Mild Nitration of Pyrazolin-5-ones by a Combination of Fe(NO3)3 and NaNO2: Discovery of a New Readily Available Class of Fungicides, 4-Nitropyrazolin-5-ones

Article abstract of DOI:10.1002/chem.201806172

4-Nitropyrazolin-5-ones have been synthesized by the nitration of pyrazolin-5-ones at room temperature by employing the Fe(NO₃)₃/NaNO₂ system. The method demonstrated selectivity towards the 4-position of pyrazolin-5-ones

Full text of DOI:10.1002/chem.201806172

A Journal of
Accepted Article
Title: Mild nitration of pyrazolin-5-ones by a combination of Fe(NO3)3
and NaNO2. Discovery of a new easily available class of
fungicides – 4-nitropyrazolin-5-ones
Authors: Igor B. Krylov, Alexander S. Budnikov, Elena R. Lopat’eva,
Gennady I. Nikishin, and Alexander Terent'ev
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: Chem. Eur. J. 10.1002/chem.201806172
Link to VoR: http://dx.doi.org/10.1002/chem.201806172
Supported by

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
Mild nitration of pyrazolin-5-ones by a combination of Fe(NO3)3
and NaNO2. Discovery of a new easily available class of
fungicides – 4-nitropyrazolin-5-ones
Igor B. Krylov,[a,b] Alexander S. Budnikov,[a,b,c] Elena R. Lopat’eva,[a,c] Gennady I. Nikishin,[a] Alexander
O. Terent’ev*[a,b,c]
Abstract: 4-Nitropyrazolin-5-ones were synthesized by nitration of
pyrazolin-5-ones
at
room
temperature
employing
the
Fe(NO3)3/NaNO2 system. The method demonstrated selectivity
towards position 4 of pyrazolin-5-ones even in the presence of NPh
and allyl substituents, which are sensitive to nitration. It was shown
that other systems containing Fe(III) and nitrites, namely Fe(NO3)3/t-
BuONO, Fe(ClO4)3/NaNO2, and Fe(ClO4)3/t-BuONO are also
effective. Presumably, Fe(III) ions oxidized nitrite (NaNO2 or t-
BuONO) with the formation of NO2 free radicals that served as the
nitrating agent for pyrazolin-5-ones. The synthesized 4-
nitropyrazolin-5-ones were discovered to be
a new class of
fungicides. Their in vitro activity against phytopathogenic fungi was
comparable or even superior to commercial fungicides (fluconazole,
clotrimazole, triadimefon, kresoxim-methyl). Reported results
represent a promising starting point for the development of a new
type of plant protection agents that are easily synthesized from
widely available reagents.
Introduction
Nitro compounds are widely used as reagents in the synthesis of
fine chemicals, drugs, explosives, fuels etc. Nitrogen dioxide
(NO2) is one of the most simple and effective nitrating agents,[1]
but it is not convenient in operation and storage due to its
volatility, toxicity and corrosive properties. Therefore, in recent
years great efforts were made to develop systems for the
generation of NO2 in situ.[2-33] Nitrates and nitrites, such as
Scheme 1. Present work in the context of published results on arene nitration
by Fe(NO3)3 and nitration of pyrazolin-5-ones
(NH4)2Ce(NO3)6,[2]
Cu(NO3)2,[3-5]
AgNO3,[6]
Mg(NO3)2,[7]
the Fe(NO3)3•9H2O/TEMPO system[16] (Scheme 1b). However,
in both cases elevated temperatures are necessary for iron (III)
nitrate activation.
Fe(NO3)3•9H2O,[8-19] t-BuONO,[20-25] NaNO2,[26-29] and AgNO2,[30-
32]
are available and convenient nitrating agents and precursors
of NO2. Fe(NO3)3•9H2O has found the widest application in
The introduction of the nitro group into pyrazolin-5-ones
has not been extensively studied. Preparation of 4-
nitropyrazolin-5-ones by oxidation of the corresponding 4-
oximinopyrazolin-5-ones by ozone[34] or by nitration of pyrazolin-
5-ones with isoamyl nitrite[35] were reported. However, in these
studies, nitro derivatives were not fully characterized, and the
yields of the products were not given. In most cases, nitration of
pyrazolin-5-ones was carried out using nitric acid or
HNO3/H2SO4 mixture under heating (Scheme 1c).[36-40]
Disadvantages of these procedures are harsh acidic conditions
and low selectivity. Thus, in the case of phenyl-substituted
pyrazolin-5-ones, nitration of both phenyl and pyrazolone rings
occurred.[38]
nitration reactions due to its low toxicity, availability and low
decomposition temperature with release of NO2.
Recently, Chandrasekharam and Gao reported the ortho-
nitration of N-acylanilines by Fe(NO3)3•9H2O[13,18] (Scheme 1a).
Sharada’s group achieved the nitration of 2H-indazoles by
[8-19,33]
[a]
Igor B. Krylov, Alexander S. Budnikov, Elena R. Lopat’eva, Gennady
I. Nikishin, Alexander O. Terent’ev
N. D. Zelinsky Institute of Organic Chemistry of the Russian
Academy of Sciences
47 Leninsky prosp., Moscow 119991, Russian Federation
E-mail: alterex@yandex.ru
[b]
[c]
Igor B. Krylov, Alexander S. Budnikov, Alexander O. Terent’ev
All-Russian Research Institute for Phytopathology, B. Vyazyomy,
Moscow Region 143050, Russian Federation
Alexander S. Budnikov, Elena R. Lopat’eva
One of the main problems of selective oxidative
functionalization of pyrazolin-5-ones, especially 4-substituted
derivatives, is their tendency to undergo hydroxylation[41,42] and
oxidative dimerization.[41,43-45] These processes easily proceed
even under the action of molecular oxygen at room
Mendeleev University of Chemical Technology of Russia
9 Miusskaya sq., Moscow 125047, Russian Federation
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
temperature.[45] In addition, oxidative destruction of the
pyrazolin-5-one ring is also known.[46,47] Among the recent works
devoted to the functionalization of pyrazolin-5-ones by the attack
such properties are not intrinsic or typical for the pyrazolin-5-one
scaffold. Instead, these compounds are widely recognized as
anti-inflammatory and analgesic drugs. In the present work, high
fungicidal activity of the synthesized 4-nitropyrazolin-5-ones was
discovered. It should be emphasized that 4-nitropyrazolin-5-
ones represent a new class of potent and readily accessible
fungicides. The long-term demand for the search of new types of
fungicides for agriculture and medicine[78,79] is due to the
development of fungal resistance against widely used
compounds.[80-83] Currently, only six families of agrochemical
fungicides classified by mode of action dominate around 80% of
the world market.[82] The most important fungicide families are
of electrophiles[48-55] or radicals[56-58] at the position
4 of
heterocycle, only one involved creation of C-N bond, in which
azodicarboxylates were used as N-electrophiles.[52]
In the present work, we proposed a Fe(NO3)3/NaNO2
nitrating system, which made it possible to synthesize 4-
nitropyrazolin-5-ones having a substituent at C-4 under ambient
conditions (Scheme 1d). The method is tolerant to easily
oxidizable functional groups, such as allyl, benzyl, and N-phenyl
and avoids typical oxidative processes of pyrazolin-5-ones:
hydroxylation[41,42] and oxidative dimerization. [41,43-45] It should be
noted that previously reported procedures (Scheme 1c) were
described only for 4-unsubstituted pyrazolin-5-ones.
The choice of pyrazolin-5-ones as substrates for nitration
in the present study is associated with a wide range of their
biological activities (Scheme 2). These include anti-inflammatory
and analgesic, antitumor,[59] antimicrobial,[60,61] hypoglycemic,[62]
antitubercular,[63] herbicidal[64-66] and fungicidal,[64,67-71] p38
inhibiting,[72] HIV integrase inhibiting,[73] 4-phosphodiesterase
inhibiting,[74,75] and HNO-donor properties.[76,77]
demethylation
inhibitors
(DMIs,
e.g.
triazoles),
“multisite/chemical reactives” such as dithiocarbamates, Qo-site
inhibitors of complex III such as strobilurin derivatives, and
succinate-dehydrogenase inhibitors (SDHIs).[82] It is known that
compounds with different modes of action are desirable for the
minimization of the risk of resistance development. The other
side of the described issue of deficiency in the fungicide arsenal
is the fact that an alarmingly high number of molecules used in
crop protection are either structurally or pharmacologically
related to drugs utilized in medicine.[84] Overuse of compounds
with a common mode of action extends risk of resistance
development in pathogenic fungi.
To sum up, the present paper consists of two parts: (1) the
development of Fe(III) salt / nitrite system for room temperature
nitration of pyrazolin-5-ones, and (2) the discovery of 4-
nitropyrazolin-5-ones as a new potent class of fungicides.
Results and Discussion
At the first stage of the present study, the nitration conditions
were optimized using 4-benzyl-3-methylpyrazolin-5-one 1a as a
model substrate. The influence of nitrating system composition,
solvent, and temperature on the yield of nitropyrazolin-5-one 2a
was studied (Table 1).
Runs 1-3 showed that Fe(NO3)3•9H2O is an effective
reagent for nitration of pyrazolin-5-one 1a at 60-80°C, but at
room temperature 4-nitropyrazolin-5-one 2a was obtained in
only 33% yield (run 4). Apparently, the elevated temperature
was necessary for the decomposition of Fe(NO3)3•9H2O with the
release of the active nitrating agent NO2.[8-19,33] The introduction
of NaNO2 into the reaction allowed the room temperature
nitration of pyrazolin-5-one 1a with high yields (runs 5-7). The
optimal ratio of reagents was pyrazolin-5-one: Fe(NO3)3•9H2O:
NaNO2 = 1:2:1 (run 5). When the amount of NaNO2 was doubled,
the yield of 2a decreased from 83% (run 5) to 62% (run 6).
Increasing the amount of Fe(NO3)3 (run 7) did not lead to a
significant increase of yield of 2a in comparison to run 5. In runs
5, 8-11, the influence of the solvent on the yield of 2a was
studied, the best result was obtained in MeCN (run 5, yield 83%).
Scheme 2. Examples of bioactive compounds and drugs with pyrazolin-5-one
heterocycle.
Although some pyrazolin-5-ones of quite complicated
structure were reported to possess fungicidal activity,[64,67-71],
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
mediated nitration,[11,12,16] 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) was an effective additive to increase the yields of nitro
derivatives. In run 12 with addition of 10 mol% TEMPO, the yield
of product 2a decreased in comparison to run 5. In runs 13-15,
components of nitration systems were varied. Combinations
NaNO2/Fe(NO3)3, t-BuONO/Fe(NO3)3, t-BuONO/Fe(ClO4)3, and
NaNO2/Fe(ClO4)3 showed comparable efficiency, yields were in
the range 74 - 84%. Thus, both the salt NaNO2 and the organic
nitrite t-BuONO can be used. The replacement of iron (III) nitrate
with perchlorate (runs 5 and 15, 13 and 14) did not lead to
significant changes in the yield 2a, or led to its increase. The
effectiveness of Fe(ClO4)3 indicates that the nitrate ions are not
obligatory for nitration when NaNO2 or t-BuONO are present in
the reaction mixture. Fe3+ ions and nitrites play the key role. In
runs 16-19, replacement of iron salts with nitrates of other
metals resulted in low yields of 2a, which did not exceed 22%.
With the optimized conditions in hand (Table 1, run 5), we tested
the scope of the developed nitration procedure (Table 2).
Table 1. Optimization of the reaction conditions for nitration of 1a[a]
.
Run
Oxidant (molar ratio
Nitrite
Solvent
T
Yield[b]
%
,
oxidant / 1a)
(molar ratio
nitrite / 1a)
(°C)
1
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (1)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (4)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
Fe(NO3)3•9H2O (2)
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
AcOH
MeOH
TFE
60
74
67
51
33
83
62
87
52
<5
26
33
52
74
2
-
80
3
-
60
4
-
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
5
NaNO2 (1)
NaNO2 (2)
NaNO2 (2)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
6
Table 2. The synthesis of nitropyrazolin-5-ones 2a-l by the nitration of
pyrazolin-5-ones 1a-l[a]
.
7
8
9
10
11
12[c]
13
C2H4Cl2
MeCN
MeCN
t-BuONO
(1)
14
Fe(ClO4)3•nH2O (2)
t-BuONO
MeCN
RT
81
(1)
15
16
17
18
19
Fe(ClO4)3•nH2O (2)
(NH4)2Ce(NO3)6 (2)
Cu(NO3)2•2.5H2O (2)
Co(NO3)2•6H2O (2)
Pb(NO3)2 (2)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
NaNO2 (1)
MeCN
MeCN
MeCN
MeCN
MeCN
RT
RT
RT
RT
RT
84
7
22
10
<5
[a] General reaction conditions: oxidant (1-4 mmol, 404-1616 mg) was added
over 5-10 seconds to a stirred mixture of 4-benzyl-3-methylpyrazolin-5-one 1a
(1 mmol, 188 mg), solvent (5 mL) and NaNO2 or t-BuONO (0-2 mmol, 0-138
mg) at given temperature; stirring was continued at the same temperature for
20 min. [b] Isolated yield. [c] Before the addition of iron (III) nitrate, 10 mol% of
TEMPO (15 mg, 0.1 mmol) was added.
[a] General reaction conditions: Fe(NO3)3•9H2O (2 mmol, 808 mg) was added
over 5-10 seconds to a stirred mixture of pyrazolin-5-one 1 (1 mmol), MeCN (5
mL) and NaNO2 (1 mmol, 69 mg) at room temperature; stirring was continued
for 20 min. [b] The amounts of NaNO2 and Fe(NO3)3•9H2O were doubled:
NaNO2 (2 mmol, 138 mg) Fe(NO3)3•9H2O (4 mmol, 1616 mg). [c] Order of
addition of reagents was changed: Fe(NO3)3•9H2O (2 mmol, 808 mg) was
added over 5-10 seconds to a stirred mixture of NaNO2 (1 mmol, 69 mg) and
MeCN (5 mL), after 5 min, pyrazolin-5-one was added over 5-15 seconds,
stirring was continued for 20 min [d] The synthesis was scaled up to 1.08 g (7
mmol) of pyrazolin-5-one 1d and afforded 1.33 g (6.68 mmol) 2d.
In protic solvents (AcOH, MeOH, TFE, runs 8-10) the yield did
not exceed 52%. A possible reason was interaction of the
solvents and H2O with NO2, the plausible nitrating reagent
generated in situ. In the nonpolar solvent C2H4Cl2, which was
widely used previously for nitration by Fe(NO3)3•9H2O,[9,11-13,16,17]
2a was obtained in low yield (33%, run 11), which can be
explained by the low solubility of the reagents at room
4-Nitropyrazolin-5-ones with various substituents were
successfully synthesized, including benzyl and allyl (2a,b), alkyl
(2c-g), condensed cyclohexyl (2h,l), 2-cyanoethyl (2i), and
phenyl (2j-l). Under the general reaction conditions (pyrazolin-5-
temperature. In
a number of studies on Fe(NO3)3•9H2O
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
one: Fe(NO3)3•9H2O: NaNO2 = 1:2:1, RT, 20 min) pyrazolin-5-
ones 1a-f,h,i were nitrated smoothly to give 4-nitropyrazolin-5-
ones 2a-f,h,i in 61-84% yield. It should be noted that allyl moiety
was well tolerated under reaction conditions, affording the
corresponding nitrated product 2b in 84% yield, despite that NO2
can react with C=C double bond.[85-88] A relatively low yield of
nitro derivative 2g (53%) was obtained in the case of pyrazolin-
5-one containing the isopropyl substituent at position C4, which
can be explained by the steric hindrance at the reaction center.
Doubling the excess of NaNO2 and Fe(NO3)3•9H2O allowed to
increase the yield of 2g to 74%, (table 2, note b).
In the case of the general reaction procedure Fe(NO3)3
was added to the mixture of NaNO2 and pyrazolin-5-one
(referred to as “standard order of addition”), so Fe3+ ions could
react with NaNO2 or pyrazolin-5-one. Employing this procedure
moderate to low yields were obtained for pyrazolin-5-ones
containing Ph-substituent at positions N1 or C3 (products 2j-l,
16-53%). We proposed that oxidation of these pyrazolin-5-ones
by Fe3+ occurred faster[57] than generation of NO2 from nitrite ion.
To minimize side oxidation of 1j-l by Fe(NO3)3, a series of
experiments were conducted, where Fe(NO3)3 was allowed to
react with NaNO2 first, and only then pyrazolin-5-ones 1j-l were
added to the reaction mixture (such procedure is referred below
as “inverse order of addition”). In this case the yields of the
target nitropyrazolin-5-ones 2j-l increased to 58-77% (note c).
In the gram-scale synthesis 95% (1.33 g) isolated yield of
2d was achieved, which indicates good scalability of the
developed protocol (Table 2, note d).
As was mentioned before in the comments to table 2, the
standard order of addition of reagents implied addition of
Fe(NO3)3•9H2O to the mixture of NaNO2, pyrazolin-5-one, and
MeCN. Changed order of addition of reagents was used to
increase the yield of products 2j-l and implied addition of
pyrazolin-5-one to the mixture of Fe(NO3)3•9H2O, NaNO2 and
MeCN. In this order of addition, Fe(NO3)3 was allowed to react
with NaNO2 before pyrazolin-5-one was added. In the case of
the standard order of addition of reagents, Fe(III) can react
simultaneously with NaNO2 and pyrazolin-5-one, which was
undesirable for pyrazolin-5-ones that are easily undergo side
oxidation processes under action of Fe(III).[57] Scheme 4 shows
the isolated yields of the target nitropyrazolin-5-ones 2a and 2k
depending on the order of addition of reagents.
The plausible reaction pathway is shown in Scheme 3.
First, NO2 is generated by the oxidation of the nitrite ion by
Fe3+.[26-29] Then two sequences are possible: (1) the attack of
NO2 on pyrazolin-5-one 1a-l with formation of radical A followed
by its oxidation by Fe3+ or NO2, and (2) the abstraction of
hydrogen atom from the pyrazolin-5-one 1a-l by NO2 with
formation of radical B followed by its coupling with the second
NO2 molecule. Addition of free radicals to the pyrazolin-5-ones
via intermediates A or B is supported by the previously reported
reaction between pyrazolin-5-ones and N-oxyl radicals.[57] Both
hydrogen atom abstraction reactions[87-90] and reactions of
addition to double C=C bonds[85-88] are typical for NO2. For the
iron (III) nitrate mediated nitration reactions, the NO2 free radical
was previously suggested to be the active nitration agent.[8-19,33]
Scheme 4. Influence of the order of addition of reagents on the yields of
nitropyrazolin-5-ones 2a and 2k
In the case of pyrazolin-5-one 1a, a change in the order of
addition of reagents did not lead to significant changes in yield
2a (83% for the standard procedure and 74-84% for the inverse
order of addition). When reaction time between Fe(NO3)3•9H2O
and NaNO2 in the inverse order of addition was increased from 5
to 10 min the 2a yield slightly decreased (84% and 74%,
respectively) which can be attributed to the decomposition of the
generated NO2 over a period of 10 min.
In the case of pyrazolin-5-one 1k, the inverse order of
addition of reagents significantly increased the yield of 2k
compared to the standard order of addition. Under standard
conditions, the formation of 2k (yield 16%) was accompanied by
oxidative dimerization of 1k (diastereomeric dimers 3-meso and
3-racemic were isolated in yields of 44% and 32%, respectively).
Scheme 3. Possible pathway of the radical nitration of pyrazolin-5-ones by
Fe3+ / NaNO2 combination.
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
The use of the inverse order of addition of reagents allowed to
avoid oxidative dimerization and afforded 2k in 37-58% yield.
The optimal reaction time between Fe(NO3)3•9H2O and NaNO2
was 5 min (the yield of 2k 58%). In the case of longer reaction
times between NaNO2 and Fe(NO3)3 the yield of 2k decreased
(53% for 10 min, 49% for 15 min), apparently, for the same
reason as in case of experiment with 2a, due to gradual
decomposition of the nitration agent (NO2). Shorter time (0.5
min) of interaction between Fe(NO3)3•9H2O and NaNO2 gave a
37% yield of 2k that was average between yield using the
standard order of addition (16%) and the yield with optimal time
of 5 min (58%), which can be attributed to the incomplete
reaction between Fe(NO3)3•9H2O and NaNO2 after 0.5 min.
Control experiments were conducted to support the
plausible roles of Fe3+ ions and NO2 in the reaction of pyrazolin-
5-ones with Fe(NO3)3/NaNO2 system (Scheme 5).
product 5b, it was slightly increased by raising the temperature
to 80 °C, extending the reaction time to 40 min and doubling the
amounts of Fe(NO3)3 and NaNO2.
Table 3. The synthesis of nitro derivatives 5a-e by the nitration of substituted
barbituric acid 4a, substituted Meldrum’s acid 4b, substituted malononitriles
4c,d and cyanoacetic ester 4e [a]
.
[a] Standard conditions: Fe(NO3)3•9H2O (2 mmol, 808 mg) was added over 5-
10 seconds to a stirred mixture of CH-acid 4a-e (1 mmol), MeCN (5 mL) and
NaNO2 (1 mmol, 69 mg) at room temperature; stirring was continued for 20
min. [b] The amounts of NaNO2 and Fe(NO3)3•9H2O were doubled: NaNO2 (2
mmol, 138 mg) Fe(NO3)3•9H2O (4 mmol, 1616 mg), the temperature was
increased to 80 °C, reaction time was 40 min [c] Fe(NO3)3•9H2O (2 mmol, 808
mg) was added over 5-10 seconds to
a stirred mixture of substituted
Scheme 5. Control experiments: a) nitration of 1a by NO2 as single reagent, b)
oxidative dimerization of 1k by iron (III) perchlorate
malononitrile 4c,d or cyanoacetic ester 4e (1 mmol), MeCN (5 mL) and NaNO2
(1 mmol, 69 mg) at 80°C; stirring was continued at the same temperature for
20 min.
In the case of malononitrile 4c the reaction did not proceed at
standard room temperature conditions; 89% of 4c was
recovered. However, nitration of malononitriles 4c,d and
cyanoacetic ester derivative 4e was successfully conducted at
80°C, nitro products 5c-e were obtained in 17-56% yields (Table
3).
The possibility of nitration of pyrazolin-5-ones by NO2 was
confirmed by the experiment in which solution of pyrazolin-5-one
1a in MeCN was treated with NO2 gas yielding the desired nitro-
pyrazolin-5-one 2a (Scheme 5a).
As was mentioned above, a low yield of 2k in the case of a
standard order of addition of reagents was explained by the side
oxidation reactions of 1k under the action of Fe3+. This
hypothesis was confirmed by the experiment in which pyrazolin-
5-one 1k was treated by Fe(ClO4)3 in the absence of nitrating
agents (Scheme 5b). Oxidative dimerization of pyrazolin-5-one
1k with formation of two diastereomeric products 3 was
observed.
In vitro fungicidal activity of the synthesized
nitrocompounds
In the second part of our research, the synthesized 4-
nitropyrazolin-5-ones 2 were discovered as a new class of
fungicides. Phytopathogenic fungi against which synthesized
compounds were tested are a dangerous threat to crop
production (affected agricultural plants include cereals, rice,
maize, apple, potato etc.). In agriculture and medicine, new
types of fungicides are always demanded to struggle the fungal
resistance development. There are hundreds of available
commercial fungicidal substances, but currently only six modes
of action are used in products that dominate around 80% of the
fungicide market.[82] New classes of active fungicidal compounds
are necessary to guarantee safe crop production and maintain
At the next stage of our study, the applicability of the
proposed system for the nitration of various CH acids was
investigated. The prerequisite for this experiments was that
deprotonated or tautomeric forms of CH-acids contained
conjugated -systems that could be attacked by NO2 similarly to
pyrazolin-5-one -system.[57,91-93] Indeed,
a series of nitro
derivatives of CH-acids 4a-e were synthesized using the
developed Fe(NO3)3/NaNO2 system (Table 3). Under standard
conditions (substrate: Fe(NO3)3•9H2O: NaNO2 = 1: 2: 1, RT, 20
min) barbituric acid 4a and Meldrum’s acid 4b give the
corresponding nitration products 5a and 5b with low yields; for
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
the activity of known effective fungicides by resistance
management.[94,95] It should be noted that compounds tested in
the present study are structurally not related to the compounds
with known fungicidal activity and thus their fungicidal activity
was not predictable. Indeed, fungicidal activity is not intrinsic for
the pyrazolin-5-one structural fragment and nitro groups are
rarely present in the structures of commercial fungicides. The
rare examples of fungicidal compounds containing NO2 group
are dinitrophenol fungicides.[96] There are dozens of nitro-
containing drugs, including antimicrobial and anti-parasitic ones.
Almost all of them are nitroarenes or nitroheteroarenes and they
are characterized by a C(sp2)-NO2 fragment. The problems in
the application of these classes of bioactive molecules include
the potential lack of selectivity, as well as genotoxic, mutagenic
and carcinogenic properties.[97] The obvious distinguishing
structural feature of compounds 2a-l compared to known nitro-
containing biocides is the tert-C(sp3)-NO2 fragment. Such
principal structural difference allows supposing that the toxicity
issues characteristic of nitroarenes and nitroheteroarenes may
not be inherent to 4-nitropyrazolin-5-ones 2a-l.
Table 4. Fungicidal activity of the synthesized compounds 2a,j,k,l and 5a,b and
starting pyrazoline-5-one 1k.
Mycelium growth inhibition a, %; IC50, mg/L in parentheses
Compound
V. i.
R. s.
F. o.
F. m.
B. s.
S. s.
100
(2.7)
100
(8.8)
90
(3.3)
100
(5.8)
100
(5.0)
81
(11)
100
89
50
69
94
50
44
14
76
11
34
11
50
46
36
15
The nitropyrazolin-5-ones 2a,j,k,l and nitro derivatives of
barbituric and Meldrum’s acids 5a and 5b were tested according
to a standard procedure[98] against six phytopathogenic fungi
from different taxonomic classes: V.i. - Venturia inaequalis, R.s.
5
6
- Rhizoctonia solani, F.o. - Fusarium oxysporum, F.m.
-
Fusarium moniliforme, B.s. - Bipolaris sorokiniana, S.s. –
Sclerotinia sclerotiorum (Table 4). The inhibition of the mycelium
growth in the potato-sucrose agar containing tested compounds
(30 mg/L) served as measure of fungicidal activity. Widely
known fungicidal compounds fluconazole, clotrimazole,
triadimefon, and kresoxim-methyl were used as a reference
compounds. IC50 values of the selected compounds (2k,
triadimefon, and kresoxim-methyl) are given in parentheses.
Nitropyrazolin-5-ones 2k and 2l containing a phenyl
substituent at the nitrogen atom N-1 showed a pronounced
fungicidal activity with respect to all tested species of
phytopathogenic fungi. Nitropyrazolin-5-one 2k surpassed
commercial fungicidal active substances used as standards.
Figure 1 shows petri dishes where almost complete mycelial
growth inhibition for compound 2k was observed. Nitropyrazolin-
5-ones 2a and 2j with unsubstituted amide nitrogen are
significantly inferior in activity compared to the 2k and 2l, which
can be explained by the insufficient lipophilicity of 2a and 2j.[81,99]
It should be noted that the starting pyrazolin-5-one 1k without
nitro group exhibits only a slight mycelial growth inhibition, which
confirms the key role of the nitro group in pyrazolin-5-one in the
manifested fungicidal activity. Nitro derivatives 5a,b of barbituric
and Meldum’s acids did not show pronounced fungicidal activity.
Thus, after initial tests 4-nitropyrazolin-5-ones were identified as
22
30
11
10
39
14
22
37
7
6
3
9
21
34
8
7
27
15
Fluconazole
Clotrimazole
Triadimefon
45
49
45
95
72
94
31
99
79
99
58
91
47
(>30)
53
(27)
80
(10)
67
(15)
70
(4.0)
56
(18)
Kresoxim-methyl
96
(1.1)
87
(0.019)
65
(0.65)
72
(1.4)
56
(19)
41
(>30)
a
new promising class fungicidal compounds against
phytopathogenic fungi that cause serious damage[100-102] in the
cultivation of crops.
a
Mycelium growth inhibition values were measured at 30 mg/L
concentrations of the tested compounds in the nutrient medium
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
Figure 1. Photo demonstrating almost complete mycelial growth inhibition by compound 2k in concentration 30 mg/L
in their metabolism, and hence, toxicity issues associated with
the formation of nitrogen containing products of reduction[97] may
not be of relevance.
Reactivity of nitro group in 4-nitropyrazolin-5-
ones 2a,k under reductive conditions
Conclusions
One of the main ways of metabolism of the nitro group in
living organisms is the reduction, which includes the formation of
radical
species,
nitroso
compounds
(R-N=O)
and
The system Fe(NO3)3/NaNO2 was proposed for room
temperature nitration of pyrazolin-5-ones. The developed
method is compatible with functional groups that are sensitive to
nitration conditions, such as N-phenyl, benzyl, and allyl. The
Fe(NO3)3/NaNO2 system allows to avoid side oxidation
processes, that are typical for pyrazolin-5-ones, such as
hydroxylamines (RNHOH).[97,103,104] Therefore, 4-nitropyrazolin-5-
ones can be considered as compounds that may be
metabolically- and structurally-related to the reported HNO
donors.[76,77] The key structural feature of the mentioned
compounds responsible for the demonstrated activity is easily
cleavable C-N bond at C4 position of pyrazolin-5-one. Taking
into account the connection of high antifungal activity of 4-
nitropyrazolin-5-ones with the presence of nitro group in the
pyrazolin-5-one heterocycle, initial experiments on chemical
reactivity of synthesized 4-nitro-pyrazolin-5-ones under reductive
conditions were made.
oxidative
dimerization
and
hydroxylation.
1-Phenyl-4-
nitropyrazolin-5-ones showed excellent fungicidal activity in vitro
against phytopathogenic fungi. It should be noted that
synthesized compounds are structurally not related to known
classes of fungicidal substances (such as azoles, strobilurins,
SDHIs, dinitrophenols) and discovery of their high fungicidal
activity was not predictable. These compounds were identified
as a promising starting point for development of novel and easily
available class of fungicides.
The reactivity of the nitro group in synthesized 4-nitropyrazolin-
5-ones is significantly different from that of the nitro group in the
majority of organic compounds. It is well known that
hydrogenation over a Pd/C catalyst is a reliable reduction
method of nitro group to amino group in high yields.[105-107]
However, hydrogenation of 4-nitropyrazolin-5-ones 2a and 2k
over standard Pd/C (10%) catalyst at RT and atmospheric
pressure of H2 resulted in C-N bond cleavage and formation of
unsubstituted pyrazolin-5-ones 1a and 1k (Scheme 6).
Experimental Section
In all experiments RT stands for 22-25 °C. Iron(III) perchlorate hydrate
reagent grade (Fe(ClO4)3•nH2O, Alfa Aesar, anhydrous basis purity ca.
65%), Fe(NO3)3•9H2O 99+%, (NH4)2Ce(NO3)6 99%, Pb(NO3)2 99%,
Cu(NO3)2•2.5H2O 98%, Co(NO3)2•6H2O 99+%, NaNO2 99%, t-BuONO
90%, 2,2,6,6-Tetramethylpiperidinooxy (TEMPO) 98%, N2H4•H2O (64%
hydrazine), phenylhydrazine 98% were used as is from commercial
sources. CH2Cl2, C2H4Cl2, and MeOH were distilled prior to use. MeCN
and EtOAc were distilled over P2O5. Glacial acetic acid was used as is
from commercial sources. Preparation of the starting pyrazolin-5-ones is
described in the ESI.
Experimental details for Table 1 (Optimization of the reaction
conditions for nitration of 1a)
Scheme 6. The Pd/C catalyzed reduction of 4-nitropyrazolin-5-ones 2a,k by
molecular hydrogen
Oxidant
Cu(NO3)2•2.5H2O, Co(NO3)2•6H2O, Pb(NO3)2, 1-4 mmol, 404-1616 mg)
was added for 5-10 seconds to stirred mixture of 4-benzyl-3-
methylpyrazolin-5-one 1a (1 mmol, 188 mg), solvent (5 mL) and nitrite
(Fe(NO3)3•9H2O,
Fe(ClO4)3•nH2O,
(NH4)2Ce(NO3)6,
The cleavage of the tert-С(sp3)-N bond of 4-nitropyrazolin-
5-ones under the reductive conditions may play a significant role
a
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
(NaNO2 or t-BuONO, 0-2 mmol, 0-138 mg) at given temperature; stirring
was continued at the same temperature for 20 min. The reaction mixture
was diluted with CH2Cl2 (10 mL) and 3% aqueous solution of HCl (30 mL)
and shaken. The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), then all organic extracts were
combined. Organic extracts were washed with water (2 × 20 mL), dried
over MgSO4, and rotary evaporated under water-jet vacuum. Nitration
product 2a was isolated by column chromatography on silica gel using
the EtOAc/CH2Cl2 = 1/20 eluent.
brine (140 mL), dried over MgSO4, and rotary evaporated under water-jet
vacuum. Nitration product 2d was isolated by column chromatography on
silica gel using the EtOAc/CH2Cl2 = 1/20 eluent.
4-Allyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2b: slightly brown viscous
gum; 1H NMR (300.13 MHz, CDCl3): δ = 8.92 (bs, 1H), 5.59-5.20 (m, 3H),
3.18 (dd, J = 13.7, 6.8 Hz, 1H), 3.04 (dd, J = 13.7, 7.0 Hz, 1H), 2.10 (s,
3H); 13С NMR (75.47 MHz, CDCl3): δ = 167.7, 154.0, 126.2, 123.4, 91.8,
36.1, 14.0; FT-IR (KBr): max = 3528, 1730, 1557, 1422, 1404, 1384,
1350, 1305, 1264, 942, 818, 761, 746, 694, 611, 548 cm-1; elemental
analysis calcd. (%) for C7H9N3O3: C 45.90, H 4.95, N 22.94; found: C
45.98, H 4.90, N 22.98.
4-Benzyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2a: yellow powder; mp
= 84-85 °C dec.; 1H NMR (300.13 MHz, CDCl3): δ = 8.53 (bs, 1H, NH),
7.35-7.26 (m, 3H, meta,para-Ph), 7.23-7.14 (m, 2H, ortho-Ph), 3.79 (d, J
= 13.5 Hz, 1H, CH2), 3.62 (d, J = 13.5 Hz, 1H, CH2), 2.16 (s, 3H, CH3);
13С NMR (75.47 MHz, CDCl3): δ = 167.8 (O=C-NH), 153.8 (C=N), 129.9
(CAr), 129.8 (ortho-CHAr), 129.2 (meta-CHAr), 128.6 (para-CHAr), 93.2 (C-
NO2), 37.7 (CH2), 14.4 (CH3); 15N NMR (40.56 MHz, CDCl3): δ = -4.5
(NO2), -54.9 (C=N), -207.0 (O=C-NH); FT-IR (KBr): max = 3238, 1733,
1564, 1352, 1312, 1271, 773, 757, 711, 699, 604 cm-1; HR-MS (ESI): m/z
= 256.0698, calcd. for C11H11N3O3+Na+: 256.0693; elemental analysis
calcd. (%) for C11H11N3O3: C 56.65, H 4.75, N 18.02; found: C 56.47, H
4.58, N 17.77.
4-Ethyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2c: yellow powder; mp =
64-66 C; 1H NMR (300.13 MHz, CDCl3): δ = 9.01 (bs, 1H), 2.51 (dq, J =
14.9, 7.5 Hz, 1H), 2.28 (dq, J = 14.9, 7.5 Hz, 1H), 2.09 (s, 3H), 0.90 (t, J
= 7.5 Hz, 3H); 13С NMR (75.47 MHz, CDCl3): δ = 168.0, 154.2, 93.5, 25.1,
13.7, 6.8; FT-IR (KBr): max = 3323, 3259, 1742, 1717, 1561, 1546, 1358,
821, 663, 582 cm-1; HR-MS (ESI): m/z
C6H9N3O3+Na+: 194.0536.
= 194.0530, calcd. for
4-Butyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2d: slightly brown
1
viscous gum; H NMR (300.13 MHz, CDCl3): δ = 8.70 (bs, 1H), 2.55-2.38
Experimental details for Table 2 (The synthesis of 4-nitropyrazolin-
5-ones 2-l by the nitration of pyrazolin-5-ones 1a-l)
(m, 1H), 2.31-2.15 (m, 1H), 2.08 (s, 3H), 1.47-1.30 (m, 2H), 1.30-1.01 (m,
2H), 0.92 (t, J = 7.3 Hz, 3H); 13С NMR (75.47 MHz, CDCl3): δ = 168.0,
154.4, 92.9, 31.3, 24.4, 22.5, 13.75, 13.71; FT-IR (KBr): max = 3279,
2963, 2935, 2875, 1739, 1556, 1432, 1383, 1352, 1251, 819, 760 cm-1;
HR-MS (ESI): m/z = 222.0842, calcd. for C8H13N3O3+Na+: 222.0849.
General procedure: Fe(NO3)3•9H2O (2 mmol, 808 mg) was added for 5-
10 seconds to a stirred mixture of pyrazolin-5-one 1 (1 mmol), MeCN (5
mL) and NaNO2 (1 mmol, 69 mg) at room temperature; stirring was
continued at room temperature for 20 min. Products 2a, 2d-h were
isolated as described above in experimental details for Table 1. Products
2k,l were isolated analogously, but CH2Cl2 was used as eluent for
column chromatography. In the case of products 2b, 2c, 2i, 2j reaction
mixture was diluted with EtOAc (10 mL) and a solution prepared from
brine (20 mL), H2O (14 mL) and concentrated HCl (2 mL), and shaken.
The organic layer was separated and the aqueous layer was extracted
with EtOAc (2 × 10 mL) and washed with brine (20 mL). Nitration
products 2b, 2c, 2i, 2j were isolated by column chromatography on silica
gel using the EtOAc/CH2Cl2 = 1/20 eluent.
4-Hexyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2e: amber viscous gum;
1H NMR (300.13 MHz, CDCl3): δ = 8.98 (bs, 1H), 2.45 (td, J = 12.8, 4.8
Hz, 1H), 2.21 (td, J = 12.8, 4.8 Hz, 1H), 2.08 (s, 3H), 1.46-1.02 (m, 8H),
0.87 (t, J = 6.4 Hz, 3H); 13С NMR (75.47 MHz, CDCl3): δ =168.2, 154.5,
93.0, 31.5, 31.3, 29.0, 22.5, 22.2, 14.1, 13.7; FT-IR (thin layer): max
=
3278, 2958, 2931, 2861, 1737, 1557, 1381, 1349, 819, 760 cm-1;
elemental analysis calcd. (%) for C10H17N3O3: C 52.85, H 7.54, N 18.49;
found: C 53.13, H 7.78, N 18.06.
4-Methyl-4-nitro-3-propyl-1H-pyrazolin-5-one, 2f: yellow powder; mp =
67-69 C dec.; 1H NMR (300.13 MHz, CDCl3): δ = 9.05 (bs, 1H), 2.38-
2.25 (m, 2H), 1.84 (s, 3H), 1.76-1.57 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13
С
Procedure b for synthesis 2g (experiment according to note b):
Fe(NO3)3•9H2O (4 mmol, 1616 mg) was added for 5-10 seconds to a
stirred mixture of pyrazolin-5-one 1g (1 mmol, 140 mg), MeCN (5 mL)
and NaNO2 (2 mmol, 138 mg) at room temperature; stirring was
continued at room temperature for 20 min. Nitration product was isolated
as described above in experimental details for Table 1.
NMR (75.47 MHz, CDCl3): δ = 169.1, 158.5, 89.6, 29.5, 18.4, 17.5, 13.7;
FT-IR (KBr): max = 3300, 1736, 1711, 1568, 1560, 1384, 667 cm-1; HR-
MS (ESI): m/z = 208.0696, calcd. for C7H11N3O3+Na+: 208.0693.
4-Isopropyl-3-methyl-4-nitro-1H-pyrazolin-5-one, 2g: slightly yellow
powder; mp = 80-81 C dec.; 1H NMR (300.13 MHz, CDCl3): δ = 8.74 (bs,
1H), 3.01-2.85 (m, 1H), 2.13 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.01 (d, J =
7.1 Hz, 3H); 13С NMR (75.47 MHz, CDCl3): δ = 167.3, 153.8, 95.9, 32.8,
Procedure c (experiments in Table 2 with note c): Fe(NO3)3•9H2O (2
mmol, 808 mg) was added over 5-10 seconds to a stirred mixture of
NaNO2 (1 mmol, 69 mg) and MeCN (5 mL) at room temperature; after 5
min pyrazolin-5-one 1j-l (1 mmol, 174-214 mg) was added over 5-15
seconds. Stirring was continued at room temperature for 20 min. Nitration
products 2j-l were isolated as described above in general procedure.
16.2, 14.9, 14.5; FT-IR (KBr): max
= 3285, 1726, 1555, 1471, 1436,
1397, 1377, 1356, 1342, 1265, 822, 757, 727, 680, 565 cm-1; elemental
analysis calcd. (%) for C7H11N3O3: C 45.40, H 5.99, N 22.69; found: C
45.64, H 6.16, N 22.60.
Scaled up synthesis of 2d (according to note d): Fe(NO3)3•9H2O (14
mmol, 5.656 g) was added over 5-10 seconds to a stirred mixture of
pyrazolin-5-one 1d (7 mmol, 1.08 g), MeCN (35 mL) and NaNO2 (7 mmol,
483 mg) at room temperature; stirring was continued at room
temperature for 20 min. The reaction mixture was diluted with EtOAc (70
mL) and a solution prepared from of brine (105 mL), H2O (70 mL) and
concentrated HCl (10 mL), and shaken. The organic layer was separated
and the aqueous layer was extracted with EtOAc (2 × 70 mL), then all
organic extracts were combined. Organic extracts were washed with
3a-Nitro-2,3a,4,5,6,7-hexahydro-3H-indazol-3-one, 2h: white powder.
mp = 127-128 C dec.; H NMR (300.13 MHz, CDCl3): δ = 9.21 (bs, 1H),
1
3.18-3.01 (m, 1H), 2.85-2.68 (m, 1H), 2.50-2.29 (m, 1H), 2.21-2.06 (m,
1H), 1.97-1.82 (m, 1H), 1.81-1.64 (m, 1H), 1.62-1.38 (m, 2H); 13С NMR
(75.47 MHz, CDCl3): δ = 168.1, 158.1, 89.1, 33.6, 27.5, 21.0; FT-IR
(KBr): max = 3336, 1721, 1557, 1351, 1339, 1325, 829 cm-1; elemental
analysis calcd. (%) for C7H9N3O3: C 45.90, H 4.95, N 22.94; found: C
45.87, H 4.83, N 22.87.
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
3-(3-Methyl-4-nitro-5-oxo-4,5-dihydro-1H-pyrazol-4-yl)propanenitrile,
2i: slightly yellow powder; mp = 105-107 C; 1H NMR (300.13 MHz,
DMSO-d6): δ = 12.10 (bs, 1H), 2.78-2.65 (m, 2H), 2.65-54 (m, 2H), 2.07
(s, 3H); 13С NMR (75.47 MHz, DMSO-d6): δ = 167.1, 153.0, 118.5, 91.5,
25.7, 13.4, 10.6; FT-IR (KBr): max = 3249, 2263, 1735, 1556, 1345, 1256,
826, 674, 604, 552 cm-1; elemental analysis calcd. (%) for C7H8N4O3: C
42.86, H 4.11, N 28.56; found: C 42.93, H 4.08, N 28.39.
C); 1H NMR (300.13 MHz, CDCl3): δ = 7.85 (d, J = 7.9 Hz, 4H), 7.45-
7.31 (m, 4H), 7.18 (t, J = 7.3 Hz, 2H), 2.19 (s, 6H), 1.60 (s, 6H); 13С NMR
(75.47 MHz, CDCl3):  = 173.1, 159.8, 137.7, 129.0, 125.4, 119.3, 55.7,
16.0, 15.4; HR-MS (ESI): m/z = 397.1634, calcd. for C22H22N4O2+Na+:
397.1635; elemental analysis calcd. (%) for C22H22N4O2: C 70.57, H 5.92,
N 14.96; found: C 70.63, H 5.94, N 14.91.
Inverse order of addition of reagents. Fe(NO3)3•9H2O (2 mmol, 808
mg) was added for 5-10 seconds to a stirred mixture of NaNO2 (1 mmol,
69 mg) and MeCN (5 mL); stirring was continued at room temperature for
0.5-15 min and then pyrazolin-5-one 1a or 1k (1 mmol, 188 mg) was
added over 5-15 seconds; stirring was continued at room temperature for
20 min. Nitration products 2a or 2k were isolated as described above for
standard order of addition.
4-Methyl-4-nitro-3-phenyl-1H-pyrazolin-5-one, 2j: white powder; mp =
1
138-140 C; H NMR (300.13 MHz, CDCl3): δ = 9.14 (bs, 1H), 7.70-7.55
(m, 2H), 7.54-7.37 (m, 3H), 2.07 (s, 3H); 13С NMR (75.47 MHz, CDCl3): δ
=169.3, 154.7, 131.6, 129.5, 128.2, 126.0, 88.9, 19.3; FT-IR (KBr): max
=
3242, 1727, 1550, 1385, 769, 758, 693, 651 cm-1; elemental analysis
calcd. (%) for C10H9N3O3: C 54.79, H 4.14, N 19.17; found: C 54.78, H
4.12, N 19.16.
Experimental details for Scheme 5.
3,4-Dimethyl-4-nitro-1-phenylpyrazolin-5-one, 2k: slightly yellow
crystals; mp = 40-41 C; 1H NMR (300.13 MHz, CDCl3): δ = 7.94-7.84 (m,
2H), 7.51-7.39 (m, 2H), 7.32-7.22 (m, 1H), 2.22 (s, 3H), 1.95 (s, 3H); 13С
NMR (75.47 MHz, CDCl3): δ = 164.6, 154.7, 137.0, 129.2, 126.2, 119.0,
91.8, 17.8, 13.3; FT-IR (thin layer): max = 1731, 1597, 1558, 1501, 1383,
1368, 1294, 1147, 759, 691 cm-1; HR-MS (ESI): m/z = 256.0697, calcd.
for C11H11N3O3+Na+: 256.0693.
a) Nitration of 4-benzyl-3-methylpyrazolin-5-one 1a with gaseous
NO2. Mixture of 4-benzyl-3-methylpyrazolin-5-one 1a (1 mmol, 188 mg)
and MeCN (5 mL) at room temperature was treated with gaseous NO2
that was generated by thermal decomposition of three portions of finely
powdered Pb(NO3)2 (4 g, 12 mmol per each portion). A second and a
third portions of Pb(NO3)2 were added when emission of brown gas from
the previous portion had ceased. Decomposition of Pb(NO3)2 was
performed in the glass flask. Each portion was heated about 10 minutes.
After the third portion was added, the hose connecting the flask where
Pb(NO3)2 was decomposed with the flask containing pyrazolin-5-one and
MeCN was disconnected and stirring of reaction mixture was continued
at room temperature for another 10 minutes. Thus, the total reaction time
was 40 min. The nitration product 2a was isolated as described above in
experimental details for Table 1.
3a-Nitro-2-phenyl-2,3a,4,5,6,7-hexahydro-3H-indazol-3-one, 2l: amber
1
powder; mp = 86-87 C; H NMR (300.13 MHz, CDCl3): δ = 7.89 (d, J =
8.1 Hz, 2H), 7.50-7.38 (m, 2H), 7.31-7.21 (m, 1H), 3.26-3.12 (m, 1H),
2.97-2.83 (m, 1H), 2.59-2.42 (m, 1H), 2.30-2.10 (m, 1H), 2.04-1.74 (m,
2H), 1.70-1.48 (m, 2H); 13С NMR (75.47 MHz, CDCl3): δ = 164.0, 157.5,
137.1, 129.1, 126.1, 119.0, 91.3, 33.9, 27.54, 27.47, 21.0; FT-IR (KBr):
max = 1726, 1557, 1500, 1385; elemental analysis calcd. (%) for
C13H13N3O3: C 60.23, H 5.05, N 16.21; found: C 60.27, H 5.18, N 16.08.
b) The reaction of 3,4-dimethyl-1-phenylpyrazolin-5-one 1k with iron
(III) perchlorate: Fe(ClO4)3•nH2O (817 mg, 1.5 mmol) was successively
added to a stirred at room temperature mixture of 3,4-dimethyl-1-
phenylpyrazolin-5-one 1k (282 mg, 1.5 mmol) and MeCN (5 mL); stirring
was continued at room temperature for 20 min. The reaction mixture was
diluted with CH2Cl2 (10 mL) and H2O (25 mL) and shaken. The organic
layer was separated and the aqueous layer was extracted with CH2Cl2 (2
× 10 mL), and all organic extracts were combined. Organic extracts were
washed with water (2 × 20 mL), dried over MgSO4, and rotary evaporated
under water-jet vacuum. Meso-4,4',5,5'-Tetramethyl-2,2'-diphenyl-
2,2',4,4'-tetrahydro-3H,3'H-[4,4'-bipyrazole]-3,3'-dione 3-meso (135 mg,
0.361 mmol, 48%) and racemic-4,4',5,5'-Tetramethyl-2,2'-diphenyl-
2,2',4,4'-tetrahydro-3H,3'H-[4,4'-bipyrazole]-3,3'-dione 3-racemic (104
mg, 0.278 mmol, 37%) were isolated by column chromatography on silica
gel using the EtOAc/benzene eluent; the volume part of EtOAc was
gradually increased from 0 to 10%.
Reaction conditions for Scheme 4.
Standard order of addition. Fe(NO3)3•9H2O (2 mmol, 808 mg) was
added over 5-10 seconds to a stirred mixture of pyrazolin-5-one 1k (1
mmol, 188 mg), MeCN (5 mL) and NaNO2 (1 mmol, 69 mg) at room
temperature; stirring was continued at room temperature for 20 min. The
reaction mixture was diluted with CH2Cl2 (10 mL) and 3% solution of HCl
(30 mL) and shaken. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (2 × 10 mL), then all organic extracts
were combined. Organic extracts were washed with water (2 × 20 mL),
dried over MgSO4, and rotary evaporated under water-jet vacuum.
Column chromatography on silica gel using the CH2Cl2 as eluent gave
4,5-dimethyl-4-nitro-2-phenyl-2,4-dihydro-3H-pyrazol-3-one 2k (38 mg,
0.163 mmol, 16%), meso-4,4',5,5'-tetramethyl-2,2'-diphenyl-2,2',4,4'-
tetrahydro-3H,3'H-[4,4'-bipyrazole]-3,3'-dione 3-meso (82 mg, 0.219
mmol, 44%) and racemic-4,4',5,5'-tetramethyl-2,2'-diphenyl-2,2',4,4'-
tetrahydro-3H,3'H-[4,4'-bipyrazole]-3,3'-dione 3-racemic (60 mg, 0.160
mmol, 32%).
Experimental details for Table 3 (The synthesis of nitroderivatives
5a-e by the nitration of substituted barbituric acid 4a, substituted
Meldrum acid 4b, substituted malononitriles 4c,d and cyanoacetic
ester 4e)
Meso-3,3',4,4'-tetramethyl-1,1'-diphenyl-[4,4'-bipyrazol]-5,5'-dione, 3-
meso: white powder; mp = 161-162 C (Lit.45 mp = 163-164 C); 1H NMR
(300.13 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 4H), 7.49-7.34 (m, 4H),
7.22 (t, J = 7.3 Hz, 2H), 1.93 (s, 6H), 1.73 (s, 6H); 13С NMR (75.47 MHz,
CDCl3):  = 173.1, 161.9, 137.6, 129.2, 125.7, 119.1, 54.5, 14.7, 14.6;
HR-MS (ESI): m/z = 397.1637, calcd. for C22H22N4O2+Na+: 397.1635;
elemental analysis calcd. (%) for C22H22N4O2: C 70.57, H 5.92, N 14.96;
found: C 70.52, H 5.95, N 14.91.
Procedure
a
for the synthesis of nitroderivatives 5a-с.
Fe(NO3)3•9H2O (2 mmol, 808 mg) was added for 5-10 seconds to a
stirred mixture of 4a-с (1 mmol, 156-276 mg), MeCN (5 mL) and NaNO2
(1 mmol, 69 mg) at room temperature; stirring was continued at room
temperature for 20 min. The reaction mixture was diluted with CH2Cl2 (10
mL) and 3% aqueous solution of HCl (30 mL) and shaken. The organic
layer was separated and the aqueous layer was extracted with CH2Cl2 (2
× 10 mL), and all organic extracts were combined. Organic extracts were
washed with water (2 × 20 mL), dried over MgSO4, and rotary evaporated
Racemic-3,3',4,4'-tetramethyl-1,1'-diphenyl-[4,4'-bipyrazol]-5,5'-dione,
3-racemic: slightly yellow powder; mp = 141-142 C (Lit.45 mp = 140-141
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
under water-jet vacuum. Nitration products 5a-b were isolated by column
chromatography on silica gel using the PE/CH2Cl2 = 1/10 eluent.
Experiment with 2-benzylmalononitrile 4c gave the starting compound
(139 mg, 0.890 mmol, 89%) after evaporation step.
(KBr): max = 1758, 1576, 1262, 1015, 851, 700 cm-1; elemental analysis
calcd. (%) for C12H12N2O4: C 58.06; H 4.87; N 11.29; found: C 58.12; H
4.87; N 11.25.
Reaction conditions for Scheme 6.
5-(4-Methoxybenzyl)-1,3-dimethyl-5-nitropyrimidine-2,4,6(1H,3H,5H)-
trione, 5a: slightly yellow powder; mp = 102-103 C dec.; 1H NMR
(300.13 MHz, CDCl3): δ = 6.92 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz,
2H), 3.83 (s, 2H), 3.77 (s, 3H), 3.19 (s, 6H); 13С NMR (75.47 MHz,
CDCl3): δ = 162.5, 160.2, 148.9, 130.6, 121.0, 114.7, 92.8, 55.4, 41.9,
29.2; FT-IR (KBr): max = 1696, 1570, 1515, 1445, 1379, 1351, 1299,
1257, 1242 cm-1; elemental analysis calcd. (%) for C14H15N3O6: C 52.34,
H 4.71, N 13.08; found: C 52.43, H 4.80, N 12.91.
Pd/C catalyst (10%, 40 mg) was added to a solution of 4-nitropyrazolin-5-
one 2a or 2k (1 mmol, 233 mg) in MeOH (5 mL) and hydrogenation was
carried at RT and atmospheric pressure of H2 for 24 h. Reaction mixture
was filtered through celite, and the filtrate was rotary evaporated under
water-jet vacuum. Evaporation gave 4-benzyl-3-methylpyrazolin-5-one 1a
(175 mg, 0.931 mmol, 93%) or 3,4-dimethyl-1-phehylpyrazolin-5-one 1k
(184 mg, 0.980 mmol, 98%), respectively.
5-(4-Methoxybenzyl)-2,2-dimethyl-5-nitro-1,3-dioxane-4,6-dione, 5b:
slightly yellow powder; mp = 119-120 C dec.; 1H NMR (300.13 MHz,
CDCl3): δ = 7.07 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.88 (s, 2H),
3.78 (s, 3H), 1.82 (s, 3H), 1.08 (s, 3H); 13С NMR (75.47 MHz, CDCl3): δ =
160.2, 160.0, 131.6, 120.5, 114.9, 109.2, 90.8, 55.5, 41.7, 29.8, 27.9; FT-
IR (KBr): max = 1785, 1752, 1576, 1515, 1365, 1316, 1307, 1288, 1258,
1178 cm-1; elemental analysis calcd. (%) for C14H15NO7: C 54.37, H 4.89,
N 4.53; found: C 54.29, H 4.89, N 4.55.
Experimental detail for fungicidal activity testing (Table 4)
Tests of fungicidal activity were carried out according to a standard
procedure[98 against six phytopathogenic fungi from different taxonomic
classes: V.i. - Venturia inaequalis, R.s. - Rhizoctonia solani, F.o. -
Fusarium oxysporum, F.m. - Fusarium moniliforme, B.s. - Bipolaris
sorokiniana, S.s. – Sclerotinia sclerotiorum. Test substances preliminarily
dissolved in acetone (concentration 3 mg/mL) were introduced into liquid
sugar-potato agar having a temperature of 50-55 ° C, so that the final
concentration of the substance in the nutrient medium was 30 mg/L (0.9
mL of solution in acetone per 90 mL agar). After thorough mixing, the
agar was poured over sterile Petri dishes and, after cooling to room
temperature, the pieces of mycelium from the peripheral growth zone of
the mycelium of a three to five-day culture of the fungus were transferred
to them with a needle. The control is a colony grown in the same nutrient
medium without the addition of the active substance. 72 hours after
inoculation, the diameters of the formed fungal colonies were measured.
The indicator of fungicidal activity is suppression of mycelium growth in
comparison with the control, calculated as ((Dc - Ds) / Dc) * 100%, where
Dc - diameter of colony of fungus in control medium, Ds - colony diameter
in medium with the tested substance added. In order to estimate IC50
values, series of test solutions of compounds in acetone were prepared
by serial dilution by a factor of 3 (3 mg/mL, 1 mg/mL, 0.333 mg/mL, 0.111
mg/mL, 0.0370 mg/mL, 0.0123 mg/mL, 0.00412 mg/mL, 0.00137 mg/mL,
0.000457 mg/mL). Prepared solutions were tested for the fungicidal
activity according to the standard procedure described above.
Procedure b for synthesis 5b (according to note b): Fe(NO3)3•9H2O
(4 mmol, 1616 mg) was added for 5-10 seconds to a stirred at 80 °C
mixture of 5-(4-methoxybenzyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 4b (1
mmol, 264 mg), MeCN (5 mL) and NaNO2 (2 mmol, 138 mg) stirring was
continued at 80 °C for 40 min. Nitration product 5b was isolated as
described above for the synthesis of 5a-b according to procedure a.
The synthesis of nitroderivatives 5c-e by the nitration of substituted
malononitriles 4c,d and cyanoacetic ester 4e (according to note c).
Fe(NO3)3•9H2O (2 mmol, 808 mg) was added for 5-10 seconds to a
stirred at 80 °C mixture of compound 4c-e (1 mmol, 156-203 mg), MeCN
(5 mL) and NaNO2 (1 mmol, 69 mg); stirring was continued at 80 °C for
20 min. The reaction mixture was diluted with CH2Cl2 (10 mL) and 3%
aqueous solution of HCl (30 mL) and shaken. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2 × 10 mL),
and all organic extracts were combined. Organic extracts were washed
with water (2 × 20 mL), dried over MgSO4, and rotary evaporated under
water-jet vacuum. Nitration products 5c-e were isolated by column
chromatography on silica gel using the EtOAc/PE = 3/10 eluent.
Acknowledgements
2-Benzyl-2-nitromalononitrile, 5c: white powder; mp = 98-99 C; 1H
NMR (300.13 MHz, CDCl3): δ = 7.58-7.41 (m, 3H), 7.41-7.32 (m, 2H),
3.86 (s, 2H); 13С NMR (75.47 MHz, CDCl3): δ = 130.5, 130.2, 129.8,
127.6, 108.2, 78.9, 45.1; FT-IR (KBr): max = 1593, 1347, 1310, 717, 704,
698 cm-1; elemental analysis calcd. (%) for C10H7N3O2: C 59.70, H 3.51,
N 20.89; found: C 59.60, H 3.35, N 20.53.
This work was supported by the Russian Science Foundation
(Grant 17-73-10405).
Keywords: nitration • pyrazolin-5-ones • fungicidal compounds •
crop protection • nitrogen dioxide
2-(4-Methoxybenzyl)-2-nitromalononitrile, 5d: white powder; mp = 93-
1
94 C; H NMR (300.13 MHz, CDCl3): δ = 7.29 (d, J = 8.6 Hz, 2H), 6.97
1
2
3
4
5
6
M. Shiri, M. A. Zolfigol, H. G. Kruger, Z. Tanbakouchian,
Tetrahedron 2010, 66, 9077–9106. DOI: 10.1016/j.tet.2010.09.057
Z.-Q. Zhang, T. Chen, F.-M. Zhang, Org. Lett. 2017, 19, 1124–
1127. DOI: 10.1021/acs.orglett.7b00040
(d, J = 8.6 Hz, 2H), 3.85 (s, 3H), 3.84 (s, 2H); 13С NMR (75.47 MHz,
CDCl3): δ = 161.3, 131.5, 119.4, 115.2, 108.3, 79.0, 55.5, 44.8; FT-IR
(KBr): max = 1594, 1519, 1271, 1177, 1024, 839, 803 cm-1; elemental
analysis calcd. (%) for C11H9N3O3: C 57.14, H 3.92, N 18.17; found: C
57.44, H 4.01, N 17.96.
Z. Fan, J. Ni, A. Zhang, J. Am. Chem. Soc. 2016, 138, 8470–8475.
DOI: 10.1021/jacs.6b03402
M. Gao, R. Ye, W. Shen, B. Xu, Org. Biomol. Chem. 2018, 16,
2602–2618. DOI: 10.1039/C8OB00332G
Ethyl 2-cyano-2-nitro-3-phenylpropanoate, 5e: slightly yellow powder;
mp = 34 C; 1H NMR (300.13 MHz, CDCl3): δ = 7.42-7.34 (m, 3H), 7.34-
7.27 (m, 2H), 4.49-4.32 (m, 2H), 3.84 (d, J = 14.4 Hz, 1H), 3.73 (d, J =
14.4 Hz, 1H), 1.34 (t, J = 7. Hz, 3H); 13С NMR (75.47 MHz, CDCl3): δ =
159.3, 130.1, 129.9, 129.30, 129.27, 111.0, 90.1, 65.9, 41.3, 13.8; FT-IR
A. Bose, P. Mal, Chem. Commun. 2017, 53, 11368–11371. DOI:
10.1039/C7CC06267B
Y. Dou, B. Ying, P. Zhang, Q. Zhu, Eur. J. Org. Chem. 2018, 2018,
4571–4576. DOI: 10.1002/ejoc.201800912
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
7
8
9
Y.-M. Li, T. Yang, J.-L. Zhou, J. Li, Y. Shen, C. Gao, Synthesis
37 K.-A. Kovar, W. Rohlfes, H. Auterhoff, Arch. Pharm. 1981, 314,
532–541. DOI: 10.1002/ardp.19813140611
2018, 50, 3460–3466. DOI: 10.1055/s-0037-1610070
T. Taniguchi, T. Fujii, H. Ishibashi, J. Org. Chem. 2010, 75, 8126–
8132. DOI: 10.1021/jo101769d
38 A. G. Burton, M. Dereli, A. R. Katritzky, H. O. Tarhan, J. Chem.
Soc.,
Perkin
Trans.
2,
1974,
382-388.
DOI:
D. Sar, R. Bag, D. Bhattacharjee, R. C. Deka, T. Punniyamurthy, J.
Org. Chem. 2015, 80, 6776–6783. DOI: 10.1021/acs.joc.5b00820
10.1039/P29740000382
39 Y. C. Fiamegos, G. A. Pilidis, G. Varvounis, J. Heterocycl. Chem.
2001, 38, 1065–1069. DOI: 10.1002/jhet.5570380509
10 Y. Liu, M. Zu, X. Zou, Q. Zheng, X. Li, Z. Zhou, Q. Tang, S. Zhang,
L. Zhang, Y. Li, Asian J. Chem. 2014, 26, 241-246. DOI:
10.14233/ajchem.2014.15819
40 J. Bergman, S. Bergman, T. Brimert, Tetrahedron 1999, 55,
10447–10466. DOI: 10.1016/S0040-4020(99)00570-0
11 T. Naveen, S. Maity, U. Sharma, D. Maiti, J. Org. Chem. 2013, 78,
5949–5954. DOI: 10.1021/jo400598p
41 X. Sheng, J. Zhang, H. Yang, G. Jiang, Org. Lett. 2017, 19, 2618–
2621. DOI: 10.1021/acs.orglett.7b00951
12 V. A. Motornov, V. M. Muzalevskiy, A. A. Tabolin, R. A. Novikov, Y.
V. Nelyubina, V. G. Nenajdenko, S. L. Ioffe, J. Org. Chem. 2017,
82, 5274–5284. DOI: 10.1021/acs.joc.7b00578
42 F. Xue, X. Bao, L. Zou, J. Qu, B. Wang, Adv. Synth. Catal. 2016,
358, 3971–3976. DOI: 10.1002/adsc.201601070
43 M. Schulz, M. Meske, J. Prakt. Chem./Chem.-Ztg. 1993, 335, 607.
DOI: 10.1002/prac.19933350706
13 Y. Gao, Y. Mao, B. Zhang, Y. Zhan, Y. Huo, Org. Biomol. Chem.
2018, 16, 3881–3884. DOI: 10.1039/C8OB00841H
44 G. A. Eller, G. Vilkauskaitė, A. Šačkus, V. Martynaitis, A. D.
Mamuye, V. Pace, W. Holzer, Beilstein J. Org. Chem. 2018, 14,
1287–1292. DOI: 10.3762/bjoc.14.110
14 C.-M. Wang, K.-X. Tang, T.-H. Gao, L. Chen, L.-P. Sun, J. Org.
Chem. 2018, 83, 8315–8321. DOI: 10.1021/acs.joc.8b01016
15 Y. He, N. Zhao, L. Qiu, X. Zhang, X. Fan, Org. Lett. 2016, 18,
6054–6057. DOI: 10.1021/acs.orglett.6b02998
45 S. Veibel, Acta Chem. Scand. 1972, 26, 3685–3690. DOI:
10.3891/acta.chem.scand.26-3685
16 A. Murugan, K. R. Gorantla, B. S. Mallik, D. S. Sharada, Org.
Biomol. Chem. 2018, 16, 5113–5118. DOI: 10.1039/C8OB00931G
17 B. Vinayak, A. Ashok, M. Chandrasekharam Eur. J. Org. Chem.
2017, 2017, 7127–7132. DOI: 10.1002/ejoc.201701187
46 H. Weber, E. Wollenberg, Arch. Pharm. 1988, 321, 551–553. DOI:
10.1002/ardp.19883210912
47 T. Gillmann, S. Heckhoff, T. Weeber, Synth. Commun. 1994, 24,
2133–2138. DOI: 10.1080/00397919408010226
18 B. Vinayak, D. V. Ramana, B. Chiranjeevi, M. Chandrasekharam,
48 S. Mao, X. Geng, Y. Yang, X. Qian, S. Wu, J. Han, L. Wang, RSC
Adv. 2015, 5, 36390–36393. DOI: 10.1039/C5RA03819G
49 Y.-H. Liao, W.-B. Chen, Z.-J. Wu, X.-L. Du, L.-F. Cun, X.-M. Zhang,
W.-C. Yuan, Adv. Synth. Catal. 2010, 352, 827–832. DOI:
10.1002/adsc.200900764
ChemistrySelect
2016,
1,
3974–3978.
DOI:
10.1002/slct.201600906
19 R. S. Varma, K. P. Naicker, P. J. Liesen, Tetrahedron Lett. 1998,
39, 3977–3980. DOI: 10.1016/S0040-4039(98)00740-0
20 S. Maity, T. Naveen, U. Sharma, D. Maiti, Org. Lett. 2013, 15,
3384–3387. DOI: 10.1021/ol401426p
50 Z. Wang, Z. Yang, D. Chen, X. Liu, L. Lin, X. Feng, Angew. Chem.,
Int. Ed. 2011, 50, 4928–4932. DOI: 10.1002/anie.201008256
51 Z. Wang, Z. Chen, S. Bai, W. Li, X. Liu, L. Lin, X. Feng, Angew.
21 W.-T. Wei, W.-M. Zhu, W.-W. Ying, Y.-N. Wang, W.-H. Bao, L.-H.
Gao, Y.-J. Luo, H. Liang, Adv. Synth. Catal. 2017, 359, 3551–3554.
DOI: 10.1002/adsc.201700870
Chem.,
Int.
Ed.
2012,
51,
2776–2779.
DOI:
10.1002/anie.201109130
22 Y. Liu, J.-L. Zhang, R.-J. Song, P.-C. Qian, J.-H. Li, Angew. Chem.,
Int. Ed. 2014, 53, 9017–9020. DOI: 10.1002/anie.201404192
23 P. Saxena, M. Kapur, Chem. - Asian J. 2018, 13, 861–870. DOI:
10.1002/asia.201800036
52 Z. Yang, Z. Wang, S. Bai, X. Liu, L. Lin, X. Feng, Org. Lett. 2011,
13, 596–599. DOI: 10.1021/ol102804p
53 X. Bao, B. Wang, L. Cui, G. Zhu, Y. He, J. Qu, Y. Song, Org. Lett.
2015, 17, 5168–5171. DOI: 10.1021/acs.orglett.5b02470
24 D. Tu, J. Luo, C. Jiang, Chem. Commun. 2018, 54, 2514–2517.
DOI: 10.1039/C8CC00267C
54 A. O. Terent’ev, V. A. Vil’, E. S. Gorlov, O. N. Rusina, A. A.
Korlyukov, G. I. Nikishin, W. Adam, ChemistrySelect 2017, 2,
3334–3341. DOI: 10.1002/slct.201700720
25 B. Majhi, D. Kundu, S. Ahammed, B. C. Ranu, Chem. - Eur. J.
2014, 20, 9862–9866. DOI: 10.1002/chem.201403325
26 J. R. Hwu, K.-L. Chen, S. Ananthan, J. Chem. Soc., Chem.
Commun. 1994, 1425–1426. DOI: 10.1039/C39940001425
27 M. Venkat Ram Reddy, B. Mehrotra, Y. D. Vankar, Tetrahedron
Lett. 1995, 36, 4861–4864. DOI: 10.1016/0040-4039(95)00839-5
28 X. Yang, C. Xi, Synth. Commun. 2007, 37, 3381–3392. DOI:
10.1080/00397910701484025
55 T. Kittikool, A. Thupyai, K. Phomphrai, S. Yotphan, Adv. Synth.
Catal. 2018, 360, 3345–3355. DOI: 10.1002/adsc.201800464
56 P. Sun, D. Yang, W. Wei, L. Jiang, Y. Wang, T. Dai, H. Wang, Org.
Chem. Front. 2017, 4, 1367–1371. DOI: 10.1039/C7QO00218A
57 I. B. Krylov, S. A. Paveliev, B. N. Shelimov, B. V. Lokshin, I. A.
Garbuzova, V. A. Tafeenko, V. V. Chernyshev, A. S. Budnikov, G.
I. Nikishin, A. O. Terent’ev, Org. Chem. Front. 2017, 4, 1947–1957.
DOI: 10.1039/C7QO00447H
29 K. Jayakanthan, K. Madhusudanan, Y. D. Vankar, Tetrahedron
2004, 60, 397–403. DOI: 10.1016/j.tet.2003.11.013
58 K. Yang, X. Bao, Y. Yao, J. Qu, B. Wang, Org. Biomol. Chem.
2018, 16, 6275-6283. DOI: 10.1039/C8OB01645C
30 D. Nageswar Rao, S. Rasheed, G. Raina, Q. N. Ahmed, C. K.
Jaladanki, P. V. Bharatam, P. Das, J. Org. Chem. 2017, 82, 7234–
7244. DOI: 10.1021/acs.joc.7b00808
59 S. Wu, Y. Li, G. Xu, S. Chen, Y. Zhang, N. Liu, G. Dong, C. Miao,
H. Su, W. Zhang, C. Sheng, Eur. J. Med. Chem. 2016, 115, 141-
147. DOI: 10.1016/j.ejmech.2016.03.039
31 W. Zhang, J. Zhang, S. Ren, Y. Liu, J. Org. Chem. 2014, 79,
11508–11516. DOI: 10.1021/jo502145v
60 A. M. Vijesh, A. M. Isloor, S. Isloor, K. N. Shivananda, P. C.
Shyma, T. Arulmoli, Der Pharma Chemica 2011, 3, 454–463.
61 R. Venkat Ragavan, V. Vijayakumar, N. Schuetha Kumari, Eur. J.
32 S. Maity, S. Manna, S. Rana, T. Naveen, A. Mallick, D. Maiti, J. Am.
Chem. Soc. 2013, 135, 3355–3358. DOI: 10.1021/ja311942e
33 K. Wieczorek-Ciurowa, A. J. Kozak, J. Therm. Anal. Cal. 1999, 58,
647-651. DOI: 10.1023/a:1010112814013
Med.
Chem.
2009,
44,
3852–3857.
DOI:
10.1016/j.ejmech.2009.04.010
34 T. Curtius, J. Prakt. Chem. 1912, 85, 37.
62 N. Das, A. Verma, P. K. Shrivastava, S. K. Shrivastava, Indian J.
Chem. 2008, 47B, 1555–1558.
35 T. Ajello, Gazz. Chim. Ital. 1940, 70, 401.
36 T. Iseki, T. Sugiura, S. Yasunaga, M. Nakasima, Ber. Dtsch. Chem.
63 P. Gunasekaran, S. Perumal, P. Yogeeswari, D. Sriram, Eur. J.
Ges. (A and
B
Series) 1941, 74, 1420–1424. DOI:
Med.
Chem.
2011,
46,
4530–4536.
DOI:
10.1002/cber.19410740811
10.1016/j.ejmech.2011.07.029
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
64 R. Gehring, M. Lindig, H.-J. Wroblowsky, H.-J. Santel, R. R.
Schmidt, W. Brandes, R. H. Strang, US5028717A, 1991.
65 P. Mueller, H. Wolf, K. Luerssen, H.-J. Santel, R. R. Schmidt,
CA2078163A1, 1991.
92 I. B. Krylov, A. O. Terent’ev, V. P. Timofeev, B. N. Shelimov, R. A.
Novikov, V. M. Merkulova, G. I. Nikishin, Adv. Synth. Catal. 2014,
356, 2266–2280. DOI: 10.1002/adsc.201400143
93 I. B. Krylov, A. O. Terent’ev, Russ. J. Org. Chem. 2015, 51, 10–13.
DOI: 10.1134/s1070428015010029
66 T. Konotsune, K. Kawakubo, US4414392A, 1983.
67 K. Jelich, W. Kramer, W. Brandes, G. Hanssler, P. Reinecke,
US4666933A, 1987.
94 H. Ishii, D. W. Hollomon, Eds., Fungicide Resistance in Plant
Pathogens, Springer Japan, 2015. DOI: 10.1007/978-4-431-
55642-8
68 S.S. Nayal, C.P. Singh, Asian J. Chem. 1999, 11, 207-212.
69 M. Kidwai, R. Mohan, J. Korean Chem. Soc. 2004, 48, 177-181.
DOI: 10.5012/jkcs.2004.48.2.177
95 F. van den Bosch, R. Oliver, F. van den Berg, N. Paveley, Annu.
Rev. Phytopathol. 2014, 52, 175–195. DOI: 10.1146/annurev-
phyto-102313-050158
70 V. Gopalsamuthiram, WO2011051958A1, 2011.
71 M. R. D. Reddy, A. R. G. Prasad, Y. N. Spoorthy, L. R. K. R.
Ravindranath, Adv. Pharm. Bull. 2013, 3, 153-159. DOI:
10.5681/apb.2013.026
96 W. Krämer, U. Schirmer, P. Jeschke, and M. Witschel (Eds.),
Modern Crop Protection Compounds, 2nd edition, Wiley-VCH,
2012.
72 M. P. Clark, S. K. Laughlin, M. J. Laufersweiler, R. G. Bookland, T.
A. Brugel, A. Golebiowski, M. P. Sabat, J. A. Townes, J. C.
VanRens, J. F. Djung, et al., J. Med. Chem. 2004, 47, 2724–2727.
DOI: 10.1021/jm049968m
97 M.C. Chung, P.L. Bosquesi, J.L. dos Santos, Curr. Pharm. Des.
2011, 17, 3515-3526. DOI: 10.2174/138161211798194512
98 a) S. V. Popkov, L. V. Kovalenko, M. M. Bobylev, O. Y. Molchanov,
M. Z. Krimer, V. P. Tashchi, Y. G. Putsykin, Pestic. Sci. 1997, 49,
125–129. DOI: 10.1002/(SICI)1096-9063(199702)49:2<125::AID-
PS506>3.0.CO;2-0; b) H. Itoh, H. Kajino, T. Tsukiyama, J.
Tobitsuka, H. Ohta, Y. Takahi, M. Tsuda, H. Takeshiba, Bioorg.
Med. Chem. 2002, 10, 4029–4034. DOI: 10.1016/S0968-
0896(02)00302-4; c) H. Xu, L. Fan, Eur. J. Med. Chem. 2011, 46,
364–369. DOI: 10.1016/j.ejmech.2010.10.022; d) Metodicheskie
73 V. Hadi, Y.-H. Koh, T. W. Sanchez, D. Barrios, N. Neamati, K. W.
Jung, Bioorg. Med. Chem. Lett. Letters 2010, 20, 6854–6857. DOI:
10.1016/j.bmcl.2010.08.057
74 I. Schlemminger, B. Schmidt, D. Flockerzi, H. Tenor, C. Zitt, A.
Hatzelmann, D. Marx, C. Braun, R. Kuelzer, A. Heuser, H.-P. Kley
and G. J. Sterk, WO2010055083, 2008.
75 B. Schmidt, C. Scheufler, J. Volz, M. P. Feth, R.-P. Hummel, A.
Hatzelmann, C. Zitt, A. Wohlsen, D. Marx, H.-P. Kley, D. Ockert,
A. Heuser, J. A. M. Christiaans, G. J. Sterk, and W. M. P. B.
Menge, WO2008138939, 2010.
recomendatsii
po
opredeleniyu
fungitsidnoi
aktivnosti
for
novykhsoedinenii
(Methodological
Recommendations
Estimation of the FungicidalActivities of Novel Compounds).
Cherkassy: NIITEKhIM; 1984, 32 (in Russian); e) P. K. Singh, J.
Agric. Food Chem. 2012, 60, 5813–5818. DOI: 10.1021/jf300730f;
f) L. Pan, X. Li, C. Gong, H. Jin, B. Qin, Microb. Pathog. 2016, 95,
186–192. DOI: 10.1016/j.micpath.2016.04.012.
76 D. A. Guthrie, A. Ho, C. G. Takahashi, A. Collins, M. Morris, J. P.
Toscano, J. Org. Chem. 2015, 80, 1338–1348. DOI:
10.1021/jo502330w
77 S. Nourian, R. P. Lesko, D. A. Guthrie, J. P. Toscano, Tetrahedron
2016, 72, 6037–6042. DOI: 10.1016/j.tet.2016.08.016
78 K. Myung, C. J. R. Klittich, Drug Discovery Today, 2015, 20, 7–10.
DOI: 10.1016/j.drudis.2014.08.010
99 R. Pontzen and P. Baur, Impact of Physicochemical Parameters
on Fungicide Activity in Modern Fungicides and Antifungal
Compounds VI, 2010, Friedrichroda, Germany ISBN: 978-3-
941261-10-5
79 J. Jampilek, Expert Opin. Drug Discovery, 2015, 11, 1–9. DOI:
10.1517/17460441.2016.1110142
100 T. K. Chattapadhyay, P. Dureja, J. Agric. Food Chem. 2006, 54,
2129–2133. DOI: 10.1021/jf052792s
80 J. A. Lucas, N. J. Hawkins, B. A. Fraaije, Adv. Appl. Microbiol.
2015, 29–92. DOI: 10.1016/bs.aambs.2014.09.001
101 P. Walczak, J. Pannek, F. Boratyński, A. Janik-Polanowicz, T.
Olejniczak, J. Agric. Food Chem. 2014, 62, 8571–8578. DOI:
10.1021/jf502148h
81 Y. Zhang, B. A. Lorsbach, S. Castetter, W. T. Lambert, J. Kister, N.
X. Wang, C. J. R. Klittich, J. Roth, T. C. Sparks, M. R. Loso, Pest.
Manag. Sci. 2018, 74, 1979–1991. DOI: 10.1002/ps.5037
82 P. Jeschke, Pest Manag. Sci. 2015, 72, 433–455. DOI:
10.1002/ps.4190
102 L. Jiang, P. Jin, L. Wang, X. Yu, H. Wang, Y. Zheng, Sci. Hortic.
2015, 192, 218–223. DOI: 10.1016/j.scienta.2015.06.015
103 A. L. Smith, A. L. Erwin, T. Kline, W. C. T. Unrath, K. Nelson, A.
Weber, W. N. Howald, Antimicrob. Agents Chemother. 2007, 51,
2820–2829. DOI: 10.1128/AAC.00087-07
83 T. C. Sparks, B. A. Lorsbach, Pest Manag. Sci. 2016, 73, 672–677.
DOI: 10.1002/ps.4457
104 K. Durchschein, B. Ferreira-da Silva, S. Wallner, P. Macheroux, W.
Kroutil, S. M. Glueck, K. Faber, Green Chem. 2010, 12, 616. DOI:
10.1039/B922691E
84 H. X. Ngo, S. Garneau-Tsodikova, K. D. Green, Med. Chem.
Comm. 2016, 7, 1285–1306. DOI: 10.1039/c6md00222f
85 F. Bernard, M. Cazaunau, Y. Mu, X. Wang, V. Daële, J. Chen, A.
105 H. Li, F. Li, B. Frett, Synlett 2014, 25, 1403–1408. DOI: 10.1055/s-
0033-1339025
Mellouki, J. Phys. Chem.
A 2013, 117, 14132–14140. DOI:
10.1021/jp408771r
106 A. A. Zabierek, K. M. Konrad, A. M. Haidle, Tetrahedron Lett. 2008,
49, 2996–2998. DOI: 10.1016/j.tetlet.2008.02.169
86 S. De Jong, D. G. Nosal, D. J. Wardrop, Tetrahedron 2012, 68,
4067–4105. DOI: 10.1016/j.tet.2012.03.036
107 W. Zhou, S. Li, W. Lu, J. Yuan, Y. Xu, H. Li, J. Huang, Z. Zhao,
87 P. Gray, A. D. Yoffe, Chem. Rev. 1955, 55, 1069–1154. DOI:
10.1021/cr50006a001
Med.
Chem.
Comm.
2016,
7,
292–296.
DOI:
10.1039/C5MD00469A
88 W. A. Pryor, J. W. Lightsey, D. F. Church, J. Am. Chem. Soc. 1982,
104, 6685–6692. DOI: 10.1021/ja00388a035
89 R. G. Coombes, A. W. Diggle, S. P. Kempsell, Tetrahedron Lett.
1994, 35, 6373–6376. DOI: 10.1016/S0040-4039(00)73436-8
90 A. Shenghur, K. H. Weber, N. D. Nguyen, W. Sontising, F.-M. Tao,
J. Phys. Chem.
A
2014, 118, 11002–11014. DOI:
10.1021/jp508516c
91 A. O. Terent’ev, I. B. Krylov, V. P. Timofeev, Z. A. Starikova, V. M.
Merkulova, A. I. Ilovaisky, G. I. Nikishin, Adv. Synth. Catal. 2013,
355, 2375–2390. DOI: 10.1002/adsc.201300341
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
This article is protected by copyright. All rights reserved.

10.1002/chem.201806172
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
I. B. Krylov, A. S. Budnikov, E. R.
Lopat’eva, G. I. Nikishin, A. O.
Terent’ev*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm))
Page No. – Page No.
Mild nitration of pyrazolin-5-ones by a
combination of Fe(NO3)3 and NaNO2.
Discovery of a new easily available
class of fungicides – 4-nitropyrazolin-
5-ones
A new class of potent and structurally simple fungicides was discovered along with
an original method for their preparation. The in vitro activity of the synthesized 4-
nitropyrazolin-5-ones against phytopathogenic fungi is comparable or superior to
commercial fungicides (fluconazole, clotrimazole, triadimefon, kresoxim-methyl).
This article is protected by copyright. All rights reserved.