Pyridinium bromide as a mediator in electrochemical reactions: The preparation of cyclopropane-1,1-dicarbonitriles

Article abstract of DOI:10.24820/ark.5550190.p011.041

Pyridinium bromide has been tested as a new mediator for electrochemical transformations in methanol and acetonitrile. An efficient protocol for the synthesis of cyclopropanes via the electrochemical transformations of alkylidenemalononitriles and C-H aci

Full text of DOI:10.24820/ark.5550190.p011.041

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Arkivoc 2019, part vi, 325-335
Pyridinium bromide as a mediator in electrochemical reactions: the preparation
of cyclopropane-1,1-dicarbonitriles
Anatoly N. Vereshchagin,* Evgeniya O. Dorofeeva, Michail N. Elinson, and Mikhail P. Egorov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation
Email: vereshchagin@ioc.ac.ru
Received 08-07-2019
Accepted 11-24-2019
Published on line 12-25-2019
Abstract
Pyridinium bromide has been tested as a new mediator for electrochemical transformations in methanol and
acetonitrile. An efficient protocol for the synthesis of cyclopropanes via the electrochemical transformations
of alkylidenemalononitriles and C-H acids (malononitrile, malonic ester, N,N-dimethylbarbituric acid,
pyrazolin-5-ones) has been developed. The chemistry proceeds in a simple undivided cell under constant
current conditions employing a substoichiometric amount of PyHBr that serves both as a redox catalyst and a
supporting electrolyte; in this manner additional conducting salt is not required.
Keywords: Electrosynthesis, mediators, pyridinium bromide, C-H acids, cyclopropanes
DOI: https://doi.org/10.24820/ark.5550190.p011.041
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Introduction
Electrosynthesis is a competitive method in modern organic chemistry.1-4 The importance of electrochemical
synthesis lies in its great and, in some cases, unique possibilities for performing various transformations of
organic compounds.5
In recent decades, indirect electrooxidation of organic compounds has been the subject of intensive
studies.6,7 Halides are popular inorganic mediators.8-10 Their advantages include accessibility and low cost, as
well as the fact that the majority of the processes catalyzed by these mediators are performed in an undivided
cell.
C-H acids are convenient synthons for the preparation of different classes of compounds by indirect
electrooxidation in the presence of alkali halides as mediators. Electrochemical transformations involving
different types of C-H acids were studied. These processes are carried out in an undivided cell at constant
current. Electrolysis of malononitrile or malonic esters in alcohols affords cyclopropanes.11,12 Multicomponent
transformations of malonic acid derivatives using electrolysis media lead to the stereoselective formation of
polysubstituted three-carbon rings.13-15 Cross-dehydrogenative coupling of β-diketones or β-ketoesters (C-H
reagents) with carboxylic acids (O-H reagents) results in selective formation of intermolecular С-O coupling
products.16 Cyclic β-diketones enter into electrochemically induced multicomponent reactions with formation
of pyrans17,18 and furans.19
Electrochemical processes involving heterocyclic C-H acids are of considerable interest, since they allow
the synthesis of a various types of heterocyclic compounds with a wide range of biological and pharmaceutical
properties.20 The 2,4,6(1H,3H,5H)-pyrimidinetriones, also called barbiturates (derivatives of barbituric acid),
are a well-known class of drugs that act as central nervous system depressants, and by virtue of this, they
produce a wide spectrum of effects, ranging from mild sedation to anaesthesia.21,22 An electrochemical
strategy for the synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones is described, using an electrogenerated
anion of barbituric acid in a one-pot, three component condensation of an aromatic aldehyde, Meldrum's acid
(one more heterocyclic C-H acid) and barbituric acid in ethanol in an undivided cell and in the presence of
sodium bromide.23
Among 2,4,6(1H,3H,5H)-pyrimidinetriones, spirobarbiturates are a particular class of compounds with
pronounced pharmacological and physiological activity.24-26 Our previous work described the indirect
electrocatalytic transformation involving barbituric acids with formation of spiro compounds: furo[2,3-d]-
pyrimidines,27 terpyrimidines28 and spirobicycles containing cyclopropane and pyrimidine fragments.29
A
spirocyclopropyl moiety joined to a heterocyclic ring has attracted particular attention due to a wide number
of pronounced pharmacological applications.30,31
Pyrazolones are another important class of heterocycles possessing important biological properties.32 The
C-H acid 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is a neuroprotective agent.33 The indirect
electrooxidation of edavarone and analogues in the presence of sodium halides as mediators in alcohols has
been described. Thus, Zeng et al. have carried out dehydrodimerization and dehydrotrimerization of pyrazol-5-
ones.34 Electrolysis of edavarone with aromatic aldehydes leads to the formation of 4,10-dimethyl-2,8,11-
triphenyl-2,3,8,9-tetraazadispiro[4.0.4.1]undeca-3,9-diene-1,7-diones,35 which was recently patented as an
advanced glycation end product (AGE) formation inhibitor intended for treatment of human schizophrenia.36
Despite the advantages and significant achievements described, the use of alkali metal halides as a
mediator in alcohol solutions for carrying out electrochemical transformations of organic compounds has
several disadvantages. Thus, the need to use methanol or ethanol as a solvent does not allow the
transformation of organic compounds which are insoluble or poorly soluble in alcohol, which limits the choice
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Vereshchagin, A. N. et al.
of the starting compounds and narrows the scope of the application of the electrocatalytic methodology.
Further, there are also significant limitations due to the occurrence of a number of side reactions. Thus, the
co-electrolysis of cyclohexylidenemalononitrile and malononitrile in ethanol in the presence of sodium
bromide results in formation of the expected tetracyanocyclopropane with a tricyclic pyrroline as a side
product.37 This result is a consequence of the ethoxide attack on the cyano-groups of the cyclopropane. To
avoid this side reaction, it is necessary to use an aprotic solvent such as acetonitrile, dimethylformamide or
dimethylsulfoxide. However, sodium halides do not dissolve in these solvents.
As is well known, quaternary ammonium salts are widely used in electrochemistry as supporting
electrolytes. Recently Little, Zeng et al. reported the development of an electrochemically initiated oxidative
amination of benzoxazoles38 and sulfonamides39 using tetraalkylammonium halides and ammonium iodide as
redox catalysts, respectively.
Now we present pyridinium bromide as a new mediator in electrochemical transformations involving
benzylidenemalononitriles and C-H acids.
Results and Discussion
We started using benzylidenemalononitrile 1a and malononitrile 2a as model substrates and performed a
constant current electrolysis at 100 mA/cm2 in an undivided cell, using a graphite rod (area 5 cm2) as the
anode and a Fe plate (area 5 cm2) as the cathode (Scheme 1, Table 1).
Scheme 1
Initially, we optimized the catalytic efficacy of PyHBr in methanol (entries 1-10). The current density of 50
mA cm-2, 0.75 equivalent of PyHBr, 20 °C, 2.2 F mol-1 were found to be the optimum conditions (entry 5). Using
smaller amounts of PyHBr in the electrolysis leads to the formation of 3a in lower yields (entries 1, 2).
Apparently, this is due to the incomplete regeneration of the mediator under electrolysis conditions. Raising
the current density to 100 mA cm-2 (entry 4) or the temperature to 30 °C (entry 8) also result in a decrease of
the yield, possibly due to the acceleration of undesired direct electrochemical processes leading to the
oligomerization of the reactants. Low yields and incomplete conversion of starting compounds were observed
when electrolysis was carried out at 10 °C (entry 7). Ethanol is a slightly less effective solvent than methanol,
in view of the yield. PyHBr is soluble in aprotic solvents. Acetonitrile, DMF and DMSO were tested as solvents
for electrolysis (Table 1, entries 12-14). It was found that acetonitrile is also effective in the synthesis of 3a
under electrolysis conditions (entry 12).
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Table 1. Initial optimization of the electrochemical synthesis of tetracyanocyclopropane 3a using PyHBr as
mediatora
Current
density/
mA cm-2
100
100
100
100
100
100
100
100
50
Electricity
passed/
F mol-1
2.0
Equiv. of
PyHBr
Yield of 3a
Entry
Solvent
T/°C
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
0.3
0.5
0.75
1.0
20
20
20
20
20
20
10
30
20
20
20
20
20
20
25c
42
60
60
68
61
44
32c
72
68
62
72
35c
25c
2.0
2.0
2.0
2.2
2.5
2.2
2.2
2.2
2.2
2.2
2.2
2.2
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
25
50
50
50
MeCN
DMF
DMSO
50
2.2
a Benzylidenemalononitrile 1a (10 mmol), malononitrile 2a (10 mmol), 20 mL of solvent, undivided cell.
b Isolated yield. c NMR data.
From the results described above, we conclude that the optimal reaction conditions require using 75 mol%
of PyHBr as mediator and supporting electrolyte, and 50 mA cm-2 of current density at 20 °C. The reaction is
best performed in an undivided cell using methanol or acetonitrile as the solvent without the need for
additional conducting salt. It should be noted that PyHBr is an effective mediator both in methanol and in
acetonitrile with a current density of 50 mA cm-2. Previous electrochemical methods for the synthesis of
tetracyanocyclopropanes 3 were carried out utilizing alkali metal halides as mediators with a current density
of 100 mA cm-2.11 However, the existing method is only applicable in alcohols, since alkali halides are insoluble
in aprotic solvents such as acetonitrile. As a result, we have now the opportunity to conduct an
electrochemical reaction in a new medium.
Scheme 2
Under the optimal conditions, as determined above, we then studied the scope and generality of the
protocol by examining reactions of benzylidenemalononitriles 1 (with both electron-withdrawing and electron-
donating substituents on the aromatic ring), and with different types of C-H acids: acyclic malononitrile 2a or
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dimethyl malonate 2b (Scheme 2, Table 2); heterocyclic 1,3-dimethylbarbituric acid 2c and edavarone (3-
methyl-1-phenyl-2-pyrazolin-5-one) 2d (Scheme 3, Table 3).
Table 2. Electrochemical synthesis of cyclopropanes 3 using noncyclic C-H acids 2a,b and PyHBr as
mediatora
Entry
Olefin
1a
1b
1c
1d
1a
1b
1c
1d
R
H
C-H acid
2a
X
CN
CN
CN
Cyclopropane
Yield of 3, (%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
72
66
58
48
67
63
64
38
4-Me
3-Br
4-NO2
H
4-Me
3-Br
4-NO2
2a
2a
2a
2b
2b
2b
2b
CN
COOMe
COOMe
COOMe
COOMe
3g
3h
a Benzylidenemalononitrile 1 (10 mmol), C-H acid 2 (10 mmol), 20 mL of acetonitrile, undivided cell, 20 °C,
2.2 F mol-1, current density 50 mA cm-2. b Isolated yield.
Scheme 3
Table 3. Electrochemical synthesis of cyclopropanes 3 using heterocyclic C-H acids 2c,d and PyHBr as
mediatora
Entry
Olefin
R
C-H acid
X+Y
Cyclopropane
Yield of 3, (%)b
1
1a
H
2c
3i
78
2
3
4
5
1b
1c
1d
1e
4-Me
3-Br
4-NO2
3-OMe
2c
2c
2c
2c
3j
3k
3l
65
74
54
66
3m
6
1a
H
2d
3n
55 (4:1)c
7
8
9
1b
1c
1d
1e
4-Me
3-Br
4-NO2
3-OMe
2d
2d
2d
2d
3o
3p
3q
3r
62 (5:2)c
59 (3:1)c
35 (3:2)c
64 (6:1)c
10
a Benzylidenemalononitrile 1 (10 mmol), C-H acid 2 (10 mmol), 20 mL of acetonitrile, undivided cell, 20 °C,
2.2 F mol-1 , current density 50 mA cm-2. b Isolated yield. c Ratio of izomers.
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4-Methyl-7-oxo-2,6-diaryl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitriles 3m-3p were obtained as
mixtures of diastereomers. The structures of the major (2RS,3SR) 3m-3p isomers were established earlier on
the data of NOESY.40 It should be noted that sodium bromide in methanol is a more effective mediator than
PyHBr in acetonitrile for the electrochemical synthesis of spirocyclopropanes 3i-3p.29,40 Apparently this is due
to the particularity of the reaction mechanism (Scheme 4).
A possible mechanism for the current transformation is proposed (Scheme 1). Bromine is formed at the
anode and can be observed by its color. Deprotonation of the pyridinium cation at the cathode leads to the
formation of pyridine. The evolution of hydrogen at the cathode is observed, especially when electrolysis is
conducted without stirring of the reaction mixture. Deprotonation of the C-H acid by pyridine in solution and
further bromination of the C-H acid anion forms the C-H acid A. Next, the ylide B is formed from the
intermediate A by action of pyridine. Finally, addition of B to alkylidenemalononitrile gives rise to
cyclopropane 3. The last step was postulated by Abaszadeh in the chemical synthesis of cyclopropanes from
pyridinium ylides and benzylidenemalononitriles.41
Scheme 4
Conclusions
Summarizing, we have tested a novel mediator for electrochemical transformations. The electrochemical
synthesis was performed under high constant current density in a simple undivided cell using a
substoichiometric amount of pyridinium bromide as mediator. Utilization of pyridinium bromide allows to
perform the electrolysis both in alcohols and aprotic solvents such as acetonitrile. After optimization of the
reaction conditions, the tetracyanocyclopropanes, dimethyl 2,2-dicyano-3-arylcyclopropane-1,1-dicarb-
oxylates and two types of spirocyclopropanes: 5,7-dimethyl-4,6,8-trioxo-2-aryl-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitriles and 4-methyl-7-oxo-2,6-diaryl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitriles have been
synthesized. The reactions proceed in a simple undivided cell employing a substoichiometric amount of PyHBr
that serves both as a mediator and a supporting electrolyte; in this manner additional conducting salt is not
required. The developed technique allows the synthesis of gram-scale amounts of the target compounds.
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Experimental Section
General. All melting points were measured with a Gallenkamp melting point apparatus. 1H NMR and 13C NMR
were recorded with a Bruker AM300 at ambient temperature in DMSO-d6 or CDCl3 solutions with working
frequencies of 300.13 MHz and 75.47 MHz respectively. Chemical shifts values are given in δ scale relative to
Me4Si. IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets. Mass-spectra
(EI = 70 eV) were recorded with a Finningan MAT INCOS 50 spectrometer. High-resolution mass spectrometry
(HRMS) (electrospray ionization, ESI) was measured on a BrukermicroTOF II instrument; external or internal
calibration was done with an Electrospray Calibrant Solution (Fluka). Benzylidenemalononitriles 1 were
synthesized by the condensation of the corresponding aromatic aldehydes and malononitrile via the
Knoevenagel condensation.15
General procedure. An undivided cell was equipped with a graphite anode (area 5 cm2) and Fe cathode (area 5
cm2) and connected to a DC regulated power supply. To the cell were added the desired
benzylidenemalononitrile 1 (10 mmol), C-H acid 2 (10 mmol), PyHBr (7.5 mmol), and 20 mL of acetonitrile. The
mixture was electrolyzed (2.2 F mol-1) using constant current conditions (50 mA/ cm2) at 20 °C under magnetic
stirring. When the reaction was completed, the solvent was removed under reduced pressure. The residue
was poured into water, and the product was then extracted with dichloromethane (3 × 20 mL), dried over
Na2SO4, and concentrated in vacuum. The residue was purified by crystallization from methanol to afford the
desired cyclopropane 3.
3-Phenyl-1,1,2,2-tetracyanocyclopropane (3a). White solid; 1.57 g (72%); mp 226-228 °C (lit.42 mp 229-230
°C). 1H NMR (DMSO-d6): δ 5.10 (1H, s, CH), 7.48-7.80 (5H, m, Ar) ppm.
3-(4-Methylphenyl)-1,1,2,2-tetracyanocyclopropane (3b). White solid; 1.53 g (66%); mp 224-227 °C (lit.42
mp 226-229 °C). 1H NMR (DMSO-d6): δ 2.31 (3H, s, CH3), 5.20 (1H, s, CH), 7.28 (2H, d, J 8.0 Hz, Ar), 7.65 (2H, d, J
8.0 Hz, Ar) ppm.
3-(3-Bromophenyl)-1,1,2,2-tetracyanocyclopropane (3c). White solid; 1.72 g (58%); mp 184-186 °C (lit.42
1
mp 186-187 °C). H NMR (DMSO-d6): δ 5.31 (1H, s, CH), 7.44 (1H, t, J 8.5 Hz, Ar), 7.68 (1H, d, J 8.5 Hz, Ar),
7.87(1H, d, J 8.5 Hz, Ar), 8.22 (1H, s, Ar) ppm.
3-(4-Nitrophenyl)-1,1,2,2-tetracyanocyclopropane (3d). White solid; 1.26 g (48%); mp 232-234 °C (lit.42
mp 232-234 °C). 1H NMR (DMSO-d6): δ 5.52 (1H, s, CH), 8.20 (2H, d, J 8.8 Hz, Ar), 8.35 (2H, d, J 8.8 Hz, Ar) ppm.
Dimethyl 2,2-dicyano-3-phenylcyclopropane-1,1-dicarboxylate (3e). White solid; 1.90 g (67%); mp 124-126
1
°C. (lit.12 mp 126-128 °C). H NMR (DMSO-d6): δ 3.75 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.41 (s, 1H, CH), 7.35-
7.50 (m, 5H, Ph) ppm.
Dimethyl 2,2-dicyano-3-(4-methylphenyl)cyclopropane-1,1-dicarboxylate (3f). White solid; 1.87 g (63%); mp
1
134-13135 °C. (lit.12 mp 137-139 °C). H NMR (CDCl3): δ 2.39 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 3.96 (s, 1H, CH),
3.98 (s, 3H, OCH3), 7.18-7.30 (m, 4H, Ar) ppm.
Dimethyl 2,2-dicyano-3-(3-bromophenyl)cyclopropane-1,1-dicarboxylate (3g). White solid; 2.32 g (64%); mp
110-111 °C (lit12 mp 110-111 °C). 1H NMR (CDCl3): δ 3.80 (s, 3H, OCH3), 3.95 (s, 1H, CH), 3.97 (s, 3H, OCH3), 7.26-
7.35 (m, 2H, Ar), 7.50-7.55 (m, 2H, Ar) ppm.
Dimethyl 2,2-dicyano-3-(4-nitrophenyl)cyclopropane-1,1-dicarboxylate (3h). White solid; 1.25 g (38%); mp
1
141-143 °C. (lit.12 mp 140-142 °C). H NMR (CDCl3): δ 3.85 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 4.05 (s, 1H, CH),
7.62 (2H, d, J 8.0 Hz, Ar), 8.30 (2H, d, J 8.0 Hz, Ar) ppm.
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5,7-Dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3i). White solid; 2.40 g
(78%); mp. 258-260 °C (lit.29 mp 259-260 °C). 1H NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 3.27 (s, 3H, CH3), 4.36 (s,
1H, CH), 7.32-7.40 (m, 3H, Ar), 7.44-7.50 (m, 2H, Ar) ppm.
5,7-Dimethyl-2-(4-methylphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3j). White solid;
1
2.09 g (65%); mp. 203-204 °C (lit.29 mp 203-204 °C). H NMR (DMSO-d6): δ 2.30 (s, 3H, CH3), 3.12 (s, 3H, CH3),
3.26 (s, 3H, CH3), 4.29 (s, 1H, CH), 7.17 (d, J 7.9 Hz, 2H, Ar), 7.33 (d, J 7.9 Hz, 2H, Ar) ppm.
2-(3-Bromophenyl)-5,7-dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3k). White solid;
2.86 g (74%); mp. 222-224 °C (lit.29 220-222 °C). 1H NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 3.28 (s, 3H, CH3), 4.39
(s, 1H, CH), 7.35 (t, J 7.9 Hz, 1H, Ph), 7.50-7.57 (m, 2H, Ph), 7.77-7.79 (m, 1H, Ph) ppm.
5,7-Dimethyl-2-(4-nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3l). Yellowish solid;
1.90 g (54%); mp. 219-221 °C (lit.29 219-221 °C). 1H NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 3.30 (s, 3H, CH3), 4.55
(s, 1H, CH), 7.82 (d, J 8.4 Hz, 2H, Ar), 8.24 (d, J 8.4 Hz, 2H, Ar).
5,7-Dimethyl-2-(3-methoxyphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3m). White
1
solid; 2.23 g (66%); mp. 232-234 °C. H NMR (DMSO-d6): δ 3.12 (s, 3H, CH3), 3.26 (s, 3H, CH3), 4.08 (s, 1H, CH),
3.76 (s, 3H, OCH3), 6.90-7.12 (m, 2H, Ar), 7.20-7.44 (m, 2H, Ar) ppm; 13C NMR (DMSO-d6): δ 23.4, 28.4, 29.1, 40.1,
41.2, 55.5, 109.4, 110.9, 112.4, 115.9, 120.7, 128.2, 130.6, 150.3, 157.0, 160.6, 163.0 ppm. IR (KBr): 768, 1396,
1424, 1440, 1684, 1708, 2248 cm-1. HRMS (ESI) 339.1093 [M+H]+, calcd for C17H15N4O4: 339.1099.
4-Methyl-7-oxo-2,6-diphenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3n). White solid; 1.79 g (55%);
1
diastereomeric ratio 4:1; mp 187-189 °C (lit.43 mp 187-189 °C). H NMR (DMSO-d6) major diastereoisomer: δ
1.71 (s, 3H, CH3), 4.20 (s, 1H, CH), 7.38-7.52 (m, 8H, Ar), 7.95 (d, J 7.9 Hz, 2H, Ar) ppm; minor diastereoisomer:
δ 2.35 (s, 3H, CH3), 4.94 (s, 1H, CH), 7.19-7.35 (m, 8H, Ar), 7.85 (d, J 7.9 Hz, 2H, Ar) ppm.
4-Methyl-2-(4-methylphenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3o). White
1
solid; 2.10 g (62%); diastereomeric ratio 5:2; mp 168-170 °C (lit.43 mp 175-178 °C). H NMR (DMSO-d6) major
diastereoisomer: δ 1.88 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.93 (s, 1H, CH), 7.20-7.32 (5H, m, Ar), 7.43-7.51 (2H, m,
Ar), 7.94-8.01 (2H, m, Ar) ppm; minor diastereoisomer: δ 2.36 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.99 (s, 1H, CH),
7.20-7.32 (5H, m, Ar), 7.38-7.43 (2H, m, Ar), 7.87-7.94 (2H, m, Ar) ppm.
2-(3-Bromophenyl)-4-methyl-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3p). White
1
solid; 2.39 g (59%); diastereomeric ratio 3:1; mp 194-196 °C (lit.43 mp 198-200 °C). H NMR (DMSO-d6) major
diastereoisomer: δ 1.74 (c, 3H, CH3), 4.18 (c, 1H, CH), 7.39-7.62 (m, 5H, Ar), 7.83-7.93 (m, 3H, Ar), 8.03 (c, 1H,
Ar) ppm; minor diastereoisomer: δ 2.33 (c, 3H, CH3), 4.94 (c, 1H, CH), 7.20-7.42 (m, 6H, Ar), 7.68 (d, J 7.5 Hz,
2H, Ar), 7.96 (c, 1H, Ar) ppm.
4-Methyl-2-(4-nitrophenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3q). White
1
solid; 1.30 g (38%); diastereomeric ratio 3:2; mp 169-172 °C (lit.43 mp 161-163 °C). H NMR (DMSO-d6) major
diastereoisomer: δ 1.70 (s, 3H, CH3), 4.33 (s, 1H, CH), 7.26-7.32 (m, 1H, Ar), 7.49-7.56 (m, 2H, Ar), 7.80 (d, J 8.7
Hz, 2H, Ar), 7.88-7.94 (m, 2H, Ar), 8.33 (d, J 8.7 Hz, 2H, Ar) ppm; minor diastereoisomer: δ 2.27 (s, 3H, CH3),
5.10 (s, 1H, CH), 7.21-7.26 (m, 1H, Ar), 7.42-7.49 (m, 2H, Ar), 7.76-7.85 (m, 2H, Ar), 7.80 (d, J 8.7 Hz, 2H, Ar),
8.33 (d, J 8.7 Hz, 2H, Ar) ppm.
4-Methyl-2-(3-methoxyphenyl)-7-oxo-6-phenyl-5,6-diazaspiro[2.4]hept-4-ene-1,1-dicarbonitrile (3r). White
solid; 2.28 g (64%); diastereomeric ratio 6:1; mp 188-190 °C. 1H NMR (DMSO-d6) major diastereoisomer: δ 1.78
(s, 3H, CH3), 3.78 (s, 3H, OCH3), 4.02 (s, 1H, CH), 7.20-7.32 (5H, m, Ar), 7.34-7.52 (2H, m, Ar), 7.88-7.96 (2H, m,
Ar) ppm; 13C NMR (DMSO-d6): δ 16.6, 20.4, 40.7, 44.9, 55.5, 111.1, 111.7, 114.8, 118.5 (2C), 119.8, 123.7, 129.3
(2C), 129.6, 130.9, 132.6, 133.4, 150.8, 159.8, 165.1. IR (KBr): 768, 1248, 1424, 1480, 1608, 1708, 2254 cm-1.
HRMS (ESI) 357.1360 [M+H]+, calcd for C21H17N4O2: 357.1352.
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Acknowledgements
The reported study was funded by RFBR according to the research project № 18-33-00301.
References
1. Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230.
https://doi.org/10.1021/acs.chemrev.7b00397
2. Jiang, Y.; Xu, K.; Zeng, C. Chem. Rev. 2018, 118, 4485.
https://doi.org/10.1021/acs.chemrev.7b00271
3. Vereshchagin, A. N. Russ. Chem. Bull. 2017, 66, 1765.
https://doi.org/10.1007%2Fs11172-017-1950-1
4. Shatskiy, A.; Lundberg, H.; Karkas, M. D. ChemElectroChem 2019, 6, doi: 10.1002/celc.201900435
https://onlinelibrary.wiley.com/doi/full/10.1002/celc.201900435
5. Liang, S.; Xu, K.; Zeng, C. C.; Tian, H. Y.; Sun, B. G. Adv. Synth. Catal. 2018, 360, 4266.
https://onlinelibrary.wiley.com/doi/full/10.1002/adsc.201800519
6. Ogibin, Y. N.; Elinson, M. N.; Nikishin, G. I. Russ. Chem. Rev. 2009, 78, 89.
http://dx.doi.org/10.1070/RC2009v078n02ABEH003886
7. Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492.
https://pubs.rsc.org/en/content/articlelanding/2014/CS/c3cs60464k#!divAbstract
8. Shono, T. Tetrahedron 1984, 40, 811.
https://doi.org/10.1016/S0040-4020(01)91472-3
9. Steckhan, E. Top. Curr. Chem. 1987, 142, 1.
https://link.springer.com/chapter/10.1007/3-540-17871-6_11
10. Elinson, M. N.; Dorofeeva, E. O.; Vereshchagin, A. N.; Nikishin, G. I. Russ. Chem. Rev. 2015, 84, 485.
http://dx.doi.org/10.1070/RCR4465
11. Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.; Vereshchagin, A. N.; Nikishin, G. I. Russ. Chem. Bull.,
Int. Ed. 2003, 52, 2241.
https://link.springer.com/article/10.1023%2FB%3ARUCB.0000011885.10104.da
12. Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.; Vereshchagin, A. N.; Gorbunov, S. V.; Nikishin, G. I.
Russ. Chem. Bull., Int. Ed. 2005, 54, 1593.
https://link.springer.com/article/10.1007%2Fs11172-006-0008-6
13. Elinson, M. N.; Feducovich, S. K.; Starikova, Z. A.; Vereshchagin, A. N.; Nikishin, G. I. Tetrahedron 2004, 60,
11743.
https://doi.org/10.1016/j.tet.2004.10.003
14. Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.; Vereshchagin, A. N.; Nikishin, G. I. Russ. Chem. Bull.,
Int. Ed. 2005, 54, 673.
https://doi.org/10.1007/s11172-005-0304-6
15. Vereshchagin, A. N.; Elinson, M. N.; Egorov, M. P. RSC Adv. 2015, 5, 98522.
https://doi.org/10.1039/C5RA19690F
16. Bityukov, O. V.; Matveeva, O. K.; Vil’, V. A.; Kokorekin, V. A.; Nikishin, G. I.; Terent’ev, A. O. J. Org. Chem.,
2019, 84, 1448.
https://doi.org/10.1021/acs.joc.8b02791
17. Wang, L.; Gao, J.; Wan, L.; Wang, Y.; Yao, C. Res. Chem. Intermed. 2015, 41, 2775.
Page 333
©AUTHOR(S)

Arkivoc 2019, vi, 325-335
Vereshchagin, A. N. et al.
https://doi.org/10.1007/s11164-013-1387-6
18. Elinson, M. N.; Vereshchagin, A. N.; Ryzhkov, F. V. Chem. Rec. 2016, 16, 1950.
https://doi.org/10.1002/tcr.201600044
19. Yao, C.; Wang, Y.; Li, T.; Yu, C.; Li, L.; Wang, C. Tetrahedron 2013, 69, 10593.
http://dx.doi.org/10.1016/j.tet.2013.10.056
20. Elinson, M. N.; Vereshchagin, A. N.; Ryzhkov, F. V. Curr. Org. Chem. 2017, 21, 1427.
http://dx.doi.org/10.2174/1385272820666161017170200
21. Brunton, L. L.; Chabner, B. A.; Knollmann, B. C. Keith, L. P. Goodman & Gilman’s the Pharmacological Basis
of Therapeutics, 12th ed.; The McGraweHill Companies: New York, NY, 2011.
22. Johns, M. W. Drugs 1975, 9, 448.
https://doi.org/10.2165/00003495-197509060-00004
23. Veisi, H.; Maleki, A.; Omrani, Z.; Lotfi, S. RSC Adv. 2014, 4, 55313.
https://doi.org/10.1039/c4ra08251f
24. Dundee, J. W.; Mcilroy, P. D. A. Anaesthesia 1982, 37, 726.
https://doi.org/10.1111/j.1365-2044.1982.tb01310.x
25. Galati, E. M.; Monforte, M. T.; Miceli, N.; Raneri, E. Farmaco 2001, 56, 459.
https://doi.org/10.1016/S0014-827X(01)01062-X
26. Lomlin, L.; Einsiedel, J.; Heinemann, F.W.; Meyer, K.; Gmeiner, P. J. Org. Chem. 2008, 73, 3608.
https://doi.org/10.1021/jo702573z
27. Vereshchagin, A. N., Elinson, M. N.; Tretyakova, E. O.; Zaimovskaya, T. A.; Stepanov, N. O.; Gorbunov, S. V.;
Belyakov, P. A.; Nikishin, G. I. Tetrahedron 2012, 68, 1198.
https://doi.org/10.1016/j.tet.2011.11.057
28. Vereshchagin, A. N.; Elinson, M. N.; Dorofeeva, E. O.; Bushmarinov, I. S.; Gorbunov, S. V.; Belyakov, P. A.;
Chizhov, A. O.; Nikishin, G. I. J. Mol. Cat. A: Chem. 2012, 363-364, 69.
https://doi.org/10.1016/j.molcata.2012.05.018
29. Dorofeeva, E. O.; Elinson, M. N.; Vereshchagin, A. N.; Stepanov, N. O.; Bushmarinov, I. S.; Belyakov, P. A.;
Sokolova, O. O.; Nikishin, G. I. RSC Adv. 2012, 2, 4444.
https://doi.org/10.1039/C2RA20078C
30. Sandanayaka, V.P.; Prashad, A.S.; Yang, Y.; Williamson, R.T.; Lin, Y.I.; Mansour, T.S. J. Med. Chem. 2003, 46,
2569.
https://doi.org/10.1021/jm034056q
31. Laroche, C.; Behr, J.-B.; Szymoniak, J.; Bertus, P.; Schutz, C.; Vogel, P.; Plantier-Royon, R. Bioorg. Med.
Chem. 2006, 14, 4047.
https://doi.org/10.1016/j.bmc.2006.02.005
32. Varvounis, G. Adv. Het. Chem. 2009, 98, 143.
https://doi.org/10.1016/S0065-2725(09)09802-X
33. Yoshida, H.; Yanai, H.; Namiki, Y.; Fukatsu-Sasaki, K.; Furutani, N.; Tada, N. CNS Drug Rev., 2006, 12, 9.
https://doi.org/10.1111/j.1527-3458.2006.00009.x
34. Li, W. C.; Zhang, Z. Z.; Zeng, C. C.; Hu, L. M.; Tian, H. Y. Curr. Org. Synth. 2014, 11, 454.
https://doi.org/10.2174/15701794113109990002
35. Elinson, M. N.; Dorofeeva, E. O.; Vereshchagin, A. N.; Nasybullin, R. F.; Egorov, M. P. Catal. Sci. Technol.,
2015, 5, 2384.
https://doi.org/10.1039/c4cy01681e
36. Itokawa, M.; Miyata, T.;. Arai, M. Eur. Pat. Appl., EP 2189537 A1, 2010.
Page 334
©AUTHOR(S)

Arkivoc 2019, vi, 325-335
Vereshchagin, A. N. et al.
https://depatisnet.dpma.de/DepatisNet/depatisnet?action=pdf&docid=EP000002189537A1
37. Elinson, M. N.; Feducovich, S. K.; Vereshchagin, A. N.; Dorofeev, A. S.; Dmitriev, D. E.; Nikishin, G. I. Russ.
Chem. Bull., Int. Ed. 2003, 52, 2235.
https://link.springer.com/article/10.1023%2FB%3ARUCB.0000011884.08799.a7
38. Gao, W. J.; Li, W. C.; Zeng, C. C.; Tian, H. Y.; Hu, L. M.; Little, R. D. J. Org. Chem., 2014, 79, 9613.
https://doi.org/10.1021/jo501736w
39. Jiang, Y.; Wang, Q. Q.; Liang, S.; Hu, L. M.; Little, R. D. J. Org. Chem. 2016, 81, 4713.
https://10.1021/acs.joc.6b00615
40. Elinson, M. N.; Dorofeeva, E. O.; Vereshchagin, A. N.; Korshunov, A. D.; Egorov, M. P. Res. Chem. Intermed.
2016, 42, 2191.
https://doi.org/10.1007/s11164-015-2142-y
41. Abaszadeh, M.; Seifi, M. Org. Biomol. Chem. 2014, 12, 7859.
https://doi.org/10.1039/c4ob01305k
42. Elinson, M. N.; Vereshchagin, A. N.; Stepanov, N. O.; Ilovaisky, A. I.; Vorontsov, A. Y.; Nikishin, G. I.
Tetrahedron 2009, 65, 6057.
https://doi.org/10.1016/j.tet.2009.05.062
43. Vereshchagin, A. N.; Elinson, M. N.; Korshunov, A. D.; Korolev, V. A.; Egorov, M. P. Heterocycl. Commun.
2015, 21, 355.
https://doi.org/10.1515/hc-2015-0141
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