NaSCN–(NH4)2Ce(NO3)6 system in heterocycle thiocyanation: synthesis of novel highly potent broad-spectrum fungicides for crop protection

Article abstract of DOI:10.1007/s10593-021-02938-y

[Figure not available: see fulltext.] A method for thiocyanation of pyrroles, indoles, pyrazolones, and pyrimidine-2,4,6-triones with the NaSCN–(NH₄)₂Ce(NO₃)₆ system was proposed. The most important result was the synthesis of dithiocyanated pyrroles with high fungicidal activity against various phytopathogenic fungi.

Full text of DOI:10.1007/s10593-021-02938-y

DOI 10.1007/s10593-021-02938-y
Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
NaSCN–(NH4)2Ce(NO3)6 system in heterocycle thiocyanation: synthesis
of novel highly potent broad-spectrum fungicides for crop protection
Mikhail Yu. Sharipov1,2,3, Igor B. Krylov1,2,4*, Ivan D. Karpov2,3,
Olga V. Vasilkova2,3, Anna-Maria V. Oleksiienko2,3, Alexander O. Terent'ev1,2,4
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: krylovigor@yandex.ru
2 D. Mendeleyev University of Chemical Technology of Russia,
9 Miusskaya Sq., Moscow 125047, Russia
3 Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
31 Leninsky Ave., Moscow 119991, Russia
4 State Scientific Institution ''All-Russian Research Institute of Phytopathology'',
Possesion 5, Institute St., Bolshie Vyazemy 143050,
Odintsovo distr., Moskow reg., Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2021, 57(5), 531–537
Submitted February 3, 2021
Accepted April 1, 2021
A method for thiocyanation of pyrroles, indoles, pyrazolones, and pyrimidine-2,4,6-triones with the NaSCN–(NH4)2Ce(NO3)6 system was
proposed. The most important result was the synthesis of dithiocyanated pyrroles with high fungicidal activity against various
phytopathogenic fungi.
Keywords: cerium ammonium nitrate, pyrroles, fungicides, rhodanation, thiocyanation.
Recently, thiocyanates have attracted more and more
attention of chemists due to the discovery of efficient
preparation routes and new possibilities for their use.1 In
addition to the wide range of uses of thiocyanates in
preparative chemistry, aliphatic and aromatic thiocyanates
are well known as having insecticidal,2 fungicidal,3 and
bactericidal3a,c,f,4 activity, and are being investigated as
anticancer compounds.5 For example, methyl thiocyanate is
an industrial precursor of methyl isothiocyanate, which, in
turn, is used in agriculture as a fumigant for the control of
nematodes and as a means for the destruction of
phytopathogenic fungi.1a Methylene bis(thiocyanate),
ethylene thiocyanate, and various dinitrothiocyanato-
benzenes 1 have found widespread use as fungicides.
2-Thiocyanatoethyl dodecanoate (2) (Lethane 60) and 2-(2-
butoxyethoxy)ethyl thiocyanate (3) (Lethane 384) are used
as contact insecto-acaricides. 2-[(Thiocyanatomethyl)-
sulfanyl]benzothiazole (4) (Busan) has been used for a long
time as a herbicide. (3-Thiocyanatopropyl)triethoxysilane
(5) is used as a hardening additive in the production of
elastomers6 (Fig. 1).
A fairly large number of methods for the preparation of
monothiocyanated pyrroles are described in the literature,
mainly based on the use of oxidants in a pair with a source
of the thiocyanate group MSCN (M = K, NH4).
Approaches to the synthesis of α,α'-dirhodanopyrroles are
0009-3122/21/57(5)-0531©2021 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
product; the yield of dithiocyanate did not exceed 6%.18 In
this work, the range of application of the –SCN–CAN
thiocyanation system was expanded for the efficient
synthesis of hard-to-access dirhodanopyrroles by changing
the synthesis procedure and the ratio of reagents.
Additionally, rhodanation of other N-heterocyclic
compounds, such as pyrazolones, derivatives of indole and
pyrimidine-2,4,6(1H,3H,5H)-trione was carried out using
this system. It should be noted that the synthesized
pyrazolone and pyrimidine-2,4,6-trione rhodanides are
previously unknown heterocyclic thiocyanates.
Figure 1. Thiocyanates used in industry and agriculture.
much less developed; isolated examples of the synthesis of
these compounds by rhodanation of pyrroles by the action
of KSCN3b,7 or Pb(SCN)28 in combination with Br2 exist. The
formation of α,α'-dirhodanopyrrole as a minor product was
observed during monorhodanation of pyrrole by the action
of NH4SCN–Oxone,9 KSCN – graphene oxide (cat.) – H2O2,10
NH4SCN–DEAD,11 NH4SCN–Fe3O4–H2O2,12 NH4SCN–
2,2'-azobenzothiazole,13 NH4SCN–KHSO4–NH4VO3,14 and
The optimization of the synthesis conditions was carried
out using the example of the thiocyanation reaction of
N-methylpyrrole (6a). We studied the effect of the solvent,
the order of mixing of the reagents and their ratio on the
yield of product 7a (Table 1).
In the initial experiment, a mixture of pyrrole 6a and
NaSCN in AcOH was subjected to the action of CAN (the
ratio of reagents 6a:NaSCN:CAN = 1:3:3). As a result, the
target product 7a was obtained in a moderate 46% yield
(Table 1, entry 1). In entry 2, the effect of changing the
order of mixing the reagents was investigated: first, CAN
reacted with NaSCN in AcOH, then N-methylpyrrole (6a)
was added. If we assume that CAN serves to form a
relatively stable rhodanating agent from NaSCN, such a
change in the order of mixing of the reagents should not
lead to a significant change in the yield, as, for example, in
the rhodanation of β-keto esters and β-diketones by the
NaSCN–CAN system.21 However, in reality, as a result of
such a change in the methodology, the yield of compound
7a decreased to trace amounts, which indicates the low
stability of the active rhodanating agent in this system. A
15
NH4SCN–I2 rhodanating systems (the yield of α,α'-di-
rhodanopyrrole, as a rule, did not exceed 15%). Similar
results were obtained by rhodanation of N-methylpyrrole.15
N-Methyl-α,α'-dirhodanopyrrole was obtained by electro-
chemical rhodanation of N-methylpyrrole by the action of
NH4SCN at a controlled potential with a yield of 52%.3f
Without potential control, the yield was only 15%, which
significantly limits preparative possibilities of electro-
chemical rhodanation of pyrroles.16 The dirhodanation of
pyrrole was also carried out using the NH4SCN–DDQ
system with a product yield of 32–41%.17 The SciFinder
database contains only three sources of information on
N-substituted dirhodanopyrroles in addition to N-methyl-
pyrrole.3a,c,7 Systems NH4SCN–(NH4)2S2O8–FeCl33a and
3c
Table 1. Optimization of conditions of synthesis
of 1-methyl-2,5-dithiocyanato-1H-pyrrole (7a)*
KSCN–(NH4)2S2O8–CuSO4 make it possible to obtain
dirhodanides from N-methylpyrrole and N-phenylpyrrole in
44–48 and 71–82% yields, respectively. Thus, α,α'-di-
rhodanopyrroles are poorly studied compounds and there
are an extremely limited number of approaches to their
synthesis. The disadvantages of the existing methods are
their nonuniversality,3a,c difficult scalability,3f or the use of
hazardous and inconvenient reagents, such as Br2.3b,7,8
Notwithstanding, α,α'-dirhodanopyrroles are of great
interest as compounds with fungicidal and bactericidal
activity.3a–c,7
Molar ratio
6a:NaSCN:CAN
Yield of product 7a,
Entry
Solvent
%
1
2**
3
1:3:3
1:3:3
1:5:6
1:6:5
1:6:6
1:6:7
1:7:6
1:6:6
1:6:6
1:6:6
1:6:6
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
EtOAc
Me2CO
EtOH
46
Traces
55
In this work, we propose a convenient NaSCN–
(NH4)2Ce(NO3)6 (CAN) system for the synthesis of a wide
range of α,α'-dirhodanopyrroles, and, for the first time,
carried out systematic tests of their fungicidal activity
against a wide range of phytopathogenic fungi allowing to
judge the prospects of this class of compounds as
components of crop protection products. The activity
shown by them under standardized conditions is
comparable to or exceeds the activity of modern fungicidal
active substances triadimefon and kresoxim-methyl.
4
53
5
67
6
48
7
56
8
58
9
66
10
11
47
MeOH
51
Previously, the –SCN–CAN system was already used for
the thiocyanation of aromatic and heteroaromatic com-
pounds,18 styrenes,19 ketones,20 β-dicarbonyl compounds,21
and cyclopropanols.22 CAN was also used as a catalyst for
the preparation of vicinal rhodano alcohols from epoxides.23
In the thiocyanation of pyrroles using the –SCN–CAN
system by Nair et al., monothiocyanate was the main
* General procedure: CAN (3.289–7.675 g, 6–14 mmol) was added to a stirred
mixture of N-methylpyrrole (6a) (0.162 g, 2 mmol), NaSCN (0.487–1.135 g,
6–14 mmol), and solvent (15 ml) at room temperature, and stirring was
continued for 1 h.
** NaSCN (0.487 g, 6 mmol) was added to a mixture of CAN (3.289 g,
6 mmol) and AcOH (15 ml), and the mixture was stirred at room
temperature for 10 min. Then, N-methylpyrrole (6a) (0.162 g, 2 mmol)
was added, and stirring was continued for 24 h.
532

Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
24
possible rhodanating agent is thiocyanogen (SCN)2
Using half as much NaSCN and CAN, monothio-
cyanation of substituted indole 8 at position 3 was carried
out, and product 9 was isolated in a high yield (89%)
(Scheme 2). Similar results were obtained earlier for
rhodanation of other substituted indoles.18 It should be
noted that compound 9 and its structural analogs exhibit
high and selective cytotoxic activity toward cancer cells.5
formed during one-electron oxidation of the thiocyanate
ion.24c,25 (SCN)2 is quite stable as a solution in AcOH (can
be stored for several days);24d,e however, its reactivity
apparently increases significantly in the presence of CAN,
which made it possible to synthesize dithiocyanatopyrrole
7a. In this case, the reaction taking place is an electrophilic
aromatic substitution, and CAN acts as the one-electron
oxidizer of the thiocyanate ion and the acid26 activating
(SCN)2 for the electrophilic attack of pyrrole 6a. The use of
Lewis and Brønsted acids in electrophilic thiocyanation is
quite widespread.27 The possibility of the studied reaction
proceeding via the formation of (SCN)2 is in agreement
with the recent work, in which the thiocyanation of
enamines structurally related to the substrates from this
work was carried out by the action of (SCN)2 generated in
situ.28 However, the exact structure of the electrophilic
rhodanating agent formed in the –SCN–CAN system cannot
be determined from the available data. Moreover, in
addition to electrophilic rhodanation, mechanisms of
radical rhodanation of heterocyclic compounds are also
known, which also cannot be completely ruled out.3f,25,27a,b
Next, the ratio of the reagents was varied. An increase in
the amounts of NaSCN and CAN up to the ratio
6a:NaSCN:CAN = 1:6:6 made it possible to achieve the
highest yield of product 7a, 67% (Table 1, entry 5). A
further increase in the excess of NaSCN or CAN led to
lower yields (48–56%, entries 6–7). In entries 8–11,
EtOAc, Me2CO, EtOH, and MeOH were tested as solvents.
The highest yield (66%) of the target dirhodanide 7a was
attained using Me2CO (entry 9); however, it did not exceed
the yield obtained using AcOH (entry 5).
Scheme 2
At the next stage, the NaSCN–CAN system proposed in
this work was used to synthesize novel classes of
heterocyclic thiocyanates – rhodanopyrazolones and substi-
tuted pyrimidine-2,4,6(1H,3H,5H)-trione thiocyanate. Mono-
thiocyanation of pyrazolones 10a–d was performed using
the molar ratio of reagents 10:NaSCN:CAN = 1:3:3.
Rhodanides 11a–c unsubstituted at the nitrogen atom were
obtained from pyrazolones 10a–c in high yields (87–95%).
Product 11d from N-phenyl-substituted pyrazolone 10d
was obtained in a moderate yield (46%, Scheme 3), which
may be due to the high tendency of the starting pyrazolone
to oxidation.29
Scheme 3
R1
R1
CAN (3 equiv)
N
N
NaSCN (3 equiv)
HN
N
O
O
AcOH, rt, 1 h
Using the optimized reaction conditions (entry 5), a
number of N-alkyl- and N-aryl-1H-pyrrole dithiocyanates
were synthesized. Dithiocyanatopyrroles 7b–d,f,g with a
primary alkyl, phenyl, or benzyl substituent at the nitrogen
atom were obtained in high yields (70–92%). Pyrrole 7e
was obtained in moderate yield (55%) from N-(sec-butyl)-
1H-pyrrole 6e (Scheme 1).
Me
Me
2 SCN
R2
10a–d
R
11a–d
Ph
N
NH
N
NH
N
NH
N
N
Me
Me
O
Me
NC
O
Me
O
Me
O
SCN
SCN
Bn SCN
5
Scheme 1
Me SCN
11d (46%)
11a (89%)
11b (87%)
11c (95%)
Following a similar procedure, thiocyanate 13 was
obtained in high yield from pyrimidine-2,4,6(1H,3H,5H)-
trione 12 (Scheme 4). It should be noted that the phenyl
ring with the electron-donating methoxy group remained
unaffected.
Scheme 4
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Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
The structure of the obtained products was confirmed by
Studies of the fungicidal activity were carried out using
potato dextrose agar as a nutrient medium for the
pathogen.30,29b,31 A standard concentration (30 mg/l) was
selected for testing, which makes it possible to evaluate the
fungicidal activity of the compounds in comparison with
triadimefon and kresoxim-methyl. The selected reference
substances are active ingredients of modern commercial
fungicidal preparations.
1H and 13C NMR spectroscopy and high-resolution mass
spectrometry data. A common feature in the spectral
characteristics of all synthesized thiocyanates is the
presence in the 13C NMR spectrum of a signal in the range
of 107.1–110.4 ppm corresponding to the carbon atom of
the thiocyanate group.24a
In this work, we investigated the in vitro fungicidal
activity of a number of synthesized heterocyclic thio-
cyanates against a wide range of phytopathogenic fungi
that pose a serious threat to crop production. 14 typical
phytopathogenic organisms capable of rapid reproduction
and development of resistance causing significant damage
to agriculture were selected as test microorganisms:
Venturia inaequalis, the causative agent of apple scab
(ascomycota fungi); Rhizoctonia solani, the causative agent
of rhizoctonia, root rot of many crops (imperfect fungi);
Fusarium oxysporum and Fusarium moniliforme, the
causative agents of fusarioses, diseases of grain crops
(imperfect fungi); Bipolaris sorokiniana, the causative
agent of root rot of grain crops (imperfect fungi);
Sclerotinia sclerotiorum, the causative agent of white rot of
sunflower and many vegetable crops (imperfect fungi);
Fusarium graminearum, the causative agent of fusarium
ear blight of wheat, barley (ascomycota fungi); Fusarium
heterosporum, the causative agent of root rot, tracheo-
mycotic wilting of soybeans (deuteromycete fungi);
Fusarium culmorum, the causative agent of barley root rot
(ascomycota fungi); Fusarium gibbosum, the causative
agent of root rot, tracheomycotic wilting of peas (class of
deuteromycetes); Fusarium nivale (Microdochium nivale),
the causative agent of snow mold of grain crops
(deuteromycete fungi); Fusarium sporotrichiella, the
causative agent of fusarium head blight of wheat spike
(sordariomycete fungi); Alternaria alternata, the causative
agent of fusarium ear blight of wheat (ascomycota fungi);
Phoma eupyrena, the causative agent of dark-brown
spotting of wheat and barley (ascomycota fungi) (Table 2).
The obtained data allow us to conclude that practically
all pyrrole dithiocyanates 7a–g exhibit high fungicidal
activity, comparable to or superior to that of the reference
substances. The rhodanides of pyrazolones 11b,d exhibited
only moderate fungicidal activity (Table 2).
Such a high fungicidal activity of pyrrole dithiocyanates
makes them promising substances for practical application
in plant protection. It should be noted that the developed
method is convenient for obtaining thiocyanates of various
structures for biological tests; however, the development of
more convenient methods for scale-up syntheses that do not
use excessive amounts of oxidants based on transition
metals is also in demand. For the production of multigram
amounts of pyrrole dithiocyanates according to the
proposed method, the regeneration of CAN by the
reoxidation of Ce(III) to Ce(IV) can be recommended. For
example, this can be accomplished by anodic oxidation of
its reduced form, which has been proposed when it is
employed as an etchant.32
To conclude, a method has been developed for the
thiocyanation of N-substituted pyrroles, indoles, and
pyrimidine-2,4,6(1H,3H,5H)-triones, as well as N-unsubsti-
tuted and N-substituted pyrazolones with the NaSCN–CAN
system. Fungicidal tests of a number of synthesized
thiocyanates were carried out on 14 phytopathogenic fungi.
The most pronounced activity was found for N-methyl-,
N-hexyl-, N-isopentyl-, N-(sec-butyl)-, and N-benzyl-
2,5-dithiocyanatopyrroles, which are superior in fungi-
toxicity to commercial drugs triadimefon and kresoxim-
methyl.
Table 2. Fungicidal activity of compounds 7a–g and 11b,d* (suppression of mycelium development, %)
Compound
Phytopathogenic fungi
NaSCN
Triadimefon**
Kresoxim-methyl***
7a
7b
7c
7d
7e
7f
7g
11b 11d
Venturia inaequalis
Rhizoctonia solani
100 100 100
100 100 100
69 100 59
87 100 74
100
97
60
99
75
47
99
93
90
88
8
37
71
21
54
71
29
40
28
55
49
13
12
5
47
53
80
67
70
56
51
79
77
34
96
87
65
72
56
41
59
76
43
66
55
15
24
44
18
20
19
14
15
Fusarium oxysporum
Fusarium moniliforme
Bipolaris sorokiniana
Sclerotinia sclerotiorum
Fusarium graminearum
Fusarium heterosporum
Fusarium culmorum
Fusarium gibbosum
100
92
65
87
77
99
81
46
94
33
100 100
100 100
58 100 39
71 100 60
7
7
100
97
50
87
20
5
100 100
74 100 48
67 100 47
62 100 55
61 100 43
6
100 100 100
3
100
100
96
82
83
70
23
18
Fusarium nivale
(Microdochium nivale)
Fusarium sporotrichiella
100
99
94
73
55 100 45
67
18
35
2
54
68
100 100
74 100 58
48 100 31
59 100 71
93
80
12
11
36
37
71
45
1
2
80
39
26
56
65
Alternaria alternata
Phoma eupyrena
100 100 100
100 100 100
100
14
100
* Concentration of test compounds in the nutrient medium was 30 mg/l.
** 1-(4-Chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one.
*** Methyl (E)-2-(methoxyimino)-2-{2-[(2-methylphenoxy)methyl]phenyl}acetate.
534

Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
Experimental
fractions were combined and dried over anhydrous Na2SO4.
The solvent was evaporated on a rotary evaporator by a
water jet vacuum pump. 1-Methyl-2,5-dithiocyanato-1H-
pyrrole (7a)3a was isolated by column chromatography on
silica gel (eluent AcOEt – petroleum ether, 5:95). Yield
179–262 mg (46–67%), yellowish crystals, mp 117–119°C,
1H and 13C NMR spectra (300 and 75 MHz,
respectively) were acquired on a Bruker Avance II
spectrometer in СDCl3 (compounds 7a–g, 9, 11b,c,d, and
13) or DMSO-d6 (compound 11a); the internal solvent
signals were used as internal standards (СDCl3: 7.26 ppm
for 1Н nuclei, 77.2 ppm for 13С nuclei; DMSO-d6: 2.50 ppm
1
Rf 0.7 (eluent EtOAc – petroleum ether, 1:2). H NMR
spectrum, δ, ppm: 3.95 (3H, s, NCH3); 6.72 (2H, s, H Ar).
13C NMR spectrum, δ, ppm: 32.8; 108.5; 113.8; 120.8.
Found, m/z: 217.9821 [M+Na]+. С7H5N3NaS2. Calculated,
m/z: 217.9817.
Synthesis of 2,5-dithiocyanato-1H-pyrroles 7a–g
(General method). A 100-ml flask was charged with
N-substituted pyrrole 6a–g (2 mmol) and AcOH (15 ml),
and NaSCN (0.973 g, 12 mmol) was added with stirring.
After complete dissolution of NaSCN (about 10 min), CAN
(6.578 g, 12 mmol) was added in small portions. Stirring at
room temperature was continued for 1 h. The isolation of
products 7a–g was carried out similarly to the isolation of
compound 7a.
1
for Н nuclei, 39.5 ppm for 13С nuclei). High-resolution
mass spectra were recorded on a Bruker maXis mass
spectrometer by electrospray ionization33 in the positive ion
registration mode (capillary voltage 4500 V). Scanning
range m/z 50–3000, external calibration (Fluka
Electrospray Calibrant Solution). A syringe injection of
solutions of compounds in MeCN was used, the flow rate
was 3 μl/min. Spray gas N2 (0.4 bar), drying gas N2 (4.0 l/min),
interface temperature 180°C. All recorded spectra were
processed using the Bruker Compass DataAnalysis 4.0
software.
EtOAc, Me2CO, petroleum ether, and CH2Cl2 were
purified by distillation. Glacial AcOH, EtOH, MeOH,
1-methyl-2-phenylindole (8) (99%, Sigma), CAN (99%,
Acros), and NaSCN (99%, Acros) were used without
additional purification. N-Substituted pyrroles were
obtained by alkylation of pyrrole (compounds 6a–d)34 or
by condensation of 2,5-dimethoxytetrahydrofuran with the
corresponding primary amines (compounds 6e–g).35
Pyrazolones 10a–d were obtained by condensation of the
corresponding β-keto esters with N2H4·H2O or PhNHNH2
according to the previously described procedures.29a
Compound 12 was obtained by the reaction of 1,3-di-
methylpyrimidine-2,4,6(1H,3H,5H)-trione with 4-methoxy-
benzaldehyde followed by reduction of the condensation
product with the Zn–AcOH system.36
1-Methyl-2,5-dithiocyanato-1H-pyrrole (7a). Yield
262 mg (67%).
1-Hexyl-2,5-dithiocyanato-1H-pyrrole (7b). Yield 372 mg
(70%), yellowish oil, Rf 0.3 (eluent EtOAc – petroleum
1
ether, 5:95). H NMR spectrum, δ, ppm (J, Hz): 0.91 (3Н,
t, J = 6.9, CH3); 1.27–1.54 (6H, m, 3CH2); 1.81–1.91 (2H,
m, CH2); 4.29–4.34 (2H, m, NCH2); 6.74 (2H, s, H Ar).
13C NMR spectrum, δ, ppm: 14.0; 22.6; 26.5; 31.2; 31.3;
46.8; 108.9; 113.3; 121.5. Found, m/z: 288.0589 [M+Na]+.
С12H15N3NaS2. Calculated, m/z: 288.0600.
1-Isopentyl-2,5-dithiocyanato-1H-pyrrole (7c). Yield
392 mg (78%), yellowish oil, Rf 0.2 (eluent EtOAc –
1
petroleum ether, 5:95). H NMR spectrum, δ, ppm (J, Hz):
1.06 (6H, d, J = 6.9, 2CH3); 1.68–1.89 (3H, m, CH, CH2);
4.25–4.42 (2H, m, NCH2); 6.74 (2H, s, H Ar). 13C NMR
spectrum, δ, ppm: 22.4; 26.5; 40.0; 45.4; 108.8; 113.2;
121.5. Found, m/z: 274.0437 [M+Na]+. С11H13N3NaS2.
Calculated, m/z: 274.0443.
When pyrroles are rhodanated by the NaSCN–CAN
system, nitrogen oxides can be liberated from the reaction
mixture; therefore, the synthesis must be carried out in a
fume hood. Room temperature was 20–26°С.
Optimization of the conditions of the synthesis of
1-methyl-2,5-dithiocyanato-1H-pyrrole (7a). N-methyl-
pyrrole (6a) (0.162 g, 2 mmol) and the solvent (15 ml)
were loaded into a 100-ml flask, and NaSCN (0.487–1.135 g,
6–14 mmol) was added with stirring. Complete dissolution
of NaSCN was achieved, and after 10 min, CAN (3.289–
7.675 g, 6–14 mmol) was added in small portions (about 10
portions) over 1–2 min. Stirring at room temperature was
continued for 1 h (Table 1, entries 1, 3–11).
In entry 2, the same amounts of reagents were used as in
entry 1, but the order of mixing the reagents was changed.
First, AcOH (15 ml), CAN (3.289 g, 6 mmol), and NaSCN
(0.487 g, 6 mmol) were loaded into the flask; the mixture
was stirred at room temperature for 10 min. Then,
N-methylpyrrole (6a) (0.162 g, 2 mmol) was introduced,
and stirring was continued at room temperature for 24 h.
After the completion of the reaction, the reaction
mixture was evaporated on a rotary evaporator at reduced
pressure provided by a water jet pump. The resulting
mixture was diluted with CH2Cl2 (20 ml), H2O (20 ml), and
saturated aqueous NaHCO3 (20 ml), shaken, and the
organic layer was separated. The aqueous layer was
additionally extracted with CH2Cl2 (2×20 ml). All organic
1-Octyl-2,5-dithiocyanato-1H-pyrrole (7d). Yield 475 mg
(81%), yellowish oil, Rf 0.6 (eluent EtOAc – petroleum
1
ether, 1:5). H NMR spectrum, δ, ppm: 0.79–0.99 (3H, m,
CH3); 1.20–1.52 (10H, m, 5CH2); 1.77–1.98 (2H, m, CH2);
4.24–4.42 (2H, m, NCH2); 6.74 (2H, s, H Ar). 13C NMR
spectrum, δ, ppm: 14.2; 22.7; 26.8; 29.1; 29.2; 31.3; 31.8;
46.8; 108.9; 113.3; 121.5. Found, m/z: 316.0901 [M+Na]+.
С14H19N3NaS2. Calculated, m/z: 316.0913.
1-(sec-Butyl)-2,5-dithiocyanato-1H-pyrrole (7e). Yield
261 mg (55%), yellowish crystals, mp 93–95°С,
1
Rf 0.6 (eluent EtOAc – petroleum ether, 1:3). H NMR
spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 7.4, CH2CH3);
1.73 (3H, d, J = 7.1, CHCH3); 1.95–2.15 (1H, m) and 2.15–
2.37 (1H, m, CH2); 4.79–4.98 (1H, m, CH); 6.75 (2H, s,
H Ar). 13C NMR spectrum, δ, ppm: 11.4; 21.1; 29.7; 57.6;
109.1; 122.5. Found, m/z: 260.0293 [M+Na]+.
С10H11N3NaS2. Calculated, m/z: 260.0287.
1-Phenyl-2,5-dithiocyanato-1H-pyrrole (7f).3a Yield
473 mg (92%), white crystals, mp 158–160°С, Rf 0.4
(eluent EtOAc – petroleum ether, 1:5). 1H NMR spectrum,
δ, ppm: 6.89 (2H, s, H Ar); 7.29–7.50 (2H, m, H Ph); 7.50–
7.76 (3H, m, H Ph). 13C NMR spectrum, δ, ppm: 109.0;
115.8; 121.4; 129.0; 129.9; 130.6; 135.3. Found, m/z:
535

Chemistry of Heterocyclic Compounds 2021, 57(5), 531–537
279.9976 [M+Na]+. С12H7N3NaS2. Calculated, m/z:
279.9974.
1-Benzyl-2,5-dithiocyanato-1H-pyrrole (7g).3b Yield 450 mg
(83%), yellowish crystals, mp 93–96°С, Rf 0.5 (eluent
EtOAc – petroleum ether, 1:5). 1H NMR spectrum, δ, ppm:
5.60 (2H, s, CH2); 6.85 (2H, s, H Ar); 6.95–7.07 (2H, m,
H Ph); 7.31–7.45 (3H, m, H Ph). 13C NMR spectrum,
δ, ppm: 49.6; 108.4; 114.3; 121.9; 126.2; 128.5; 129.3;
135.4. Found, m/z: 294.0127 [M+Na]+. С13H9N3NaS2.
Calculated, m/z: 294.0130.
5-(4-Methoxybenzyl)-1,3-dimethyl-5-thiocyanato-
pyrimidine-2,4,6(1H,3H,5H)-trione (13). Yield 440 mg
(88%), colorless oil, Rf 0.3 (eluent EtOAc – petroleum ether,
1
1:5). H NMR spectrum, δ, ppm (J, Hz): 3.22 (6H, s,
2NCH3); 3.57 (2H, s, CH2); 3.76 (3H, s, OCH3); 6.76 (2H,
d, J = 8.5, H Ar); 6.98 (2H, d, J = 8.5, H Ar). 13C NMR
spectrum, δ, ppm: 29.4; 42.8; 55.3; 59.6; 107.8; 114.5; 124.0;
131.0; 149.0; 160.0; 165.6. Found, m/z: 372.0420 [M+K]+.
С15H15KN3O4S. Calculated, m/z: 372.0415.
The study of the fungicidal activity of compounds 7a–g
and 11b,d was carried out in vitro against 14 types of
phytopathogenic fungi (Sclerotinia sclerotiorum, Fusarium
oxysporum, Fusarium moniliforme, Bipolaris sorokiniana,
Venturia inaequalis, Rhizoctonia solani, Fusarium gram-
inearum, Fusarium heterosporum, Fusarium culmorum,
Fusarium gibbosum, Fusarium nivale, Fusarium sporo-
trichiella, Alternaria alternata, Phoma eupyrena) by
measuring the suppression of mycelium growth in potato-
dextrose agar as a nutrient medium (400 g potatoes, 40 g
dextrose, 20 g agar, 2 l H2O).30,29b,31 The test compounds
were dissolved in Me2CO to give 3.0 × 103 mg/l solutions
that were poured into a sterile melted nutrient medium at a
temperature not exceeding 60°C. The final concentration of
the compound in the nutrient medium was 30 mg/l. After
that, the nutrient medium was poured into Petri dishes, into
which, after cooling, identical pieces from the mycelium
growth zone of the investigated fungi were placed. After
keeping the Petri dishes for 3 days at 25°C in the dark,
the diameter of the colonies was measured. The proportion
of inhibition of mycelium growth was calculated as
((B–A)/B)×100%, where A is the mycelium diameter (mm)
in the dish with the test compound, B is the mycelium
diameter (mm) in the control dish supplemented with
Me2CO without the test compound. Each experiment was
carried out three times with averaging of the result. The
commercial fungicidal active ingredients triadimefon and
kresoxim-methyl were used as references.
Synthesis of rhodanides 9, 11a–d and 13 (General
method). A 100-ml flask was charged with substrate 8, 10a–d,
or 12 (1.5 mmol) and AcOH (15 ml), and NaSCN (0.365 g,
4.5 mmol) was added with stirring. After complete
dissolution of NaSCN (about 10 min), CAN (2.467 g,
4.5 mmol) was added in small portions (about 10 portions)
over 1–2 min. Stirring at room temperature was continued
for 1 h. The isolation of products was carried out similarly
to the isolation of compound 7a.
1-Methyl-2-phenyl-3-thiocyanato-1H-indole (9).5,16,37
Yield 353 mg (89%), white crystals, mp 83–84°С, Rf 0.6
(eluent EtOAc – petroleum ether, 1:5). 1H NMR spectrum,
δ, ppm: 3.71 (3H, s, CH3); 7.31–7.70 (8H, m, H Ar); 7.83–
7.91 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 31.9;
89.7; 110.4; 112.3; 119.1; 122.1; 123.7; 128.6; 128.9;
129.3; 129.7; 130.8; 137.3; 146.6.
3-(3-Methyl-5-oxo-4-thiocyanato-4,5-dihydro-1H-pyra-
zol-4-yl)propionitrile (11a). Yield 278 mg (89%),
colorless oil, Rf 0.4 (eluent EtOAc – petroleum ether, 1:5).
1H NMR spectrum, δ, ppm: 2.12 (3H, s, CH3); 2.16–2.29
(1H, m) and 2.33–2.58 (3H, m, 2CH2); 11.87 (1H, br. s,
NH). 13C NMR spectrum, δ, ppm: 12.1; 13.4; 26.3; 56.7;
108.1; 118.4; 155.4; 172.1. Found, m/z: 231.0318 [M+Na]+.
С8H8N4NaOS. Calculated, m/z: 231.0311.
4-Benzyl-5-methyl-4-thiocyanato-2,4-dihydro-3H-pyra-
zol-3-one (11b). Yield 320 mg (87%), colorless oil, Rf 0.5
(eluent EtOAc – petroleum ether, 1:3). 1H NMR spectrum,
δ, ppm (J, Hz): 2.24 (3H, s, CH3); 3.17 (1H, d, J = 13.4)
and 3.43 (1H, d, J = 13.4, CH2); 7.07–7.22 (2H, m, H Ph);
7.22–7.38 (3H, m, H Ph); 8.88 (1H, br. s, NH). 13C NMR
spectrum, δ, ppm: 14.5; 38.5; 58.6; 107.1; 128.6; 129.1;
129.4; 132.1; 156.5; 172.6. Found, m/z: 246.0699 [M+H]+.
С12H12N3OS. Calculated, m/z: 246.0696.
1
Supplementary information file containing H and 13C
NMR spectra of compounds 7a–g, 9, 11a–d, and 13 is
available at the journal website at http://link.springer.com/
journal/10593.
4-Hexyl-5-methyl-4-thiocyanato-2,4-dihydro-3H-pyra-
zol-3-one (11c). Yield 341 mg (95%), colorless oil, Rf 0.5
(eluent EtOAc – petroleum ether, 1:5). 1H NMR spectrum,
δ, ppm: 0.74–0.95 (3H, m, CH3); 1.03–1.42 (8H, m, 4CH2);
1.75–1.92 (1H, m) and 1.94–2.10 (1H, m, CH2); 2.15 (3H,
s, NCH3); 9.32 (1H, br. s, NH). 13C NMR spectrum, δ, ppm:
13.7; 14.0; 22.4; 24.6; 28.9; 31.2; 32.4; 58.1; 107.2; 157.2;
173.1. Found, m/z: 240.1166 [M+H]+. С11H18N3OS.
Calculated, m/z: 240.1165.
This work was supported by the Russian Science
Foundation (grant 19-73-20190).
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