Room-Temperature, Metal-Free, and One-Pot Preparation of 2H-Indazoles through a Mills Reaction and Cyclization Sequence

Article abstract of DOI:10.1002/chem.201902242

The Mills reaction and cyclization of readily available 2-aminobenzyl alcohols and nitrosobenzenes using thionyl bromide provided 2H-indazoles in up to 88 % yields. In the metal-free process, acetic acid played a crucial role for the both Mills reaction and cyclization. A brominated 2H-indazole could also be obtained through the one-pot sequence.

Full text of DOI:10.1002/chem.201902242

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Accepted Article
Title: Room-Temperature, Metal-Free and One-Pot Preparation of 2H-
Indazoles via Mills Reaction and Cyclization Sequence Masaru
Kondo,* Shinobu Takizawa, Yuzhao Jiang, Hiroaki Sasai
Authors: Masaru Kondo, Shinobu Takizawa, Yuzhao Jiang, and Hiroaki
Sasai
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Room-Temperature, Metal-Free and One-Pot Preparation of 2H-Indazoles
via Mills Reaction and Cyclization Sequence
Masaru Kondo,*[a] Shinobu Takizawa,[a,b] Yuzhao Jiang,[a] Hiroaki Sasai[a]
Abstract: The Mills reaction and cyclization of readily available 2-
various substituents at the C3 position of indazole). Herein, we
demonstrate an operationally simple, one-pot, and metal-free
aminobenzyl alcohols and nitrosobenzenes using thionyl bromide
provided 2H-indazoles in up to 88% yields. In the metal-free process, synthesis of 2H-indazoles using 2-aminobenzyl alcohols,
acetic acid played a crucial role for the both Mills reaction and
cyclization. A brominated 2H-indazole could also be obtained via the
one-pot sequence.
nitrosobenzenes, and brominating agents such as PBr3 or SOBr2
in acetic acid at room temperature.
Indazoles are a useful class of N-heteroaromatic compounds
because they are crucial structural motifs of unnatural
pharmaceuticals
and
biologically
active
compounds,[1]
particularly, bioisosteres for indoles and benzimidazoles.[1e]
A
large number of 2H-indazole derivatives have been
demonstrated for use as important biologically active
compounds[1c-h] such as niraparib (PARP inhibitor)[2] and liver X
receptor agonist,[3] in addition to fluorescent agents for cellular
imaging in the field of chemical biology (Figure 1). [4] Because of
the high utility of N-substituted indazoles, much attention has
been devoted to establish novel and efficient strategies for their
preparation. However, N-functionalization of indazoles often
results in a mixture of 1H- and 2H-indazoles because the latter
is thermodynamically disfavored in comparison with the former
(energy difference between them is 2.3 kcal/mol).[1e,5,6] Therefore,
regioselective construction of the 2H-indazole skeleton remains
a challenging task in organic synthesis.[4a,7]
Scheme 1. One-pot syntheses of 2H-indazoles.
We envisioned that the Mills reaction of 2-aminobenzyl alcohols
with nitrosobenzenes would efficiently furnish an azobenzene
intermediate in acetic acid, [8] which would be converted into 2H-
indazole via cyclization by a brominating agent, with easily
removable side products such as H2O, SO2, or HBr (Scheme 1d).
Figure 1. Examples of biologically active compounds and fluorophore bearing
a 2H-indazole backbone.
Recently, there have been a few remarkable reports on the one-
pot syntheses of 2H-indazoles. The synthesis involves
a
copper-catalyzed three-component reaction (Scheme 1a),[7a,b]
condensation, and Cadogan reductive cyclization using
organophosphorus reagents (Scheme 1b),[7c-f] or tandem
Scheme 2. Preliminary result for synthesis of 2H-indazole 4aa using Mills
reaction/cyclization
palladium-catalyzed
deacylative
cross-coupling
and
denitrogenative cyclization (Scheme 1c).[7g] However, these
reactions have inherent limitations such as the need for elevated
temperatures and transition-metal reagents in addition to the
narrow substrate scope (in particular, the difficulty in introducing
We preliminarily examined the Mills reaction of commercially
available 2-aminobenzyl alcohol 1a with nitrosobenzene 2a (2.0
eq.) in acetic acid, and cyclization of azobenzene 3a using PBr3
(1.5 eq.) at room temperature in a stepwise manner. These
reactions provided azobenzene 3a in 93% yield and 2-phenyl-
2H-indazole 4aa in 80% yield with high purity, respectively (74%
yield in 2 steps). This result encouraged us to investigate a one-
pot sequence combining the Mills reaction and cyclization.
Fortunately, the desired product 4aa was obtained in 72%
overall yield in this tandem reaction, without detrimental effects
(Scheme 2).
[a]
[b]
Dr. M. Kondo, Dr. S. Takizawa, Y. Jiang, Prof. Dr. H. Sasai,
The Institute of Scientific and Industrial Research (ISIR), Osaka
University, Mihogaoka, Ibaraki-shi, Osaka 567-0047 (Japan)
E-mail: mkondo@sanken.osaka-u.ac.jp
https://www.sanken.osaka-u.ac.jp/labs/soc/socmain_english.html
Dr. S. Takizawa
Artificial Intelligence Research Center, ISIR, Osaka University
Supporting information for this article is given via a link at the end of
the document.
On the basis of the abovementioned finding, we optimized the
reaction conditions (the type of additive and its ratio) to improve
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10.1002/chem.201902242
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the yield in the cyclization step (Table 1). In the absence of the
additive, 2H-indazole 4aa was not formed (entry 1). When PBr3
or SOBr2 was used as the brominating reagent, 4aa was
obtained in good yield (entries 2 and 3). Chlorinating agents
(entries 4 and 5: PCl3, SOCl2), Appel reaction conditions[9] (entry
6: I2/PPh3), and a strong acid[10] (entry 7: trifluoroacetic acid)
were less effective for this procedure. Increasing the amount of
SOBr2 to 3.0 eq. improved the yield of 4aa slightly (entry 8). In
order to demonstrate the scalability of this methodology, a gram-
scale reaction was carried out under the optimal conditions to
obtain 4aa in 80% yield (entry 9).
meta- or ortho- position, furnished the corresponding products
4ac and 4ad in 72% and 66% yields, respectively. Other 4-
halonitrosobenzenes 2e and 2f having a fluoro or a bromo group
were also effectively transformed into the desired 2H-indazoles
4ae and 4af (81% and 80% yields, respectively). Treatment with
another electron-deficient nitrosobenzene 2g bearing an
ethoxycarbonyl group provided 4ag in the highest yield (88%).
The use of 2h with an electron-donating methyl group as the
substrate under the optimal conditions led to the formation of
2H-indazole 4ah in 77% yield.
Next, we then turned our attention to the scope of 2-
aminobenzyl alcohols 1b-1j bearing various substituents on the
aromatic ring (Scheme 4). 2-Aminobenzyl alcohols with an
electron-withdrawing chloro group at the 4- and 5-positions
afforded the desired 2H-indazoles 4ba and 4ca in 52% and 74%
yields, respectively. The reaction of nitrosobenzene 2a with
electron-rich 2-aminobenzyl alcohols [R1 = 4-MeO (1d); 3-MeO
(1e)] gave 4da and 4ea, which was converted into liver X
receptor agonist 5 by arylation at the C3 position, as shown in
Scheme 5.[11] To suppress undesired side reactions when using
1d and 1e, the less reactive PBr3 was preferred over SOBr2.
Table 1. Optimization of reaction conditionsa
Yield [%]
in 2 stepsb
Entry
Additive
Eq.
1
2
-
-
-
PBr3
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
72
3
SOBr2
PCl3
75
4
66
5
6c
SOCl2
I2 + PPh3
TFAg
61
-
-
7
8d
9d,f
SOBr2
SOBr2
82 (80)e
80e
aGeneral reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol) in AcOH (0.5 mL) at r.t.
for 18 h, followed by treatment with additive (0.15 mmol) at r.t. for 1 h. b1H NMR
yield using trimethoxybenzene as an internal standard. cI2 (0.15 mmol), PPh3 (0.15
mmol), 1H-imidazole (0.2 mmol) were used. dSOBr2 (0.3 mmol) was used. eIsolated
overall yield. fOne gram of 1a was used. gTrifluoroacetic acid.
aReaction conditions: 1 (0.1 mmol), 2a (0.2 mmol) in AcOH (0.5 mL) at r.t. for 18 h, followed
by treatment with SOBr2 (0.3 mmol) at r.t. for 1 h. bIsolated overall yield. cPBr3 (0.4 mmol)
was used instead of SOBr2.
Scheme 4. Scope of 2-aminobenzyl alcoholsa
aReaction conditions: 1a (0.1 mmol), 2 (0.2 mmol) in AcOH (0.5 mL) for 18 h at r.t., followed
by treatment with SOBr2 (0.3 mmol) for 1 h at r.t. bIsolated overall yield.
Notably, various C3-substituted indazoles could be synthesized
by utilizing commercially available 1-(2-aminophenyl)ethanol 1f
and 2-aminobenzhydrol 1g; in these cases, C3-methyl and
phenyl 2H-indazoles 4fa and 4ga were obtained in moderate
yields. Moreover, the reaction of nitrosobenzene 2a with
electron-deficient 2-aminobenzhydrols 1h-1j [R2 = 4-ClC6H4 (1h);
3-ClC6H4 (1i); 2-ClC6H4 (1j)] gave the corresponding products
4ha-4ja (51-71% yields). Additionally, electron-rich and sterically
bulky starting materials 1k and 1l [R2 = 4-MeOC6H4 (1k); 2-
Scheme 3. Scope of nitrosobenzenes
With the optimized reaction conditions in hand, we next
investigated the scope of substrates for this reaction system.
Initially, we evaluated a wide range of nitrosobenzenes 2
(Scheme 3). p-Chloronitrosobenzene 2b reacted with 2-
aminobenzyl alcohol 1a to give the desired product 4ab in 82%
yield. Nitrosobenzene 2c and 2d, which has chloro substituent at
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10.1002/chem.201902242
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naphtyl (1l)] were converted into desired 2H-indazoles 4ka and
4la in acceptable yields. Finally, the use of 1m bearing a CF3
group allowed the formation of fluorescent 2H-indazole 4ma in
76% yield.[12]
with dearomatization of the benzene ring by the acetate anion.In
conclusion, we have developed a metal-free and operationally
simple method for the synthesis of 2H-indazoles via Mills
reaction and cyclization. The present reaction is applicable to
both non-substituted 2H-indazoles and C3-substituted 2H-
indazoles, which has been
a long-standing challenge in
synthetic chemistry. The one-pot 2H-indazole synthesis,
followed by bromination, provides synthetically useful 3-
brominated 2H-indazoles. Further investigation into the reaction
mechanism and the practical application of this protocol for other
N-heteroaromatic compounds are in progress.
Scheme 5. Synthesis of liver X receptor agonist 5
Experimental Section
To increase the utility of this reaction, we investigated the one-
pot synthesis of 3-bromo-2H-indazole, which can be transformed
into a variety of 3-functionalized 2H-indazoles (Scheme 6).[13] As
expected, 2H-indazole 4aa was obtained first, which upon
subsequent treatment with bromine provided 3-bromo-2H-
indazole 6 in 64% overall yield over 3 steps.
General procedure for one-pot synthesis of 2H-indazole via
Mills reaction and cyclization sequence
A solution of 2-aminobenzyl alcohol 1a (12.3 mg, 0.1 mmol) and
nitrosobenzene 2a (21.4 mg, 0.2 mmol) in acetic acid (0.5 mL)
was stirred for 18 h, then treated with SOBr2 (23 μL, 0.3 mmol)
for 1 h. The reaction mixture was neutralized with saturated
NaHCO3 aq. solution and extracted with AcOEt. The combined
organic layer was dried over Na2SO4, filtrated, and evaporated
under vacuum. The crude residue was purified by silica column
chromatography (Hexane/AcOEt = 95/5) to afford 2H-indazole
4aa (15.5 mg, 80%) as a white solid.
Scheme 6. One-pot synthesis of 3-bromo-2H-indazole 6
To gain mechanistic insight into the key cyclization step, the
following control experiment was performed. When cyclization of
the intermediate azobenzene 3a was carried out in
dichloromethane using SOBr2, 2H-indazole 4aa was not formed.
This result indicated that acetic acid would also play a crucial
role in the cyclization step as well as the Mills reaction (Scheme
7a). Judging from the reaction outcome, the cyclization would
proceed via intramolecular SN2 cyclization, as shown in Scheme
7b. Initially, bromosulfinilation of the OH group by SOBr2 occurs,
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP18K14221 in Grant-in-Aid for Young Scientists, JP16K08163
in Grant-in-Aid for Scientific Research (C), JP18H04412 in
Middle Molecular Strategy, Iketani Science and Technology
Foundation. We acknowledge the technical staff of the
Comprehensive Analysis Center of ISIR, Osaka University
(Japan).
Keywords: indazole · one-pot reaction · nitrogen heterocycles ·
metal-free· cyclization
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Chemistry - A European Journal
COMMUNICATION
Layout 2:
COMMUNICATION
Masaru Kondo,* Shinobu Takizawa,
Yuzhao Jiang, Hiroaki Sasai
Page No. – Page No.
Room-Temperature, Metal-Free and
One-Pot Preparation of 2H-Indazoles
via Mills Reaction and Cyclization
Sequence
The Mills reaction and cyclization of readily available 2-aminobenzyl alcohols and
nitrosobenzenes using thionyl bromide provided 2H-indazoles in up to 88% yields.
In the metal-free process, acetic acid played a crucial role for the both Mills reaction
and cyclization. A brominated 2H-indazole could also be obtained via the one-pot
sequence.
This article is protected by copyright. All rights reserved.