Microwave assisted solvent-free C-H amination by silica-supported manganese dioxide

Article abstract of DOI:10.1016/j.tetlet.2016.04.061

An effective and convenient method has been developed for the preparation of 1-unsubstituted 1H-indazoles via C-H amination of N-acetylhydrazones in the presence of a catalytic amount of manganese dioxide under microwave irradiation. This new method featured easy operation and relatively short reaction-time.

Full text of DOI:10.1016/j.tetlet.2016.04.061

Accepted Manuscript
Microwave assisted solvent-free C–H amination by silica-supported manganese
dioxide
Sufen Cao, Wenhu Duan
PII:
S0040-4039(16)30422-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.04.061
TETL 47561
Reference:
Tetrahedron Letters
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28 January 2016
17 April 2016
18 April 2016
Please cite this article as: Cao, S., Duan, W., Microwave assisted solvent-free C–H amination by silica-supported
manganese dioxide, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.04.061
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Microwave assisted solvent-free C–H amination by silica-supported manganese
dioxide
Sufen Caoa and Wenhu Duana,b,*

1
Tetrahedron Letters
Microwave assisted solvent-free C–H amination by silica-supported manganese
dioxide
Sufen Caoa and Wenhu Duana,b,
a School of Pharmacy, East China University of Science & Technology, Shanghai 200237, PR China
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An effective and convenient method has been developed for the preparation of 1-unsubstituted
1H-indazoles via C‒H amination of N-acetylhydrazones in the presence of a catalytic amount of
manganese dioxide under microwave irradiation. This new method featured easy operation and
relatively short reaction-time.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
C–H amination
1H-Indazole
Microwave assisted
Silica-supported manganese dioxide
1. Introduction
The abundance of 1H-indazole ring systems in bioactive
agents interests the synthetic community in the synthesis of its
derivatives. Axitinib (Fig. 1A) is a launched VEGFR-2 (FLK-
1/KDR) inhibitor for cancer treatment;1 GSK-2269557 (Fig. 1B)
selectively inhibits PI3Kδ;2 LY-2874455 (Fig. 1C) inhibits the
FGFR kinase family;3 and GDC-0810 (Fig. 1D) is an estrogen
receptor destabilizer.4 Syntheses of 1H-indazoles via direct C–H
amination without palladium catalyst where hydrazones are
converted to 1H-indazoles by various reagents have been
reported (Scheme 1).5-9 Some methods require an oxygen
atmosphere and suffer from long reaction-time.6, 8 It is noted that
a free NH in the indazole moiety can be served as a start point to
prepare various N-substituted derivatives; more importantly, a
NH may also participate in the ligand-protein interactions. For
example, the NH in the indazole moiety of pictilisib forms one
hydrogen bond with the PI3Kγ (PDB ID: 3DBS).10 However,
these reported palladium-free methods are only applicable to the
synthesis of N-aryl substituted 1H-indazoles (Scheme 1),5-9
leaving the synthesis of 1-unsubstituted 1H-indazoles as an
unmet task. Therefore, we wished to develop a new approach to
access 1-unsubstitued 1H-indazoles.
According to Zhang’s work,8 a nitrogen radical was generated
by Fe(III) to initiate the reaction and the resulting Fe(II) was
oxidized by O2 to regenerate Fe(III). An oxidant that could
generate a nitrogen radical without affecting the C=N double
bond in a substrate will be suitable for the reaction. Besides,
———
Figure 1. 1H-Indazole derivatives of pharmaceutical importance.1-4
 Corresponding author. Tel.: +86-021-50806032; fax: +86-021-50806032; e-mail: whduan@simm.ac.cn

2
Scheme 1. 1-Aryl-1H-indazoles constructed by C–H activation reaction.5-9
Scheme 3. (i) Preparation and oxidation of 3. Reaction condition: (a)
TEA, n-BuOH, 120 oC, 4.5 h, argon atmosphere, ground 4Å molecular sieve,
80.0%; (b) MnO2, argon atmosphere, ground 4Å molecular sieve, 60.8%. (ii)
A tentative mechanism for the formation of 5.
easy removal and storage of the oxidant would also be a practical
concern. Pure oxygen was excluded for its gaseous nature.
We first chose active MnO2 as the oxidant. Unfortunately,
oxidation of (diphenylmethylene)hydrazine (1) by active MnO2
gave benzophenone instead of 1H-indazole 2. The mechanism for
this reaction might be (Scheme 2): 1) transferring one electron to
MnO2, the substrate transformed into a nitrogen radical
intermediate which underwent tautomerism to give a benzhydryl
radical; 2) the benzhydryl radical was assumed to abstract one
hydroxyl group from O=MnOH generated from the reduction of
MnO2, affording diazenyldiphenylmethanol; 3) the subsequent
O–H bond cleavage by MnO2 yielded an oxygen radical; and
finally 4) accompanied by an emission of nitrogen gas,
benzophenone was formed. This was considered as the driving
force of this undesired reaction. To this end, the amino group in
the substrate 1 was protected to replace the N‒H bond with a
N‒X bond (X could be C or S), which was expected to hamper
the formation of nitrogen gas.
Although this reaction did not give the desired product, it
provided us some useful information: MnO2 was able to oxidize
the substrate without affecting the C=N double bond, and a
nitrogen radical could be generated.
2. Result and discussion
To verify this notion, we investigated a model reaction
(Scheme 4), the oxidation of benzophenone phenylhydrazone
15
(6).5-9,
It has been reported that 6 could be converted to
benzophenone (63%) and biphenyl (34%) by 19.7 equiv of active
o
MnO2 at 80 C in benzene.15 We proposed that there were two
possible ways to control the reaction. 1) As shown in Scheme 4,
the reaction pathways diverged at the nitrogen radical
intermediate. The crux was the tautomerism between the nitrogen
radical and the benzhydryl radical. where the reactivity and
stability of the radicals affected their population. 2) According to
Bhatnagar’s work,15 the formation of benzophenone required the
participation of MnO2 in two oxidative steps. The first oxidation
converted the substrate 6 to the common intermediate, a nitrogen
radical, and the second oxidation afforded benzophenone.
Therefore, we varied the oxidant/substrate ratio and found that
when 1.0 equiv of MnO2 was applied, the cyclized product 7 was
obtained in a yield of 28.2%, along with benzophenone in a yield
It has been reported that by the treatment of Pb(OAc)4 and
subsequent BF3·OEt2, N-benzoyl-hydrazones could be converted
into N-benzyl-1H-indazoles.9, 11-13 In these reactions, the nitrogen
lone pair electrons attacked the phenyl ring to furnish the
indazole skeleton. The model substrate 3 (Scheme 3) was
prepared
from
benzophenone
and
benzylhydrazine
14
dihydrochloride (4). The oxidation of 3 by γ-MnO2 gave a
dehydrogenation product 5, which had a large conjugated system.
o
of 48.3% under microwave irradiation at 130 C. In contrast, the
o
unprotected substrate 1 was converted to benzophenone at 50 C
when l.0 equiv of MnO2 was used under microwave irradiation.
Compared to substrate 1, substrate 6 might benefit from the
conjugation provided by its aryl group on the nitrogen atom.8
Therefore, a protecting group should be installed to provide a
conjugated system and no vicinal hydrogen which would
facilitate the formation of the undesired product. Acetyl, which
could be readily removed by acidic hydrolysis, was chosen as the
protecting group since a carbonyl could provide p orbitals for
conjugation and insulate the radical from methyl hydrogens.
Benzophenone and hydrazine hydrate were heated in ethanol
to give hydrazone 1, and subsequent acetylation afforded 8
(Scheme 5)16. A mixture of 8, γ-MnO2 (1.0 equiv), and ground
o
4Å molecular sieve subjected to microwave irradiation at 210 C
for 30 minutes afforded 2 in 53.6% yield and benzopheone in
6.5% yield. An attempt to reduce the oxidant/substrate ratio was
impeded by the poor homogeneity of the reaction mixture.
Thereby, we tried silica-supported MnO2,17 which would make
the oxidant more dispensed.
Scheme 2. A proposed mechanism for the formation of benzophenone.

3
Scheme 4. The reaction pathway diverged at nitrogen radical intermediate.
maximum conversion of the starting material together with a
minimum formation of the byproduct would give the best
outcome of cyclization. Therefore, we fixed the oxidant/substrate
ratios to 0.08. Next, we shortened the reaction times (entry 5 and
entry 6). No significant difference was observed for these two
entries. To determine the isolated yields, we repeated entry 5 and
entry 6 (entry 12 and entry 13) and isolated every compounds. To
our delight, a mixture of silica-supported MnO2 (0.08 euqiv) and
Scheme 5. Preparation and oxidation of N'-(diphenylmethylene)aceto-
hydrazide (8). (a) Hydrazine hydrate, EtOH, p-TsOH.H2O, reflux, 6.5 h,
88.7%; (b) toluene, acetic anhydride, 100 oC, 1 h, 77.4% (c) MnO2, ground
4Å molecular sieve.
o
8 subjected to microwave irradiation at 150 C for 15 minutes
afforded cyclized products in 87.5% yield (Table 1, entry 12).
Heating 8 with silica gel alone under the same condition did not
produce a trace of 2 or 9.
The Rf value of benzophenone and 3-phenyl-N-acetylindazole
were close, and multiple development was needed to separate
these two compounds on TLC plate. Therefore, we used HPLC to
monitor the reactions during the optimization of the reaction
conditions. A standard sample of 3-phenyl-N-acetylindazole 9
was prepared by acetylation of 2.
In addition, commercially available MnO2 (Table 1, entry 11)
could also oxidize the substrate to the cyclized products under
microwave irradiation, but at a higher temperature (210 oC vs 150
oC in entry 12) and more MnO2 (34.5 equiv vs 0.08 equiv in entry
12) was needed.
First, we set the reaction times to 45 minutes and varied the
oxidant/substrate ratios in the first four entries. The conversion of
the starting materials seemed to be practically unchanged in entry
2‒4 (Table 1). When more MnO2 was used, the formation of
benzophenone increased (Table 1, entry 1‒4). We thought a
Table 1
Optimization of reaction conditionsa
Entry Temperature
(oC)
Oxidant/substrate Reaction time
Percentage
of 8
Percentage
of 2
Percentage
of 9
Percentage of
benzophenone
Yield of
cyclized
products
(%)
Notes
ratio (equiv)
(min)
1
2
3
4
5
150
150
150
150
150
0.04
0.08
0.13
0.19
0.08
45
45
45
45
15
11.7
3.0
2.8
3.2
3.2
17.2
19.2
29.4
37.2
23.4
67.2
73.0
63.2
52.7
69.9
3.7
4.3
4.3
6.0
3.1
-
-
-
-
-
A, B
A, B
A, B
A, B
A, B

4
6
150
170
190
210
210
210
150
150
0.08
34.5
34.5
34.5
34.5
34.5
0.08
0.08
30
45
45
45
15
30
15
30
2.5
53.1
30.2
4.4
10.2
2.4
6.7
0
20.5
1.6
71.5
42.1
62.1
74.6
74.9
75.2
60.0
77.3
5.3
2.8
3.4
7.7
4.8
6.8
2.4
10.9
-
A, B
B, C
B, C
B, C
B, C
B, C
A, D
A, D
7
-
8
4.0
-
9
12.8
9.5
-
10
11
12
13
-
15.1
27.5
10.9
-
87.5
88.2
a ZORBAX Eclipse Plus column (C18, 4.6×150 mm, 5 μm); MeCN : H2O = 45:55 to MeCN : H2O =70:30 in 50 min; 0.5 mL/min; detecting wavelength: 254 nm;
reference wavelength: 360 nm; retention time: 8: 15.46 min, 2 : 50.65 min, 9 : 17.38 min, benzophenone: 28.22 min.
A: MnO2 prepared according to the known procedure with minor modificaiton17 (for detail, see supplementary material)
B: The content of the reaction mixture was determined by HPLC and expressed as percentage of peak area
C:MnO2 purchased from Sinopharm Chemical Reagent Co., Ltd. (China)
D: Isolated yield
Table 2
Synthesis of 3,6-disubstitued idazoles
Entry
R1
R2
Temperature MnO2
Reaction
time (min)
Yield of
Yield of
Yield of
Yield of
(A/C ring fused
product):
Yield of
cyclized
products
(%)
(oC)
(equiv)
11 (%)a
12 (%)a
13 (%)a
14 (%)a
(B/C ring fused
product)
1
OMe
Me
Cl
OMe
Me
Cl
150
150
150
150
230
210
210
150
150
150
150
150
150
0.08
0.08
0.08
0.08
0.08
0.20
0.20
0.08
0.08
0.08
0.08
0.08
0.08
5
61.8
66.7
50.1
50.7
-
27.2
18.1
31.3
27.1
33.9
13.3
51.2
19.3
12.0
19.1
14.3
-
-
-
-
89.0
84.8
81.4
77.8
33.9
66.5
65.5
86.8
89.1
78.2
83.0
55.2
46.9
2
5
-
-
-
3
5
-
-
-
4
F
F
5
-
-
-
5
NO2
NO2
H
NO2
H
30
10
10
10
10
10
10
10
10
-
-
-
6
-
-
53.2
14.3
9.7
27.6
19.1
14.3
-
20:80
78:22
72:28
32:68
47:53
57:43
56:44
46:54
7
NO2
H
-
-
8
OMe
H
43.4
16.6
17.4
33.0
30.8
21.7
14.4
32.9
22.6
21.4
24.4
20.3
9
OMe
H
10
11
12
13
Cl
H
Cl
F
H
H
F
-
4.9
a Isolated yield
With the optimized reaction condition, we then investigated
the substrate scope of the reaction (Table 2 and Table 3). Since
the reaction is a redox reaction, the electronegativity of the
substituents affected the reaction substantially. The electron-
donating substituents favored the reaction while the electron
withdrawing substituents retarded the cyclization. The substrate
10a, with two methoxy substituents, gave cyclized products in
yields of the cyclized products dropped to 66.5% and 65.5%,
respectively. The dinitro-substituted substrate 10e (Table 2, entry
5) gave a low yield (33.9%), albeit a harsh reaction condition was
employed. The electron-deficient dipyridine compound 15 also
gave a low yield (21.5%, Table 3). β-Substituted naphthelene
derivative 18 gave a higher yield (87%) than the sterically
crowded α-substituted naphthelene derivative 21 (35.4%, Table
3). Moderate regioselectivity (Table 2, entries 6‒13) was
observed for the asymmetric substrates. The electronegativity of
the substituents rather than the configuration of the starting
materials seemed to govern the orientation of the cyclization,
o
89.0% yield after 5 minutes of microwave irradiation at 150 C
(Table 2, entry 1). The mononitro-substituted substrates, 10f and
10g (Table 2, entries 6 and 7), required longer reaction time and
elevated temperature to achieve complete conversion, and the

5
Shanghai
Science
and
Technology
Commission
Table 3
(1315431901300) for their financial support.
Amination of different aryl hydrogens
References and notes
1.
2.
Grünwald, V.; Merseburger, A. S. Onco. Targets Ther. 2012, 5,
111.
Down, K.; Amour, A.; Baldwin, I. R.; Cooper, A. W.; Deakin, A.
M.; Felton, L. M.; Guntrip, S. B.; Hardy, C.; Harrison, Z. A.;
Jones, K. L. J. Med. Chem. 2015, 58, 7381.
Zhao, G.; Li, W. Y.; Chen, D.; Henry, J. R.; Li, H. Y.; Chen, Z.;
Zia-Ebrahimi, M.; Bloem, L.; Zhai, Y.; Huss, K. Mol. Cancer
Ther. 2011, 10, 2200.
Lai, A.; Kahraman, M.; Govek, S.; Nagasawa, J.; Bonnefous, C.;
Julien, J.; Douglas, K.; Sensintaffar, J.; Lu, N.; Lee, K. J. J. Med.
Chem. 2015.
3.
4.
5.
6.
7.
Kashiwa, M.; Sonoda, M.; Tanimori, S. Eur. J. Org. Chem. 2014,
4720.
Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J. Org. Chem. 2013,
78, 3636.
Yu, J.; Lim, J. W.; Kim, S. Y.; Kim, J.; Kim, J. N. Tetrahedron
Lett. 2015, 56, 1432.
8.
9.
Zhang, T. S.; Bao, W. L. J. Org. Chem. 2013, 78, 1317.
Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc. 1965, 3048.
10. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.;
Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S.
A. J. Med. Chem. 2008, 51, 5522.
11. Lee, F. Y.; Lien, J. C.; Huang, L. J.; Huang, T. M.; Tsai, S. C.;
Teng, C. M.; Wu, C. C.; Cheng, F. C.; Kuo, S. C. J. Med. Chem.
2001, 44, 3746.
12. Park, J. W. Patent WO 2007065010 A2, 2007.
13. Kuo, T. H.; Lin, T. H.; Yang, R. S.; Kuo, S. C.; Fu, W. M.; Hung,
H. Y. J. Med. Chem. 2015, 58, 4954.
Substrate Temperature
(oC)
Reaction time
(min)
Yield of cyclized
product (%)
15
18
21
150
150
190
45
45
45
21.5
87.0
35.4
14. Fatiadi, A. J. Synthesis 1976, 1976, 65.
15. Bhatnagar, I.; George, M. V. J. Org. Chem. 1967, 32, 2252.
16. Somogyi, L. Tetrahedron 1985, 41, 5187.
17. Liu, K. T.; Shih, M. H.; Huang, H. W.; Hu, C. J. Synthesis 1988,
715.
which implied an E-Z isomerization prior to the cyclization.
Microwave irradiation of 10f and silica-supported MnO2 at 150
oC for 5 minutes gave a mixture of isomers, 10f and 10g. In this
reaction, 10f would encounter three energy barriers (Table 2,
entry 6) : first, when the temperature rose to 150 oC, 10f
overcame the energy barrier of the isomerization, equilibrium
between 10f and 10g was expected; second, the mixture was
further heated to a higher temperature and eventually overcame
the potential barrier of the cyclization of the more electron-rich
ring, the unsubstituted ring in this case, giving 14f; and finally,
the third energy barrier was overcome at an even higher
temperature, both 12f and 14f were accessible at this stage while
14f had the higher reaction rate. The regioselectivity of this
reaction was an overall result of isomerization and cyclization
affected by reaction temperature and the substituents on the
phenyl rings.
Supplementary Material
Supplementary data
(experimental procedures
and
characterization data for the compounds 1, 2, 3, 5, 7‒9, 10a‒10m,
11a‒11d, 11h‒11m, 12a‒12k, 13h‒13m, 14f‒14k, 14m and
15‒22) can be found, in the online version, at
Deprotection of cyclized products was exemplified by the
acidic hydrolysis of 1-acetylindazole 9. After cyclization, the
crude product was added to a mixture of MeOH and 6N HCl and
heated at reflux for an hour, giving 1H-indazole 2 in 83.6% yield
in two steps.
Conclusion
In conclusion, we developed an efficient and simple method to
synthesize 1-unsubstituted 2-aryl-1H-indazoles via direct C–H
amination. All reagents could be easily handled in open air.
Acknowledgments
We gratefully thank the National Natural Science Foundation
of China (81273365, 81573271, 81422047, 81321092, and
81473243), National Science & Technology Major Project “Key
New
Drug Creation
and Manufacturing
Program”
(2014ZX09304002-008-001 and 2012ZX09301001-007), the

6
Highlights
Solvent and palladium free microwave-assisted
direct C‒H aminiation was reported.
N-Unsubstituted 1H-indazoles instead of N-aryl
1H-indazoles were constructed.
Tuning the reaction condition and substrates altered
the reaction pathway.