A ruthenium-catalyzed alkenylation-annulation approach for the synthesis of indazole derivatives via C-H bond activation

Article abstract of DOI:10.1039/c8ob00999f

Ruthenium catalyzed oxidative alkenylation of N-aryl pyridazinediones and N-aryl phthalazinediones with acrylates and subsequent intramolecular cyclization of the resulting product in water as a green solvent were accomplished. Diverse derivatives of pyridazino[1,2-a]indazoles and indazolo[1,2-b]phthalazines were readily prepared in moderate to high yields by this methodology from easily accessible starting materials via cascade directed C-H bond activation/annulation reactions.

Full text of DOI:10.1039/c8ob00999f

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Biomolecular Chemistry
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A ruthenium-catalyzed alkenylation–annulation
approach for the synthesis of indazole derivatives
via C–H bond activation†
Cite this: DOI: 10.1039/c8ob00999f
Maral Gholamhosseyni and Ebrahim Kianmehr
*
Ruthenium catalyzed oxidative alkenylation of N-aryl pyridazinediones and N-aryl phthalazinediones with
acrylates and subsequent intramolecular cyclization of the resulting product in water as a green solvent
were accomplished. Diverse derivatives of pyridazino[1,2-a]indazoles and indazolo[1,2-b]phthalazines
were readily prepared in moderate to high yields by this methodology from easily accessible starting
materials via cascade directed C–H bond activation/annulation reactions.
Received 28th April 2018,
Accepted 23rd July 2018
DOI: 10.1039/c8ob00999f
rsc.li/obc
Cross-dehydrogenative alkenylation of arenes and heteroarens
via the transition metal-catalyzed transformation of aromatic
carbon–hydrogen (C–H) bonds which avoids the need for func-
1
tionalized starting materials has been proven as a powerful
2
alternative to Heck type reactions and thus has emerged as a
straightforward and economical tool for the synthesis of
organic compounds. The current approach is advantageous in
that it enables the direct formation of target molecules
without requiring pre-functionalization of the starting
materials, thereby minimizing undesired waste in fewer reac-
3
tion steps. Although a wide variety of Pd and Rh-catalyzed oxi-
4
dative coupling reactions have been developed, there are few
5
examples of the less expensive ruthenium complexes.
Fig. 1 Some examples of bioactive compounds with indazole structural
motif.
The indazole containing structural motif is frequently
present at the core of pharmaceuticals. It has been shown that
this class of compound exhibits a broad range of useful
6
pharmacological effects including antitumor, anti-inflamma-
1
2
-aryl-1H-indazoles via copper-catalyzed coupling reactions in
012 (Scheme 1). Rhodium(III)-catalyzed C–H bond addition
7
8
9
10
tory, anti-HIV, anti-bacterial and contraceptive activity. For
example, several indazolium alkaloids and indazolones were
1
3
of azobenzenes to aldehydes for the synthesis of indazoles was
1
1
reported to show antidiabetic (Fig. 1A and B) and anti-
inflammatory activities (Fig. 1C and D).
1
4
reported by Lian in 2013 (Scheme 1). Rh(III)-Catalyzed C–H
cleavage of arylhydrazines as another approach for the syn-
thesis of 2,3-dihydro-1H-indazoles was reported separately by
1
2
Due to the need for efficient ways to synthesize more elabor-
ate structures possessing biological activity, the development
of novel and convenient methods for the preparation of the
indazole core structure is of great interest to medicinal che-
mists. Construction of the indazole unit, a recurring structural
motif found in many pharmaceuticals and functional
materials, has rarely been reported. Aryl iodides and N-acyl-N′-
substituted hydrazines were used by Ma for the synthesis of
1
5a,b
Kim and Liu in 2014 (Scheme 1).
Wu et al. reported a
Rh(III)-catalyzed [4 + 1] annulation of propargyl alcohols with
1
5c
various heterocyclic scaffolds under air atmosphere in 2018.
As part of our ongoing interest in exploring C–C bond for-
16
mations through CDC reactions, herein we report an efficient
and highly regioselective procedure for oxidative C–H bond
alkenylation of N-aryl pyridazinediones and N-aryl phthalazine-
diones followed by an intermolecular Michael reaction in water as
a nontoxic and environmentally friendly reaction medium.
School of Chemistry, College of science, University of Tehran, Tehran 1417614411,
Iran. E-mail: kianmehr@khayam.ut.ac.ir
Our study commenced with probing various solvents, cata-
lysts, additives and oxidants for the envisioned oxidative alke-
nylation of 1-phenyl-1,2-dihydropyridazine-3,6-dione 1a to
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob00999f
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Scheme 1 Selected approaches to synthesis of indazole derivatives.
a
Table 1 Optimization of the reaction conditions
a
Entry
Catalyst (5 mol%)
Additive (10 mol%)
Oxidant (1 equiv.)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
[{RuCl
[{RuCl
[{RuCl
[{RuCl
[{RuCl
[{RuCl
2
2
2
2
2
2
(p-cymene)}
(p-cymene)}
(p-cymene)}
(p-cymene)}
(p-cymene)}
(p-cymene)}
2
2
2
2
2
2
]
]
]
]
]
]
KPF
KPF
KPF
KPF
KPF
KPF
KPF
KPF
KPF
KPF
—
6
6
6
6
6
6
6
6
6
6
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
AgOAc
2 3
Ag CO
K S O
2 2 8
2
2
2
2
2
2
·H
·H
·H
·H
·H
·H
2
2
2
2
2
2
O
O
O
O
O
O
DCE
Toluene
PhCl
80
21
33
79
50
10
95
20
30
10
45
93
20
54
52
0
THF
3
CH CN
DMSO
[{RuCl
2
(p-cymene)}
2
]
2
·H
2
O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
2
H O
[{RuCl
[{RuCl
[{RuCl
[{RuCl
[{RuCl
2
2
2
2
2
(p-cymene)}
(p-cymene)}
(p-cymene)}
(p-cymene)}
(p-cymene)}
2
]
]
]
]
]
2
2
2
2
0
1
2
3
4
5
6
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
·H
·H
·H
·H
·H
·H
2
O
2
O
2
O
2
O
2
O
2
O
AgSbF
6
RuCl
RuCl
2
(PPh
)
3 3
KPF
KPF
KPF
KPF
6
6
6
6
2
(COD)
Pd(OAc)
—
2
a
General reaction conditions: 1a (1 equiv., 0.5 mmol), 2a (3 equiv., 1.5 mmol), 2 mL solvent, 24 h, 120 °C.
furnish methyl-2-(6,9-dioxo-6,9-dihydro-11H-pyridazino[1,2-a] entries 1–7) so it proved to be the solvent of choice. To our
indazol-11-yl)acetate 3a (Table 1). Among representative sol- delight, with [{RuCl (p-cymene)} ] as a catalyst, KPF as an
vents including DCE, toluene, H O, PhCl, THF, CH CN and additive and Cu(OAc) ·H O as the oxidant, the product was
DMSO, H O turned out to be the most appropriate (Table 1, obtained in 95% yield in water as the solvent (Table 1, entry 7).
2
2
6
2
3
2
2
2
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a
Table 2 Substrate scope
a
Reaction conditions: Substrate 1 (1 equiv., 0.5 mmol), acrylate derivatives 2 (3 equiv., 1.5 mmol), [{RuCl
2
(p-cymene)}
2
] (5 mol%), Cu(OAc)
2
·H
2
O
b
(1 equiv., 0.5 mmol), KPF
6
(10 mol%) in water (2.0 mL) at 120 °C for 24 h. DCE was used as the solvent.
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Scheme 2 Possible reaction mechanism.
1
7
The effects of oxidants, additives and catalysts on the reactivity
On the basis of previous mechanistic reports, a plausible
were studied. An aerobic oxidative alkenylation with stoichio- mechanism for the ruthenium-catalyzed oxidative vinylation–
metric amounts of Cu(OAc) ·H O proved to be effective among annulation is illustrated in Scheme 2. The reaction proceeds
2
2
various terminal oxidants.
The use of silver(I) salts such as AgOAc and Ag
by N–H assisted C–H bond ruthenation of the substrate 1 to
pro- form a ruthenacycle complex A. Subsequent migratory inser-
2
CO
3
vided less satisfactory results (Table 1, entries 8 and 9) and a tion of the acrylate, along with β-hydride-elimination leads to
poor result was obtained when K was used as an oxidant intermediate C which reductively eliminates to alkenylated
Table 1, entry 10). Use of KPF and AgSbF as an additive product D. Finally the desired product (3a–t) is obtained by an
proved to be efficient in this reaction (Table 1, entries 11 and intramolecular aza-Michael addition reaction of D under the
2). Screening the catalyst yielded [{RuCl (p-cymene)} ] as the reaction conditions.
best among RuCl (PPh , RuCl (COD) and Pd(OAc) (Table 1,
entries 13–15). Decreasing the amount of catalyst below
mol% led to insufficient outcomes. Predictably, the reaction Conclusions
2 2 8
S O
(
6
6
1
2
2
2
3
)
3
2
2
5
didn’t proceed in the absence of catalyst (Table 1, entry 16).
With the optimized reaction conditions identified, we next
examined the scope and versatility of this reaction using
different derivatives of N-aryl pyridazinediones and N-aryl
phthalazinediones (Table 2). The substrates with both elec-
tron-donating and electron withdrawing groups on aryl rings
reacted smoothly and resulted in the corresponding products
In summary,
a
highly efficient [{RuCl (p-cymene)} ]/
2 2
Cu(OAc) ·H O/KPF system in water as an environmentally
2
2
6
benign, nontoxic reaction medium for tandem oxidative C–H
bond alkenylation, aza-Michael addition reactions of N-aryl
pyridazinediones and N-aryl phthalazinediones with acrylates
has been reported in an atom- and step-economical fashion.
3
a–q in moderate to high yields. The excellent chemo- and
site-selectivity of the ruthenium catalyst was illustrated by suc-
cessful C–H/N–H functionalization with substrates bearing a
range of substituents such as fluoro, bromo, and methyl. The
reaction was not successful with methyl methacrylate (3u). To
further explore the potential of this methodology for the syn-
thesis of indazole derivatives, we investigated the reaction with
pyrazolidinone backbone, 1-phenyl-3-pyrazolidinone, and the
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
corresponding indazole derivatives 3r and 3s were obtained in We gratefully acknowledge the financial support from the
moderate yields.
Research Council of the University of Tehran and the Iran
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National Science Foundation (INSF, no. 96008622). We thank
Dr Karol Gajewski, Natural Resources Canada, for helpful com-
ments on this work.
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