Regioselective Synthesis of Pyranone-Fused Indazoles via Reductive Cyclization and Alkyne Insertion

Article abstract of DOI:10.1021/acscombsci.7b00170

A novel and efficient method for the one-pot synthesis of 2H-indazole from readily available building blocks is reported. The reaction of 2-nitrobenzylamines with zinc and ammonium formate underwent partial reduction to nitroso-benzylamine followed by an intramolecular cyclization to afford 2H-indazole via N-N bond formation. The carboxylic acid moiety of indazole was proceeded to regioselective alkyne insertion under ruthenium catalysis to form pyranone-fused indazoles. The regioselectivity is influenced by the weak coordination of indazole ring nitrogen to the metal center.

Full text of DOI:10.1021/acscombsci.7b00170

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Article
Regioselective Synthesis of Pyranone-fused Indazoles
via Reductive Cyclization and Alkyne Insertion
Tz-Yi Wu, Sandip Dhole, Manikandan Selvaraju, and Chung-Ming Sun
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00170 • Publication Date (Web): 30 Jan 2018
Downloaded from http://pubs.acs.org on January 31, 2018
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Regioselective Synthesis of Pyranone-fused Indazoles via
Reductive Cyclization and Alkyne Insertion
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Tz-Yi Wu, † Sandip Dhole, † Manikandan Selvaraju † and Chung-Ming Sun* †‡
†
Department of Applied Chemistry, National Chiao-Tung University, 1001, Ta-Hseuh Road,
Hsinchu 300-10, Taiwan.
‡ Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-
Chuan 1st Road, Kaohsiung 807-08, Taiwan.
Graphic abstract
R2
O
H
O
H
R3
1. Hydrolysis
O
H
NO2
N
Zn
2. Alkyne insertion
O
O
H
N
N
N
R1
O
N
R1
R2
R3
-I
HCOONH4
R1
H
3. Arylation, R4
R4
Abstract
A novel and efficient method for the one-pot synthesis of 2H-indazole from readily available
building blocks is reported. The reaction of 2-nitrobenzylamines with zinc and ammonium formate
underwent partial reduction to nitroso benzylamine followed by an intramolecular cyclization to
afford 2H-indazole via N-N bond formation. The carboxylic acid moiety of indazole was
proceeded to regioselective alkyne insertion under ruthenium catalysis to form pyranone-fused
indazoles. The regioselectivity is influenced by the weak co-ordination of indazole ring nitrogen
to the metal center.
Introduction
The indazole scaffold is a ubiquitous structural motif found in many natural products,
agrochemicals and pharmaceutically important molecules.1 In particular, 2H-indazole has
been recognized as a privileged pharmacophore with a broad range of physiological and
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pharmacological activities and it also acts as a bioisosteric replacement for other
heterocycle structures such as indoles and benzimidazole.2 For example, Niraparib is a
known PARP inhibitor for the treatment of ovarian cancer.3 2-Benzyl-3-phenyl-7-
(trifluoromethyl)-2H-indazole has been used a selective liver X receptor modulator. A
substituted indazole with pyrazine and azetidine is identified as a glucokinase K activator.4-
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5
O
N
NH2
O
HN
CF3
N
N
N
N
N
N
N
O
NH
N
F
O
Niraparib
Glucokinase K activator
PARP-1&2 inhibitor
Liver X Receptor Modulator
OH
OH
O
O
OH
O
O
O
O
COOH
O
O
OH
NM-3
antitumor agent
Cytogenin
antitumor agent
Oospolactone
antifungal agents
Figure 1. Biologically active indazoles and coumarin derivatives
Similarly, iscoumarin is a well-known heterocycle for its diverse physiological and
medicinal applications. Oosponal and Oospolactone have demonstrated their potent
antifungal and antibiotic activities.6 Cytogenin exhibits significant immunomodulating,
antitumor and antiarthritic activities.7 Moreover, the synthetic drug NM-3 is in the clinical
trials for its potent antitumour function.8 Owing to their biological significance, numerous
synthetic methods have been reported in the literature. Among them, the direct N-alkylation
or arylation of indazole is quite challenging due to the preferential formation of the
thermodynamically more stable 1H-indazole or a mixture of 1H-indazole and 2H -indazole
through their tautomeric forms.9 In addition, the separation of N1 and N2 alkylated mixtures
is laborious and tedious. As an alternative, one of the first methods to prepare 2H-indazole
was reductive cyclization of ortho-imino-nitrobenzenes mediated by excess of triethyl
phosphite at high temperature.10 Subsequently, many other methods such as transition metal
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catalyzed cyclization of iminonitroaromatics and 2-azidoimines were developed.11 A
variety of other methods including benzyne [3+2] cycloaddition, zincate addition to
diazonium salts, and alkylation of 1H-indazoles have also been reported.12 Among them,
reductive cyclization of 2-nitrobenzylamines by using Sn, Ti, Zn and In have attracted
considerable attention because of the readily available starting material.13 Nevertheless,
these methods still suffer from setbacks such as unsatisfying yields, longer and harsh
reaction conditions. Consequently, there is still a need to develop an operationally simple
and easy means to access this important class of heterocycles. In our strategy, N2-
substituted indazole was obtained selectively with appropriately substituted ortho-nitro
benzyl amines via partial reduction followed by intramolecular N-N bond formation.
Similarly, among many available synthetic methods for the preparation of isocoumarin,
transition-metal catalyzed protocols are proven to be a concise and efficient strategy.
Especially, less expensive ruthenium (II) catalyzed, chelation assisted C-H
activation/annulation of aromatic carboxylic acid with internal alkynes has received much
attention in the recent years.14
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Fused heterocycles containing two or more pharmacophores have played a very
important role in both medicinal chemistry and organic synthesis.15 While indazoles and
coumarin are well presented, indazole fused with pyranone bi-heterocycle is rarely reported
in the literature and no attempt has been made to the synthesize of pyranone-fused
indazoles. In continuation with our research interest on the development of efficient
methods for hybrid heterocycles,16 we report herein a novel, atom economic and
regioselective synthesis of indazole fused pyranone via a sequential, stepwise pathway as
shown in Scheme 1. In our methodology, methyl 4-(bromomethyl)-3-nitrobenzoate acts as
a basic substrate to build an indazole skeleton by nucleophilic aliphatic substitution with
primary amines followed by reductive cyclization. Later, the strategically positioned
methyl ester is hydrolyzed to a carboxylic acid which subsequently undergoes
regioselective alkyne insertion through ruthenium catalysis to furnish pyranone-fused
indazoles. To the best of our knowledge, construction of indazole fused pyranone via step-
wise reductive cyclization and alkyne insertion has never been reported.
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R2
R3
R2
+
+
R3
O
O
O
NO2
Br
N
1. N-alkylation
HO
O
1. alkyne insertion
R1
N
N
O
N
R1
2. C
2.Reductive
cyclization
3-arylation
-NH
R1
9
2
I
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R4
R4
Scheme 1. A proposed synthetic route for the synthesis of pyranone-fused indazoles
Result and Discussion
Our preliminary investigation began with the reaction of methyl 4-(((thiophene-2-
ylmethyl)amino)methyl)-3-nitrobenzoate {1} in the presence of zinc and ammonium
1
formate in methanol to prepare diamine product 2´{1}(Table 1) for the possible synthesis
of quinazoline with aldehydes.
Table 1. Optimization of the reaction conditions[a]
O
O
O
N
O2
H
N
N
NH2
+
O
O
O
N
H
N
S
1
{1}
2
{1}
2'
{1}
S
S
Yield (%)
2´{1}
Entry
Reductive agents
2{1}
1
2
3
4
5
Zn (2 equiv)/ HCOONH4 (1 equiv)
Pd/C (2 equiv) / H2
45
19
85
82
9
0
0
Pd/C (2 equiv)/ HCOONH4 (1 equiv)
Zn (3 equiv)/ HCOONH4 (1 equiv)
Zn (5 equiv)/ HCOONH4 (1 equiv)
62
76
0
a
Reaction conditions: the reaction was carried out in 0.165 mmol scale with various reductive agents in
methanol at room temperature for 1 h.
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However, to our surprise the reaction furnished an unknown compound (45%) as the
major product together with the diamine 2´{1} (19%). The absence of benzyl methylene
peak and the appearance of characteristic signal of C(3)-H as a sharp singlet in the aromatic
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region (7.95 ppm) confirmed the formation of 2H-indazole
2
{1}. Further, the structure of
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2
{1} was ascertained by X-ray single crystallography (Figure 2) which indicates the N-N
bond formation.
H (7.95 ppm)
N
N
O
S
O
2
{1}
Figure 2. ORTEP diagram of compound 2{1}
We reasoned that under reductive condition, the nitro group underwent partial
reduction to nitroso benzyl amine which cyclized intramolecularly to furnish indazole via
N-N bond formation. This unprecedented result encouraged us to develop an exclusive
method to selectively synthesize indazole ring owing to their notable biological property.
In order to study the formation of 2{1} exclusively, the reaction conditions were optimized
with various reducing agents as shown in Table 1. When the same reaction was carried out
in the presence of palladium on charcoal with hydrogen gas or ammonium formate, only
diamine
increases the yield of
However, an exclusive formation of
2
´{
1}
(entries 2 and 3) was obtained. Increasing the amount of zinc, significantly
{1} with the diminished formation of ´{1} (entries 4 and 5).
{1} in 76% yield was accomplished when ammonium
2
2
2
formate in methanol was added drop wise to the reaction mixture (entry 5).
With the optimized conditions in hand, the scope of the reaction was evaluated. As
shown in Table 2, various substituted 2-nitrobenzylamines were tested for this unique
transformation. For alkyl substituted substrates, the corresponding 2H-indazoles were
obtained in good to excellent yields. However, moderate yields were obtained in the case
of aromatic substituted (
2
{5} and
2
{19}) and bulky substituted (
2
{8} and {9}) 2-
2
nitrobenzylamine accompanied with compounds
2
´{5}, 2´{19}, 2´{8}, and 2´{9}. The
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moderate yields of indazole formation may be due to the resonance stabilization of nitrogen
lone pair of aniline type amine within the aromatic ring in the nitroso form (Scheme 2, A).
Table 2. Synthesis of 2H-indazoles via reductive cyclization
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O
O
H
3C
H
3C
NO2
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N
Zn, HCOONH4
O
O
N
R1
H
N
MeOH, rt, 15 min
R1
2
1
O
O
O
O
O
H3C
NO2
H
N
H3C
NO2
H
N
H3C
NO2
H
N
H3C
NO2
H
N
H3C
NO2
O
O
O
O
O
H
N
1
{5}
1
S
1
1
{3}
1
{4}
{1}
O
{2}
O
OMe
NO2
H
N
O
O
O
O
O
H3C
NO2
H
N
H
NO2
H
N
H3C
H
3C
NO2
H
N
H
3C
NO2
H
N
3C
O
O
O
O
O
1
1
1
1
1
{10}
N
{8}
{6}
{7}
{9}
O
O
O
O
O
H3C
NO2
H
NO2
3C
H3C
NO2
H
N
H
3C
NO2
H
N
H3C
NO2
H
N
O
O
O
O
Ph
O
H
N
H
N
Br
1
1
{12}
1
{11}
O
1
{14}
{13}
O
1
{15}
O
O
O
O
O
H3C
H3C
NO2
H
3C
NO2
H
N
H3C
NO2
H
N
H3C
NO2
H
N
H3C
NO2
H
N
O
O
O
O
O
H
N
Ph
1
1
1
1
{20}
{16}
{17}
1
{18}
N
Ph
O
{19}
O
NO2
O
H
N
1
{21}
Entry
Product
2{1}
2{2}
2{3}
2{4}
2{5}
2{6}
2{7}
2{8}
Isolated yield (%)
Entry
Product
2{11}
2{12}
2{13}
2{14}
2{15}
2{16}
2{17}
2{18}
Isolated yield (%)
1
2
3
4
5
6
7
8
76
79
62
65
47
49
71
53
11
12
13
14
15
16
17
18
70
66
75
75
72
78
68
71
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2{9}
51
80
19
20
21
2{19}
2{20}
2{21}
45
65
79
10
2{10}
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Based on the literature reports, a tentative mechanism for the synthesis of 2H-
indazole is depicted in Scheme 2. Initially, 2-nitrobenzylamine was reduced to nitroso
compound in the presence of zinc and ammonium formate via reductive addition of two
A
hydrogen atoms. It is noteworthy that, because of the presence of nucleophilic benzyl
nitrogen at the ortho-position, the reduction of nitro group with zinc under acidic condition
stop at nitroso state for the possible formation of N-N bond. Then, an intramolecular
nucleophilic addition of benzyl amine on nitroso group delivered intermediate
B, upon
elimination of water to produce 2H-indazoles. The driving force for the proton elimination
in the final step is due to the formation of the more stable, aromatic like 2H-indazole.
Scheme 2. A plausible mechanism for the formation of 2H-indazoles
OH
N
O
O
N
O
O
N
O
O
O
N
H+
Zn
2H+
OH2
R
O
O
O
OH
R
O
O
OH
R
+2e
HN
HN
HN
HN
R
H
N
O
O
O
N
O
OH2
O
OH
N
H+
O
N
N
O
O
O
H
R
N R
-H
N R
2O
N R
-H
2O
)
H
B
A
B (HCOO
2
(Nitroso)
In light of a successful reductive cyclization process for the regioselective synthesis
of 2H-indazoles, the next task is aiming to build a pyranone framework by utilizing an
acidic form of indazole through metal mediated alkyne insertion. Our attempt was initiated
by the base hydrolysis (aq. NaOH) of indazole esters to the corresponding acid derivatives.
After synthesizing these acids, we carried out an oxidative coupling of 3{14,1} with
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diphenylacetylene
4
{1} in the presence of [RuCl2(p-cymene)]2 (5 mol %), Cu(OAc)2.H2O
5
6
7
(2 equiv) as an oxidant and AgOTf (20 mol %) as an additive in refluxing p-xylene (5 mL)
for 12 h to deliver the desired product {14,1} in 45% yield (see Supporting Information,
5
8
9
Table S1, entry 1). Encouraged by this promising result, further screening of the reaction
conditions was carried out as shown in see Supporting Information File in Table S1. From
these results, we concluded that [RuCl2(p-cymene)]2 (5 mol %), Cu(OAc)2.H2O (2 equiv)
as an oxidant and AgOTf (20 mol %) as an additive in t-butanol under microwave
irradiation at 100 °C for 30 minutes provided the optimal results. (See Supporting
Information, Table S1).
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Table 3. Indazole-directed regioselective synthesis of fused bi-heterocycles
R3
H1
R2
[RuCl2(p-cymene)]2
.H
O
R2
2O, AgOTf
Cu(OAc)2
O
N
HO
+
R1
N
N
t-Butanol, MW(100°C)
30 min
O
R1
N
H2
R3
H2
3
4
5
R2
R3
R2
R2
R3
O
O
O
O
N
N
N
O
N
HO
HO
HO
HO
N
N
N
R3
3
R
=Ph
R
=Et
R2=Me, R3=Ph
3
3
2=R3
2=R3
3
3
{14}
{11}
{21}
4
4
4
{3}
{1}
{2}
O
O
O
R2
R3
R2
R2
N
N
N
N
HO
HO
N
R3
R3
3
{2}
{13}
{10}
-
-
=4-OMe-C
=4-CF
3-C
6H4
2=R3
2=R3
2=R3
R
R
6H4
R
=COOEt
O
O
O
4
4
4
{6}
{4}
{5}
R2
N
N
N
HO
Br
HO
HO
N
N
N
Alkynes
3
{3}
3
{16}
R3
2=R3=C
3
{12}
OMe
R
4H
3S 4
{7}
Acids
Entry
Product
Isolated yield (%)
Entry
Product
Isolated yield (%)
1
5{14,1}
82
12
5{2,1}
77
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2
3
5{21,2}
5{21,3}
5{11,1}
5{11,2}
5{11,3}
5{13,1}
5{13,2}
5{13,3}
5{10,1}
5{10,3}
79
13
14
15
16
17
18
19
20
21
22
5{2,2}
5{2,3}
75
69
67
65
74
71
ND
79
74
81
68
77
81
69
82
79
68
85
72
4
5{3,1}
5
5{12,1}
5{9,1}
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6
7
5{16,3}
5{17,4}
5{17,5}
5{17,6}
5{17,7}
8
9
10
11
With the optimized reaction condition in hand, we probed the substrate scope of
ruthenium catalyzed oxidative annulation with various substituted indazoles and internal
alkynes (Table 3). A broad range of functional groups were well-tolerated and a variety of
N2 substituted (alkyl, aryl, heterocyclic) indazoles were synthesized in excellent yields.
Remarkably, the coupling reaction occurred regioselectively with C-H1 bond due to the
possible chelation of indazole nitrogen to the metal center. We next investigated the scope
of the reaction by using various disubstituted alkynes such as alkyl, aryl, and electron-rich
and electron deficient symmetrical alkynes which converted to the products with moderate
to excellent yields. However, with diethyl acetylenedicarboxylate, no conversion was
observed under the same reaction condition.
The reaction of unsymmetrical alkyne (prop-1-yn-1-yl benzene) with indazoles
3
is highly regioselective in which the alkyne carbon bearing phenyl group is attached to the
acid group site and the alkyne carbon bearing a methyl group is connected to the ortho-
carbon of the acid to give the desired products (
5{21,3}, 5{11,3}, 5{13,3}, 5{10,3}, 5{2,3}
and {16,3}) in good yields. The reason for the high regioselectivity would be the steric
5
repulsion between the bulky phenyl group and the indazole ring. The observed
regioselectivity is ascertained by X-ray single crystallography studies and the ORTEP
diagrams of the representative compounds 5{2,3} are shown in Figure 3. Interestingly, we
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didn’t observe any decarboxylative cyclization product in the present catalytic reaction
system.
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O
N
O
N
5
{2,3}
Figure 3. ORTEP diagram of compounds 5{2,3}
A plausible mechanism for the ruthenium-catalyzed regioselective C-H bond
activation/annulation reaction is illustrated in Scheme 3. The catalytic cycle commences
with the formation of five membered ruthenacycle A via acetate assisted irreversible C-H1
bond activation with the liberation of acetic acid. The regioselective C-H1 bond activation
is governed by the weak co-ordination of indazole ring nitrogen to the metal center.
Subsequently, an alkyne insertion furnished seven membered ruthenacycle which upon
reductive elimination yields the desired pyranone-fused with indazole. The resulting Ru(0)
is reoxidized to Ru(II) in the presence of Cu(II) salts to reinitiate the catalytic cycle.
Scheme 3. A plausible catalytic cycle for the regioselective alkyne annulation with acids
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IICl
[Ru
2(p-cymene)]2
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6
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8
H1
OH
Ag+
N
CuI
O
H2
N R1
2HOAc
N R1
R2
CuII
[RuII
X]
R3
(OAc)2
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O
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X= p-cymene
N
O
Ru(0)
N R1
H2
reductive
elimination
X
RuII
O
N
R2
O
X
II
Ru
H2
R3
N
O
N R1
O
H2
alkyne insertion
R3
R2
After the successful synthesis of pyranone-fused indazoles, we extended this methodology
for alkene insertion to the synthesis of indazole-fused furanone scaffold. Gratifying, under the
optimized condition, oxidative coupling with tert-butyl acrylate took place smoothly to produce
the target molecule in 82% yield (Scheme 4).
Scheme 4. Alkenylation/cyclization cascade for the synthesis of indazole-fused furanone
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O
O
O
O
S
[RuCl
Cu(OAc)2
2(p-cymene)]2
.H
O
N
O
HO
2O, AgOTf
N
O
+
N
N
S
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t-Butanol, MW(100°C)
30 min
3{10}
6
{10} (82 %)
Similarly, we have successfully carried out selective C3-arylation of indazole fused
pyranone with aryl halides in the presence of Pd/Ag catalytic system in water as shown in
(Table 4).
Table 4. Selective arylation of indazole-fused pyranone 5{21,2}
R5
I
7
O
O
Pd(OAc)2 (10 mol%)
Ag
N
N
O
2CO
O
3 (1 eq)
N
N
H
2O,reflux,12 h
H
5
{21,2}
8
R5
MeO
I
H
I
3C
Aryl halides(7)
7
7
{2}
{1}
O
O
N
N
O
O
N
N
OMe
CH3
78%
80%
8
8
{21,2,1}
{21,2,2}
Conclusion
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In summary, a new synthetic route to prepare pyranone-fused indazole was explored
by employing readily available substrates. The 2H-indazole core is accomplished via
reductive cyclization for N-N bond formation in the presence of zinc/ammonium format at
ambient temperature. Subsequently, the strategically positioned carboxylic derivatives
were successfully employed as a suitable substrate for the regioselective C-H bond
activation /annulation with internal alkynes to deliver indazole-fused pyranones. The new
protocol offers a concise route for the construction of these bi-heterocycles with diverse
functionalization.
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EXPERIMENTAL SECTION
Experimental procedure for the synthesis of Methyl 2-(thiophen-2-ylmethyl)-2H-indazole-6-
carboxylate 2{1}.
To a solution of methyl 3-nitro-4-(((thiophen-2-ylmethyl)amino)methyl)benzoate 1{1}
(100 mg, 0.326 mmol) in methanol (6 mL) was added zinc (104 mg, 1.633 mmol) followed
by ammonium formate (20 mg, 0.344 mmol) in methanol (1 mL) was added dropwise. The
resulting reaction mixture was stirred at room temperature for 1 h. After the completion of
the reaction, the reaction mixture was filtered through a pad of celite and washed with
methanol (10 mL). The filtrate was evaporated and dissolved in CH2Cl2 (15 mL). The
precipitated ammonium formate was filtered off. The resulting crude product was purified
by silica gel column chromatography (EtOAc/Hexane = 3/10) to afford the desired product
2
{1} (67 mg, 76 %)
Methyl 2-(thiophen-2-ylmethyl)-2H-indazole-6-carboxylate 2{1}
Brown solid; yield 67 mg, 76%; mp 94-96 °C; 1H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 7.96
(s, 1H), 7.71 (dd, J = 8.8, 1.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 5.2, 1.2 Hz, 1H),
7.16 (d, J = 3.6 Hz, 1H), 7.01 (dd, J = 5.2, 3.6 Hz, 1H), 5.79 (s, 2H), 3.95 (s, 4H); 13C NMR (75
MHz, CDCl3) δ 183.1, 167.9, 148.5, 137.1, 128.5, 128.3, 127.6, 127.4, 124.5, 123.1, 121.9, 121.8,
120.7, 52.6; IR (cm-1, neat): 2948, 1714, 1502; MS (EI-MS) m/z: 272 (M+); HRMS: calculated for
C14H12N2O2S m/z: 272.0619; found 272.0618.
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Experimental procedure for the synthesis of 2-cyclopentyl-8,9-diphenylpyrano[3,4-
g]indazol-6(2H)-one 5{14,1}.
To an oven dried microwave vial was added 2-cyclopentyl-2H-indazole-6-carboxylic acid
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8
9
(70 mg, 0.304 mmol), diphenyl acetylene (65 mg, 0.365 mmol), [RuCl2(p-cymene)]2 (9 mg,
0.0152 mmol), Cu(OAc)2.H2O (121 mg, 0.608 mmol) followed by AgOTf ( 16 mg, 0.0608
mmol) in t-BuOH (3 mL). The reaction tube was sealed and irradiated at a ceiling
temperature of 100 °C using 150 W for 30 min. Upon completion of reaction, the residue
was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting
crude product was purified by column chromatography (EtOAc/hexane= 1/5) on silica gel
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to afford compound 5{14,1} (101 mg, 82 %)
2-cyclopentyl-8,9-diphenylpyrano[3,4-g]indazol-6(2H)-one 5{14,1}.
Brown semi solid; yield 62 mg, 71%; 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 1H), 7.87
(s, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.40–7.32 (m, 7H), 7.21–7.19 (m, 3H), 4.64 (quint, J = 7.4 Hz,
13
1H), 1.99–1.93 (m, 2H), 1.82–1.75 (m, 2H), 1.58–1.51 (m, 4H); C NMR (75 MHz, CDCl3) δ
163.4, 153.0, 143.9, 136.9, 133.7, 132.6, 132.0, 129.8, 129.1, 128.3, 128.1, 127.8, 125.4, 122.2,
121.2, 120.6, 117.3, 117.1, 64.9, 33.9, 25.1;IR (cm-1, neat): 2954, 1714, 1492; MS (EI-MS) m/z:
406 (M+); HRMS: calculated for C27H22N2O2 m/z: 406.1681; found 406.1681.
ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the ACS Publications website at DOI:
Full characterization and spectroscopic data (1H and 13C NMR, HRMS, FT-IR) of compounds 2,
5, 6 and 8
X-ray crystallography of 2{1} (CIF)
X-ray crystallography of 5{2,3} (CIF)
X-ray crystallography of 5{3,1} (CIF)
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AUTHOR INFORMATION
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Corresponding authors
*E-mail: cmsun@mail.nctu.edu.tw
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
The authors thank the Ministry of Science and Technology of Taiwan for the financial
assistance and Mr. Han-Yuan Hsu to prepare some compounds in the initial study.
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Regioselective Synthesis of Pyranone-fused Indazoles via
Reductive Cyclization and Alkyne Insertion
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Tz-Yi Wu, Sandip Dhole, Manikandan Selvaraju and Chung-Ming Sun*
Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University,
Hsinchu 300-10, Taiwan
R2
O
H
O
R3
1. Hydrolysis
O
H
NO2
H
N
N
Zn
2. Alkyne insertion
O
O
N
N
R1
O
N
R1
R2
R3
-I
HCOONH4
H
R1
H
3. Arylation, R4
R4
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