Photocatalyst-free Synthesis of Indazolones under CO2 Atmosphere

Article abstract of DOI:10.1002/asia.201900306

A convenient photocatalyst-free method for the synthesis of redox-active 1,2-dihydro-3H-indazol-3-one derivatives from (2-nitroaryl)methanol and amines was developed. The reaction proceeded efficiently at room temperature by irradiation of UV light under CO₂ atmosphere (1.0 atm, flow) without any photocatalysts or additives. This mild, operationally simple method shows wide functional tolerance. The carbamate formed in situ from CO₂ and amine is proposed to be the key of this reaction. Some of these compounds synthesized by the present method were found to exhibit high anticancer activities, which can lower the viability of cancerous cell lines such as HeLa, MCF-7 and U87.

Full text of DOI:10.1002/asia.201900306

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Photocatalyst-free Synthesis of Indazolones under CO2
Atmosphere
Authors: Tianbao Yang, Huiai Lu, Renhua Qiu, Ling Hong, Shuang-
Feng Yin, and Nobuaki Kambe
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Photocatalyst-free Synthesis of Indazolones under CO2
Atmosphere
Tianbao Yang,† Huiai Lu,¶ Renhua Qiu,*,†,‡ Ling Hong,*,¶ Shuang-Feng Yin,† Nobuaki Kambe*,†,‡
Abstract: A convenient photocatalyst-free method for the synthesis
of redox-active 1,2-dihydro-3H-indazol-3-one derivatives from (2-
nitroaryl)methanol and amines was developed. The reaction
proceeded efficiently at room temperature by irradiation of UV light
under CO2 atmosphere (1.0 atm, flow) without any photocatalysts or
additives. This mild, operationally simple method shows wide
functional-tolerance. The carbamate formed in-situ from CO2 and
amine is proposed to be the key of this reaction. Some of these
compounds synthesized by the present method were found to exhibit
high anticancer activities, which can lower the viability of cancerous
cell line such as Hela, MCF-7 and U87.
In Scheme 1, route (a), aldehyde intermediates were
synthesized under light or under strong acidic conditions and
subsequent cyclization with amines gave indazolones. In route (e),
these two step were performed concomitantly by irradiation under
aqueous media including a buffer. We also examined the reaction
of (2-nitrophenyl)methanol with amines under light using various
acid additives and found that carboxylic acids promoted this
reaction (eq. 1). These results also imply that weaker acids are
more suitable. During the optimization of this reaction conditions,
we found that the desired product 3a was obtained in high yield
when the reaction was run under CO2 atmosphere. CO2 is a green
and environmental, sustainable, and ideal C1 resource.[8]
Although, liquid CO2 has been employed as a unique solvent for
organic compounds and applied to synthetic reactions, use of CO2
as a mediator for organic reactions is rare.[9] The overall
transformation of the present reaction includes C-N[10] bond and
N-N bond constructions[7b,11] via C(sp3)-H and N-H bonds
cleavage by UV light irradiation under CO2 atmosphere (1.0 atm,
flow), to furnish indazolones in up to 96% yield in only one step
without any photocatalyst, acid, or base. The reaction pathway is
discussed based on control experiments. The anticancer activities
of products are also evaluated.
Indazolones[1] attract attention by their biological activities (Figure
1), and their heterocyclic skeleton was found in anti-inflammatory
agents[2], 5-lipoxygenase inhibitors[3], hypolipidemic agents (N2--
butylindazolone)[4] or antitumor agents in human tumor cells[5].
Until recently, four synthetic routes for indazolones were known
as shown in Scheme 1 (a-d).[6] However these routes need
tedious multistep operations from common starting materials (2-
nitrophenyl)methanol and some routes suffered from low yields.
Quite recently, photo-induced efficient synthetic method was
published as shown in Scheme 1 (e1)[7] while our similar project
is ongoing. Therefore, we herein disclose our study for
straightforward
synthesis
of
indazolones
from
(2-
nitroaryl)methanol and alkyl amine under UV light and CO2
atmosphere (e2).
Figure 1. Selected examples of biological active 2-substitued indazolones.
Scheme 1. Synthesis of indazolones.
[†]
Mr. T.B. Yang, Dr. R.H. Qiu, Prof. S.F. Yin, Prof. N. Kambe
State Key Laboratory of Chemo/Biosensing and Chemometrics,
College of Chemistry and Chemical Engineering, Hunan University,
Changsha, 410082, P. R. China
E-mail: renhuaqiu@hnu.edu.cn (R.Q.).
[‡]
[¶]
Dr. R.H. Qiu, Prof. N. Kambe
Graduate School of Engineering, Osaka University, Suita, Osaka,
565-0871, Japan
E-mail: kambe@chem.eng.osaka-u.ac.jp (N. K.).
Ms. H.A. Lu, Prof. L. Hong
College of Biology, Huazhong University of Science and
Technology, Wuhan, 430074, Hubei, P. R. China
E-mail: lhong@mail.hust.edu.cn (L. H.)
The reaction was run using the 26 W UV lamp (300-400 nm)
by irradiating
a
THF solution (4.0 mL)
of
a
(2-
nitrophenyl)methanol 1a and an amine 2a in a 10 mL bottle
through a filter to select 350-380 nm light with a continuous
introduction of CO2 gas at rt (see SI for optimization of
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10.1002/asia.201900306
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conditions). As shown in eq. 1, 3a was obtained in 91% yield after
24 h. When the reaction was performed using CH3COOH,
CCl3COOH, or CF3COOH under nitrogen, the yield was
decreased to 84%, 80%, 0%, respectively. The structure of 3a
was confirmed by single-crystal X-ray analysis (see the structure
in Table 1).[12] It is worthy to note that 3a was found to be effective
for 5-lipoxygenme (5-LPO).[3] Under the optimization conditions,
we then explored the scope of substrates. As shown in Table 1,
3-F-, 4-Cl-, 4-Br- and 4-I-benzylamines reacted with 2-nitrobenzyl
alcohol (1a) to afford the corresponding products 3b3e in 75%,
78%, 75% and 57% yields, respectively. Benzylamines bearing a
methyl or tert-butyl group exhibited higher yields (3f3h, 96%,
81%, 83%). Introduction of an electron-withdrawing CF3 group
resulted in moderate yields (3i, 3j, 51%, 43%). Electron-donating
p-methoxy and p-amino groups (3k, 83%, 3m, 93%) provided
better yields comparing with m-methoxy groups (3l, 57%). These
results indicate that substituents on the aromatic ring exert a clear
-Methyl benzylamine and -methyl
Table 2 summarizes the results of reactions using alkyl amines
without aromatic rings (Table 2). Simple primary and secondary
alkyl amines reacted with 2-nitrobenzyl alcohol giving rise to
4a4e in moderate to good yield (58-85%). Notably, 4b was found
to be effective as an inhibitor in both 5-lipoxygenme (5-LPO) and
cyclooxygenase (CO) by oral dose.[3-4] The present one-operation
procedure (63%) is operationally simple and provides an efficient
method with high atom-economy in comparison with the reported
method (see SI).[14] Although, tert-butylamine gave no desired
product due to the steric hindrance, laurylamine having a long
carbon chain gave an excellent yield (4f, 80%). Aminoethers and
an aminoalchol also yielded the expected products (4g4i, 4k
70%, 76%, 90%, 65%). N-Boc-protected ethylenediamine reacts
with 2-nitrobenzyl alcohol to afford 4j in high yield (82%).
Alkylamines carrying a nonaromatic ring such as cyclopropyl,
tetrahydrofuranyl, pyranyl, and cyclohexenyl group underwent
cyclization to afford the corresponding products in good yields (4l,
4m, 4n, 4o, 94%, 83%, 78%, 73%).
naphthalene-methyl amine also gave the desired products 3n
(46%) and 3o (34%), albeit in somewhat lower yields due to the
steric hindrance. Not only benzylamines, alkyl amines, such as
phenethylamine and 4-phenylbutylamine, also reacted with 2-
nitrobenzyl alcohol efficiently (3p, 3q, 73%, 83%). Besides, alkyl
amines having a thienyl or furfuryl ring also provided 3r3t in
moderate to good yields (65%, 68%, 81%). To our delight,
tryptamine, a core structure of bioactive compounds possessing
high potential for the treatment of various diseases such as
migraine, obesity and tumors[13], gave the desired product 3u in
69% yield. Gram-scale reaction was carried out using the flow
photoreaction apparatus by mixing CO2 and THF solution of 1a
(7.0 mmol) and 2a (8.4 mmol) under irradiation of 350-380 nm
light, and the desired product 3a was obtained in 73% yield (1.14
g) with high selectivity (see SI).
Table 2. Substrates Scope with Alkyl Amines without Aryl Ring [a]
.
[a] 1 (0.2 mmol), 2 (0.24 mmol), 4 mL THF, 26 W UV lamp, 24 h; isolated yield.
Table 1. Substrates Scope of Alkyl Amines with (Hetero)aryl Ring[a]
.
Introduction of a halide atom on the aromatic ring of 2-
nitrobenzyl alcohol 1 resulted in low yields (5a, 5b, 41%, 33%),
while methyl and methoxy substituents did not affect the reaction
giving 5c and 5d in 57% and 66% yield, respectively. 2-
Nitrobenzyl alcohol 1 possessing a naphthalene, furan, thiophene
ring at the para position also afforded the desired products
(5e5g) in 73%, 56%, 25% yield, respectively.
Table 3. Substrates Scope of Substituted 2-Nitrobenzyl Alcohol [a]
.
[a] 1a (0.2 mmol), 2a (0.24 mmol), 4 mL THF, 26 W UV lamp with a filter (350-
380 nm), 24 h; isolated yield. [b] 7 mmol scale reaction.
[a] 1 (0.2 mmol), 2 (0.24 mmol), 4 mL THF, 26 W UV lamp, 24 h; isolated yield.
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Indazolones are attractive heterocyclic compounds possessing
high bioactivities.[2-5] Therefore, we selected 28 compounds in 100
M and subjected them to preliminary screening for anticancer
activities in Hela (human cervical cancer cell), EJ and MDA-MB-
231, MCF-7 (human breast cancer cell), PC-3 and U87. Using
CCK-8 assay, it was shown that compounds 3a, 3c, 3d, 3f, 3i, 3q
and 4e can lower the viability of cancerous cell line such as Hela,
MCF-7 and U87 as shown in Figure 2. The further investigation
about their bioactivities is still under research in our lab (detailed
bioactivity experiments see SI).
decreased sharply during 0-5 hour as the product was formed.
The concentration of the benzylammonium carbamate gradually
decreased as the benzylamine 2a was consumed. Next, the same
reaction was monitored (0-16 h) with ON/OFF switching of
irradiation and the yield of product 3a was plotted in Figure 3b.
This result clearly shows that the reaction promoted by UV light
irradiation.
Scheme 2. Control experiments.
Figure 3. (a)Time course (0-12 h) calculated by 1H NMR. (b)Time course with
ON/OFF irradiation (0-16 h) calculated by GC analysis.
Figure 2. Anticancer Activities of Compounds in Cancerous Hela, MCF-7, and
U87 cell lines (100 M).
The following control experiments were performed to probe the
reaction mechanisms. Benzylamine absorbed CO2 quickly to form
the corresponding benzylammonium N-benzylcarbamate
quantitatively (Scheme 2a). As mentioned in Scheme 2b,
irradiating a mixture of 2-nitrobenzyl alcohol and a small excess
of the carbamate yielded 3a in 94% under N2 atmosphere and the
reaction did not proceeded without light. Interestingly, the use of
benzamine-hydrochloride salt instead of the carbamate gave no
desired product (Scheme 2c). Without CO2 or carbamate, no
reaction takes place under N2 atmosphere (Scheme 2d),
indicating CO2 is a key to promote this reaction efficiently.
Addition of TEMPO or BHT suppressed the reaction (Scheme 2e),
indicating the radical process may be involved. Interestingly,
cyclopropylmethanamine reacted with 1a in the presence of only
5 mol% benzylammonium carbamate affording product 4l having
a cyclopropyl group in 65% yield (Scheme 2f) with a trace amount
of 3a. These results suggest that CO2 may play a role as effective
“weak acid” by forming ammonium carbamates in the present
reaction. CO2 can be removed easily after the reaction.
Scheme 3. Mechanistic hypotheses.
With these control experiments and a reported literature[15], we
proposed a possible mechanism in Scheme 3. CO2 quickly reacts
with benzylamine (2a) to form the carbamate (intermediate A).
Under UV light irradiation, 2-nitrobenzyl alcohol (1a) affords the
corresponding nitroso benzene (intermediate B).[16] Then these
two intermediates react to generate compound D. Subsequent
intramolecular addition of amine to nitroso group affords E. This
intermediate E eliminates water to form F which gives the product
(3a) by tautomerism.
In summary, a simple, scalable, and efficient method for the
synthesis of the indazolones from primary amines and (2-
Figure 3a shows the time course of the reaction of 1a with 1.2
equivalent of 2a using the same apparatus. The benzyl alcohol 1a
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10.1002/asia.201900306
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nitroaryl)methanols under light is described, in which C(sp3)-H
and N-H bonds are cleaved and C-N and N-N bonds are
constructed. This reaction proceeds at ambient temperature and
pressure under CO2 atmosphere using a variety of benzylamines
and alkylamines. This reaction is promoted by an ammonium
carbamate ([RNH3]+[OC(O)NHR]-) generated in situ from RNH2
and CO2 as a weak acid, and any other additives such as
transition metals, photocatalysts, acids or bases are not needed.
Furthermore, CO2 can be easily removed from the reaction
system and the present procedure is suitable for large scale
production. Some of these compounds synthesized by the
present method were found to exhibit potent anticancer activities,
which can lower the viability of cancerous cell line such as Hela,
MCF-7 and U87.
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Acknowledgements
The authors thank the Natural Science Foundation of China
(21676076, 21725602, 21878071), Hu-Xiang High Talent of
Hunan Province (2018RS3042), and Recruitment Program for
Foreign Experts of China (WQ20164300353) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: photocatalyst-free • metal-free • indazolones •
synthetic methods • anticancer
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Entry for the Table of Contents (Please choose one layout)
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Tianbao Yang,† Huiai Lu,¶ Renhua
Qiu,*,†,‡ Ling Hong,*,¶ Shuang-Feng
Yin,† Nobuaki Kambe*,†,‡
Page 1. – Page 4.
Photocatalyst-free Synthesis of
Indazolones under CO2 Atmosphere
Photo-promoted synthesis of 1,2-dihydro-3H-indazol-3-one derivatives was
accomplished by treatment of (2-nitroaryl)methanol with diverse amines under CO2
(1.0 atm, flow) atmosphere without any photocatalyst. The present method is
operationally simple and affords good yields under mild conditions. Some products
showed potent bioactivities as redox-active 5-lipoxygenase inhibitors, and lowered
the viability of cancerous cell line such as Hela, MCF-7 and U87.
This article is protected by copyright. All rights reserved.