Catalyst-free and selective oxidation of pyridine derivatives and tertiary amines to corresponding N-oxides with 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane

Article abstract of DOI:10.1007/s13738-015-0776-8

The catalyst-free oxidation of various pyridine derivatives and tertiary amines to their corresponding N-oxides with 1,1,2,2-tetrahydroperoxy-1,2-diphenylethane as an efficient oxidant has been developed. The methodology proved to tolerate a number of functional groups. The reactions proceeded smoothly under solvent-free and mild conditions at room temperature. All the products were easily extracted from the reaction mixtures in excellent yields. Graphical abstract: The catalyst-free oxidation of various pyridine derivatives and tertiary amines to their corresponding N-oxides with 1,1,2,2-tetrahydroperoxy-1,2-diphenylethane as an efficient oxidant has been developed. The methodology proved to tolerate a number of functional groups. The reactions proceeded smoothly under solvent-free and mild conditions at room temperature. All the products were easily extracted from the reaction mixtures in excellent yields.

Full text of DOI:10.1007/s13738-015-0776-8

J IRAN CHEM SOC (2016) 13:645–651
DOI 10.1007/s13738-015-0776-8
ORIGINAL PAPER
Catalyst‑free and selective oxidation of pyridine
derivatives and tertiary amines to corresponding N‑oxides
with 1,2‑diphenyl‑1,1,2,2‑tetrahydroperoxyethane
Davood Azarifar1 · Boshra Mahmoudi1
Received: 9 June 2015 / Accepted: 2 November 2015 / Published online: 18 November 2015
© Iranian Chemical Society 2015
Abstract The catalyst-free oxidation of various pyri-
dine derivatives and tertiary amines to their corresponding
N-oxides with 1,1,2,2-tetrahydroperoxy-1,2-diphenyle-
thane as an efficient oxidant has been developed. The meth-
odology proved to tolerate a number of functional groups.
The reactions proceeded smoothly under solvent-free and
mild conditions at room temperature. All the products were
easily extracted from the reaction mixtures in excellent
yields.
Graphical abstract The catalyst-free oxidation of vari-
ous pyridine derivatives and tertiary amines to their corre-
sponding N-oxides with 1,1,2,2-tetrahydroperoxy-1,2-di-
phenylethane as an efficient oxidant has been developed.
The methodology proved to tolerate a number of functional
groups. The reactions proceeded smoothly under solvent-
free and mild conditions at room temperature. All the prod-
ucts were easily extracted from the reaction mixtures in
excellent yields.
Keywords Oxidation · Pyridine-N-oxide · 1,2-Diphenyl-
1,1,2,2-tetrahydroperoxyethane · Catalyst-free
Introduction
Heterocyclic N-oxides such as pyridine-N-oxide (PNO) and
its derivatives represent an important class of compounds
with ever-increasing importance owing to their useful-
ness as synthetic intermediates and biological value [1, 2].
Also, these compounds have been used as oxidants, auxil-
iary agents, protecting groups, and ligands in metal com-
plexes and catalysts [3–7], and as useful reagents in radi-
cal decarboxylations [1, 2]. In addition, a wide variety of
pyridine-N-oxides have been explored which exhibit anti-
HIV activity [8–10]. A number of pyridine-N-oxides such
as pyridine-N-oxide congener JPL-133 have been known
as active inhibitors towards HIV-1 strains targeting HIV-1
reverse transcriptase (RT) and/or HIV-2 strains [8–11].
Also, other closely related pyridine-N-oxide derivatives are
known which act against human cytomegalovirus.
The methods described in the literature for preparation
of pyridine-N-oxides are usually accomplished employing
peracids [12], such as peracetic acid, m-chloroperbenzoic
acid (MCPBA) [13–16], magnesium monoperphthalate
* Davood Azarifar
dazarifar@gmail.com; azarifar@basu.ac.ir
1
Faculty of Chemistry, Bu-Ali Sina University,
Hamedan 65178, Iran
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J IRAN CHEM SOC (2016) 13:645–651
[17], esters of N-hydroxy-2-thiopyridone [18], HOF.CH3N
complex [19], or through cycloaddition reactions [20–23],
and by ring transformation of isoxazoles [24].
Typical preparation
of 1,2‑diphenyl‑1,1,2,2‑tetrahydroperoxyethane
Over the last few decades, several approaches to PNO
have been developed using metal-based catalysts, aque-
ous hydrogen peroxide, and molecular oxygen as oxidants
desirable to the chemical industry due to the minimized
waste production associated with the stoichiometric rea-
gents [25–30]. However, many of these catalysts are toxic
and/or expensive which typically require special condi-
tions to produce reasonable yields. Dioxiranes have been
reported as versatile oxidizing agents to quantitatively and
preferentially oxidize the aromatic azines such as pyridines
and quinolines to the corresponding N-oxides [31–34].
Regarding the world-wide increasing concern on the
environmental care, the scientists are encouraged to develop
more eco-friendly processes which replace the hazardous
catalysts and reagents with more benign and green solid cat-
alysts. In the present research, we have developed a conven-
ient and catalyst-free approach for the conversion of various
pyridine derivatives and tertiary amines to their correspond-
ing N-oxides using 1,2-diphenyl-1,1,2,2-tetrahydroperox-
yethane as an effective and high potent green oxidant.
Following our previously reported procedure [40], this
compound was prepared from SbCl3-catalyzed reaction
of benzil with 30 % aqueous H2O2 as described below
(Scheme 1).
To a stirred solution of benzil (210 mg, 1 mmol) in
CH3CN (5 mL) was added SbCl3 (23 mg, 0.1 mmol) and
the resulting mixture was stirred for 5 min at room tem-
perature. Then, aqueous 30 % H2O2 (5 mmol) was added
to the reaction mixture and let to stir for 24 h at room tem-
perature. After completion of the reaction as monitored
by TLC, water (5 mL) was added and the product was
extracted with EtOAc (3 × 5 mL). The combined organic
layer was dried over anhydrous MgSO4 and evaporated
under reduced pressure. The residue was purified by silica-
packed column chromatography (hexane–EtOAc) to afford
pure product in 97 % yield (300 mg); mp 97–100 °C. Simi-
larly, other gem-dihydroperoxides examined in Table 2 for
comparison were prepared following the same procedure.
Typical procedure for oxidation of pyridines
and tertiary amines to corresponding N‑oxides
Experimental setup
To a solution of pyridine derivative 1 or tertiary amine 2
(1 mmol) in acetonitrile (5 mL) was added 1,2-diphenyl-
1,1,2,2-tetrahydroperoxyethane (1 g, 3 mmol). The result-
ing mixture was stirred at room temperature for an appro-
priate time (Table 2). After completion of the reaction as
monitored by TLC, the reaction mixture was diluted with
toluene (10 mL) and water (6 mL). The aqueous layer
which contained the product was separated from the
organic layer and evaporated under reduced pressure to
leave the product. The products were characterized on the
basis of their melting points, elemental analysis and IR, 1H
NMR and 13C NMR spectral analysis.
Materials and instrumentation
Material and instruments
Chemicals were purchased from Merck chemical company
and used without further purification. FT-IR spectra were
recorded on a Shimadzu 435-U-04 spectrophotometer (KBr
pellets). The NMR spectra were recorded on 90 MHz JEOL
FX 90Q, 200 MHz Varian and 400 MHz BRUKER spec-
trometers in CDCl3 or DMSO-d6 solutions using TMS as
internal standard. Melting points were determined in open
capillary tubes with a Stuart SMP3 apparatus and were
uncorrected.
Results and discussion
Caution Although we did not encounter any problem with
1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane and other
hydroperoxides, it is potentially explosive and should be
handled with precautions; all reactions should be carried
out behind a safety shield inside a fume hood and transition
metal salts or heating should be avoided.
In continuation of our ongoing research on the synthesis of
various hydroperoxides [35–40], and their applications as
high potent oxidants for various organic transformations
[41–48], we were encouraged to investigate the hitherto
unexplored oxidative potential of 1,2-diphenyl-1,1,2,2-tet-
rahydroperoxyethane for oxidative conversion of pyridines
Scheme 1 SbCl3-catalyzed
synthesis of 1,2-diphenyl-
1,1,2,2-tetrahydroperoxyethane
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647
Scheme 2 Oxidation of
pyridine derivatives and tertiary
amines to corresponding
N-oxides with 1,2-diphenyl-
1,1,2,2-tetrahydroperoxyethane
Table 1 Screening the conditions of the model oxidation of pyridine
1a to pyridine-N-oxide 3a with 1,2-diphenyl-1,1,2,2-tetrahydroperox-
yethane
The effects of solvent and the oxidant loading on the reac-
tion were screened using different solvents such as n-hex-
ane, Et2O, EtOAc, CH3CN, with different amounts of the
oxidant (Table 1). As seen in Table 1, we discovered that
the best result in terms of the yield (98 %) and reaction
time (3 min) were obtained when CH3CN was used as the
solvent of choice with using three equimolar amount of
the oxidant (entry 4). We also noticed that, using higher
and lower oxidant loadings resulted in reduced yields and
higher reaction times (entries 5 and 6).
Entry
Solvent
Oxidant (mmol)
Time (min)
Yield (%)a
1
2
3
4
5
6
n-Hexane
Et2O
3
3
3
3
4
2
120
120
60
3
25
45
65
98
95
65
EtOAc
CH3CN
CH3CN
CH3CN
8
15
Moreover, a comparison for the efficiency of the oxi-
dative activity of 1,2-diphenyl-1,1,2,2-tetrahydroperox-
yethane in oxidation of pyridine with several other pre-
viously reported gem-dihydroperoxides [40, 43], under
optimized conditions is presented. The results summarized
in Table 2 show that 1,2-diphenyl-1,1,2,2-tetrahydroperox-
yethane is superior in terms of yield, reaction time and easy
extraction of the pyridine oxide from the reaction mixture
by water due to its high solubility in water, whereas the
remaining oxidant and the reproduced benzil in the reaction
mixture both remained insoluble in water.
Conditions: pyridine (1 mmol), solvent (5 mL), r.t
a
Isolated yield
Table 2 Comparison of oxidative activity of 1,2 diphenyl-1,1,2,2-
tetrahydroperoxyethane with some various gem-dihydroperoxides in
the oxidation of pyridine to pyridine N-oxide
Entry
Oxidant
Time (min) Yield (%)
1
3
98
To establish the generality of the reaction, a series of
pyridine derivatives 1a–r and tertiary amine 2s–t bearing
different substituent groups were reacted with the oxidant
1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane under the
optimized conditions and the results are summarized in
Table 3. In general, the reactions proceeded almost rapidly
and smoothly to furnish the respective N-oxides 3a–q and
4t products in excellent and comparable yields (98–78 %)
irrespective of the nature of the substituent groups on the
aromatic ring. However, 2-benzoylpyridine 1j and 3-benzo-
ylpyridine 1k exhibited no reactivity in this reaction which
remained almost intact after a long reaction time (entries j
and k). It is interesting to note that, in 2,2′-bipyridine (entry
n), 4,4′-bipyridine (entry o) and 2,4,6-trimethylpyrimidine
(entry r), the ring nitrogen atoms were both converted to
N-oxides in this reaction.
On the basis of the formation of benzil and hydrogen
peroxide which were detected in the course of the reac-
tion, a plausible reaction mechanism proposed to explain
the oxidation of pyridine derivatives and tertiary amines
with 1,2-diphenyl-1,1,2,2-tetrahydroxyethane is depicted
in Scheme 3. The reaction is likely initiated by nucleo-
philic attack of the pyridine nitrogen atom on the peroxidic
oxygen of the oxidant to produce the intermediate I which
2
3
120
180
42
30
3
4
240
240
trace
10
a
Conditions: pyridine (1 mmol), oxidant (3 mmol), CH3CN (5 mL),
r.t
and tertiary amines into their corresponding N-oxides. As
shown in Scheme 1, various substituted pyridines 1 and ter-
tiary amines 2 were reacted with 1,2-diphenyl-1,1,2,2-tet-
rahydroperoxyethane as an efficient oxidant. The reactions
proceeded smoothly in acetonitrile at room temperature to
afford the corresponding N-oxides 3 and 4, respectively, in
excellent yields (Scheme 2).
To screen the reaction parameters, we preliminarily
reacted pyridine 1a with 1,2-diphenyl-1,1,2,2-tetrahydrop-
eroxyethane at room temperature as the model reaction.
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J IRAN CHEM SOC (2016) 13:645–651
Table 3 Catalyst-free oxidation
of pyridine derivatives and
tertiary amines to corresponding
N-oxides with 1,2-diphenyl-
1,1,2,2-tetrahydroperoxyethane
Entry
substrate
product
Time (min) Yield (%)b
98
M.p. (ºC)c
3
67
a
10
89
166
120
b
c
15
8
91
87
105
d
12
15
5
86
78
93
90
115
102
69
e
f
g
h
8
180
14
87
294
i
120
trace
-
j
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J IRAN CHEM SOC (2016) 13:645–651
649
Time (min) Yield (%)b
M.p. (ºC)c
Table 3 continued
Entry
substrate
product
120
trace
-
k
5
92
162New
l
15
93
146New
m
11
93
104New
n
9
97
93
120New
o
10
56
p
13
78
106
q
r
15
86
57
10
7
86
87
43
47
s
t
a
Reaction conditions: substrate
(1 mmol), 1,2-diphenyl-1,1,2,2-
tetrahydroxyethane (3 mmol),
CH3CN (5 mL), r.t
b
Isolated yield
The melting points of the
c
known products were compared
with those reported in the litera-
ture [10, 20, 30, 49–52]
undergoes similar reaction with a second molecule of pyri-
dine to provide the expected N-oxide and benzil as identi-
fied in the reaction mixture.
Structures of the products were established on the basis
of their physical and spectroscopic (IR, 1HNMR, and
13CNMR) analysis and those of the known products are
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J IRAN CHEM SOC (2016) 13:645–651
Scheme 3 Proposed mecha-
nism for the N-oxidation of
pyridine derivatives and tertiary
amines with 1,2-diphenyl-
1,1,2,2-tetrahydroperoxyethane
compared with the reported data (Table 2). The characteris-
tic data for the new products 3l–o are given below.
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