Reactions between 5-Nitroso-1,3-diphenyltetrazolium salts and electron-rich arenes, amines, thiophenol, sulfoxides, and thioanisole

Article abstract of DOI:10.1246/bcsj.20180315

A series of reactions between 5-nitroso-1,3-diphenyltetrazo-lium tetrafluoroborate and methoxybenzenes, amines, thiols, sulfoxides, and sulfides, most of which are generally accepted as being inert to nitroso groups, is reported here. The tetrazolium-activated nitroso functionality is capable of oxidizing the aforementioned substrates to give the corresponding oxidized products, and the nitroso tetrazolium itself is transformed into the corresponding amide or hydroxyamide, depending on the nature of the reaction partners. In the case of thioanisole, an addition product was obtained.

Full text of DOI:10.1246/bcsj.20180315

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Reactions between 5-Nitroso-1,3-diphenyltetrazolium Salts and Electron-rich Arenes,
Amines, Thiophenol, Sulfoxides, and Thioanisole
Yuta Matsukawa, Tsunehisa Hirashita,* and Shuki Araki
Advance Publication on the web January 11, 2019
doi:10.1246/bcsj.20180315
© 2019 The Chemical Society of Japan
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Publication manuscripts.

Reactions between 5-Nitroso-1,3-diphenyltetrazolium Salts and Electron-rich Arenes,
Amines, Thiophenol, Sulfoxides, and Thioanisole
Yuta Matsukawa, Tsunehisa Hirashita*, and Shuki Araki
Life Science and Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology Gokiso-cho, Showa-ku, Nagoya,
Aichi, 466-8555 Japan
hirasita@nitech.ac.jp
Tsunehisa Hirashita
Tsunehisa Hirashita is an Associate Professor of Nagoya Institute of Technology (NITech). He received his Ph.D. degree
from NITech (1999, Professor M. Kawai). He was appointed as an Assistant Professor of NITech (Professor S. Araki’s
group) in 2002, and was promoted to an Associate Professor in 2011. He spent one year (2005-2006) in the group of
Professor R. A. Sheldon at Delft University of Technology (The Netherlands). His current research interest is mainly in the
development of clean chemical methods for organic reactions, specifically in the area of “greener” solvents such as (near-
critical) water and (meso) ionic liquids.
Abstract
alcohols6 and works well as a catalyst for the aerobic oxidation
of alcohols.7 The unusual oxidizing ability exhibited by the
nitroso tetrazolium compounds prompted us to consider the
potential of salt 1 as an oxidizing agent for a variety of
compounds other than alcohols.
In this paper, we reveal that salt 1 can oxidize a broad range
of compounds, including electron-rich arenes, amines, thiols,
sulfoxides, and sulfides, most of which are considered to be inert
to nitroso compounds.
A series of reactions between 5-nitroso-1,3-diphenyltetrazolium
tetrafluoroborate and methoxybenzenes, amines, thiols,
sulfoxides, and sulfides, most of which are generally accepted as
being inert to nitroso groups, is reported here. The tetrazolium-
activated nitroso functionality is capable of oxidizing the
aforementioned substrates to give the corresponding oxidized
products, and the nitroso tetrazolium itself is transformed into
the corresponding amide or hydroxyamide, depending on the
nature of the reaction partners. In the case of thioanisole, an
addition product was obtained.
Keywords: mesoionic compounds, nitroso compounds,
heterocycles
1. Introduction
(1)
C-Nitroso compounds play important roles as precursors
to azo compounds and 1,2-oxazine rings,1 spin-trapping agents,2
and they have physiologically active substances.3 Synthesis of
C-nitroso compounds is achieved through the nitrosation of
arenes, oxidation of amines or hydroxyamines, or reduction of
nitro compounds.4 Aromatic C-nitroso compounds undergo
addition reactions with a variety of compounds. Alkenes or
dienes afford “ene” and hetero Diels–Alder products.
Condensation reactions of C-nitroso compounds with active
methylene compounds or amines are known as the Ehrlich–
Sachs reaction or Mills reaction, respectively. C-Nitroso
compounds form a reversible redox system consisting of the
corresponding amines, hydroxyamines, and nitro compounds.5
Some reactions of nitrosobenzene are summarized in Scheme 1.
2. Results
2.1 Methoxybenzenes. We examined stoichiometric
oxidation reactions of a series of methoxybenzenes using 1 at
ambient temperature (Table 1). 1,3,5-Trimethoxybenzene was
oxidized to 2,6-dimethoxy-p-benzoquinone in moderate yields
under both argon and O2 atmospheres; concomitantly, 1 was
reduced to amide 3. Although the treatment of 1,3-
dimethoxybenzene with 1 gave methoxy-p-benzoquinone, its
yield was low and a complicated mixture was obtained. The
reaction of anisole proved to be very slow. p-Benzoquinone was
obtained in 5% yield even after a long reaction time, and a large
amount of anisole was recovered intact.
PhS
Ph
H
PhNHOH
N
N
Ph
H
Ph
N
PhSH
+
H
N
Ph
+ others
Ph
N
ref. 9
ref. 6
2.2 Amines. The reaction of aniline with 1 resulted in a
complicated mixture, even at a low temperature; however, 3 was
quantitatively obtained (Scheme 2). A similar result was
obtained upon the reaction of 1 with p-aminobenzyl alcohol
irrespective of the presence of an acid. The reaction of
hydrazobenzene with 1 proceeded quickly in a clean manner to
give azobenzene and 2 in high yields. In the oxidation of
benzhydrylamine, a homo-coupled imine was obtained in
moderate yield accompanied by the formation of benzophenone.
We confirmed that the reaction under argon resulted in a similar
PhNO
PhCH2NH2
SnCl2
ref. 8
N
Ph
ref. 7
+
Ph
Ph
PhNH2
O
N
Ph
N
Scheme 1. Reactions of nitrosobenzene
We focused on the redox activity of the nitroso group in
this redox system and found that 5-nitroso-1,3-
diphenyltetrazolium salt 1, which is, obtained from salt 2 (eq 1),
is capable of functioning as an oxidizing agent for a variety of
outcome. Reaction of
1
with benzylamine gave N-
benzylidenebenzylamine. In this case, contrary to the results
obtained with anilines, 1 was largely converted not into amide 3

Table 1. Reactions of 1 with methoxybenzenes.a
Yield (%)
p-benzoquinones
Recovery of
methoxybenzene (%)
Entry
methoxybenzene
Time [h]
3
1
2b
3
1,3,5-trimethoxybenzene
1,3,5-trimethoxybenzene
1,3-dimethoxybenzene
methoxybenzene (anisole)
1
1
1
49
43
15
5
88
58
75
19
25
25
27
59
4c
20
aReaction conditions: Methoxybenzene (100 mol %) and 1 in MeCN at room temperature. bUnder argon. cIn MeCN-d3.
but olate 4.
conversion; the yield of dimethyl sulfone was comparable under
argon (eq 3). Diphenyl sulfoxide was also oxidized by 1 to give
diphenyl sulfone in good yield. Through oxidation of the
sulfoxides, particularly dimethyl sulfoxide, azotetrazolium salt
58 was formed.
O
S
+
1
R
R
MeCN, rt
O
Ph
N
2BF4
O
N
N
Ph
(3)
N
N
N
S
N
N
+
4
+
N
R
R
Ph
N
Ph
5
R = Me, 10 min: 94% (86%)a 17% (25%)a
21% (26%)a
2%
R = Ph, 30 min:
73%
17%
aUnder argon.
2.5 Sulfides. Diphenyl sulfide gave no product upon
treatment with 1; however, thioanisole was quantitatively
converted into coupling product 6 (eq 4). Reaction with dibutyl
sulfide gave a complex mixture.
(4)
Scheme 2. Reactions of 1 with amines. aUnder argon. bAt -45
ºC. cp-TsOH (100 mol %) was added.
2.6 Stannous chloride. The reduction of 1 with SnCl2
proceeded to give 2 almost quantitatively, irrespective of the
presence of hydrochloric acid (Scheme 3, left).
2.3 Thiol. Thiophenol was oxidized to diphenyl disulfide
and thiosulfonate under ambient conditions, and 1 was primarily
transformed into amide 3 (eq 2). In contrast to the above-
mentioned results, the product yields from reaction under an
argon atmosphere were noticeably lower than those obtained
under air. Although the formation of diphenyl thiosulfonate
seemed to stem from the further oxidation of diphenyl disulfide,
treatment of diphenyl disulfide with 1 resulted in quantitative
recovery of the starting materials.
(2)
Scheme 3. Reactions of 1 with SnCl2 and water.
2.7 Base and water. Treatment of 1 with an equimolar
amount of aqueous sodium hydroxide rapidly afforded 4, while
1 stayed comparatively intact under neutral aqueous conditions.
Hydrolysis of 1 to 4 in the presence of a large excess of water
(20 equiv) was estimated to be around 10% after 1 h, and it took
three days for complete conversion (Scheme 3, right).
aUnder argon.
2.4 Sulfoxide. Dimethyl sulfoxide was easily oxidized to
dimethyl sulfone. The absence of O2 scarcely affected this

or H2O.
The oxidation of sulfoxides to sulfones proceeds with
3. Discussion
Oxidations of methoxybenzenes to p-benzoquinones have
been previously achieved by H2O2 in the presence of metal
catalysts,9 with the yield of p-benzoquinone decreasing as the
number of methoxy groups decreases.10 This trend was also seen
in the oxidation of methoxybenzenes with 1. The success of the
reaction under argon indicates that the oxygen atom of 1 is
transferred to the methoxybenzene aromatic ring. In the case of
1,3-dimethoxybenzene, both the yield of the p-benzoquinone
and the recovery of 1 were relatively low despite a high level of
conversion to 3, suggesting that unexpected oxidation reactions
occurred. The formation of olate 4 (13%) observed in the
reaction of 1 with anisole is most likely from the hydrolysis of
intact 1. This will be discussed later.
Generally, aromatic nitroso compounds undergo
condensation with aromatic amines to produce azobenzenes,
which is known as the Mills reaction. The electron withdrawing
nitroso alkane CF3NO also condenses with primary amines to
give an azo compound.11 In the reaction between 1 and aromatic
amines, however, the corresponding azo compounds were not
obtained, but instead 3 and an undefined black solid were
primarily formed, implying an undesirable oxidation leading to
aniline black occurred. Hydrazobenzene proved to be oxidized
by 1 in a similar manner to PhNO; azobenzene and
hydroxyamine 2-H were produced (Scheme 4, path a).12 The
oxidation of benzylamine with nitroso compounds depends on
the nature of the nitroso compound. For example, PhNO gives
N-benzylidenebenzylamine and azoxybenzene,13 while
nitrosocarbonyl compounds undergo a substitution reaction with
benzylamine to produce amides.4e,14 The reaction of 1 with
benzylamine is similar to the case of PhNO, where the nitrogen
atom in benzylamine attacks the N site of the nitroso group (path
b). In the treatment of 1 with water under basic or neutral
conditions, the substitution reaction proceeds in a similar manner
to that involving nitrosocarbonyl compounds (path c). This event
can be rationalized by assuming that the positive charge in the
tetrazolium ring enhances its electrophilicity and facilitates the
substitution reaction at the 5-carbon. Nitroso arenes are reduced
to amines by SnCl2 in hydrochloric acid.15 Interestingly, the
reduction of 1 with SnCl2 readily proceeded under neutral
conditions and halted at the stage of hydroxyamide 2 without
further reduction to 3, even in the presence of hydrochloric acid.
hydrogen peroxide or peracids.16 As a number of reactions and
spectral measurements of nitroso compounds have been carried
out in DMSO, nitroso compounds are considered to be inert to
sulfoxides.17 This sharply contrasts with the oxidation of DMSO
by nitroso compound 1 shown in eq 3. Dioxygen is not required
in the reaction of DMSO with 1, and the oxygen atom of 1 is
presumably transferred to the sulfur atom through an attack at
the oxygen atom of 1 to give sulfones and 5 (Scheme 5, path a).
At first glance, the latter seems to be a Mills-type product from
1 and 3. The dication 5, however, was not obtained from the
direct treatment of 1 with 3, indicating that pathways other than
a simple condensation reaction are involved. Alberti and co-
workers reported that PhNO reacts with PhSH to give a variety
of products as shown in eq 5.18 They proposed that PhS(O2)-SPh
is formed by the self-coupling of Ph(O)S• radical generated from
the fission of an adduct intermediate Ph-NH-OSPh. Diphenyl
disulfide is thus not incorporated in the process that results in
phenyl benzenethiosulfonate from PhSH.
Ph
O
S
O
N
S
Ph
S
Ph
Ph
Ph
N
S
Ph
+
+
+
Ph
Ph
N
+
H
H
50%
OH
17%
17%
(5)18
PhNO
+
O
S
N
N
Ph
+
S
Ph
PhSH
15%
15%
O
S
Ph
N
Ph
PhNH2
PhNO2
trace
+
+
+
Ph
S
Ph
N
O
Scheme 5. Transformations of sulfur functionalities with 1.
In contrast to nitrosobenzene, nitrosotetrazolium
1
predominantly gave phenyl benzenethiosulfonate and amide 3
upon the coupling of PhSH (eq 2), which can be rationalized by
assuming that the formation of radical pairs of Ph(O)S• and
ArNH• (where Ar = diphenyltetrazolium) would occur more
Scheme 4. Transformations of the nitroso group of 1 by amines

readily than the case involving PhNO (Scheme 4b). This
scenario is supported by the empirical results that phenyl
benzenethiosulfonate was obtained even under argon and
diphenyl disulfide did not react with 1. No sulfonic acid and
sulfonamides were isolated in the reactions of PhSH or
sulfoxides. The preference for sulfoxides over sulfides is
characteristic of oxidation with 1, because aromatic and aliphatic
sulfides are generally more easily oxidized than sulfoxides.19
There have been no attempts to examine the reaction properties
of nitroso compounds toward sulfides, and only a few reactions
of nitroxyl radical species have been applied to coupling at the
a-carbon of alkyl sulfides.20 The addition of nitroso tetrazolium
to thioanisole 6 is probably triggered by oxidation of the sulfur
atom leading to a sulfonium intermediate, followed by an attack
of hydroxy amide 2.21 Because amines, diphenylsulfoxide, and
thiophenol were found to add across the nitroso group of 1 in a
characteristic manner, the presumed intermediates shown in
Schemes 3 and 4 are valid. However, organic radicals such as the
galvinoxyl radical reacted promptly with nitrosotetrazolium salt
1 to give a complex mixture. Owing to this, it is difficult to use
organic radicals in the present reactions. Hence, we conducted
preliminary DFT calculations of the adduct intermediates and
compared them with the corresponding adducts formed in the
reverse mode. These calculations support that the proposed
intermediates have a significant advantage over the other
adducts (Table 2).
values are reported as
tetramethylsilane (TMS:
d
(ppm) with reference to
ppm for 1H NMR),
0
hexafluorobenzene (C6F6: –162.2 ppm for 19F NMR), or residual
solvent signals MeCN-d3 (1.94 ppm for 1H NMR and 118.3 ppm
for 13C NMR), acetone-d6 (2.05 ppm for 1H NMR and 29.8 ppm
for 13C NMR), and DMSO-d6 (2.50 ppm for H NMR). High-
resolution mass spectra (HRMS) were recorded using an ESI-
TOF spectrometer.
1
General Materials. All solvents and chemicals were used as
received, unless otherwise noted. MeCN was dried by
distillation from CaH2 powder. 1,3-Dimethoxybenzene, anisole,
aniline, benzhydrylamine, benzylamine, thiophenol, dimethyl
sulfoxide, diphenyl sulfide, and thioanisole were purified by
Kugelrohr distillation. Phenyl benzenethiosulfonate22 and 5-
nitroso-1,3-diphenyltetrazolium tetrafluoroborate (1)6 were
prepared according to procedures described in literature.
Nitrosotetrazolium salt 1 is insoluble in less polar solvents and
unstable in polar solvents such as THF, DMF, and acetone.
Acknowledgement
Financial support for this work by the Sasakawa Scientific
Research Grant (28-303) is gratefully acknowledged.
Supporting Information
Detailed experimental procedures, spectroscopic data for the
products (1H NMR spectra for 2,6-dimethoxy-p-benzoquinone,
methoxy-p-benzoquinone, benzophenone benzhydrylimine, N-
benzylidenebenzylamine, azobenzene, diphenyl disulfide,
phenyl benzenethiosulfonate, dimethyl sulfone, diphenyl
sulfone, and 6. 13C NMR spectra for 6. 19F NMR spectra for 6.
ESI-TOF MS spectra for 6. IR spectra for 2,6-dimethoxy-p-
benzoquinone, dimethyl sulfone, and 6.) are described.
This material is available on http://dx.doi.org/10.1246/bcsj.***.
Table 2. Comparison of the Gibbs free energies of the presumed
intermediates in Schemes 3 and 4.a
N-adduct
Gb
−3673339c
−3673329c
−4641154
−4641208
−3846424
−3846616
O-adduct
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diphenyltetrazolium tetrafluoroborate 1 toward a spectrum of
substrates, including electron rich arenes, amines, and sulfur-
containing compounds. This activated nitroso compound is
capable of oxidizing a variety of substrates, some of which are
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