Palladium-catalyzed cyclizative carbonylation of azobenzenes toward 3H-Indazol-3-ones using formic acid as CO source

Article abstract of DOI:10.1016/j.tetlet.2018.02.006

A palladium-catalyzed cyclizative carbonylation of azobenzenes has been developed to access 1-acyl 2-aryl 3H-indazol-3-ones in moderate to good yields with good functional compatibility. This procedure proceeded with the sequential ortho-C–H carbonylation and cyclization, where formic acid served as the CO source. The practicability of this transformation was further increased by the employment of facilely available azobenzenes derivatives as one-handled starting materials.

Full text of DOI:10.1016/j.tetlet.2018.02.006

Accepted Manuscript
Palladium-Catalyzed Cyclizative Carbonylation of Azobenzenes toward 3H-
Indazol-3-ones Using Formic Acid as CO Source
Ning Gu, Song Sun, Jiang Cheng
PII:
S0040-4039(18)30163-1
https://doi.org/10.1016/j.tetlet.2018.02.006
TETL 49691
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
4 January 2018
30 January 2018
2 February 2018
Please cite this article as: Gu, N., Sun, S., Cheng, J., Palladium-Catalyzed Cyclizative Carbonylation of Azobenzenes
toward 3H-Indazol-3-ones Using Formic Acid as CO Source, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.02.006
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Palladium-Catalyzed Cyclizative
Carbonylation of Azobenzenes toward 3H-
Indazol-3-ones Using Formic Acid as CO
Source
Ning Gu,a Song Sun,a and Jiang Chenga,*

1
Tetrahedron Letters
Palladium-Catalyzed Cyclizative Carbonylation of Azobenzenes toward 3H-Indazol-
3-ones Using Formic Acid as CO Source
Ning Gu,a Song Sun,a and Jiang Chenga,*
aSchool of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Ke y Laboratory of
Fine Petrochemical Engineering, Changzhou University, Changzhou, 213164, P. R. China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A palladium-catalyzed cyclizative carbonylation of azobenzenes has been developed to access 1-
acyl 2-aryl 3H-indazol-3-ones in moderate to good yields with good functional compatibility.
This procedure proceeded with the sequential ortho- C-H carbonylation and cyclization, where
formic acid served as the CO source. The practicability of this transformation was further
increased by the employment of facilely available azobenzenes derivatives as one-handled
starting materials.
Available online
Keywords:
palladium-catalyzed
cyclizative carbonylation
1-acyl 2-aryl 3H-indazol-3-ones
ortho- C-H functionalization
.
Indazolones are ubiquitous in many synthetic and natural
products with biological interests.1 Moreover, they served as
analgesic,2 anticancer,3 antihypertensive, 4 and anti-inflammatory
5
agents.
The annulation of ortho- difunctionalized starting
materials provided straightforward pathways for constructing 3H-
indazol-3-ones. For example, Correa,6 and Park7 independently
reported the access of such frameworks via oxidative N–N bond
formation of 2-amino benzoic acid amide as the key step
(Scheme 1, eq 1). Conrad described the construction of 3H-
indazol-3-ones proceeding with Davis- Beirut Reaction.8
Recently, Shi developed the transformation of 2-nitro benzoic
acid amide in the presence of low-valent titanium reagent toward
3H-indazol-3-ones (Scheme 1, eq 2).9 The intramolecular C-N
bond formation provided an alternative pathway leading to 3H-
indazol-3-ones (Scheme 1, eq 3).10 Nevertheless, in all the
aforementioned procedures, it is sometimes commercially
unavailable in the case of more functional groups on the phenyl
ring of the ortho- disubstituted starting material to access product
with diversity and complexity. As such, the participation of
readily available starting material substrates with mono- handle
on the phenyl, such as azobenzene,11 showed its advantage in
cyclizative carbonylation catalyzed by cobalt, albeit under high
CO pressure (70 atm.) and reaction temperature (190 oC, Scheme
1, eq 4).12
intensive investigated in organic chemistry. Various carbon
monoxide surrogates were well developed, including metal
carbonyls,13 aldehydes,14 formamides,15 methyl alcohol and
so forth.16 Cacchi and Wu developed the using of formic
acid as the CO source in carbonylation reaction.17 To the
best of our knowledge, example on cyclizative carbonylation
Although CO is often used in carbonylation reaction as
the cheapest C1 sources, it is extremely limited in some
applications because of its toxic, flammable and odourless
characteristics. To overcome these disadvantages, recently,
the CO gas-free carbonylation procedures have been

2
Tetrahedron
of C(sp2)-H bond with formic acid as the CO source was
58%), and bromo (2i, 66%) tolerated well, which provided
handles for further functionalization. The structure of 2k
was further confirmed by X-ray crystallography study.19 To
our delight, the practicability was increased as this
procedure was applicable in a 2 mmol scale reaction with a
comparable yield (2a, 76%).
rarely reported or studied before.18 Herein, we wish to apply
this strategy to the Pd-catalyzed cyclizative carbonylation of
azobenzenes leading to 1-acyl 2-aryl 3H-indazol-3-ones in
moderate to good yields with good functional compatibility
(Scheme 1, eq 5).
Table 1. Screening the optimized reaction condition.a
Figure
1
Substrates scope of symmetric substituted
azobenzenes.a
entry
1
Pd source
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
PdCl2(PPh3)2-
PdCl2
oxidant
CuBr
base
yield (%)b
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
--
19
2
Cu(OAc)2
CuI
10
3
0
4
CuCl2
K2S2O8
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
--
15
5
0
6
83, 64c, 26d
7
76
73
71
0
8
9
Pd(acac)2-
--
10
11
12
13
14
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
Pd(OAc)2-
0
CuBr2
CuBr2
CuBr2
20
47
55
K2CO3
Na2CO3
a
Reaction conditions: azobenzene 1a (0.2 mmol), Pd source (10 mol %),
oxidant (1 equiv), base (1 equiv), HCOOH (6.6 equiv) and acetic anhydride
(2 mL), under 1 atm O2, 140 oC, 48 h. b Isolated yield. c Under air. d Under N2.
Initially, the reaction of azobenzene 1a (0.2 mmol),
formic acid (6.6 equiv), Pd(OAc)2 (10 mol %), CuBr (1.0
equiv) and Na2HPO4 o(1.0 equiv) in acetic anhydride (2 mL)
under oxygen at 140 C for 48 h was tested. Fortunately, the
cyclizative carbonylation product 2a was isolated in 19%
yield (Table 1, entry 1). Among the oxidants screened, such
as Cu(OAc)2 (10%), CuI (0%), CuCl2 (15%) and K2S2O8
(0%), CuBr2 was the best (83%, Table 1, entries 2-6). This
procedure became sluggish under either air (64%) or N2
(26%, entry 6) atmosphere. Replacing Pd(OAc)2 with
PdCl2(PPh3)2 (76%), PdCl2 (73%) and Pd(acac)2 (71%),
slightly decreased the reaction efficiency (Table 1, entries 7-
9). The reaction did not work at all in the absence of either
palladium or copper (Table 1, entries 10-11). The yield
dramatically decreased to 20% without base (entry 12). The
tested bases, such as K2CO3 (47%) and Na2CO3 (55%) was
inferior to Na2HPO4 (Table 1, entries 13 and 14).
a
Reaction conditions: substituted azobenzene 1 (0.2 mmol), Pd(OAc)2 (10
mol %), CuBr2 (1 equiv), Na2HPO4 (1 equiv), HCOOH (6.6 equiv) in acetic
anhydride (2 mL), under O2, 140 oC, 48 h. 1a (2 mmol) , Pd(OAc)2 (10
b
mol %), CuBr2 (1 equiv), Na2HPO4 (1 equiv), HCOOH (6.6 equiv) in acetic
anhydride (2 mL), under 1 atm O2, 140 oC, 48 h.
After the establishment of the optimized conditions, the
scope of symmetric azobenzenes was tested, as shown in
Figure 1. The reaction of para- substituted azobenzenes
provided the cyclizative carbonylation products in moderate
Next, the scope of anhydrides and unsymmetric
azobenzenes was studied, as shown in Figure 2. To our
delight, butyric, isobutyric and propionic anhydride
provided the cyclizative carbonylation products in moderate
yields (2b
azobenzenes, the cyclization preferred to regioselectively
take place on the less hindrance site in moderate yields (2h
66%; 2i, 67%), and no regioselective isomers were tested by
1HNMR and GC-MS. However, ortho- disubstituted
analogues failed to work under the procedure. To our
delight, 3,4- and 3,5-disubstituted analogues ran smoothly
under the procedure and 2j-2l were isolated in 57%, 49%
and 44% yields, respectively. Notably, some functional
-2g, 58-64%). In the case of meta- substituted
yields (2m-2o, 40-64%). Unfortunately, methylaryldiazenes
did not work under the procedure. Being tautomers of azos,
substituted benzalphenylhydrazines were also tested in this
reaction. However, they also failed to work. To our delight,
,
for unsymmetric azobenzenes with 2-methylphenyl (2p
,
43%), 2-methoxy (2r, 49%), the cyclization preferred to
take place in the phenyl with ortho- substituted group and no
regioselective isomers was detected by GC-MS and 1H
NMR. However, in the case of 2,6-dimethylphenyl
analogue, the cyclization took place in the phenyl without
substituted group and 2q was isolated in 68% yield.
groups, such as fluoro (2d, 61%), chloro (2e, 47%; 2h
,
67%), trifluoromethoxy (2f, 65%), ethoxycarbonyl (2i
,

3
Figure 2 Substrates scope of anhydrides.a
A tentative reaction mechanism is outlined in Scheme 3.
Firstly, a cyclopalladation occurs to activate the ortho- C-H bond
of benzene ring to provide the intermediate A. This step was well
confirmed in the ortho- C-H functionalization of azobenzenes.20
Second, palladacycle C is produced after migratory insertion of
CO, which is generated in situ from the reaction of formic acid
with acetic anhydride as the activator.21 Then, intermediate D is
formed whereby the sequential ligand exchange and reduction by
formic acid. Afterward, the formation of C(O)-N bond furnishes
the cyclization intermediate indazolone
E via reductive
elimination. Meanwhile, Pd(0) is released and oxidized to Pd(II)
by Cu(II) to enter the catalytic cycle. Finally, the acylation of
indazolone by acetic anhydride provides the final product 2.
In conclusion, we have developed a novel palladium-
catalyzed cyclizative carbonylation of readily available
azobenzenes with formic acid as the carbonyl source,
leading to 3H-indazol-3-ones in moderate to good yields.
This procedure proceeded with sequential ortho- C-H
carbonylation and cyclization. The practicability of this
transformation was further increased by the employment of
facilely available substituted azobenzenes as one-handled
starting materials.
a
Reaction conditions: azobenzene 1a (0.2 mmol), Pd(OAc)2 (10 mol %),
CuBr2 (1 equiv), Na2HPO4 (1 equiv), HCOOH (6.6 equiv) in anhydride (2
mL), under 1 atm O2, 140 oC, 48 h.
Acknowledgments
Scheme 2 Mechanism Study
We thank the National Natural Science Foundation of
China (No. 21572025), “Innovation & Entrepreneurship
Talents” Introduction Plan of Jiangsu Province, Natural
Science Foundation of Jiangsu Province (BK20171193), the
Key University Science Research Project of Jiangsu
Province (15KJA150001), Jiangsu Key Laboratory of
Advanced Catalytic Materials & Technology (BM2012110)
and Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center for financial support. S.S.
thanks the National Natural Science Foundation of China
(No. 21602019) and Young Natural Science Foundation of
Jiangsu Province (BK20150263) for financial support.
More experiments were conducted to gain some insights into
the reaction. The intra- and inter- molecular kinetical isotope
effect (KIE) was found to be 1.6 and 1.5, respectively (Scheme 2,
eqs 1 and 2). Thus, the cleavage of the ortho- C-H bond should
be involved as the rate-determining step in this transformation.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
Scheme 3 A tentative mechanism.
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5
1. Formic acid served as the CO source in this procedure.
2. Azobenzenes derivatives could be served as one-
handled starting materials.
3. This strategy features with good yields and good
functional group compatibility.