Base promoted peroxide systems for the efficient synthesis of nitroarenes and benzamides

Article abstract of DOI:10.1016/j.tetlet.2019.151076

A useful and efficient approach for the synthesis of nitroarenes from several aromatic amines (including heterocycles) using peroxide and base has been developed. This oxidative reaction is very easy to handle and afforded the products in good yields. Formation of benzamides from benzylamine was also successfully carried out with this metal-free catalytic system in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2019.151076

Tetrahedron Letters 60 (2019) 151076
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Base promoted peroxide systems for the efficient synthesis of
nitroarenes and benzamides
Sampa Gupta , Alisha Ansari a,b, Koneni V. Sashidhara a,b,
a
⇑
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India
Academy of Scientific and Innovative Research, New Delhi 110025, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A useful and efficient approach for the synthesis of nitroarenes from several aromatic amines (including
heterocycles) using peroxide and base has been developed. This oxidative reaction is very easy to handle
and afforded the products in good yields. Formation of benzamides from benzylamine was also success-
fully carried out with this metal-free catalytic system in good to excellent yields.
Ó 2019 Elsevier Ltd. All rights reserved.
Received 3 May 2019
Revised 19 August 2019
Accepted 21 August 2019
Available online 22 August 2019
Keywords:
Aniline
Nitrobenzene
Benzyl amine
Benzamide
Oxidation
Base
Peroxide
Introduction
Nitro compounds are considered as an ‘ideal intermediates’ for
the synthesis of commercially important chemicals like dyes, per-
fumes, and pharmaceuticals [1–4]. There are numerous nitro con-
taining drugs available in the market such as nitroxoline,
oxamniquine, metronidazole, nitrofurantoin, chloramphenicol,
and nitrofural (Fig. 1) [5–10]. Due to environmental concerns the
preparation of nitro compounds in large scale by classical direct
nitration method is not a benign choice as it requires very harsh
conditions. Therefore, the direct oxidation of amines into nitro
compounds draws the attention of researchers as it is a safer pro-
cess than the classical method. Thus, several protocols have been
developed for the oxidative transformation of aryl amines to
Fig. 1. Representative nitro containing biologically active molecules.
nitroarenes (Fig. 2). Oxidants like H
2
O
2
[11], m-CPBA [12], HOF-
oxidation, use of harsh reaction conditions, poor yields, longer
reaction times, and poor selectivity. In addition to this, oxidative
CAN [13], TBHP with KI [14], peracetic acid [15], peroxyfluoroacetic
acid [16], sodium perborate with tungstophosphoric acid and
cetyl-trimethylammonium bromide (CTAB) [17], TBHP with CrS-2
method via H
friendly and cheaper reagent, since its only byproduct is water.
Due to the poor oxidizing nature of H , it needs to be coupled
2 2
O has been previously reported as environmental
[
18], TBHP with Rh
2
(cap)
4
[19], and H
2
O
2
with CaWO
4
[20], were
2 2
O
employed for this transformation. However, most of the reported
methods suffer from many shortcomings, such as uncontrolled
with a catalyst or a reagent to carry out the oxidation by activating
it to a reactive intermediate. Therefore, the development of mild
and effective protocol is highly desirable in this area.
On the other hand, amides are another important chemical
class, which are widely used as intermediates in various organic
syntheses and also an important linkage in proteins and peptides.
They are useful raw material for plastic industry, detergent,
⇑
Corresponding author at: Medicinal and Process Chemistry Division, CSIR-
Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road,
Lucknow 226031, India.
E-mail address: kv_sashidhara@cdri.res.in (K.V. Sashidhara).
https://doi.org/10.1016/j.tetlet.2019.151076
0
040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
S. Gupta et al. / Tetrahedron Letters 60 (2019) 151076
Fig. 2. Previous protocols for the synthesis of nitro benzenes and benzamides and our present study.
lubricants, pharmaceuticals, etc [21]. The traditional method for
the synthesis of amides usually involves the coupling reaction
between carboxylic acid/activated carboxylic acid with ammonia
tive catalyst [25] but it requires the protection of amine group with
BOC. Heterogeneous ruthenium catalysts Ru(OH) /Al [26,27]
and manganese oxide octahedral molecular sieves (OMS-2) [28]
are reported for oxidation of benzylamines to corresponding
x
2 3
O
[
22]. But handling problem with ammonia makes it a tedious job.
Besides this, rearrangement of ketoximes [23] and hydrolysis of
nitriles were also reported [24]. Due to reaction complications,
multiple reaction steps and formation of waste byproducts, these
methods are usually avoided.
The oxidation of benzylamines into benzamides is less dis-
cussed but is the most efficient and atom economic route for the
amides. Other than these reports RuCl
3 2 3
[29], CuBr-K CO /air [30],
ZnBr /TBHP or FeCl /TBHP [28], MnO [31] etc. catalysts have also
2
3
2
been employed. Recently, ligand free copper-manganese spinel
oxide catalysed amidation reaction has been reported from benzy-
lamine and aryl halides (Fig. 2) [32]. However, all these oxidations
of benzyl amine are metal-catalyst based oxidation reactions.
These metal catalysts are very expensive, produces unfavourable
4
amide synthesis. For this purpose in situ RuO is found to be effec-
Table 1
Results of the optimization study for oxidation of aniline to nitro benzene.a
o
yield (%)b
Entry
1c
Oxidant (equiv)
Base (equiv)
Solvent
Temp ( C)
time (min/h)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (2.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
–
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
Cs
2
CO
3
CO
3
CO
3
CO
3
CO
3
CO
3
(1.0)
(1.0)
(1.0)
(1.0)
(1.0)
(0.5)
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
rt
12 h
8 h
8 h
4 h
4 h
4 h
4 h
4 h
ND
28
49
72
89
68
70
65
ND
ND
74
84
90
72
87
21
ND
ND
c
2
40
80
80
80
80
80
80
80
80
80
rt
rt
rt
rt
rt
rt
rt
c
3
c
4
5
6
7
8
9
K
Na
–
2
CO
3
(1.0)
(1.0)
2
CO
3
4 h
4 h
10
11
12
13
14
15
16
17
18
Cs
Cs
Cs
2
CO
CO
CO
3
3
3
(1.0)
(1.0)
(1.0)
(1.0)
H O
2 2
H O
2 2
H O
2 2
H O
2 2
H O
2 2
H O
2 2
H O
2 2
H O
2 2
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
2
2
5 min
15 min
10 min
10 min
10 min
10 min
30 min
30 min
K
2
CO
3
Na
2
CO
3
(1.0)
(1.0)
K
2
CO
3
DMSO
Toluene
DCE
Cs
2
Cs
2
Cs
2
CO
3
CO
3
CO
3
(1.0)
(1.0)
(1.0)
Ethanol
a
b
c
All reactions were carried out using 1b (0.1 g, 0.93 mmol), TBHP (70 wt% in H
Isolated yields after purification.
Unreacted starting material recovered too. ND = no product.
2 2 2 2
O), H O (35 wt% in H O), solvent (4 mL) at indicated time.

S. Gupta et al. / Tetrahedron Letters 60 (2019) 151076
3
Table 2
Scope of the methodology for oxidative transformation of anilines to nitro benzenes.
Scheme 1. Scope of the methodology for oxidative transformation of
o-phenylenediamines.
and an eco-friendly metal-free protocol for the oxidation of pri-
mary amines to their corresponding amides using Cs
presence of TBHP.
2 3
CO in the
Results and discussion
Inspired from the literature reports, we planned to design an
oxidant system which could efficiently oxidize anilines to
nitrobenzenes under mild reaction conditions. The combination
of peroxides in basic medium may increase its oxidizing power.
Therefore, initially the reaction was performed by treating p-tolu-
idine (1b) as model substrate with TBHP and Cs CO using CH CN
2 3 3
as solvent at room temperature for 12 h, under the present reaction
condition, the reaction did not lead to the product formation
(Table 1, entry 1). Therefore, we conducted same reaction at
4
0 °C for 8 h, which produced 28% of the product yield with unre-
acted starting material (Table 1, entry 2). This result prompted us
to explore further for improving the yield of the product (2b). Then,
the reaction was performed by increasing the temperature to 80 °C,
the yield of the product was improved to 49% (Table 1, entry 3).
Upon increasing the amount of TBHP to 2.0 and 3.0 equiv, resulted
in the increased yield to 72% and 89%, respectively (Table 1, entries
4
2 3
–5). Subsequently, reducing the amount of Cs CO to 0.5 equiv,
waste, and are difficult to use in large scale. To the best of our
knowledge, only one protocol is available in the literature for
oxidative amidation of benzylamines under metal free conditions
deprived the yield to 68%. Whereas, other bases like K CO3 and
Na CO were unable to improve the yield (Table 1, entries 6–8).
2
2
3
Consequently, evaluation of the reaction without base or TBHP
failed to produce any product, which revealed that combination
of these reagent is indispensable for this reaction (Table 1, entries
9–10). The next set of reaction was performed to investigate the
role of oxidant by changing TBHP with H O . The reaction with
with TBHP/I
our minds, herein, we report a metal free, mild base promoted oxi-
dation of aromatic amines into nitroarenes using K CO in the
2
[33]. Keeping the above mentioned drawbacks in
2
3
presence of H
2
O
2
3
in acetonitrile (CH CN) at room temperature
2
2
Table 3
a
Results of the optimization study for oxidation of benzylamine to benzamide.
.
o
yield (%)b
Entry
1c
Oxidant (equiv)
Base (equiv)
solvent
temp ( C)
time (h)
H
H
H
2
O
2
O
2
O
2
2
2
(3.0)
(3.0)
(3.0)
K
K
2
CO
CO
3
3
(1.0)
(1.0)
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
CN
CN
CN
CN
CN
CN
CN
rt
12
8
8
4
4
4
4
4
4
ND
32
47
91
73
ND
ND
88
81
ND
c
2
3
2
40
80
80
80
80
80
80
80
80
c
Cs
Cs
Na
–
2
CO
3
(1.0)
(1.0)
(1.0)
4
5
6
7
8
9
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
–
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
2
CO
3
2
CO
3
Cs
Cs
Cs
Cs
2
CO
CO
CO
CO
3
(1.0)
(1.0)
(1.0)
(1.0)
2
2
2
3
3
3
DMF
DMSO
Toluene
1
0
4
a
b
c
All reactions were carried out using 3b (0.1 g, 0.71 mmol), TBHP (70 wt% in H
Isolated yields after purification.
Unreacted starting material recovered too. ND = no product detected.
2 2 2 2
O), H O (35 wt% in H O), solvent (4 mL) at indicated time.

4
S. Gupta et al. / Tetrahedron Letters 60 (2019) 151076
H
2
O
2
was completed within 5 min providing 2b in 74% yield
(Table 3, entry 4). Further changing Na
improve the yield (Table 3, entry 5). The role of TBHP and Cs
2
CO
3
as base did not
3
CO -
(Table 1, entry 11). Therefore, the reaction was repeated at room
2
temperature and it was found that within 15 min the reaction
afforded 2b in 84% yield (Table 1, entry 12). Encouraged from this
in this reaction were also evaluated. It was found that absence of
either of them in the reaction failed to furnish any product and
in the both cases starting material was recovered (3, entries 6–
7). Moreover, changing the solvent with DMF, DMSO provided 4b
with lower yield, while the reaction in toluene failed to afford
any product (Table 3, entries 8–10). To evaluate the role of atmo-
spheric air as an co-oxidant in the reaction, the reaction was per-
formed under both nitrogen and oxygen atmosphere. Under
nitrogen atmosphere, the reaction afforded 4b in <5%, whereas
under oxygen atmosphere, the reaction was complete in 1 h to
afford 4b in 88% yield. As there was no remarkable difference
between the yield of 4b under oxygen atmosphere and in open
air, we continued the reaction in the open flask.
result, in the next experiment K
Cs CO . To our delight, the addition of K
tion of 1b in CH CN and H , an exothermic reaction took place
2
CO
3
was used as base instead of
2
3
2
CO in the stirring solu-
3
3
2 2
O
and within 10 min, the reaction mixture turned into a yellow solid
providing 2b in 90% yield (Table 1, entry 13). Afterwards, changing
the base as Na CO provided 2b in low yield (Table 1, entry 14).
2 3
Further, the role of the solvent was screened and it was observed
that reaction furnished lower yield in DMSO and toluene, whereas
DCE and ethanol failed to provide any product (Table 1, entries 15–
1
8). Thus, the optimized condition that worked best in our hand
was treating 1b with 3.0 equiv of H , 1.0 equiv of K CO in CH -
2
O
2
2
3
3
CN as the solvent at room temperature for 10 min. The scope of the
protocol was tested with a variety of anilines (1) and it was grati-
fying to note that all the substrates afforded respective nitroarenes
Table 4
(2) in 65–94% yield (Table 2). The mono-substituted anilines (1b-
Scope of the methodology for oxidative transformation of benzylamines to
benzamides.
1
n) bearing substitution at ortho, para or meta position of the ring
smoothly afforded corresponding nitrobenzenes (2b-2n).
It was observed that electron-rich anilines provided nitro ben-
zenes with higher yields than corresponding halo analogues. Next,
the scope of the methodology was tested with various di-substi-
tuted anilines, which adequately produced nitro analogues (2o-
2
x) with good to excellent yields 70–80%. The electronic and steric
factor plays a crucial role in this reaction. It was observed that 2-
halo anilines (1m-1n) provided the nitroarenes with compara-
tively low yield, which might be due to steric hindrances. Further,
under the reaction conditions 4-nitroaniline successfully provided
1
,4-dinitrobenzene with 85% yield, however the reaction failed
with 2-nitroaniline. The conversion of 4-nitroaniline into 1,4-dini-
tro benzene (2y) is the quite remarkable. This methodology is
equally applicable to heterocyclic systemsand this was demon-
strated taking 5-amino-3-methyl-1-phenylpyrazole as an example,
wherein the desired product (2z) was found in 70% yield. Interest-
ingly, in case of o-phenylenediamines (1aa-1ab) the reaction
yielded 2-nitro anilines (2aa-2ab). However, further oxidation to
1
,2-dinitro benzene was not achieved (Scheme 1). This may be
due to the strong electron-withdrawing effect of nitro group of
2
-nitroaniline which prevents further oxidation.
Encouraged by these promising results, we tried to apply the
optimized reaction conditions for aliphatic amines as well. How-
ever, the aliphatic amines were not able to provide the nitro
derivative. Further, to explore the synthetic utility of the protocol,
we then carried out the reaction with benzylamines. Initialy, 4-
methoxybenzylamine 3b was treated under optimized reaction
2 2 2 3
condition [H O (3.0 equiv), K CO (1.0 equiv) as base at room tem-
perature], but even after 12 h the reaction was incomplete. There-
fore, the reaction temperature was increased to 40 °C, analysis
after 8 h revealed the formation of a product in minor amount with
most of the starting material was unconsumed. The reaction fur-
nished a white solid with 32% isolated yield which was spectrally
characterized as 4-methoxybenzamide (4b) instead of 1-meth-
oxy-4-(nitromethyl)benzene (Table 3, entry 2). The literature sur-
vey supported our observation that benzylic carbon is suceptable
towards oxidation and could oxidize in the presence of H
oxidant to provide benzamide as sole product.
2 2
O as
Most of the literature reported the use of either hazardous
reagents or metal-catalyst as an oxidant. Taking this challenge,
we then further optimized the reaction condition.
Therefore, the reaction was repeated by treating 3b with Cs CO
2 3
as base and increasing the reaction temperature to 80 °C for 6 h,
and this resulted in the formation of 4b in 47% yield (Table 3, entry
3
2 2
). The replacement of oxidant H O with TBHP resulted in the
completion of the reaction in 4 h to afford 4b with 91% yield

S. Gupta et al. / Tetrahedron Letters 60 (2019) 151076
5
With the optimized reaction conditions in hand, the general
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Appendix A. Supplementary data
[
(
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151076.