Efficient synthesis of 2-aryl-2: H -indazoles by base-catalyzed benzyl C-H deprotonation and cyclization

Article abstract of DOI:10.1039/d0cc05862a

A straightforward and efficient method for the preparation of 2-aryl-2H-indazoles from ortho-alkyl substituted azoxybenzenes is presented. The reaction proceeds through base-catalyzed benzyl C-H deprotonation and cyclization to afford 2-aryl-2H-indazoles

Full text of DOI:10.1039/d0cc05862a

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DOI: 10.1039/D0CC05862A
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Efficient synthesis of 2-aryl-2H-indazoles by base-catalyzed benzyl
C–H deprotonation and cyclization
Received 00th January 20xx,
Guo-Qing Jin, Wen-Xia Gao, Yun-Bing Zhou,* Miao-Chang Liu* and Hua-Yue Wu
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Previous work:
A straightforward and efficient method for the preparation of 2-
aryl-2H-indazoles from ortho-alkyl substituted azoxybenzenes is
presented. The reaction proceeds through base-catalyzed benzyl
C-H deprotonation and cyclization to afford 2-aryl-2H-indazoles in
good yields. This synthetic strategy can be applied to the
construction of several fluorescent and bioactive molecules.
O
O
N
N
Ar2
R
COOH
Ar1
Ar2
(a)
(b)
N
N
Ar1
N
N
1) Pd(OAc)2/K2S2O8
2) Pd/C, H2
R
O
N
N
Ar2
R
CHO
Ar1
Ar2
Ar1
1) Pd(TFA)2/TBHP
2) Pd/C, H2
Indazole is recognized as an important diazole compounds1
given its paramount importance in modern drug discovery.2
Particularly, 2-aryl-2H-indazoles are important synthetic
intermediates3 and crucial scaffolds found in various
biologically active molecules4 as well as fluorescent reagents
cellular imaging5 (Fig 1). Over the years, much attention has
been devoted to the development of methods for the
preparation of 2-aryl-2H-indazoles to address the ever-
increasing demands. One of classic approaches was the [3+2]
cycloaddition of benzynes with sydnones or diazocarbonyl
R
N2
O
N
N
Ar2
R
CO2R'
Ar1
Ar2
N
(c)
Ar1
N
[Cp*RhCl2]2/AgSbF6
PivOH
R
This work:
N
Ar1
Cat. CH3OK
N
Ar2
Ar1
N
(d)
Ar2
N
O
R
R
species.6
Another
synthetic
route
involved
Scheme 1. The synthesis of 2-aryl-2H-indazoles from
azoxybenzenes.
condensation/cyclization sequence was established, but it is
ineffective for the preparation of 3-substituted 2H-indazoles
and requires excessive explosive hydrazoates or tri-n-
butylphosophine.7 Recent advances demonstrated that
azobenzenes could serve as the starting material or key
intermediate in the synthesis of 2-aryl-2H-indazoles.8
Transition-metal-catalyzed C-H functionalization has
emerged as a powerful tool to construct 2-aryl-2H-indazoles. A
variety of transition metal catalysts including Rh,9 Co,10 Re,11
Pd12 have been successfully applied to the reactions between
azobenzenes and aldehydes to provide a straightforward
method to access this useful skeleton. In addition to aldehydes,
acrylates could also react with azobenzenes in the presence of
5 mol% of Rh catalyst and two equivalents of Cu(OAc)2.13
Despite its high efficiency, this protocol involving direct C−H
functionalization was limited to symmetrical azobenzenes and
R
HO
Cl
O
OMe
HO
N
OH
N
N
N
N
N
estogen receptor agonist
CF3
anti-inflammatory agent
OMe
liver X receptor agonist
(R = Cl, CN)
O
NHMe
O
NH2
often produced
unsymmetrical azobenzenes. To address the selectivity issues,
azoxybenzenes have been chose as substitute for
a mixture of regioisomers in case of
N
F
NH
N
N
HN
N
O
S
Me
O
viral polymerase inhibitor
N
N
a
niraparib (PARP inhibitor) fluorescent 2H-indazole
azobenzenes, enabling site-selective ortho-C−H bond
functionalization (Scheme 1). For instance, wang’s group
disclosed a palladium-catalyzed selective ortho-C−H acylation
of azoxybenzenes with α-oxocarboxylic acids, followed by
Fig 1. Some bioactive and fluorescent 2-aryl-2H-indazoles.
reductive cyclization to furnish 2H-indazoles (Scheme 1a).14
A
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
325035, China. E-mail: zyb@wzu.edu.cn, mcl@wzu.edu.cn
similar two-step synthetic route involving selective ortho-C−H
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
acylation of azoxybenzenes with aldehydes and reductive
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cyclization was also reported (Scheme 1b).15 Recently, You’s
group developed a one-pot synthesis of 2-aryl-2H-indazoles
through Rh-catalyzed selective C−H alkylation/decarboxylative
cyclization of azoxybenzenes with diazoesters (Scheme 1c).16
Despite its high efficiency and wide applicability, this protocol
involving ortho-C−H functionalization suffered from the use of
precious metals. To eliminate the need for precious metals, we
envisage the presence of a strong base would trigger the
R1
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DOI: 10.1039/D0CC05862A
N
N
N
O
CH3OK
DMF
R2
R2
N
R1
R3
R3
2
1
Cl
N
N
N
N
N
N
Cl
b
c
2b
2c
, 88%
, 67%
2a
, 98%
Cl
N
N
Br
CH3
N
N
N
N
nucleophilic
cyclization
of
ortho-alkyl
substituted
azoxybenzenes, leading to a wide range of 2-aryl-2H-indazoles
along with the release of H2O (Scheme 1d).
b
2d
2f
, 72%
, 95%
CH3
N
2e
F
, 70%
CH3
N
N
N
CH3
N
N
Table 1 Reaction optimization.a
2g
2h
2i
2l
, 91%
, 92%
, 94%
CH3
N
base, solvent
N
N
N
N
N
N
N
OCH3
N
NMe2
N
O
temp, time
atmoephere
c
b
2k
2n
2q
, 87%
, 90%
CH3
2j
, 87%
2a
1a
Cl
I
N
N
N
N
N
N
base
tBuOK
solvent
DMF
temp (oC)
90
yield (%)
70
35
54
28
0
entry
1
CF3
d
e
2m
2o
, 88%
, 49%
, 94%
2
tBuONa
KOH
DMF
90
F
CH3
N
N
N
N
N
3
DMF
90
N
Br
4
NaOH
DMF
90
f
2p
2s
2v
2r
, 90%
, 92%
, 95%
5
CH3
LiOH
DMF
90
N
N
N
N
6
K2CO3
Cs2CO3
CH3OK
CH3ONa
CH3OLi
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
CH3OK
DMF
90
0
N
N
CH3
CH3O
7
DMF
90
0
CF3
g
c
2t
2u
, 98%
, 98%
N
, 95%
8
DMF
90
98
16
trace
42
83
45
0
N
N
N
N
9
DMF
90
N
N
10
11
DMF
90
c
2w
, 94%
, 83%
CH3CN
DMSO
THF
90
Et
2x
, 92%
N
N
N
12
90
N
13
90
CH3
CH3
h
2z
, 51%, 89%
2y
14
, 52%
CCl4
90
aReaction conditions: 1 (0.3 mmol), CH3OK (20 mol%), DMF (2 mL),
15
n-hexane
DMF
90
0
90 oC, under N2 atmosphere, 8 h, isolated yields. bCH3OK (100 mol%).
16
cCH3OK (50 mol%). dCH3OK (100 mol%), 100 C. eCH3OK (50 mol%),
o
80
86
75
54
trace
73
100 oC. CH3OK (150 mol%), 120 oC. gCH3OK (30 mol%), 100 oC.
f
17
DMF
70
hDMSO as the solvent.
18b
19c
20d
DMF
90
bases (entries 2-8) revealed that the basicity of the base
served as an important factor in the reaction efficiency, and
the use of CH3OK as the base proved to be the best choice
(entry 8). The nature of the cation of the base was found to be
another significant factor (entries 9 and 10). Other polar
solvents such as CH3CN, THF and DMSO could also promote
this transformation, yet delivering inferior yields (entries 11-
13). However, switching the solvent to nonpolar CCl4 and n-
hexane completely shut down the reaction (entries 14 and 15).
Reducing the reaction temperature lowered the reaction
efficiency (entries 16 and 17). Control experiments
demonstrated that the presence of oxygen dramatically
depressed the yield (entries 18 and 19). Moreover, less CH3OK
led to low yield of 2a (entry 20).
DMF
90
DMF
90
aReaction conditions unless specified otherwise: 1a (0.3 mmol),
base (20 mol%), solvent (2 mL), 90 oC, under N2 atmosphere, 8
h, isolated yields. bUnder air atmosphere. cUnder O2
atmosphere. dCH3OK (10 mol%).
We initiated our investigations by employing 1-phenyl-2-(o-
tolyl)diazene 1-oxide (1a) as a model substrate to evaluate the
feasibility of direct nucleophilic cyclization to access 2-aryl-2H-
indazole (Table 1). Delightfully, we found that 70% yield of the
targeted product (2a) was obtained when the model reaction
was conducted in the presence of 0.2 equiv tBuOK in DMF at
90 oC under argon for 8 h (entry 1). Systematical screening for
Scheme 2. Scope for synthesis of 2-aryl-2H-indazoles.a
2 | J. Name., 2012, 00, 1-3
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group (products 2r and 2s), methoxy (product 2t) or trifluoromethyl
Having optimized the reaction conditions in hand, we
started to investigate the substrate scope of the
intramolecular cyclization (Scheme 2). Various R1 substituents
such as halogens, electron-neutral methyl, electron-donating
groups or electron-withdrawing group were all well tolerated
at different positions on the phenyl ring (products 2a-2m).
Steric hindrance showed no significant influence on the
efficacy of this transformation, as illustrated in the generation
of products 2f, 2i and 2j. On the other hand, a survey of R2
substituents was also investigated. The R2 substituents could
be halogens (products 2n-2q), methyl
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group (product 2u). Interestingly, a fused riDnOgIo: 1r0a.10h3e9t/eDr0oCcyCc0le58w62aAs
found to be was compatible with the reaction conditions (products
2v and 2w). In addition, 3-substituted 2H-indazoles (products 2x-2z)
could be also accessed by replacing the methyl with benzyl (R3= Ph)
or ethyl group (R3= CH3). It should be pointed out that higher CH3OK
loading or higher temperature was required for complete
conversion in some cases.
R
N
N
CH3OK (20 mol%)
90 oC, N2, 48 h
N
O
R
N
(1)
1a
R=H: , 8 mmol
solvent 1a
2dd
1dd
R=OMe:
, 8 mmol
DMF 75%
DMSO 96%
78%
89%
(I)
N
I
CF3
N
CO2H
oxidant
(2 equiv)
N
N
O
condition a
98%
N
Ph
Ref 15: condition c
95%
CH3OK (20 mol%)
DMF, 90 oC, 8 h, N2
N
N
1a
N
(2)
2a
0%
2a
3a
, about 10%
oxidant = benzoquinone or K2S2O8
CF3
total yield: 93%
A
, fluorescent 2H-indazole
(II)
OMe
CH3OK (20 mol%)
DMF, 90 oC, 8 h, N2
1a
2a
3a
(3)
N
N
I
Cl
K2S2O
K2S2O
K2S2O
K2S2O
8 (0.2 equiv):
8 (0.5 equiv):
8 (1.5 equiv):
90%
66%
22%
5%
4%
5%
7%
82%
OMe
16
OMe
c
Ref
on
i
t
8 (1.5 equiv): 0%
N
O
N
condition b
97%
condi
total yield: 80%
, liver X receptor agonist
Cl
N
N
B
CH3OK (20 mol%)
Ref
condi
16
DMF, 90 o
C
2aa
t
i
on
1a
1a
OMe
1a
2a
(4)
c
N2, 8 h
I
CN
83%
N
N
H O
(1 equiv): 9% 90%
2
H O
19% 67%
96% trace
(2 equiv):
(4 equiv):
2
H O
2
CH3OK (20 mol%)
DMSO, 90 o
C
total yield: 81%
, liver X receptor agonist
CN
2a
C
(5)
(III)
N2, 8 h
OMe
TEMPO
1,1-diphenylethylene
(2 equiv):
(2 equiv):
2a
2a
89%
94%
N
condition b
88%
N
N
OMe
N
O
MeO
2bb
MeO
Scheme 4. Gram-Scale reactions and control experiment.
Ref 17 NCS, microwave
77%
80 oC, air, CCl4, 30 min
BBr3, DCM
The important synthetic value of this protocol was further
illustrated by its application in the synthesis of several
fluorescent and bioactive molecules. For example, our method,
serving as a key step, enabled the synthesis of important
molecules including fluorescent 2H-indazole A, liver X receptor
agonist B and C,17 estogen receptor agonist D18 and anti-
inflammatory agent E19 (Scheme 3, I-IV). Furthermore, the
gram-scale synthesis of product 2a and 2dd demonstrated its
potential practicability (Scheme 4.1). Different from small-
scale reaction, gram-scale reaction required the extended
reaction time in DMSO instead of DMF as the solvent for
complete conversion. In addition to oxygen, the use of other
oxidants such as benzoquinone and K2S2O8 could suppress the
formation of the desired product (Scheme 4.2). The
examination on the amount of oxidant showed that the
product could not be completely inhibited until 1.5 equivalents
of oxidant was added (Scheme 4.3). It should be noted that the
presence of oxidants not only led to the formation of oxidation
product 3a but also inactivated the base CH3OK, thus
accounting for the low yield of 2a. The amount of water has a
significantly negative influence on the reaction conversion
N
-78 oC to rt, 12 h, N2
N
N
OH
N
OMe
80%
HO
MeO
Cl
total yield: 54%
, estogen receptor agonist
Cl
2cc
D
(IV)
N
condition b
91%
N
N
N
O
OMe
2dd
OMe
O
Br
Ref 18a: AgNO3/Na2S2O8
acetone/H2O, 76%
COOH
N
N
Ref 18b
N
N
Cu(acac)2/BHMPO
OMe
OMe
O
LiOH.H2O, 80oC
DMSO/H2O, 24h
N2, 82%
O
HO
Br
2ee
total yield: 57%
E,
anti-inflammatory agent
Scheme 3. The synthesis of several fluorescent and bioactive
o
molecules. Condition a: CH3OK (20 mol%), DMF (2 mL), 90 C,
N2, 8 h. Condition b: CH3OK (20 mol%), DMSO (2 mL), 90 oC, N2,
.
8 h. Condition c: Pd(dppf)Cl2 DCM (5 mol%), PPh3 (10 mol%),
Ag2CO3 (1 equiv), 50 oC, air, 16 h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Chapolikar, C. G. Devkate, K. D. Warad, A. P. Tayade, R. P.
(Scheme 4.4). Control reaction showed that this cyclization are
more likely to proceed via an anionic way (Scheme 4.5).
Based on above observations, a plausible mechanism for this
CH3OK-catalyzed cyclization of 1a is depicted in Scheme 5.
CH3OK deprotonates 1a to generate carbanion intermediate
M-1. The intramolecular nucleophilic cyclization of M-1
produces the intermediate M-2, followed by dehydration
isomerization reaction to provide the desired product 2a.
Obviously, M-2 hydrolyzes readily to starting material 1a,
accounting for the reaction why the reaction is sensitive to
water. On the other hand, M-2 can be oxidized to M-3 by
oxidant. Subsequently, nucleophilic attack of hydroxyl ion
toward M-3 to form acetal M-4 that is converted to M-5 with
elimination of water. Finally, M-5 was further oxidized to
product 3a.
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Pawar and A. J. Domb, Eur. J. Med. Chem., 2015, 90, 707.
DOI: 10.1039/D0CC05862A
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3
4
hydrolysis
Ph
N
H
Ph
N
N
N
-H2O
N
O
N
O
-OH
N
Ph
N
Ph
CH3OH
CH3OK
H
M-2
1a
M-1
2a
OH
[O]
CH3OK
N
Ph
N
Ph
N
Ph
N
-H2O
N
N
OH
N
[O]
N
Ph
OH
CHO
M-5
CO2H
3a
OH
M-3
M-4
OH
Scheme 5. Proposed mechanism.
5
6
In summary, we have successfully disclosed a green and
efficient method for the synthesis of 2-aryl-2H-indazoles
through base-catalyzed benzyl C-H deprotonation and
cyclization of ortho-alkyl substituted azoxybenzenes. In
contrast to previous transition-metal-catalyzed strategy, this
protocol employs cheap CH3OK as the base, eliminates the
need for oxidants and transition-metal catalysts. Remarkably,
the synthetic value and potential practicability of this protocol
are demonstrated by the synthesis of several fluorescent,
bioactive molecules and gram-scale reactions respectively.
We are grateful for financial support from the National
Natural Science Foundation of China (21901187, 21672164 and
21372177).
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Conflicts of interest
There are no conflicts to declare.
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Notes and references
1
(a) G. P. Lahm, D. Cordova and J. D. Barry, Bioorg. Med.
Chem., 2009, 17, 4127; (b) Y. Nomoto, H. Takai, T. Ohno, K.
Nagashima, K. Yao, K. Yamada, K. Kubo, M. Ichimura, A.
Mihara and H. Kase, J. Med. Chem., 1996, 39, 297; (c) R.-H. Li,
C.-K. Ding, Y.-N. Jiang, Z.-C. Ding, X.-M. An, H.-T. Tang, Q.-W.
Jing and Z.-Pi. Zhan, Org. Lett., 2016, 18, 1666; (d) H.-T. Tang,
K. Xiong, R.-H. Li, Z.-C. Ding and Z.-P. Zhan, Org. Lett., 2015,
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05862A
Cl
N
HO
OH
N
estogen receptor agonist
Ar2
Cat. CH3OK
N
N
Ar1
Ar2
N
Ar1
N
HO
-H2O
O
O
OMe
R
R
29 examples
up to 98% yield
No oxidants!
N
N
anti-inflammatory agent
etc
A facile method for the synthesis of 2-aryl-2H-indazoles by base-catalyzed benzyl C–H
deprotonation and cyclization is developed.