catalyzed vinylation reactions appear to hold
the most promise as a new 2-alkenyl-2H-indazole synthesis approach. Unfortunately, our initial
studies of this process demonstrated that reaction of indazole (
1) with β-bromostyrene is very
inefficient, producing in only 9% yield (path (a) in Scheme 1) [17]. An alternative strategy that
2
begins with conventional cyclization reactions of 2-nitrobenzaldehyde and 2-azidobenzaldehyde
are not applicable to construction of 2-alkenyl-2H-indazoles owing to the substrate limitations
associated with N-alkenyl primary amine, (path (b), Scheme 1) [
approach to 2-alkenyl-2H-indazole targets begins with alkylation of indazole with
compounds (path (c), Scheme 1). The major difficulty associated with this process is that N-1
9,10]. A potentially more productive
α
-bromocarbonyl
Molecules 2016, 21, 238; doi:10.3390/molecules21020238
www.mdpi.com/journal/molecules

Molecules 2016, 21, 238
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thermodynamic alkylation products predominate in reactions run under most basic conditions [18].
Fortunately, the results of recent studies in this area show that 2H-indazoles are generated through
gallium/aluminium- and aluminium-mediated direct regioselective alkylation reactions of an indazole
with α-bromocarbonyl compounds [19]. Below, we describe observations made in an investigation in
which this new alkylation procedure was applied to the synthesis of a variety of 2-alkenyl-2H-indazoles.
CuI
3
N
Ph
2
N
1
N
Cs2CO3
Ph
+
2
N
+
(a)
(b)
1
Br
N
N
[17]
H
1
N-1, 80%
2, N-2, 9%
Ph
R
R
O
+
H2N
N
X
N
O
[9,10]
O
2
X = NO2 or N3
O
OMe
2
N
H2N
+
OMe
NO2
N
[10]
R
N
(c)
N
3
O
2
N
O
1
Ga/Al
or Al
N
Me
Ar
R
2
N
H
N
+
N
[19]
N
O
3
Br
O
R
O
N
N
Scheme 1. Strategies for the synthesis of 2-alkenyl-2H-indazoles.
2. Results and Discussion
One approach to the synthesis of 2-alkenyl-2H-indazoles
2 from ketones 3a–j, produced by
regioselective alkylation reactions of indazoles with
a reduction-elimination strategy. Specifically, treatment of 3a
α
-bromocarbonyl compounds, is based on
with sodium borohydride generates
–
j
alcohols, which are then transformed to either chloride or mesylate derivatives to facilitate elimination
to form alkenes. The results in which this sequence is applied to selected indazole-ketones are displayed
in Table 1. Conversion of the intermediate alcohols to the corresponding chlorides was accomplished
by using phosphoryl chloride. Under these conditions, minor amounts of elimination products were
formed along with the chloride intermediates. Treatment of these mixtures with DBU led to clean
formation of the target 2-alkenyl-2H-indazoles 2. However, elimination product 2e was formed directly
when the corresponding alcohol was treated with phosphoryl chloride. A decomposition process
occurred in the chlorination reaction with alcohol intermediate indazole bearing nitro substituent
(Table 1, entry 9). The alcohols to alkene transformations can also be accomplished by first forming the
mesylate derivatives followed by DBU promoted elimination. Overall, the route B predominated in
terms of functional group compatibility and yield. The elimination reactions were observed to generate
either E-regioisomers exclusively (Table 1, entries 1, 3–6, 8 and 10) or mixtures of E and Z-isomers
(Table 1, entries 2, 7 and 9). The E double bond geometry of 2a was unambiguously assigned by using
X-ray crystallography (Figure 1) [20]. The detailed X-ray crystallographic data for 2a are provided in
the Supplementary Materials.

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Table 1. Synthesis of 2-alkenyl-2H-indazoles 2 from ketones 3.
Entry
Product
2; Yield(%) a from Route A
2; Yield (%) a from Route B
1
65
90
2
52 (10:1) c
98 (8:1) c
3
4
5
48
63
75
79
87
81 b
6
7
8
63
72 (10:1) c
24
85
84 (6.5:1) c
70
9
decomposed
75
80 (20:1) c
80
10
a: Three-step overall yield. b: Two-step overall yield. c: E/Z ratio was determined by using 1H-NMR.
Figure 1. ORTEP plot of X-ray crystallographic data for 2a.
The functionality in the side chain of indazole-ketones
3 is amenable to conversion to
α
-branched -unsaturated ketones, which have potential as anticancer drugs [21]. As expected, the
α,β

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α
-(2H-indazol-2-yl)-enones 4a
–
f
can be readily prepared by aldol condensation reactions between
ketone 3g and benzaldehyde derivatives (Scheme 2). Moreover, the indene-linked 2H-indazole
5
can be prepared through reduction of the ketone moiety in 4a followed by polyphosphoric acid
(PPA)-promoted intramolecular electrophilic aromatic substitution (Scheme 3, Equation (1)) [22].
Scheme 2. Aldol condensation reactions of 3g with aldehydes.
Scheme 3. Formation of the indene-linked 2H-indazole.
Recently, 2-aryl-2H-indazoles have been identified as a new class of fluorescent compounds [15].
In addition, coumarin derivatives have been widely studied and utilized as fluorescent probes in
living cells [23
(2)) possessing a planar, rigid
In studies pursuing this proposal we observed that coumarin-indazole
condensation reaction of the indazole-ester 3k with salicylaldehyde (Equation (2)).
–
26]. We envisioned that coumarin-substituted 2H-indazoles
-conjugated system might display interesting luminescent behavior.
can be generated by
6 (Scheme 4, Equation
π
6
Scheme 4. Synthesis of the coumarin-substituted 2H-indazoles.
It should be noted that the synthesis of coumarin-indazole
through a route that begins with reaction of 3-aminocoumarin with o-nitrobenzaldehyde (Scheme 4,
Equation (3)) [27]. In addition, coumarin derived N1-indazole was synthesized previously by palladium
6 was carried out previously
7

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catalyzed coupling of 3-bromo-coumarin with indazole (Scheme 4, Equation (4)) [28]. Interestingly, the
NMR spectroscopic data of our synthetic are totally different from those of the substance prepared
earlier as well as those of . To gain support for the structural assignment we have made to , X-ray
6
7
6
crystallographic analysis was performed (Figure 2) [29]. The conflicting observations uncovered
in this effort lend credence to our earlier statement in the Introduction section that “conventional
cyclization reactions to prepare members of the 2H-indazole family from 2-nitrobenzaldehyde and
2-azidobenzaldehyde are not applicable to the construction of 2-alkenyl-2H-indazoles”. Finally, we
determined the fluorescence properties of the new compounds prepared in this effort (Table 2). As can be
seen in Table 2, the planar, rigid
π-conjugated system 2H-indazoles 2a and
5
display strong fluorescence
and 6 possesses a large red stark shift.
Figure 2. ORTEP plot of the crystallographic data for 6.
Table 2. Fluorescence Properties a.
ε(M´1cm´1
)
Compd.
λabs (nm)
λ
em
(nm)
φ
2a
5
6
322
336
345
398, 415
402
517
35,400
29,949
24,012
0.65
0.71
0.01
a
Fluorescence measurements made on 10´5 M THF solutions of the substances.
3. Experimental Section
3.1. General Information
All commercially available chemicals were used without further purification. TLC analyses
were run on glass TLC plates (Silica gel 60 F254) and were visualized using UV and a solution of
phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was
1
performed using silica gel (70–230 mesh). H-NMR spectra were recorded on a 300 MHz spectrometer
(Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13C-NMR spectra were recorded at
75 MHz with complete proton decoupling spectrometer. Chemical shifts are reported relative to
CHCl3 [δH 7.24, δC (central line) 77.0]. Mass spectra were recorded under electron impact ionization
(EI) conditions, and high-resolution mass spectra were recorded by electron impact ionization with
magnetic sector.
3.2. Synthesis
3.2.1. General Procedure for the Synthesis of 2-Alkenyl-2H-indazoles 2 (Route A)
˝
To a cold solution (ice bath 0–5 C) of ketone
3 (0.5 mmol) in MeOH/CH2Cl2 (1/1, 10 mL) NaBH4
(0.5 mmol, 1.0 equiv.) was added slowly. The resulting mixture was warmed to ambient temperature
(ice bath removal). Reaction was monitored by TLC until no starting material was observed and
normally the reaction was stirred at ambient temperature for 2 h. The reaction was then cooled
˝
to 0–5 C and quenched with 2 N HCl (10 mL). CH2Cl2 (10 mL) was added and the mixture was

Molecules 2016, 21, 238
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transferred to a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL
ˆ
2).
The combined organic layers were dried over Na2SO4, filtered, and concentrated on a rotary evaporator.
The residue was dissolved in POCl3 (0.5 mL) and the mixture was heated to reflux (110 ˝C) under
N2 overnight. The resulting mixture was cooled to 0–5 ˝C and sat. NaHCO3 was added slowly until
no bubble was observed. EtOAc (10 mL) was added and the mixture was transferred to a separatory
funnel. The aqueous layer was back extracted with EtOAc (10 mL
ˆ
2). The combined organic layers
3 cm) and concentrated in
were dried over Na2SO4, filtered through a silica-gel pad (d l, 3 cm
ˆ
ˆ
a rotary evaporator. The residue was dissolved in DBU (1 mL) and the mixture was heated to 90 ˝C
under N2 overnight. The mixture was cooled to ambient temperature. EtOAc (10 mL) and H2O (10 mL)
were added and the mixture was transferred to a separatory funnel. The aqueous layer was back
extracted with EtOAc (10 mL
and concentrated in a rotary evaporator. The residue was purified by silica gel chromatography using
ˆ
2). The combined organic layers were dried over Na2SO4, filtered,
EtOAc/hexanes (1/9) as eluent to give the product 2.
3.2.2. General Procedure for the Synthesis of 2-Alkenyl-2H-indazoles 2 (Route B)
˝
To a cold solution (ice bath 0–5 C) of ketone
3 (0.5 mmol) in MeOH/CH2Cl2 (1/1, 10 mL)
was added NaBH4 (0.5 mmol, 1.0 equiv.) slowly. The resulting mixture was warmed to ambient
temperature (ice bath removal). Reaction was monitored by TLC until no starting material was
observed and normally the reaction was stirred at ambient temperature for 2 h. The reaction was then
˝
cooled to 0–5 C and quenched with 2 N HCl (10 mL). CH2Cl2 (10 mL) was added and the mixture was
transferred to a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL 2).
ˆ
The combined organic layers were dried over Na2SO4, filtered, and concentrated in a rotary evaporator.
The residue was dissolved in CH2Cl2 (5 mL) and the mixture was cooled 0–5 ˝C (ice bath) under N2.
Et3N (0.25 mL, 1.8 mmol) was added followed by MsCl (0.07 mL, 0.9 mmol). The resulting mixture
was warmed to ambient temperature (ice bath removal). Reaction was monitored by TLC until no
starting material was observed and normally the reaction was stirred at ambient temperature for 2 h.
˝
The resulting mixture was cooled to 0–5 C and sat. NaHCO3 (5 mL) was added slowly. The mixture
was transferred to a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL 2).
ˆ
The combined organic layers were dried over Na2SO4, filtered and concentrated in a rotary evaporator.
˝
The residue was dissolved in DBU (0.6 mL) and the mixture was heated to 90 C under N2 overnight.
The mixture was cooled to ambient temperature. EtOAc (10 mL) and H2O (10 mL) were added and the
mixture was transferred to a separatory funnel. The aqueous layer was back extracted with EtOAc
(10 mL
ˆ
2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in
a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc/hexanes
(1/9) as eluent to give the product 2.
(E)-2-Styryl-2H-indazole (2a): Following the general procedure, the title compound was obtained
(Route A: 72 mg, 65%, Route B: 99 mg, 90%). A yellow solid, mp 131–133 ˝C; TLC (EtOAc/hexanes
1
(1:4)) Rf = 0.56; H-NMR (CDCl3)
δ
7.07 (t, J = 7.8 Hz, 1 H), 7.25–7.37 (m, 4H), 7.43–7.48 (m, 3H),
117.2 (CH), 120.1 (CH),
2), 127.0 (CH), 128.0 (CH), 128.7
7.58–7.65 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H); 13C-NMR (CDCl3)
δ
120.9 (CH), 121.8 (CH), 122.0 (C), 122.2 (CH), 126.2 (CH), 126.4 (CH
ˆ
(CH
ˆ
2), 134.1 (C), 149.4 (C); IR (neat) 3131, 2950, 1645 cm´1; EI-MS m/z (rel intensity) 220 ([M]+, 56),
219 (100), 129 (97), 77 (22); HRMS [M]+ calcd for C15H12N2: 220.1000, found 220.1004.
2-(4-Bromostyryl)-2H-indazole (2b): Following the general procedure, the title compound was obtained
(Route A: 78 mg, 52%, Route B: 147 mg, 98%). A yellow solid, mp 154–156 ˝C; TLC (EtOAc/hexanes
(1:4)) Rf = 0.50; 1H-NMR (CDCl3)
δ
7.08 (dd, J = 7.8, 6.6 Hz, 1H), 7.28–7.41 (m, 3H), 7.46–7.51 (m, 3H),
7.62–7.75 (m, 3H), 8.10 (s, 0.8H), 8.13 (s, 0.1H); 13C-NMR (CDCl3)
δ
117.3, 119.8, 120.1, 121.1, 121.9,
122.0, 122.1, 122.4, 122.5, 126.5, 126.7, 127.1, 127.3, 127.9, 128.1, 128.8, 131.9, 133.2, 134.2, 149.6; IR (neat)
3062, 2950, 1653 cm´1; EI-MS m/z (rel intensity) 300 ([M + 2]+, 71), 299 (100), 298 ([M]+, 73), 118 (97);
HRMS [M]+ calcd for C15H11BrN2: 298.0106, found 298.0101.

Molecules 2016, 21, 238
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(E)-2-(4-Chlorostyryl)-2H-indazole (2c): Following the general procedure, the title compound was
˝
obtained (Route A: 61 mg, 48%, Route B: 96 mg, 75%). A yellow solid, mp 150–151 C; TLC
1
(EtOAc/hexanes (1:4)) Rf = 0.50; H-NMR (CDCl3)
δ
7.06 (dd, J = 8.1, 6.9 Hz, 1H), 7.26–7.40 (m,
117.3 (CH), 119.7 (CH),
2), 128.9 (CH 2),
6H), 7.55–7.59 (m, 2H), 7.71 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H); 13C-NMR (CDCl3)
δ
120.1 (CH), 122.0 (CH), 122.1 (C), 122.4 (CH), 126.6 (CH), 127.3 (CH), 127.5 (CH
ˆ
ˆ
132.7 (C), 133.7 (C), 149.6 (C); IR (neat) 3031, 2950, 1393 cm´1; EI-MS m/z (rel intensity) 256 ([M + 2]+,
25), 254 ([M]+, 81), 253 (100), 118 (80); HRMS [M]+ calcd for C15H11ClN2: 254.0611, found 254.0617.
(E)-2-(4-Methylstyryl)-2H-indazole (2d): Following the general procedure, the title compound was
obtained (Route A: 74 mg, 63%, Route B: 93 mg, 79%). A white solid, mp 149–151 ˝C; TLC
1
(EtOAc/hexanes (1:4)) Rf = 0.60; H-NMR (CDCl3)
δ 2.33 (s, 3H), 7.06 (t, J = 7.8 Hz, 1H), 7.15 (d,
J = 7.8 Hz, 2H), 7.23–7.45 (m, 4H), 7.58–7.63 (m, 2H), 7.74 (d, J = 8.7 Hz, 1H), 7.98 (s, 1H); 13C-NMR
(CDCl3) 21.1 (CH3), 117.2 (CH), 120.1 (CH), 121.0 (CH), 121.6 (CH), 122.1 (C), 122.2 (CH), 125.6
(CH), 126.3 (CH 2), 131.3 (C), 138.1 (C), 149.4 (C); IR (neat) 3121, 1602,
δ
ˆ
2), 126.9 (CH), 129.4 (CH
ˆ
1367 cm´1; EI-MS m/z (rel intensity) 234 ([M]+, 71), 233 (100), 218 (14), 118 (27); HRMS [M]+ calcd for
C16H14N2: 234.1157, found 234.1159.
(E)-2-(4-Methoxystyryl)-2H-indazole (2e): Following the general procedure, the title compound was
˝
obtained (Route A: 101 mg, 81%, Route B: 109 mg, 87%). A white solid, mp 137–139 C; TLC
(EtOAc/hexanes (1:4)) Rf = 0.45; H-NMR (CDCl3)
1
δ 3.78 (s, 3H), 6.88 (d, J = 8.7 Hz, 2H), 7.06 (t,
J = 8.7 Hz, 1H), 7.26 (t, J = 8.7 Hz, 1H), 7.31–7.43 (m, 3H), 7.55 (d, J = 14.7 Hz, 1H), 7.60 (d, J = 8.7 Hz
,
1H), 7.72 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H); 13C-NMR (CDCl3)
δ
55.1 (CH3), 114.2 (CH 2), 117.2 (CH),
ˆ
120.0 (CH), 120.8 (CH), 121.5 (CH), 122.1 (C), 122.2 (CH), 124.6 (CH), 126.7 (C), 126.9 (CH), 127.8
CH ˆ 2), 149.3 (C), 159.6 (C); IR (neat) 3120, 1609, 1517 cm´1; EI-MS m/z (rel intensity) 250 ([M]+, 100),
(
249 (58), 132 (93), 118 (19); HRMS [M]+ calcd for C16H14N2O: 250.1106, found 250.1104.
(E)-2-(2-(Naphthalen-2-yl)vinyl)-2H-indazole (2f): Following the general procedure, the title compound
was obtained (Route A: 85 mg, 63%, Route B: 115 mg, 85%). A yellow solid, mp 195–196 ˝C; TLC
(EtOAc/hexanes (1:4)) Rf = 0.52; 1H-NMR (DMSO-d6)
δ
7.08 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H),
7.49–7.55 (m, 2H), 7.67–7.77 (m, 3H), 7.88–7.96 (m, 4H), 8.08 (s, 1H), 8.41 (d, J = 14.1 Hz, 1 H), 8.68 (s,
1H); 13C-NMR (DMSO-d6)
117.0 (CH), 120.3 (CH), 120.9 (CH), 121.9 (CH 2), 123.4 (CH), 123.7 (CH),
δ
ˆ
126.2 (CH), 126.6 (CH), 126.8 (CH), 127.0 (CH), 127.6 (CH), 127.7 (C), 127.8 (CH), 128.4 (CH), 132.2 (C),
132.6 (C), 133.2 (C) 148.9 (C); IR (neat) 3062, 2950, 1626 cm´1; EI-MS m/z (rel intensity) 270 ([M]+, 93),
269 (100), 152 (90), 118 (11); HRMS [M]+ calcd for C19H14N2: 270.1157, found 270.1150.
2-(Prop-1-en-1-yl)-2H-indazole (2g): Following the general procedure, the title compound was obtained
(Route A: 57 mg, 72%, Route B: 66 mg, 84%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.58;
1H-NMR (CDCl3)
δ
1.85 (dd, J = 6.9, 1.8 Hz, 2.60H), 2.02 (dd, J = 6.9, 1.5 Hz, 0.40H), 5.60–5.62 (m,
0.13H), 6.39–6.99 (m, 0.87H), 7.00–7.07 (m, 2H), 7.21–7.28 (m, 1H), 7.55–7.72 (m, 2H), 7.89 (s, 0.87H),
7.96 (s, 0.13H), 8.65 (s, 0.87H), 8.70 (s, 0.13H); 13C-NMR (CDCl3)
δ 12.9, 14.8, 117.3, 117.7, 120.0, 120.5,
121.8, 121.9, 126.5, 128.3, 149.0; IR (neat) 3113, 2933, 1624 cm´1; EI-MS m/z (rel intensity) 158 ([M]+,
46), 157 (28), 131 (100), 118 (12); HRMS [M]+ calcd for C10H10N2: 158.0844, found 158.0843.
(E)-2-(3,3-Dimethylbut-1-en-1-yl)-2H-indazole (2h): Following the general procedure, the title compound
was obtained (Route A: 24 mg, 24%, Route B: 70 mg, 70%). An oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.70
1H-NMR (CDCl3)
1.18 (s, 9H), 6.59 (d, J = 14.4 Hz, 1H), 7.01 (d, J = 14.4 Hz, 1H), 7.05 (d, J = 8.7 Hz,
1H), 7.27 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 8.00 (s, 1H); 13C-NMR
;
δ
(CDCl3)
δ
25.6 (CH3
ˆ
3), 32.3 (C), 117.3 (CH), 120.0 (CH), 121.0 (CH), 121.8 (C), 122.0 (CH), 124.5 (CH),
126.5 (CH), 133.4 (CH), 149.1 (C); IR (neat) 3062, 2950, 1633 cm´1; EI-MS m/z (rel intensity) 200 ([M]+,
74), 185 (100), 131 (57), 118 (58); HRMS [M]+ calcd for C13H16N2: 200.1313, found 200.1315.
6-Nitro-2-(prop-1-en-1-yl)-2H-indazole (2i): Following the general procedure, the title compound was
˝
obtained (Route B: 81 mg, 80%). A green solid, mp 103–105 C; TLC (EtOAc/hexanes (1:4)) Rf = 0.20;
1H-NMR (acetone-d6)
δ
1.92 (d, J = 6.9 Hz, 2.85H), 2.15 (d, J = 6.9 Hz, 0.15H), 5.78–5.88 (m, 0.05H),

Molecules 2016, 21, 238
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6.68–6.80 (m, 0.95H), 7.33–7.40 (m, 1H), 7.78–7.91 (m, 2H), 8.54 (s, 1.9H), 8.55 (s, 0.1H); 13C-NMR
(acetone-d6) δ 15.0 (CH3), 115.7 (CH), 116.2 (CH), 121.1 (CH), 123.2 (CH), 123.8 (CH), 125.3 (C), 129.5
(CH), 147.7 (C), 147.8 (C); IR (neat) 3051, 1514, 1342 cm´1; EI-MS m/z (rel intensity) 203 ([M]+, 100),
176 (95), 156 (27), 130 (47); HRMS [M]+ calcd for C10H9N3O2: 203.0695, found 203.0699.
(E)-6-Bromo-2-styryl-2H-indazole (2j): Following the general procedure, the title compound was obtained
˝
(Route A: 112 mg, 75%, Route B: 120 mg, 80%). A yellow solid, mp 118–120 C; TLC (EtOAc/hexanes
(1:4)) Rf = 0.50; 1H-NMR (CDCl3)
7.15 (dd, J = 9.0, 1.5 Hz, 1H), 7.28–7.40 (m, 3H), 7.44–7.52 (m, 4H),
7.67 (d, J = 14.4 Hz, 1H), 7.89 (s, 1H), 8.09 (s, 1H); 13C-NMR (CDCl3)
119.7 (CH), 120.6 (C), 121.1 (C),
2),
δ
δ
121.5 (CH), 121.7 (CH), 122.2 (CH), 126.0 (CH), 126.1 (CH
ˆ
2), 126.5 (CH), 128.3 (CH), 128.8 (CH
ˆ
133.9 (C), 150.0 (C); IR (neat) 3062, 2950, 1625 cm´1; EI-MS m/z (rel intensity) 300 ([M + 2]+, 56), 299
(100), 298 ([M]+, 61), 77 (32); HRMS [M]+ calcd for C15H11BrN2: 298.0106, found 298.0109.
3.2.3. General procedure for the synthesis of 2-alkenyl-2H-indazoles 4:
A mixture of ketone 3g (1.0 mmol), aldehyde (1.5 mmol), and conc. HCl (3 drops) in CH3CN
(1 mL) was heated to reflux under nitrogen. Reaction was monitored by TLC until no starting material
was observed and normally the reaction was stirred under reflux for 4 h. The reaction was then cooled
to ambient temperature and quenched with sat. NaHCO3 until pH was 7. CH2Cl2 (10 mL) was added
and the mixture was transferred to a separatory funnel. The aqueous layer was back extracted with
CH2Cl2 (10 mL
ˆ
2). The combined organic layers were dried over MgSO4, filtered, and concentrated
in a rotary evaporator. The residue was purified by silica gel chromatography using EtOAc/hexanes
(1/10) as eluent to give the product 4.
(E)-3-(2H-Indazol-2-yl)-4-phenylbut-3-en-2-one (4a): Following the general procedure, the title compound
was obtained (184 mg, 70%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.35; 1H-NMR (acetone-d6)
δ
2.20 (s, 3H), 6.83 (d, J = 7.5 Hz, 2H), 7.06–7.16 (m, 3H), 7.25–7.33 (m, 2H), 7.69–7.73 (m, 2H), 7.95 (s,
1H), 8.22 (s, 1H); 13C-NMR (acetone-d6)
δ
26.3 (CH3), 119.2 (CH), 122.2 (CH), 123.3 (CH), 123.9 (C),
126.9 (CH), 127.8 (CH), 130.0 (CH
ˆ
2), 131.7 (CH
ˆ
2), 132.2 (CH), 133.1 (C), 138.2 (C), 138.3 (CH),
151.0 (C), 194.8 (C); IR (neat) 3062, 1683, 1610 cm´1; EI-MS m/z (rel intensity) 262 ([M]+, 46), 261 (100),
219 (34), 118 (41); HRMS [M]+ calcd for C17H14N2O: 262.1106, found 262.1099.
(E)-4-(4-Bromophenyl)-3-(2H-indazol-2-yl)but-3-en-2-one (4b): Following the general procedure, the title
compound was obtained (232 mg, 68%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.38; 1H-NMR
(CDCl3)
1H), 7.64 (d, J = 8.7 Hz, 1H), 7.74–7.80 (m, 2H), 7.90 (s, 1H); 13C-NMR (CDCl3)
120.4 (CH), 122.4 (C), 122.6 (CH), 124.6 (CH), 125.7 (C), 127.0 (CH), 129.9 (C), 131.6 (CH
δ
2.12 (s, 3H), 6.55 (d, J = 8.7 Hz, 2H), 7.09–7.14 (m, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.30–7.36 (m,
25.6 (CH3), 118.0 (CH),
2), 132.0
δ
ˆ
(CH
ˆ
2), 135.7 (CH), 136.4 (C), 149.8 (C), 193.9 (C); IR (neat) 3062, 1674, 1619 cm´1; EI-MS m/z (rel
intensity) 342 ([M + 2]+, 49), 341 (100), 340 ([M]+, 49), 118 (88); HRMS [M]+ calcd for C17H13BrN2O:
340.0211, found 340.0214.
(E)-4-(4-Chlorophenyl)-3-(2H-indazol-2-yl)but-3-en-2-one (4c): Following the general procedure, the title
compound was obtained (208 mg, 70%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.38; 1H-NMR
(CDCl3)
δ
2.12 (s, 3 H), 6.62 (d, J = 8.7 Hz, 2H), 7.05–7.14 (m, 3H), 7.30–7.36 (m, 2H), 7.64 (d, J = 8.7 Hz,
25.6 (CH3), 118.1 (CH), 120.4 (CH), 122.4 (C),
1H), 7.75–7.80 (m, 2H), 7.90 (s, 1H); 13C-NMR (CDCl3)
δ
122.6 (CH), 124.6 (CH), 127.0 (CH), 129.1 (CH
ˆ
2), 129.5 (C), 131.5 (CH
ˆ
2), 135.7 (CH), 136.4 (C),
137.2 (C), 149.9 (C), 194.0 (C); IR (neat) 3062, 1683, 1491 cm´1; EI-MS m/z (rel intensity) 298 ([M + 2]+,
18), 296 ([M]+, 51), 295 (100), 118 (64); HRMS [M]+ calcd for C17H13ClN2O: 296.0716, found 296.0708.
(E)-4-(2-(2H-Indazol-2-yl)-3-oxobut-1-en-1-yl)benzonitrile (4d): Following the general procedure, the title
compound was obtained (184 mg, 64%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.20; 1H-NMR
(CDCl3)
J = 8.1 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.78 (s, 1H), 7.88 (s, 1H); 13C-NMR (CDCl3)
(C), 117.8 (C), 118.0 (CH), 120.4 (CH), 122.4 (C), 122.9 (CH), 124.7 (CH), 127.3 (CH), 130.4 (CH
δ
2.16 (s, 3H), 6.68 (d, J = 8.7 Hz, 2H), 7.13 (t, J = 8.1 Hz, 1H), 7.32–7.41 (m, 3H), 7.63 (d,
25.8 (CH3), 113.8
2),
δ
ˆ

Molecules 2016, 21, 238
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132.3 (CH
ˆ
2), 134.3 (CH), 135.4 (C), 138.1 (C), 149.9 (C), 193.9 (C); IR (neat) 3064, 1677, 1631 cm´1
;
EI-MS m/z (rel intensity) 287 ([M]+, 55), 286 (100), 244 (25), 118 (30); HRMS [M]+ calcd for C18H13N3O:
287.1059, found 287.1049.
(E)-4-(2-Chlorophenyl)-3-(2H-indazol-2-yl)but-3-en-2-one (4e): Following the general procedure, the title
compound was obtained (220 mg, 74%). A yellow oil; TLC (EtOAc/hexanes (1:2)) Rf = 0.50; 1H-NMR
(CDCl3)
δ
2.21 (s, 3H), 6.30 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 7.03–7.16 (m, 2H), 7.26–7.37 (m,
25.9
2H), 7.55 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 8.10 (s, 1H); 13C-NMR (CDCl3)
δ
(CH3), 118.0 (CH), 120.4 (CH), 122.1 (C), 122.4 (CH), 125.1 (CH), 126.9 (CH), 127.0 (CH), 129.4 (CH),
129.6 (CH), 129.9 (C), 131.4 (CH), 132.5 (CH), 135.7 (C), 137.9 (C), 149.7 (C), 193.8 (C); IR (neat) 3053,
1693, 1624 cm´1; EI-MS m/z (rel intensity) 296 ([M]+, 3), 262 (18), 261 (100), 118 (9); HRMS [M]+ calcd
for C17H13ClN2O: 296.0716, found 296.0718.
(E)-4-(3,5-Dimethoxyphenyl)-3-(2H-indazol-2-yl)but-3-en-2-one (4f): Following the general procedure, the
˝
title compound was obtained (200 mg, 62%). A brown solid, mp 94–96 C; TLC (EtOAc/hexanes (1:2))
Rf = 0.35; 1H-NMR (CDCl3)
2.19 (s, 3H), 3.22 (s, 6H), 5.72 (d, J = 2.4 Hz, 2H), 6.30 (t, J = 2.4 Hz, 1H),
7.04–7.09 (m, 1H), 7.25–7.30 (m, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.72–7.75 (m, 2 H), 7.90 (s, 1H); 13C- NMR
(CDCl3) 25.7 (CH3), 54.6 (CH3 2), 104.4 (CH), 107.4 (CH 2), 117.7 (CH), 120.3 (CH), 122.4 (C),
δ
δ
ˆ
ˆ
122.5 (CH), 125.1 (CH), 126.9 (CH), 132.3 (C), 136.2 (C), 137.9 (CH), 149.7 (C), 160.4 (C
ˆ
2), 194.0 (C);
IR (neat) 3120, 1697, 1583 cm´1; EI-MS m/z (rel intensity) 322 ([M]+, 78), 321 (100), 279 (21), 189 (32);
HRMS [M]+ calcd for C19H18N2O3: 322.1317, found 322.1318.
2-(1-Methyl-1H-inden-2-yl)-2H-indazole (5). To a solution of ketone 4a (184 mg, 0.7 mmol) in MeOH
(7 mL) was added CeCl3–7H2O (135 mg, 0.36 mmol) followed by NaBH4 (28 mg, 0.7 mmol, 1.0 equiv.)
at ambient temperature. The reaction was stirred at ambient temperature for 2 h and then quenched
with H2O (10 mL). CH2Cl2 (10 mL) was added and the mixture was transferred to a separatory
funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL
layers were dried over MgSO4, filtered, and concentrated in a rotary evaporator. The residue (174 mg)
was dissolved in DCE (2.4 mL) and PPA (0.66 mL) was added. The mixture was heated to 90 C
under N2 for 2 h. The resulting mixture was cooled to 0–5 ˝C and sat. NaHCO3 was added slowly
until pH was 7. CH2Cl2 (10 mL) was added and the mixture was transferred to a separatory funnel.
ˆ
2). The combined organic
˝
The aqueous layer was back extracted with CH2Cl2 (10 mL
dried over MgSO4, filtered, and concentrated in a rotary evaporator. The residue was purified by
silica gel chromatography using EtOAc/hexanes (1/200) as eluent to give the product . (121 mg,
70%). A yellow solid, mp 74–75 C; TLC (EtOAc/hexanes (1:2)) Rf = 0.63; 1H-NMR (CDCl3)
1.52 (d,
J = 7.5 Hz, 3H), 4.23 (q, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 2H), 7.23–7.45 (m, 5H), 7.66 (d, J = 8.7 Hz
ˆ
2). The combined organic layers were
5
˝
δ
,
1H), 7.80 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H); 13C-NMR (CDCl3) δ 16.9 (CH3), 43.2 (CH), 117.4 (CH), 117.6
(CH), 120.1 (CH), 121.0 (CH), 121.5 (CH), 122.2 (C), 122.4 (CH), 122.7 (CH), 125.4 (CH), 126.9 (CH), 127.0
(CH), 141.0 (C), 145.9 (C), 149.6 (C), 149.7 (C); IR (neat) 3062, 1634, 1486 cm´1; EI-MS m/z (rel intensity)
246 ([M]+, 100), 245 (92), 231 (34), 128 (45); HRMS [M]+ calcd for C17H14N2: 246.1157, found 246.1155.
3-(2H-Indazol-2-yl)-2H-chromen-2-one (6). A mixture of ethyl 2-(2H-indazol-2-yl)acetate (204 mg,
1.0 mmol), 2-hydroxybenzaldehyde (122 mg, 1.0 mmol), and piperidine (43 mg, 0.5 mmol) in EtOH
(1 mL) was heated to reflux. After 15 h, the reaction was then cooled to ambient temperature and
quenched with sat. NH4Cl until pH was 7. CH2Cl2 (10 mL) was added and the mixture was transferred
to a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (10 mL
organic layers were dried over MgSO4, filtered, and concentrated in a rotary evaporator. The residue
was purified by silica gel chromatography using EtOAc/hexanes (1/10) as eluent to give the product
ˆ
2). The combined
˝
1
6
(167 mg, 64%). A yellow solid, mp 151–152 C; TLC (EtOAc/hexanes (1:4)) Rf = 0.45; H-NMR
(DMSO-d6) 7.11 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz
1H), 7.67–7.73 (m, 2H), 7.82 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.87 (s, 1H), 9.17 (s, 1H);
13C-NMR (DMSO-d6)
116.1 (CH), 117.0 (CH), 118.6 (C), 121.5 (CH), 122.0 (C), 122.4 (CH), 125.4 (CH),
δ
,
δ

Molecules 2016, 21, 238
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125.5 (CH), 125.8 (C), 127.9 (CH), 129.5 (CH), 132.5 (CH), 134.1 (CH), 148.6 (C), 152.0 (C), 156.2 (C);
IR (neat) 3154, 1722, 1600 cm´1; EI-MS m/z (rel intensity) 262 ([M]+, 79), 236 (77), 127 (64), 105 (100);
HRMS [M]+ calcd for C16H10N2O2: 262.0742, found 262.0734.
4. Conclusions
In conclusion, the studies described above have led to the development of a method for the
synthesis of 2-alkenyl-2H-indazoles from α-(2H-indazol-2-yl)ketones. The 2-alkenyl-2H-indazole
products may be potentially useful as fluorescent probes or as anticancer drugs.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
2/238/s1.
Acknowledgments: Financial support from the Ministry of Science and Technology of the Republic of China,
Taiwan (MOST 104-2113-M-018-005) is gratefully acknowledged. We thank the assistance from Jui-Hsien Huang’s
group for the X-ray structure determination.
Author Contributions: M.-H. Lin conceived and designed the experiments; K.-Y. Liang, C.-H. Tsai, Y.-C. Chen,
Y.-S. Li, C.-H. Chen, and H.-C. Wu performed the experiments. H.-C. Hsiao performed the X-ray analyses.
Conflicts of Interest: The authors declare no conflict of interest.
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These Data can be Obtained Free of Charge from The Cambridge Crystallographic Data Centre via
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Sample Availability: Samples of the compounds. 2a–j, 4a–f, 5 and 6 are available from the authors.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).