A Common, Facile and Eco-Friendly Method for the Reduction of Nitroarenes, Selective Reduction of Poly-Nitroarenes and Deoxygenation of N-Oxide Containing Heteroarenes Using Elemental Sulfur

Article abstract of DOI:10.1002/ejoc.202000064

A transition metal-free, environment-friendly and practical protocol was developed either for the reduction of nitroarenes or for the deoxygenation of N-oxide containing heteroarenes. The reaction proceeded with the use of a non-toxic and cheap feedstock as elemental sulfur in aqueous methanol under relatively mild conditions. Green chemistry credentials were widely favorable compared to traditional and industrial protocols with good E-factors and a low production of waste. The strategy allowed the efficient reduction of a large variety of substituted-nitroarenes including various o-nitroanilines as well as selective reduction of various poly-nitroarenes in excellent yields with a broad substrate scope. The protocol was successfully extended to the deoxygenation of some N-oxide containing heteroarenes, like benzofuroxans, phenazine N,N^'-dioxides, pyridine N-oxides, 2H-indazole N¹-oxides, quinoxaline N¹,N⁴-dioxides and benzo[d]imidazole N¹,N³-dioxides. A gram-scale example for the synthesis of luminol, in green conditions, was reported. A solid mechanism of reaction was proposed from experimental evidences.

Full text of DOI:10.1002/ejoc.202000064

A Journal of
Accepted Article
Title: A common, facile and eco-friendly method for the reduction
of nitroarenes, selective reduction of poly-nitroarenes and
deoxygenation of N-oxide containing heteroarenes
Authors: Angel Romero and Hugo Cerecetto
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000064
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000064
Supported by

10.1002/ejoc.202000064
European Journal of Organic Chemistry
1
A common, facile and eco-friendly method for the reduction of
nitroarenes, selective reduction of poly-nitroarenes and deoxygenation
of N-oxide containing heteroarenes using elemental sulfur
Angel H. Romero,a* Hugo Cerecettoa*
aLaboratorio de Química Orgánica Medicinal, Instituto de Química Biológica, Facultad de Ciencias,
Universidad de la Republica, Igual 4225, 11400 Montevideo, Uruguay.
Corresponding Authors: Prof. Dr. Angel H. Romero (E-mail:
angel.ucv.usb@gmail.com; http://orcid.org/0000-0001-8747-5153); Prof. Dr. Hugo
Cerecetto (E-mail: hcerecetto@gmail.com; https://orcid.org/0000-0003-1256-3786)
Abstract: A transition metal-free, environment-friendly and practical protocol was
developed either for the reduction of nitroarenes or for the deoxygenation of N-oxide
containing heteroarenes. The reaction proceeded with the use of a non-toxic and cheap
feedstock as elemental sulfur in aqueous methanol under relatively mild conditions.
Green chemistry credentials were widely favorable compared to traditional and
industrial protocols with good E-factors and a low production of waste. The strategy
allowed the efficient reduction of a large variety of substituted-nitroarenes including
various o-nitroanilines as well as selective reduction of various poly-nitroarenes in
excellent yields with a broad substrate scope. The protocol was successfully extended to
the deoxygenation of some N-oxide containing heteroarenes, like benzofuroxans,
phenazine N,N´-dioxides, pyridine N-oxides, 2H-indazole N1-oxides, quinoxaline N1,N4-
dioxides and benzo[d]imidazole N1,N3-dioxides. A gram-scale example for the synthesis
of luminol, in green conditions, was reported. A solid mechanism of reaction was
proposed from experimental evidences.
Keywords: reduction, nitroarenes, N-oxide containing heteroarenes, deoxygenation,
elemental sulfur, Green Chemistry.
Introduction
Nitroarenes and N-oxide containing heteroarenes are frequently encountered in the
preparation of final product in organic chemistry, bioactive compounds and
intermediates in the production of fertilizing, dyes, pigments, additives and polymers
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
2
[1]. Traditionally, the most common methods for the synthesis of anilines, from the
nitroarenes as starting materials, involves the use of large amounts of tin or zinc in
presence of a Brønsted acid at high temperature (e.g. the Bechamp´s reduction) [2]. This
type of reduction is mediated by a direct electron transfer process from metal to nitro
group. Alternatively, the reduction of nitroarene to aromatic amines can be achieved
through two chemical processes: (i) catalytic hydrogenation or (ii) hydrogenation
transfer. The first process requires the use of molecular hydrogen (H2) and catalytic
amount of specific transition-metal (iron, nickel, palladium or platinum) under special
pressure conditions [3], whereas the strategy based on hydrogenation transfer needs a
hydrogen source such as hydrides (e.g. NaBH4 or hidrosilanes) [4,5], hydrazine hydrate
[4,6], organic reagents (e.g. alcohol or formic acid) [4,7a-b] and more recently, boron
reagents [7c-d]. Despite the strategies based on these two processes have found in the
last two decades significant improvements from Green Chemistry point of view [4], the
requirements of special high pressure equipment as well as the use of flammable
hydrogen gas, hazardous reagents and sophistic organometallic complexes/
nanometallic catalyst compromise the practicality and economy of these synthetic
strategies. Other disadvantage of these traditional reductive processes (Beckman's
reduction, catalytic hydrogenation and hydrogenation transfer) is its limited efficacy for
the selective reduction of nitro group in polynitroarenes. In general, the selective
reduction of polyarenes represents a challenge for chemist in organic synthesis field and
a limited number of examples are found in literature. Some examples of reduction of
1,3-dinitrobenzene to 3-nitroaniline under catalytic hydrogenation conditions using
specific metal nano-catalyst systems (PVP-Ru/Al2O3, Ru/C, Ru-SnOx/Al2O3 or
supported gold nanocatalyst) have recently reported [8a-c]. However, these modified
catalytic hydrogenation strategies require a rigorous control of reaction condition to
obtain the monoreduced product from polynitroarenes as well as sophistic and specific
uncommon supported metal nanosystems are needed for a good selectivity. A more
accessible procedure sulfur-based (sulfide, polysulfide or hydrosulfide) have been
successfully employed to industrial level for the preparation of some monoreduced
products from the corresponding polynitroarenes, requiring prolonged time and high
temperature (>100 ºC) [8d-e]. Then, economic, efficient and eco-friendly synthetic
methods using feedstock material are required for the selective reduction of
polynitroarenes.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
3
II. Deoxygenation of N-oxide containing
I. Reduction of nitroarenes
heteroarenes
Previous works:
Previous works:
a) Metal-based
NH2
NH2
NH2
NO2
a) Metal-based
Zn/acetate,
Fe, Zn, Sn/H+,
Mo(IV) complex
N
N
O
H2/Pd Pt, Ni, etc
N
N
R
R
R
R
NaBH4/NiCl2,
FeCl2, etc
InCl3/NH4Cl
Ti(0)/THF, etc
NO2
NO2
b) Metal-free
HSiCl3/TEA
N2H4, etc
B2pin2/t-BuOK
organic sources
b) Metal-free
Ph3P at 230-280ºC
O
R
Sulfur and organic
sources at elevated
temperature
O
c) Sulfur-based
S/DMF/NaHCO3
at 130 ºC by 16 h
c) Sulfur-based
S/morpholine
N
N
N
O
O
R
ethyleneglycol
at 150-170 ºC
or S/NH3/NaOH
N
Present work: metal-free & eco-friendly sulfur as reductant & aqueous methanol & mild conditions
& highly selective
NH2
NO2
d) This work
S (4 eq.)
d) This work
S (2-3 eq.)
NaOH(2-3 eq.)
NaOH(4 eq.)
R
R
N
O
MeOH-H2O (8:2)
at 80 ºC, 2-16 h
N
MeOH-H2O (8:2)
at 80 ºC, 2-5 h
NH2
NH2
NO2
d) This work
S (4 eq.)
NaOH(4 eq.)
O2N
O2N
MeOH-H2O (8:2)
at 80 ºC, 1-12 h
NH2
d) This work
S (4 eq.)
NaOH(4 eq.)
NH2
NO2
R
R
MeOH-H2O (8:2)
at 80 ºC, 8-16 h
Scheme 1. Different methods for the reduction of aromatic nitro compounds and N-
oxide containing heteroarenes and the methods described herein.
Regarding to the deoxygenation of N-oxide containing heteroarenes, a variety of non
eco-friendly methods involving metals have been described [9]. Other non-metal
methods involving the use of sulfur-derived reagents (e.g. sulfurous acid [10a], SO2
[10b], sulfur monoxide [11], trimethyl(or triethyl)amine-SO2 complex [12], di-n-propyl
sulfoxylate [13] and CS2 [14]), phosphorus-derived reagents (e.g. PCl3 [15] and PPh3 at
high temperatures [16]) and other organic compounds [17,18] have been also reported
for the deoxygenation of N-oxide containing heteroarenes. Many of these
deoxygenation protocols are far on the Green Chemistry principles involving some
drawbacks such as the generation of complex metallic waste, large quantities of the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
4
reducing reagent, high temperatures, long reaction time, tedious purification procedure
and the use of hazardous and expensive reagents. Curiously, there are a few methods
applicable either for the reduction of nitroarenes or for the deoxygenation of N-oxide
containing heteroarenes. Zinc dust-ammonium salt system has been utilized separately
either for the reduction of nitroarenes or for the deoxygenation of N-oxide containing
heteroarenes [19,20]. Tervalent phosphorus such as (EtO)3P [21,22] reduced efficiently
N-oxide heteroarenes and, in some cases, it has been reported for reduction of
nitroarenes. Recently, diboron reagents such as bis-(pinacolato)- and
bis(catecholato)diboron also allowed efficiently the synthesis of anilines [23] and
azaheterocycles [24] from nitroarenes and deoxygenation of N-oxide containing
heteroarenes, respectively. Therefore, the design of a common, efficient and selective
protocol involving the use of feedstock material as reductant and eco-friendly-safer
solvent (water or aqueous solvent) under mild conditions is expected either for the
reduction of nitroarenes to aminoarenes or for deoxygenation of N-oxide heteroarenes.
Elemental sulfur, a by-product of oil and gas industries, is an ideal raw material as
reductant due to its abundance, low industrial cost (~120 USD per ton), high sulfur-
atom content and lack of toxic by-products. Moreover, elemental sulfur is a user-
friendliness reagent by its non-toxic, non-volatile, inodorous, non-hygroscopic, free-
flowing and bench-stable properties. Elemental sulfur in combination with base has
previously been used for the reduction of some nitroarenes; however, the reaction has
proceed under extreme conditions (high temperatures from 130 °C to 150 °C and
prolonged time of reactions) with the use of hazardous reagents such as ammonia or
environment unfriendly solvent such as DMF, that have a negative impact on the
different ecosystems (Scheme 1) [25]. With regards to deoxygenation of N-oxide
containing heteroarenes directed by elemental sulfur, a unique example has been
reported for a limited number of deactivated benzofuroxans using morpholine as base
and in ethylene glycol at extreme temperature from 145 ºC to 160 ºC [25e]. In order to
enhance the efficacy of the elemental sulfur as reductant in these reductions, we believe
that is crucial the optimization of redox process in solution. For this purpose, it is
important to consider two features: (i) the use of a strong base (e.g. NaOH) to facilitate
the oxidation of elemental sulfur to sulfur species with higher oxidation state (equations
1 and 2), (ii) the use of a polar solvent more similar to water (e.g. methanol or
methanol-H2O mixtures) that allow to an efficient dissolution of the three components
of the reaction, i.e. the inorganic base, the elemental sulfur and the starting organic
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
5
material. Then, taken into account: (i) these two mentioned issues and, (ii) the twelve
Green-Chemistry principles, herein we reported a common and eco-friendly protocol
either for the efficient and selective reduction of aromatic nitro compounds to the
corresponding amines or for the deoxygenation of a variety of N-oxide containing
heteroarenes, including benzofuroxans, phenazine N,N´-dioxides, pyridine N1-oxides,
2H-indazole N1-oxides, quinoxaline N1,N4-dioxides and 2H-benzo[d]imidazole N1,N3-
dioxides, to the corresponding reduced azaheteroarenes using a feedstock material as
elemental sulfur in aqueous methanol milieu under relatively mild conditions. The
present strategy represents an economical, practical and eco-friendly alternative to
reported protocols either for the reduction of nitroarenes with a high selectivity to the
monoreduction of polynitroarenes or for the deoxygenation of some N-oxide
heteroarenes, in particular, benzofuroxans and phenazine N,N´-dioxides.
O
Eq. 1
Eq. 2
N
NH2
N
2
2
+ 6 S + 6 NaOH
+ 2 S + 2 NaOH
2
2
+ 3 Na2S2O3
+
+
H2O
H2O
O
O
N
+
Na2S2O3
Results and discussion
Our initial study was focused on the optimization of reduction of nitroarenes to anilines
using as model 1,3-dinitrobenzene (1 equiv.), elemental sulfur (from 2 to 5 equiv.), in
presence of NaOH (from 0 to 5 equiv.), in different solvents and mixtures (MeOH, H2O,
DMF and different proportions of MeOH:H2O) at different temperatures and by 1 hour
(Table 1). Optimization experiments were focused on the determination of minimal
amounts of sulfur and base as well as on the selection of the best solvent for an accuracy
reaction. Initially, working with an excess of sulfur and sodium hydroxide (4.0 equiv.
respect to nitroarene and according to stoichiometry from Eq. 1), the optimization
solvent results showed that methanol:water mixture in proportion 8:2 was the most
convenient milieu of reaction producing the best yield of final product 2k (82 %, entry
5). It was better than sole water, methanol or DMF (entries 1-3) and other aqueous
methanol mixtures (entries 4, 6 and 7). For the best mixture of solvents, i.e.
methanol:water (8:2), it was observed a homogeneous reaction milieu after the first 10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
6
minutes initiated the heating with the complete dissolution of all inorganic and organic
reagents, which probably facilitates the redox process shown in equation 1 and thus, the
efficacy of the reaction. An incomplete dissolution of inorganic base was appreciated
for the sole methanol or methanol:water 9:1 mixture, while a partial precipitation of
organic substrate was detected for aqueous methanol with more than 20 % of water.
Thus, the partial dissolution of any of the starting reagents may have an effect in the
reaction efficacy for the mentioned methanol:water mixture as well as for sole methanol
and water solvent (entries 1-2, 4, 6 and 7). Regarding to the minimal quantities of sulfur
and base, the best reaction yields were obtained using four equivalent or more of both
reagents (entries 5 and 8). The reactions were incomplete when less than 3 equivalents
of both sulfur and base were used (entries 9-11). The particular requirement of excess in
sulfur and NaOH (1 equivalent of excess according to Eq. 1) is associated to the
disproportionation further reactions between sulfur and NaOH under heating to form
thiosulfate and sulfur anions (see below in Eq. 7) as well as other collateral reactions
(Eq. 8-10). On the other hands, the reaction temperature was crucially important, and
temperatures between 80 ºC and 90 ºC are essentials (compare entry 5 to entries 12 and
13). Lowering the reaction temperature (e.g. 50 °C) led to the incomplete conversion of
nitroarene to corresponding aniline (entry 12). Sodium hydroxide demonstrated to be
the most optimal base over NaHCO3 (compare entries 5 and 14), which confirm that the
efficient sulfur transformation to oxidized sulfur species requires the use of a strong
base. Under optimized conditions, the complete conversion of 1,3-dinitrobenzene was
achieved in 1 hour. Then, the optimized reaction conditions for the reduction of other
nitroarenes (1.0 equiv.) to the corresponding aniline were determined as the
combination of elemental sulfur (4 equiv.) with NaOH (4 equiv) in a MeOH:water, 8:2,
solvent mixture at 80 °C by 1-16 hours depending on nature of starting material (Table
2).
Table 1. Conditions optimization for the reduction of nitroarenes.a
NH2
NO2
S
NaOH
solvent
O2N
O2N
T, 1 h
1k
2k
Entries
Solvent
H2O
MeOH
DMF
NaOH eq. Sulfur eq. T (ºC) Yield (%)b
1
2
3
4
4
4
4
4
4
80
80
80
42
45
62
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
7
4
5
6
7
8
MeOH-H2O (9:1)
4
4
4
4
5
3
2
0
4
4
4c
4
4
4
4
5
3
2
4
4
4
4
80
80
80
80
80
80
80
80
50
90
80
70
82
79
61
80
70
51
0
MeOH-H2O (8:2)
MeOH-H2O (7:3)
MeOH-H2O (6:4)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
9
10
11
12
13
14
30
83
52
aReaction conditions: 1.0 mmol substrate 1a, elemental sulfur (2-5 equiv.), and base (0-5 equiv.) in 6 mL of solvent.
bYield of isolated yields of pure product 2a. cNaHCO3 as base instead of NaOH.
With the optimal reaction conditions in hand, the scope of the reduction of aromatic
nitro compounds was explored. The nitro group was chemoselectively reduced in the
presence of a variety of electron-withdrawing and electron-donor groups on aromatic
and heteroaromatic rings, affording the desired anilines, in general, in good to excellent
yields (50 to 90 %) (entries 1-22, Table 2). Nitroarenes bearing electron-withdrawing
groups, such as carboxylic acid, ketone, nitrile and nitro groups gave the desired
anilines 2b-2d, 2j and 2k in excellent yields and, in general, at lowest reaction time (1-3
hours) (entries 2-4 and 10 and 11, Table 2). The efficient and selective reduction of p-
nitrobenzonitrile to product 2d represents a valuable result due to that nitrile group is
not compatible with typical protocols including catalytic hydrogenation, hydride
addition and Bechamp´s reduction. The low reaction yield (38 %) obtained for the
substrate 1c (entry 3, Table 2), a ketone-nitroarene, may be associated to the generation
of water-soluble by-products of auto-condensation and other compounds derived from
oxidation of acetyl group by action of elemental sulfur, which has recently been
reported for acetophenone derivatives [26]. On the other hands, nitroarenes bearing
mesomeric electron-donor groups (p-mercapto, p-dimethyamino, p-methoxy) and 2-
amino-substituted nitroarenes were efficiently reduced to their corresponding anilines in
good to excellent reaction yields (70-88 %) at longer reaction time by about 8-16 hours
(entries 5-7 and 17-19, Table 2). p-Nitrotoluene and p-nitrobenzylamine were
incompatible for our protocol due to that a simultaneous oxidation of benzyl carbon was
detected, giving a complex reaction mixture containing the corresponding
benzaldehydes, benzylimines, anilines and the starting materials. These last findings
were expected because it is well documented that the benzyl carbon in toluenes or
benzyl derivatives bearing withdrawing groups (e.g. o-NO2 or p-NO2) are susceptible to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
8
the oxidation by elemental sulfur action under basic conditions [26a, 27, 28]. Thus, a
moderate reaction yield (47 %) of the desired product was obtained for the o-
nitrotoluene (entry 8, Table 2) with the partial oxidation of methyl moiety, whereas a
good conversion was found for the 3-methyl-nitroarene 1i (entry 9, Table 2) without
apparent oxidation of the corresponding methyl group. Nitro group into nitroarene
bearing azide moiety is well reduced, but the strong basic conditions also reduced the
azide group in an amino group (see entry 9, Table 2). Halogens at 3-position respect to
nitro-moiety were well tolerated under reaction conditions (entries 9, 18, 19 and 21),
proceeding with longer reaction times. Exotic moieties such as hydrazine and amide
were suitable for the protocol (see entries 12 and 16, Table 2). The reductions of 4-
nitrophenol and 2-nitrophenol to the corresponding anilines were not effective, even
when increasing the equivalents of base and sulfur and extending the reaction time,
which could be attributed to the acidity of the phenolic group and to the concomitant
increase of the electron-donor ability of the phenol as phenoxide. Only polynitro-
phenols 1m and 1o afforded the reduced products (see entries 13 and 15, Table 2).
Substituted heteroarenes such as 3-nitropyridines and nitro-1,4-phthalazindione also
were compatible for our reduction protocol, obtaining excellent yields of desired
product (85-88 %) (entries 20-22, Table 2). Finally, nitro-aliphatic and nitro-alkenyl
derivatives (e.g. trans-nitrostyrene) were not suitable substrates for this nitro-reduction,
which open the possibility to extend the current technique to the selective reduction of
nitroarenes containing a nitro-alkyl or nitro-alkenyl chain.
Table 2. Substrate scope for the reduction of nitro group in nitroarenes.a
NH2
NO2
S (4 equiv.)
NaOH (4 equiv.)
X= CH or N
R
R
MeOH:H2O (8:2)
80 ºC, 1-16h
X
X
1a-v
2a-v
Entrie
s
Nitroarenes 1a-v
Aniline 2a-vb
Time (h)
NO2
NH2
1
12
2a (82%)
1a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
9
NO2
NH2
2
3
4
2
2
COOH
1b
COOH
2b (79%)
NO2
NH2
COCH3
1c
COCH3
2c (38%)
NH2
NO2
3c
CN
CN
2d (72%)
1d
NO2
NH2
5
6
12
16
SH
2e (81%)
SH
1e
NH2
NO2
N(CH3)2
N(CH3)2
1f
2f (75%)
NH2
NO2
7
8
16
16
OCH3
2g (88%)
OCH3
1g
NO2
NH2
CH3
CH3
2h (47%)
1h
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
10
NH2
NO2
H2N
Br
N3
Br
9
16
1i
2i (47%)
NO2
NH2
10
11
12
12
1
COOH
COOH
OCH3
OCH3
1j
2j (89%)
NO2
NH2
NO2
2k (89%)
NO2
NO2
1k
NO2
NO2
12
NH2
NHNH2
2l (70%)
NO2
NHNH2
1l
NO2
13
14
12
12
NO2
NH2
OH
1m
OH
2m (71%)
NO2
NO2
NH2
NO2
OCH3
1n (81%)
NO2
OCH3
1n
NO2
15
16
8
8
O2N
NH2
O2N
NO2
OH
OH
1o
2o (87%)
NO2
NO2
NH2
NH2
NH2
NO2
H2NOC
H2NOC
1p
2p (83%)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
11
NO2
NH2
NH2
NH2
17
18
16
16
1q
2q (72%)
NH2
NH2
NO2
NH2
Br
1r
Br
2r (88%)
NH2
NH2
NO2
NH2
19
20
16
F
1s
F
2s (70%)
N
NH2
NH2
N
NH2
16
8
NO2
1t
2t (89%)
N
NH2
N
NH2
21
NH2
Cl
NO2
Cl
1u
2u (85%)
NO2
O
O
NH2
NH
NH
NH
NH
22
1
2v (88%)
O
O
1v
aReaction conditions: To a solution of substrate 1a-v (1.0-2.0 mmol) dissolved in methanol (5 mL),
followed by a minimal amount of water (1 mL) was added elemental sulfur (4.0-8.0 mmol, 4 equiv.) and
sodium hydroxide (4.0-8.0 mmol, 4 equiv.) and heated at 80 ºC. bIsolated yields of pure product 2a-v after
purification. cYield (%) determined from 1H-NMR analysis of isolated product.
In order to extend the applicability of our protocol to typical challenge in reduction of
nitro group, we worked on: (i) the selective reduction of a series of symmetric and
asymmetric dinitrobenzenes (six examples, entries 11-16, Table 2) to the corresponding
nitroanilines, and (ii) the reduction of o-nitroamines (six examples, entries 16-21, Table
2), a common toxic pollutant and harmful waste from industrial waste-water, to o-
diamines. The protocol showed to be highly selective for a variety of asymmetrical 1-
substituted-dinitrobenzenes, obtaining exclusively a mono-reduced product in excellent
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
12
yields at acceptable reaction time and with a good group tolerance (entries 11-16, Table
2). In particular, the nitro group ortho to the substituent (OH, OCH3, NHNH2, etc) was
preferentially reduced in the asymmetrical 1-substituted-2,4-dinitrobenzenes, which is
in concordance with the Zinnin´s finding for asymmetrical polynitroarenes [29a-b]. A
trinitroarene such as 2,4,6-trinitrophenol also was selectively reduced to the 2-amino-
4,6-dinitrophenol in excellent yield (87 %) without evidences of any poly-reduced
product. We think that the preferential reduction of ortho-nitro in these 1-substituted
polyarenes may be associated to the extra reactivity that may bring substitutions
possessing electron pair (OH, OCH3, NHNH2, etc) to the sulfur atom in intermediate A
(Figure 1), a chelating structure generated under basic environment, which is a more
stable intermediate than that formed from 4-nitrosubstitution. Recently, T.B. Nguyen
and co-workers demonstrated that nitro-arenes have the ability to form the Ar-N(O)S(O)
functionalization, which is stabilized by a nucleophilic vicinal ortho-carbanion to form
sultams as a reaction stable product [29b]. This fact supports our proposal that ortho-
electron donor possessing free electron pair may stabilize the intermediate X generated
during reduction process mediated by elemental sulfur. In summary, the current
technique emerges as an alternative for the selective reduction of polynitro-arenes: (i) to
traditional methods (e.g. Bechamp's reduction, hydrazine-Pd/C reaction or catalytic
hydrogenation), that are poorly selective giving mixture of reduced product or
exclusively the di-reduced product (phenylendiamines) from 1,3-dinitrobenzenes [29c]
and, (ii) to catalytic hydrogenation based on metal nano-catalyst [8a-c], which are in
general tedious, costly, with further separation and waste disposal. In addition, for the
selective reduction of polynitro-arenes, our protocol is significantly valuable from
economical and environment point of view compared with industrial selective
procedures sulfur-based (sulfide, polysulfide or hydrosulfide) by its low cost, low
potential toxic effects, low corrosion impact and facile manipulation of elemental sulfur
feedstock sources [8e-f] (see details in Supplementary material).
O
O

S
OH
S
O
O
O
N
N
N
O
O
O

S
+
HO
O
O2N
O2N
O2N
A
II
I
Figure 1. Proposed chelating intermediate X from an intramolecular ortho interaction
(compound 1m is used as model).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
13
With regards to the reduction of o-nitroanilines, they were successfully reduced to give
the corresponding o-phenylendiamines in excellent yields (> 70 %) with a good group
tolerance (entries 16-21, Table 2), representing an attractive technique with a low
environment impact to remove o-nitroanilines from industrial waste-water and other
sources. Furthermore, it is important to mention that the isolating procedure to obtain
the corresponding anilines was extremely simple and practical, requiring to evaporate
the methanol, under vacuum, filter off the product from resulting aqueous solution and
purified by flash chromatography whether is not sufficient pure from direct filtration
(see details in Supporting material).
Next, we proceeded with the deoxygenation of a series of N-oxide containing
azaheteroarenes including benzofuroxans, phenazine N,N´-dioxides, pyridine N-oxides,
2H-indazole N1-oxides, quinoxaline N1,N4-dioxides, and 2H-benzo[d]imidazole N1,N3-
dioxides. Optimization experiments were performed taken into account the optimal
condition found for reduction of nitroarenes (see Table 1). Then, we initiated with the
deoxygenation of benzofuroxans using benzofuroxan as model, elemental sulfur (2
equiv.) and sodium hydroxide (2 equiv.) in methanol:water (8:2) as solvent at 80-90 ºC
by 4-5 hours (entry 4, Table 3). Further optimization conditions including variable
amount of sulfur (1-3 equiv.) and base (0-3 equiv.), temperature (50-90 ºC) and time
were investigated (entries 1-3 and 5-10, Table 3). Two equivalents of elemental sulfur
and base were sufficient to afford a good conversion to the corresponding benzofurazan
according to stoichiometry from Eq. 2 (entry 4, Table 3). An incomplete conversion of
benzofuroxan substrate was appreciated when 1 equiv. of elemental sulfur and 1 equiv.
of NaOH were employed (entry 7, Table 3). No reaction occurred in absence of base
(entry 8, Table 3). Similarly to reduction of nitroarenes, aqueous methanol offered the
best results being the methanol:water in proportion 8:2 the most convenient mixture,
while a decrease in yield was appreciated for pure methanol (41 %), methanol:water
(9:1) (72 %), methanol:water (7:3) (68 %) and pure water (0 %) as solvent (compare
entries 1-5, Table 3). No detrimental impact on yield was observed when more than two
equivalents (three or four equiv.) of both sulfur and base were used (i.e. entry 6, Table
3). Reaction time of three to six hours and temperature of 80 ºC were found as the most
convenient conditions for the total conversion of benzofuroxan (entries 9 and 10, Table
3). Next, having the optimized conditions in hand (2.0 equiv. of sulfur, 2.0 equiv. of
NaOH in methanol:water (8:2) solvent at 80 ºC by 5 hours), we investigated the
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
14
substrate scope of the transformation using a variety of substituted benzofuroxans
(Table 4).
Table 3. Condition optimization for the deoxygenation of benzofuroxan.a
O
N
equiv. S
N
N
equiv. NaOH
O
O
MeOH-H2O
T ºC, time
N
4a
3a
Entries
Solvent
H2O
MeOH
NaOH eq. Sulfur eq. T (ºC) Yield (%)b
1
2
3
4
5
6
7
8
9
2
2
2
2
2
3
1
0
2
2
2
2
2
2
2
3
1
2
2
2
80
80
80
80
80
80
80
80
50
90
0
41
72
79
68
74
59
0
MeOH-H2O (9:1)
MeOH-H2O (8:2)
MeOH-H2O (7:3)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
MeOH-H2O (8:2)
22
78
10
aReaction conditions: 1.0 mmol substrate 3a, elemental sulfur (1-3 equiv.), and NaOH (0-3 equiv.) in solvent (6
mL).bIsolated yields of pure product 4a from column chromatography.
In general, a good group tolerance was found for the deoxygenation of
benzofuroxans with good to excellent reaction yields (from 54 % to 92 %). Some
notable points can be noted from Table 4: (i) the protocol showed to be compatible for
benzofuroxan bearing methyl and protected formyl groups (see entries 2, 7 and 8, Table
4), which is very interesting because it is well documented that they are sensitive to
oxidize by the action of elemental sulfur under basic conditions [26,27,30,31]; (ii) lower
reaction time for benzofuroxans bearing electron-withdrawing moieties were requires,
which put in evidence that electron-deficient benzofuroxan (3-4 h) are more reactive
than electron-rich benzofuroxan (4-5 h); (iii) higher reaction yields were detected for
benzofuroxans bearing electron-donor moieties (from 72 to 92 %) such as methyl,
protected formyl or ethoxy moieties compared to benzofuroxans bearing electron-
withdrawing groups (from 54 to 63 %), which may be associated to the partial
decomposition of more reactive electron-deficient benzofurazans under basic
conditions; (iv) small amount (by about 10%) of benzothiofuroxane (or benzo[c]
1
[1,2,5]thiadiazole) was identified from H-NMR as by-product into all final mixture
reactions. These results put in evidence that the appropriate selection of the solvent and
base led a significant improvement in the reductive efficacy of elemental sulfur
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
15
compared to other related sulfur-procedures. Moreover, comparison with traditional
methods [32], our protocol represents a competitive and eco-friendly alternative for the
deoxygenation of benzofuroxans to benzofurazans due to that many of them required
the use of highly toxic reagents (e.g. trisubstituted phosphines and phosphites, and
sodium azide), high cost of reagents, extreme conditions of temperature (between 140
and 250 °C), complex isolating procedure, the use of unfriendly solvent such as xylene,
benzene or ethyleneglycol and the generation of toxic hazardous waste (e.g. explosive
hydrazoic acid when azide reagent is used or phosphorus species when is used
phosphines or phosphites).
Table 4. Substrate scope for the deoxygenation of benzofuroxansa
O
2.0 equiv. S
2.0 equiv. NaOH
N
N
N
R3
O
O
R3
MeOH-H2O (8:2)
80 ºC, t
N
4a-h
3a-h
Entrie
s
Time
(h)
Substrate
Productb
O
N
N
O
N
O
1
2
3
4
4
5
4
3
N
4a (79%)
3a
O
N
H3C
N
N
H3C
O
O
N
4b (92%)
3b
Br
O
N
N
Br
O
O
N
N
4c (54%)
3c
O
N
Cl
N
Cl
O
O
N
N
4d (61%)
3d
O
EtO
N
EtO
N
O
5
4
O
N
N
4e (78%)
3e
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
16
O
N
HOOC
N
N
HOOC
O
6
7
8
3
5
4
O
N
4f (63%)
3f
O
O
N
O
O
N
O
O
O
N
N
4g (80%)
3g
3h
O
N
O
H3C
N
H3C
O
O
N
O
N
4h (72%)
aReaction conditions: To a solution of substrate 3a-h (0.5-1.0 mmol) dissolved in methanol (5 mL), followed by a
minimal amount of water (1 mL) was added elemental sulfur (1.0-2.0 mmol, 2 equiv.) and sodium hydroxide (1.0-2.0
mmol, 2 equiv.) at 80 ºC. bIsolated yields of pure product 4a-h after column chromatography or recrystallization.
Regarding to the deoxygenation of phenazine N,N´-dioxides, pyridine N-oxides, 2H-
indazole N1-oxides, quinoxaline N1,N4-dioxides and 2H-benzo[d]imidazole N1,N3-
dioxides, we performed the reaction using the optimized condition of the reduction of
nitroarenes (see Table 1) and deoxygenation of benzofuroxans (Table 4), which in
general employs NaOH as base, a methanol:water (8:2) mixture as solvent, a reaction
temperature from 80 to 90 ºC and elemental sulfur as reductant. Then, optimization
experiments were focused on the determination of the minimal amounts of sulfur and
NaOH for the reactions. Experiments revealed that three equivalent of elemental sulfur
in combination with three equivalent of sodium hydroxide in methanol:water (8:2) at 80
ºC were the optimal conditions for the deoxygenation of N,N’-dioxide containing
heteroarenes (phenazine N,N´-dioxides, quinoxaline N1,N4-dioxides and 2H-
benzo[d]imidazole N1,N3-dioxides), while two equivalent of elemental sulfur and two
equivalent of base are sufficient for the deoxygenation of pyridine N-oxides and 2H-
indazole N1-oxides (Table 5). Similarly to previous reaction, herein the use of water
resulted to be essentially important for a good efficacy of the deoxygenation of these
five heterocyclic systems. A substrate scope was performed and general results are
listed in Table 5. Results reflected the difference in reactivity among the five studied
heterocyclic systems. In general, the phenazine N,N´-dioxides reacted notably faster than
pyridine N-oxides, quinoxaline N1,N4-dioxides, 2H-indazole N1-oxides and 2H-
benzo[d]imidazole N1,N3-dioxides (compared entries 1-6 to entries 7-16). From scope
phenazine, a series of 2-amino-substituted and 2-hydroxy-substituted phenazines were
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
17
prepared in good yield (73-95 %) under relatively mild conditions (entries 1-6, Table 5).
It should be noted that substitution on both benzenic ring has an important effect on the
reactivity of the phenazine dioxides. In particular, the substitution of an amine moiety
by a hydroxyl moiety on phenazine ring reduced partially the reactivity to the
deoxygenation (compared entry 1 with entry 5, Table 5). It is associated to the phenolic
acid nature of hydroxyl group, which increase its electron-donor ability, reducing the
reactivity of nitrogen atoms. The 2-hydroxyl-substituted phenazine required, in general,
more reaction time than 2-amino-susbtituted phenazine dioxides. On the other hand, the
incorporation of a methyl group at the 8-position of phenazine ring decreased the
reactivity of the system, displaying a complex mixture of product constituting mainly by
the starting material and by a product partially reduced of phenazine N-oxide (entry 4,
Table 5) (see spectra in Supporting material). A high conversion was found for the 2-
aminophenazine dioxides bearing bromine, fluorine and hydrogen at 8-position, giving
the deoxygenated product in excellent yields (76-95 %) and relatively shorter reaction
time (entries 1-3, Table 5). In particular, the fluorine atom attached at 8-position of
phenazine dioxide 5b reacted simultaneously with methoxy anion from reaction milieu
to form the deoxygenated 2-amino-8-methoxyphenazine, which is expected due to the
susceptibility of fluorine atom to aromatic nucleophilic substitution under basic
conditions. As last example, a partially activated phenazine dioxides such as phenazine
5f was less reactive toward the total deoxygenation than 2-aminophenazine N,N´-
dioxides 5a-c, requiring longer reaction time and generating a complex mixture between
mono-reduced and deoxygenated derivatives (entry 6, Table 5).
On other hands, some other azaheteroarenes N-oxides such as pyridine N-oxides, 2H-
indazole N1-oxides, quinoxaline N1,N4-dioxides and benzo[d]imidazole N1,N3-dioxides
showed a limited substrate scope. For examples, only pyridine N-oxides containing
withdrawing NO2-moiety were compatible with the protocol (entries 7 and 8, Table 5),
yielding the products with complete moiety-reductions (nitro and N-oxide groups),
while other pyridine N-oxides were practically inert (entries 9 and 10, Table 5). Similar
phenomenon was found for 2H-indazole N1-oxides and quinoxaline N1,N4-dioxides
where the heterocyclic system bearing withdrawing moiety were significant more
reactive (entries 11 and 13, Table 5), while electron-donor-substituted 2H-indazole N1-
oxide 9b and quinoxaline N1,N4-dioxide 11b did not react under reaction conditions or
more extreme ones. Finally, 2H-benzo[d]imidazole N1,N3-dioxides displayed an
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
18
incomplete reaction after 24 h under over-reflux, giving near to 60 % of desired
products according to 1H-NMR analysis (entries 15 and 16, Table 5).
Table 5. Substrate scope for the deoxygenation of N-oxide containing heteroarenes.a
O
S (3 eq.)
NaOH(3 eq.)
GROUP I:
N
N
MeOH-H2O(8:2)
T, 2-24 h
N
O
N
6a-f, 12a-b, 14a-b
5a-f, 11a-, 13a-b
O
S (2-5 eq.)
NaOH(2-5 eq.)
N
R
GROUP II:
N
R
MeOH-H2O(8:2)
T, 2-16 h
8a-d
7a-d
CN
CN
GROUP III:
S (2 eq.)
NaOH(2 eq.)
N Ar
N Ar
N
MeOH-H2O(8:2)
T, 24 h
N
O
10a-b
9a-b
Entrie
s
Substrate
Productb
Time (temperature)
N
NH2
O
N
NH2
4 h (80 ºC)
N
1
6a (87%)
N
O
5a
O
N
H3CO
N
NH2
F
NH2
2
3
4
3 h (80 ºC)
3 h (80 ºC)
24 h (80 ºC)
N
N
6b (95%)
5b
O
O
Br
N
NH2
Br
N
NH2
N
N
O
6c (76%)
5c
O
H3C
N
NH2
H3C
N
NH2
N
N
O
6d (mixture)
5d
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
19
O
N
OH
N
OH
5
16 h (80 ºC)
12 h (80 ºC)
N
N
6e (73%)
5e
O
O
N
N
6c
N
N
5f
O
6f (mixture)
O
N
NH2
N
NH2
7d
16 h (80 ºC)
8 h (80 ºC)
24 h (90 ºC)
24 h (90 ºC)
NH2
NO2
8a (68%)
7a
O
N
NH2
N
NH2
NO2
8d
NH2
8c (81%)
Cl
Cl
7b
O
N
N
9d
COOH
8c (traces)
COOH
7c
O
N
N
10e
8d (traces)
7d
CN
CN
11e
12
24 h (90 ºC)
24 h (90ºC)
N
N
I
N
I
N
O
10a (71%)
9a
CN
CN
N
OH
N
N
OH
N
O
10b (no conversion)
9b
O
N
Cl
Cl
N
NH2
CN
Cl
Cl
NH2
CN
13
16 h (90ºC)
N
N
O
12a (67%)
11a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
20
O
N
N
14d
15f
24 h (90ºC)
24 h (80 ºC)
N
N
O
12b (traces)
11b
N
N
O
N
14a (62%)
N
O
13a
16f
N
O
Cl
N
Cl
24 h (80 ºC)
N
14b (64%)
N
O
13b
aReaction conditions: To a solution of substrate (0.5-1.0 mmol) dissolved in methanol (5 mL), followed by a
minimal amount of water (1 mL) was added corresponding elemental sulfur and sodium hydroxide at 80-90 ºC.
c
1
d
bIsolated yields of pure product after column chromatography or recrystallization. Yield from H-NMR analysis. 5
e
equiv. of elemental sulfur and 5 equiv. of NaOH were used. 2 equiv. of elemental sulfur and 2 equiv. of NaOH were
used. fYield determined from 1H-NMR analysis of isolated product.
The mechanism of reaction proposed herein was inspired into previous findings
derived from Zinnin's protocol for the reduction of nitroarenes [33]. In general, kinetic
and analytical studies have identified to the nitroso-arene and hydroxylamine-arene as
potential organic intermediates as well as to the thiosulfate as oxidized sulfur specie,
both formed during the reaction [33]. With these principles in mind, we performed two
groups of experiments: (i) focusing on the identification of sulfur anionic species
formed post-reaction and, (ii) other focusing on the identification of organic
1
intermediate species by in situ H-NMR experiments. Firstly, the expected presence of
thiosulfate anion (S2O32-) was confirmed by four analytical tests including: (i)
permanganate discoloration test, (ii) iodine/iodide discoloration test, (iii) precipitation
with aluminum (III) solution and, (iv) complexation with silver chloride [34a-d], which
all these resulted positive according equations 3-6 for crude aqueous layers either from
the reduction of 1,3-dintrobenzene reduction or from the deoxygenation of
benzofuroxan. Also, the presence of sulfur anion (S2-) was detected through the
cadmium test. This sulfur anion can be derived from the disproportionation of elemental
sulfur under strong basic and heating conditions according to Eq. 7 and 8 [34e]. The
elemental sulfur may react with sulfide and sulfite anions generated from equations 7
and 8 accordingly to equations 9 and 10. These all reactions contribute to decrease the
effective amount of elemental sulfur needed for the reduction processes, which obligates
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
21
to use a small excess of elemental sulfur for an optimal reduction of nitro-arenes or
deoxygenation of N-oxide azaheteroarenes as was described in optimization
experiments (see Tables 1 and 3).
H2O
-
2-
2 MnO4 + 16 H+ + 10 S2O3
2-
2 Mn2+ + 5 S4O6 + 8 H2O
(3)
(4)
H2O
2-
2-
2 S2O3 + I2
S4O6 + 3 I-
H2O
2-
2 Al3+ + 3 S2O3 + 3 H2O
3 SO2 + 3 S + 2 Al(OH)3
(5)
(6)
(7)
H2O
H2O
Na2[Ag(S2O3)2] + NaCl
AgCl + 2 Na2S2O3
2Na2S + Na2S2O3
+
3H2O
3H2O
6 NaOH + 4 S
6 NaOH + 3 S
H2O
H2O
H2O
2Na2S + Na2SO3
Na2S(n+1)
+
(8)
(9)
Na2S + n S
Na2S2O3
(10)
Na2SO3 + S
Regarding to the identification of organic intermediates, an experiment on resulting
reaction mixture was performed for the incomplete reduction of N,N´-dimethyl-4-
nitroaniline. This substrate was selected because it was the unique nitroarene in which it
was possible to evidence the formation of several intermediates during reaction using
TLC analysis. The reaction was stopped at 2 hour, solvent was evaporated and resulting
1
1
crude was analyzed by a H-NMR experiment. From H-NMR spectra, the starting
material, the aniline product, N,N´-dimethyl-4-hydroxylaminoaniline, a small amount of
N,N-dimethyl-4-nitrosoaniline, and a good proportion of the diazene intermediate (see
details and spectrum in Supporting information material) were identified. The chemical
shifts of hydroxylamine, nitroso- and diazene intermediates are in concordance with
typical data reported for analogues of them [35]. The detected diaryl diazene N-oxide
intermediate is derived from coupling between the N,N´-dimethyl-4-
hydroxylaminoaniline and N,N-dimethyl-4-nitrosoaniline, and its formation
demonstrated that both reduced intermediates are formed during the studied reduction of
nitroarenes (see Figure 2). The condensation between N,N´-dimethyl-4-hydroxylamino
aniline and N,N´-dimethyl-4-nitroso intermediates under a variety of reaction conditions
has been widely reported [36]. It is important to mention that the diaryl diazene N-oxide
intermediate was only detected for the reduction of N,N´-dimethyl-4-nitroaniline, which
may be associated to the presence of the electron-donating group of dialkylamine,
faciliting the nucleophilic attack from hydroxylamine nitrogen to nitroso nitrogen to
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
22
form the diaryl diazene N-oxide after dehydratation process. Multiple small peak nearby
to chemical shifts of all mentioned intermediates suggested that other short life-time
intermediates containing sulfur may be involved into the formation of nitroso- and
hydroxylamino-intermediates. The formation of intermediates containing N-S(O) bond
has been previously reported for reduction of nitro group using sulfur reductant agents
[29b, 37]. Then, with these all information in hand, we proposed a tentative mechanism
of reaction for the reduction of nitroarenes (Figure 2). Firstly, elemental sulfur reacts
with sodium hydroxide under heating in solution to form oxy-sulfur specie (HO-S-). The
nucleophilic oxy-sulfur (HO-S-) anion attacks to positive nitrogen atom of nitro group in
substrate 1a to form an unstable sulfinyl-nitroso intermediate I, which releases
nitrosoaryl intermediate II and hydro-sulfoxylate anion through a new nucleophilic
attack of hydroxide anion to sulfur atom in intermediate I. Intermediate II may react: (i)
with a nucleophilic thio-hydrosulfoxylate species [HOS(O)S-] (a thiosulfite anion)
derived from reaction between the hydro-sulfoxylate (HO-SO-) anion and elemental
sulfur to form an intermediate III or, (ii) with a nucleophilic oxy-sulfur to form
intermediate IV. Then, intermediate III and IV are attacked by hydroxide anion on
sulfur atom to form the hydroxylamino intermediate V, releasing thiosulfate and hydro-
sulfoxylate anions, respectively. The hydro-sulfoxylate anion reacts with elemental to
generate other molecule of thiosulfite anion. Finally, nucleophilic oxygen of
hydroxylamine attack to sulfur atom of thiosulfite anion to form intermediate VII,
which disproportionates to release the desired aniline VIII and two molecules of
thiosulfate anion. During the reaction, three molecules of thiosulfate are formed by each
two molecules of nitroarenes, requiring six equivalents of sulfur and six of hydroxide.
The hydroxylamine intermediate V may react with the nitroso-arene intermediate II to
display the diaryl diazene N-oxide intermediate VI. This last intermediate VI only was
detected in the reduction of N,N´-dimethyl-4-nitroaniline. From proposal mechanism, it
is clear that a strong base is essential to induce the first oxygenation of the elemental
sulfur to form the oxy-sulfur anion, which is highly rich-electron specie to initiate the
electron transfer to nitro group. Furthermore, the high nucleophilic power of hydroxide
as well as the relative stability of S-O bond facilitates the formation of oxygenated
sulfur species (e.g. thiosulfate) leading the reduction of oxidized nitrogen moieties. The
reaction between oxygenated sulfur anions and elemental sulfur suggests that polar
mixture solvent such as methanol-water that has the ability to dissolve partially both the
elemental sulfur and hydroxide sodium is essential for an optimal redox process.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
23
O
2 S
S
3 S
+
3
S OH
S
3 HO
H
S S
2
HO
2
O
OH
O
O
O
N
O
O
N
N
N
O
S OH
2
2
+
OH
2
I
II
II
1a
O
S S
S OH
OH
H
H
H
O
N
OH
S
H
S
O
O
N
S
N
2
OH
OH
OH
VIII
III
O
IV
O
O
HO
S
S
OH
+ H2O
S
S
OH
S
S
O
S
O
HO
O
O
O
H
H
O
O
S
S
N
H
O
N
S
S S
2
O
O
O
N
OH
2
OH
S S
2
OH
V
VII
General reaction:
2 PhNO2 + 6 S + 6 NaOH
O
N
N
H2O
2 PhNH2 + 3 Na2S2O3 + H2O
VI
Figure 2. Plausible proposed mechanism of reaction for nitro-arenes (compound 1a is
used as model).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
24
HO
N S
S
O
N O
S
N O
N
S
+
HO
O
IX
X
XI
XII
S
OH
O
S
O
-
N
N
S
HS2O3
S S
+
OH
O
XIV
N O
XIII
General reaction for N-oxide azaheteroarenes:
+ 2 S + NaOH
+ NaHS2O3
2 R-N
2 R-N-O
General reaction for N-dioxide azaheteroarenes:
O
N
N
+ NaHS2O3
+ 2 S + NaOH
N
N
O
Figure 3. Plausible proposed mechanism for N-oxide azaheteroarenes.
Regarding to N-oxide containing azaheteroarenes, no intermediates were detected
1
from the H-NMR experiments; however, we think that short-life sulfur intermediates
may be involved in the deoxygenation of N-oxide heteroarenes. Initially, oxygen of N-
oxide moiety of substrate IX (Figure 3) ensemble with empty orbital in elemental sulfur
to form intermediate X, which may easily to release the sulfinyl intermediate XI. The
formation of intermediate XI is well supported by the generation of thiobenzofurazan,
which were detected for the deoxygenation of benzofuroxans. Subsequently, the
desulfinylation of XI mediated by nucleophilic action of hydroxide anion lead to the
desired heteroarene XII and hydrosulfoxylate anion according to Figure 3. A thio-
hydrosulfoxylate derived from coupling between hydro-sulfoxylate (HO-SO-) and
elemental sulfur may deoxygenate other N-oxide unit from other molecule of
benzofuroxan or a second N-oxide unit in a dioxide derivative to form the reduced
product XIV, passing by intermediate XIII. In particular, N-oxide containing
heteroarene such as benzofuroxan, pyridine or indazole needed one equivalent of
elemental sulfur by substrate, while the N,N-dioxides required two equivalents of
elemental sulfur by substrate.
Next, we evaluated the green chemistry credentials for our protocol using E-factor
(see details in Supporting information for calculations) [38]. In general, the protocol
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
25
presented good E-factor values from 3.26-7.85 for reduction of nitroarenes, from 1.98-
3.01 for the deoxygenation of benzofuroxans and from 1.60-2.38 for the phenazine N,N
´-dioxides. A moderate AE value was obtained for the reduction of nitroarenes and
deoxygenation of N-oxide containing heteroarenes. To evaluate the purity of the water-
1
waste used as a solvent in our protocol, we analyzed through a simple H-NMR
experiment the resulting water mixture after reaction and the extraction with ethyl
acetate. It should be noted that water solution was free of organic compounds, which
demonstrated together to the good E-factor value the sustainability of the reaction (all
these details can be seen in supporting information material). Furthermore, we
demonstrated that resulting water solution can be re-used for further reduction of 1,3-
dinitrobenzene using only two equivalents more of elemental sulfur and sodium
hydroxide, putting in evidence the sustainability and reusability of the protocol.
To verify the scalability of the protocol, a gram-scale (2 g) synthesis of the luminol
was performed (Figure 4). Luminol is a chemiluminescence agent that presents a variety
of applications including the detection of ion concentrations in aqueous solutions [39],
monitoring H2O2-dependent reactions [40] and the detection of blood at crime scenes
[41]. In our conditions, the reaction proceeded during 1 hour under optimized
conditions of reduction with an excellent yield by about 89 % and a facile and practical
isolating procedure. Previous reports permitted the synthesis of luminol with moderate
yield using sophistic reagent such as dithionite or hazardous reagents such as ammonia
and hydrogen sulfur [42]. Therefore, our protocol represents an efficient, competitive
and eco-friendly procedure for the preparation of luminol to gram-scale.
NH2
NO2
O
O
-High reaction yield (89%)
-Practical and simple isolating procedure
-Eco-friendly protocol
-Use of raw material and safer solvent
-Mild conditions
-Low production of water waste
-Excellent sustainability and reusability
4 equiv. S
4 equiv. NaOH
NH
NH
NH
NH
MeOH-H2O (8.2)
80 ºC, 1 h
O
O
2 g
1.53 g
Figure 4. A gram-scale example for the synthesis of Luminol.
Conclusion
We developed a transition metal-free, practical and eco-friendly procedure for the
reduction of nitroarenes and for the deoxygenation of N-oxide containing heteroarenes
using a non-toxic and economical raw reducing agent such as elemental sulfur in
aqueous methanol solvent under relatively mild conditions. Our protocol provide a
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
26
variety of important compounds in organic chemistry such as substituted anilines,
benzofurazans, phenazines, pyridines, indazoles, quinoxalines and benzimidazoles,
emerging as a powerful route to the synthesis of bioactive molecules and intermediates
in organic chemistry. Compared to other reported method of reduction of nitroarenes
and deoxygenation of N-oxide containing heteroarenes, the current protocol highlights
by its simplicity, efficiency and eco-friendly characteristic with reduced compound
manipulations in work-up and purification procedures. Finally, this strategy represents a
valuable strategy for industrial applications in: (i) the preparation of valuable chemical
agent such as luminol to a gram-scale in excellent yield (89 %), (ii) selective reduction
of symmetric and asymmetric substituted dinitrobenzene to nitroanilines, and (iii)
effective conversion of pollutant o-nitroaniline to o-diamines with good Green
chemistry metrics.
Acknowledgments
The authors thank to Facultad de Ciencias (Universidad de la República, Montevideo,
Uruguay) and PEDECIBA-Química (Uruguay) for financial support. AH Romero
thanks Agencia Nacional de Investigación e Innovación (ANII) by finantial supports
under code PD_NAC_2018_1_150515. Authors are also grateful with Horacio
Pezaroglo and Gonzalo Hernández (NMR Laboratory, Facultad de Química,
Universidad de la República) for the NMR spectra.
Conflicts of interest
Authors declared not conflict of interest.
Supplementary material
1
Full experimental details, H-NMR and 13C-NMR spectra associated with the all
compounds obtained herein can be found in the online version of the Supplementary
material.
References
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
27
1. (a) S.A. Lawrence, Amines: Synthesis, Properties and Applications; Cambridge University Press:
Cambridge, 2004. (b) N. Ono, The Nitro Group in Organic Synthesis; Wiley: New York, 2001. (c) A.S.
Travis, in The Chemistry of Anilines, ed. Z. Rappoport, Wiley, 2007, ch. 13, pp. 715–782; (d) A. Albini,
Synthesis 1993, 263.
2. A. Béchamp, Annales de chimie et de physique 1854, 42, 186.
3. (a) P.N. Rylander, Hydrogenation Methods; Academic: New York, 1985. (b) M. Hudlicky, Reductions
in Organic Chemistry; Ellis Horwood Ltd: Chichester, 1984, 1. (c) G.V. Smith, F. Nothesiz,
Heterogeneous Catalysis in Organic Chemistry; Academic: New York, 1999, 71. (d) J. Song, Z.F. Huang,
L. Pan, K. Li, X. Zhang, L. Wang, J.J. Zou, Applied Catalysis B: Environmental, 2018, 227, 386. (e) H.U.
Blaser, H. Steiner, M. Studer, ChemCatChem. 2009, 1, 210. (f) C. Campos, T. Cecilia, M. Oportus, M.A.
Pena, J.L.G. Fierro, P. Reyes, P. Catal. Today, 2013, 213, 93. (g) Y. Sun, A.J. Darling, Y. Li, K.
Fujisawa. C.F. Holder, H. Liu, M.J. Janik, M. Terrones, R.E. Schaak, Chem. Sci., 2019, 10, 10310.
4. D. Formenti, F. Ferretti, F. Korbinian Scharnagl, M. Beller, Chem. Rev. 2019, 119, 2611.
5. (a) K. Junge, B. Wendt, N. Shaikh, M. Beller, Chem. Commun. 2010, 46, 1769. (b) P.K. Mandal, J.S.
McMurray, J. Org. Chem. 2007, 72, 6599. (c) M. Paul, N. Pal, A. Bhaumik, Eur. J. Inorg. Chem. 2010,
5129. (d) T. V. Nykaza, J. C. Cooper, G. Li, N. Mahieu, A. Ramirez, M. R. Luzung, A. T. Radosevich, J.
Am. Chem. Soc., 2018, 140, 15200. (e) M. Orlandi, F. Tosi, M. Bonsignore, M. Benaglia, Org. Lett. 2015,
17, 3941. (f) M. Orlandi, M. Benaglia, F. Tosi, R. Annunziata, F. Cozzi, J. Org. Chem. 2016, 81, 3037.
(g) M. Orlandi, F. Tosi, M. Bonsignore, M. Benaglia, Org. Lett. 2015, 17, 16, 3941-3943. (h) D. Porwal,
M. Oestreich, Eur. J. Org. Chem. 2016, 2016, 3307.
6. (a) Q. Shi, R. Lu, L. Lu, X. Fu, D. Zhao, Adv. Synth. Catal. 2007, 349, 1877. (b) J.K. Niemeier, D.P.
Kjell, Org. Process Res. Dev. 2013, 17, 1580. (c) F. Li, B. Frett, H. Li, Synlett, 2014, 1403. (d) R.V.
Jagadeesh, G. Wienhofer, F.A. Westerhaus, A. Surkus, M. Pohl, H. Junge, K. Junge, M. Beller, Chem.
Commun. 2011, 47, 10972. (e) B. Lakshminarayana, G. Satyanarayana, C. Subrahmanyam, ACS Omega,
2018, 3, 13065.
7. (a) D. Giomi, R. Alfini, A. Brandi, Tetrahedron 2011, 67, 167. (b) M. Miyagawa, R. Yamamoto, N.
Kobayashi, T. Akiyama, Synlett, 2019, 30, 499. (c) D. Chen, Y. Zhou, H. Zhou, S. Liu, Q. Liu, K. Zhang,
Y. Uozumi, Synlett, 2018, 29, 1765. (d) H. Hosoya, L.C.M. Castro, I. Sultan, Y. Nakajima, T. Ohmura,
K. Sato, H. Tsurugi, M. Suginome, K. Mashima, Org. Lett. 2019, 21, 9812.
8. (a) S.K. Maity; N.C. Pradhan; A.V. Patwardhan, Chemical Eng. J. 2008. 141, 187. (b) S.L. Zhao; H.D.
Liang; Y.F. Zhou, Catal. Commun. 2007, 8, 1305. (c) J. Hou; Y.H. Ma; Y.H. Li,; F. Guo; L.H. Lu, Chem.
Lett. 2008, 37, 974. (d) US Patent Nº 2669584, Selective reduction of polynitro aromatics, 1954. (e) J.P.
Idoux, J. Chem. Soc. (C), 1970, 435.
9. Some a few examples: (a) S. Kumar; A. Saini; J.S. Sandhu. Tetrahedron Lett. 2005, 46, 8737. (b) A.
Saini; S. Kumar; J.S. Sandhu. Synlett 2006, 395. (c) Y. Wang; J.H. Espenson. Org. Lett. 2000, 2, 3525.
10. (a) E. Hayashi, E. Ijima, Ch. Yakugaku Zasshi 1962, 82, 1093. (b) F.A. Daniher, B.E. Hackley Jr., J.
Org. Chem. 1966, 31, 4267.
11. B.F. Bonini, G. Maccagnani, G. Mazzanti, P. Pedrini, Tetrahedron Lett. 1979, 20, 1799.
12. G.A. Olah, M. Arvanaghi, Y.D. Vankar, Synthesis, 1980, 660.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
28
13. H. Kagami, S. Motoki, J. Org. Chem. 1978, 43, 1267.
14. T. Yoshimura, K. Asada, S. Oae, Bull. Chem. Soc. Jpn. 1982, 55, 3000.
15. W.B. Lutz, S. Lazarus, S. Klutchko, R.I. Meltzer, J. Org. Chem. 1964, 29, 1645.
16. E. Howard Jr., W.F. Olszewski, J. Am. Chem. Soc. 1959, 81, 1483.
17. M. Takeshita, S. Yoshida, Heterocycles 1990, 30, 871.
18. H.R. Bjørsvik, C. Gambarotti, V.R. Jensen, R.R. Gonzalez, J. Org. Chem. 2005, 70, 3218.
19. S. M. Kelly, B. H. Lipshutz, Org. Lett., 2014, 16, 98.
20. R. Balicki , M. Cybulski, G. Maciejewski, Synth. Commun. 2003, 33, 4137.
21. J.1.G. Cadogan, M. J. Todd, J. Chem.Soc. C :Organic, 1969, 2808. (b) R.J. Sundberg, W.G. Adams,
R.H. Smith, D.E. Blackburn Tetrahedron Lett. 1968, 777.
22. P.H. Scott, C.P. Smith, E. Rober, J.W, Churchill, Tetrahedron Lett. 1970, 1153.
23. H. Lu, Z. Geng, J. Li, D. Zou, Y. Wu, Y. Wu, Org. Lett. 2016, 18, 2774.
24. H.P. Kokatla, P.F. Thomson, S. Bae, V.R. Doddi, M.K. Lakshman, J. Org. Chem. 2011, 76, 7842.
25. (a) N.J. Hirao, Osaka Inst. Sci. Technol. 1950, 1, 57.(b) K. Niknam, A.R. Kiasat, F. Kazemi, A.
Hossieni, Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 1385. (c) A. McLaughlin, D.M. Barnes,
Tetrahedron Lett. 2006, 47, 9095. (d) Q. Shuai1, J. Li, F. Zhao, W. Su1, G. Deng, Chemical Papers,
2019, 73, 965-975. (e) I.Z. Kondyukov, Y.V. Karpychev, P.G. Belyaev, G.K. Khisamutdinov, S.I.
Valeshnii, S.P. Smirnov, V.P. Il’in, Russian J. Org. Chem. 2007, 43, 635.
26. (a) K. Wang, D. Kim, A. Dçmling, J. Comb. Chem. 2010, 12, 111. (b) A. Rais, H. Ankati, E. Biehl, J.
Heterocycl. Chem. 2009, 46, 599. (c) A.Y. Solovyev, D.A. Androsov, D.C. Neckers, J. Org. Chem. 2007,
72, 3122; (d) D.A. Androsov, A.Y. Solovyev, M.L. Petrov, R.J. Butcher, J.P. Jasinski, Tetrahedron 2010,
66, 2474.
27. (a) T.B. Nguyen, Adv. Synth. Catal. 2017, 359, 1066. (b) F.H. McMillan, J. Am. Chem. Soc. 1948, 70,
868. (b) T.B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2012, 14, 4274. (c) M.K. Denk, S.
Gupta, J. Brownie, S. Tajammul, A.J. Lough, Chem. Eur. J. 2001, 7, 4477.
28. (a) D. Kadzimirsz, D. Kramer, L. Sripanom, I. M. Oppel, P. Rodziewicz, N. L. Doltsinis, G. Dyker, J.
Org. Chem. 2008, 73, 4644. (b) A. Poser, R. Lohmayer, C. Vogt, K. Knoeller, B. Planer-Friedrich, D.
Sorokin, H. H. Richnow, K. Finster, Extremophiles 2013, 17, 1003. (c) T.B. Nguyen, L. Ermolenko, W.
A. Dean, A. Al- Mourabit, Org. Lett. 2012, 14, 5948.
29. (a) H. K. Porter, “The Zinin Reduction of Nitroarenes,” Organic Reactions 1973, 20, 455. (b) T. B.
Nguyen, P. Retailleau, Org. Lett. 2017, 19, 3879. (c) E. F. Lejarazo Gómez , E. Santos Santos, S. Suarez
Torres, J. Chem. and Chemical Eng. 2018, 12, 74.
30. (a) R. Mayer, K. Gewald, Angew. Chem. Int. Ed. Engl. 1967, 6, 294. (b) O.I. Zubruyev, N. Stiasni, C.
O. Kappe, J. Comb. Chem. 2003, 5, 145. (c) B. Bottcher, F. Bauer, Justus Liebigs Ann. Chem. 1950, 568,
218. (d) H. Xu, H. Deng, Z. Li, H. Xiang, X. Zhou, Eur. J. Org. Chem. 2013, 7054. (e) S. Tandel, I.
Bliznets, K. Ebinger, Y.A. Ma, D. Bhumralkar, M. Thiruvazhi, Tetrahedron Lett. 2004, 45, 2321. (f) F.
Shibahara, R. Sugiura, E. Yamaguchi, S. Kitagawa, T. Murai, J. Org. Chem. 2009, 74, 3566.
31. (a) T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Org. Lett. 2013, 15, 4218. (b) A. Samzadeh-
Kermani, Synlett, 2015, 26, 643. (c) H. Xie, J. Cai, Z. Wang, H. Huang, G. Deng, Org. Lett. 2016, 18,
2196.(d) B. Eftekhari-Sis, S.V. Khajeh, O. Buyukgungor, Synlett, 2013, 24, 977. (e) A.O. Lifshits, P.N.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000064
European Journal of Organic Chemistry
29
Ostapchuk, V.K. Brel, Russ. J. Org. Chem. 2015, 51, 744; (f) R. Wegler, E, Kghle, W. Schfer, Angew.
Chem. 1958, 70, 351
32. (a) J.H. Boyer, S.E. Ellzey, J Org. Chem., 1961, 26, 4684. (b) S. Merritt, S. Di Pierto, S.W. Hand, J.
Chromatogr, 1975, 112, 301. (c) F.B. Mellory, S.P. Varimbi, J. Org. Chem., 1963, 28, 1656. (d)
F.S.Levinson, M.I.Evgenev et al. Chemical & pharmaceutical journal, 2003, 37,12. (e) A.S. Baily, J.M.
Evans, J. Chem. Soc, S., 1967, №21, r.2105-2109. (f) L. Di Nunno, S. Florio, Chem. E ind (Ital), 1957,
57, 243. (g) L. Di Nunno, S. Florio, J. Chem. Soc. Perkin Trans., 1973, 1,1954.
33. (a) H.U. Blaser, Science, 2006, 313, 312. (b) P.L. Breuer, M.I. Jeffrey, Hydrometallurgy, 2003, 70,
163. (c) S.K. Maity, N.C. Pradhan , A.V. Patwardhan, Applied Catalysis A: General, 2006, 301, 251. (d)
G.D. Yadav, Y.B. Jadhav, S. Sengupta, Chemical Engineering Science, 2003, 58, 2681.
34. (a) T.R. Dulki (1996) “Ch.8: Separation by precipitation”, A manual for the chemical Analysis of
Metals, West Conshohocken, p 99. (b) A.F. Holleman, E. Wiberg, N. Wiberg (2001), Inorganic
Chemistry, San Diego, Academic Press. (c) H.M. Gordin (1913), “ElementaryChemistry, Vol. 1. (d) T.
Lister, (1945), “Classic chemistry demonstration”, (London; The Royal Society of Chemistry). (e) D.G.
Oei, Inorg. Chem., 1973, 12, 438.
35. (a) For aryl-nitroso derivatives: comparison with 4-ethyl nitrobenzene analogue, B. Priewisch, K.
Rück-Braun, J. Org. Chem. 2005, 70, 6, 2350. (b) For aryl-hydroxilamine derivatives: comparison with
4-methoxy nitrobenzene analogue, Y. Takenaka, T. Kiyosu, J.C. Choi, T. Sakakura, H. Yasuda, Green
Chem. 2009, 11, 1385. (c) For diaryl diazene N-oxide and aryl-nitroso derivatives: comparison with
diphenyl diazene N-oxide, F. Tripoteau, L. Eberlin, M.A. Fox, B. Carboni, A. Whiting, Chem. Commun.,
2013, 49, 5414.
36. (a) W.W. Wood, J.A. Wilkin, Synth. Comm. 1992, 22, 1683. (b) S. Liu, Y. Hao, J. Jiang, Ind. Eng.
Chem. Res. 2014, 53, 8372. (c) H. Tao, X.C. Liu, J.H. Su, Y.X. Wang, X.M. Gu, D.J. Yang, E.R.
Waclawik, H.Y. Zhu, Z.F. Zheng, Sci. Rep. 2019, 9, 1280. (d) H.U. Blaser, H. Steiner, M. Studer,
ChemCatChem, 2009, 1, 210. (e) W. Anderson, J. Chem. Soc., 1952, 1722.
37. A.H. Romero, J. Salazar, S.E. López, Synthesis. 2013, 45, 2043-2050.
38. R.A. Sheldon, ACS Sustain. Chem. Eng. 2018, 6, 32.
39. T. Nieman, In Chemiluminescence and Photochemical Reaction Detection in Chromatography; Birks,
J. W., Ed.; VCH: NewYork, 1989, pp 99-123.
40. J. Yuan, A.M. Shiller, Anal. Chem. 1999, 71, 1975.
41. E.J.M. Kent, D.A. Elliot, G.M. Miskelly, J. Foren. Sci. 2003, 48, 64.
42. (a) E. Huntress, L. Stanley, A. Parker, J. Am. Chem. Soc. 1934, 56, 241. (b) K.L. Williamson, In
Macroscale and Microscale Organic Experiments; 2nd ed.; D.C. Heath: Lexington, MA, 1994, pp 153-
162. (c) E.H. White, K. Matsuo, J. Am. Chem. Soc., 1967, 32, 1921.
This article is protected by copyright. All rights reserved.