Electrocatalytic and chemical methods in MHIRC reactions: The first example of the multicomponent assembly of medicinally relevant spirocyclopropylbarbiturates from three different molecules

Article abstract of DOI:10.1016/j.tet.2012.12.029

Electrolysis of aldehydes, barbituric acids, and malononitrile in alcohol in an undivided cell in the presence of sodium bromide results in efficient MHIRC formation of the corresponding spirocyclopropylbarbiturates in 50-65% substance yield. The electroc

Full text of DOI:10.1016/j.tet.2012.12.029

Accepted Manuscript
Electroсatalytic and chemical methods in MHIRC reactions: the first example of the
multicomponent assembly of medicinally relevant spirocyclopropylbarbiturates from
three different molecules
Anatolii N. Vereschagin, Michail N. Elinson, Evgeniya O. Dorofeeva, Nikita O.
Stepanov, Tatiana A. Zaimovskaya, Gennady I. Nikishin
PII:
S0040-4020(12)01871-6
10.1016/j.tet.2012.12.029
TET 23841
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 October 2012
Revised Date: 22 November 2012
Accepted Date: 11 December 2012
Please cite this article as: Vereschagin AN, Elinson MN, Dorofeeva EO, Stepanov NO, Zaimovskaya
TA, Nikishin GI, Electroсatalytic and chemical methods in MHIRC reactions: the first example of the
multicomponent assembly of medicinally relevant spirocyclopropylbarbiturates from three different
molecules, Tetrahedron (2013), doi: 10.1016/j.tet.2012.12.029.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
TETRAHEDRON
Pergamon
Electroсatalytic and chemical methods in MHIRC reactions: the first
example of the multicomponent assembly of medicinally relevant
spirocyclopropylbarbiturates from three different molecules
Anatolii N. Vereschagin a, Michail N. Elinson a,*, Evgeniya O. Dorofeeva a, Nikita O. Stepanov a,
Tatiana A. Zaimovskaya b, Gennady I. Nikishin a
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect 47, 119991 Moscow, Russia
bA. V. Topchiev Institute of Petrochemical Synthesis, Leninsky prospect 29, 119991 Moscow,
Russia
Abstract – Electrolysis of aldehydes, barbituric acids and malononitrile in alcohol in an undivided
cell in the presence of sodium bromide results in efficient MHIRC formation of the corresponding
spirocyclopropylbarbiturates in 50–65% substance yield. The electrocatalytic reaction smoothly
proceeds under neutral and mild conditions with aromatic aldehydes bearing both electron-donating
and electron-withdrawing groups. The implication of electrocatalysis in MHIRC reaction is an
efficient approach to medicinally relevant spirocyclopropylbarbiturates avoiding the inconvenient
direct use of molecular halogen or halogenated substrates.
1. Introduction
The discovery of new synthetic methodologies to facilitate the preparation of organic
compounds is a pivotal focal point of research activity in the field of modern organic, bioorganic
and medicinal chemistry.1
The cyclopropyl group is a vital structural unit in many synthetic and naturally occurring
compounds, exhibiting a wide spectrum of biologic properties ranging from enzyme inhibition to
herbicidal, antibiotic, antitumor and antiviral activities.2-4 The spirocyclopropyl moiety has also
attracted much attention due to its wide range of biological activities and pharmacological
properties.5
Pyrimidine-2,4,6-triones (barbiturates) belong to a widely-spread group of drugs used as
sedative, narcotic, anticonvulsant and antiepileptic agents.6 Currently, clinical applications of
barbiturates are expanding in connection with their anti-invasive, antitumor and antiangiogenic
effects.7 Spirobarbiturates have attracted special attention due to their unique structural assembly
and associated spectrum of biological properties.8 Thus, spirobarbiturates are known to exhibit
neuropharmacological effect9 and are inhibitors of MMP-1310 and dihydroorotate dehydrogenase
(DHODase)11.
___________________________________________________
Key words:
Spirocyclopropylbarbiturates
*Corresponding author. Tel. +7-499-137-38-42; Fax +7-499-135-53-28; e-mail address: elinson@ioc.ac.ru
Electrolysis; Electrocatalysis;
Aldehydes; Barbituric acids; Malononitrile;

ACCEPTED MANUSCRIPT
2
Moreover, the corresponding 1-phenyl-5,7-diazaspiro[2.5]octane-4,6,8-trione was patented
recently as TNF-α converting enzyme and matrix metalloproteinases inhibitor that was of
potential utility in a treatment of various inflammatory, infectious, immunological or malignant
diseases and conditions.12 Thus, the 5,7-diazaspiro[2.5]octane system appears to be of the interest
because it incorporates a spiro cyclopropane and a hexahydropyrimidine-2,4,6-trione heterocyclic
ring, which are both promising with respect to biological responses.
2. Results and Discussion
During the course of our studies on cascade and multicomponent reactions, we suggested a
new strategy to the cyclopropane ring structure by the chemical and electrocatalytic construction
of the functionally substituted cyclopropane ring13 from only CH-acids,14 activated olefins and
CH-acids,15 carbonyl compounds and CH-acids.16 The first synthesis of the cyclopropane
structure from three different molecules was also achieved by us as a multicomponent cascade
process in an electrocatalytic manner.17
One of our last results in this area was the cascade chemical transformation of
alkylidenemalononitriles and malononitrile into tetracyanosubstituted cyclopropanes realized
under the action of active halogen containing compounds in ethanol in the presence of bases
(Scheme 1).18 In this type of the reaction halogenation of the CH-acid was followed by a Michael
addition step, and is turned MHIRC – Michael Halogenation Initiated Ring Closure reaction by
analogy with MIRC - Michael Initiated Ring Closure reaction19 (Scheme 1).
R1
2
R
CN
CN
XHal
1
NC
NC
CN
CN
CN
CN
R
C
+
C
_
B
2
3
R
R OH,
O
N
X = I, Br,
Hal = I, Br
O
Scheme 1. Cascade transformation of alkylidenemalononitriles and malononitrile into
tetracyanosubstituted cyclopropanes.
In the present study we report our results on chemical and electrocatalytic use of MHIRC
reactions strategy in the synthesis of spirocyclopropylbarbiturates.
The first stage of our research was the direct ‘one-pot’ chemical cascade transformation of
benzylidenemalononitriles 1 and N,N′-dialkylbarbituric acids 2 into 5,7-dialkyl-4,6,8-trioxo-2-
phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles 3 (Scheme 2, Tables 1,2), by the action of

ACCEPTED MANUSCRIPT
3
bromine in ethanol in the presence of EtONa (Method A) for preliminary communication see Ref.
20.
R1
O
O
R2
O
R2
O
CN
CN
Br2
R2
O
NC
NC
R1
N
N
N
+
EtONa/EtOH
O
N
Method A
R2
1a-i
2a,b
a R = Me, b R=Et
3a-k
a R1 = H, b R1 = 4-Me, c R1 = 2-MeO,
d R1 = 4-t-Bu, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 3-Br, h R1 = 4-NO2, i R1 = 4-Cl
a R1 = H, R2 = Me; b R1 = 4-Me, R2 = Me; c R1 = 2-MeO, R2 = Me;
d R1 =4-t-Bu, R2 = Me; e R1 = 2-Cl, R2 = Me; f R1 = 3-Cl, R2 = Me;
g R1 =3-Br, R2 = Me; hR1 = 4-NO2, R2 = Me; i R1 = H, R2 = Et;
j R1 = 4-Me, R2 = Et; kR1 = 4-Cl, R2 = Et
Scheme 2. Cascade transformation of benzylidenmalononitriles 1 and barbituric acids 2 into
spirocyclopropylbarbiturates 3 (Method A).
To evaluate the synthetic potential of the Method
A
and to optimize
the conditions, the transformation of benzylidenemalononitrile 1a and N,N′-dimethylbarbituric
acid 2a into 5,7-dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3a
was studied (Table 1).
Table 1 Influence of EtONa quantity on the 5,7-dimethyl-4,6,8-trioxo-2-phenyl-
5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile 3a yield a
N
1
Quantity of EtONa (equivalents)
0.5
Yield of 3a b (%)
59
2
3
4
5
1.0
1.2
1.5
71
95
83
67
2.0
a 10 mmol of 1a, 10 mmol of 2a, 20 mL of EtOH, 0.5-2.0 equiv. of EtONa, 10 mmol of
bromine, time of the reaction – 3 hours.
b Isolated yields (isolation by filtration of the reaction mixture).
Excellent conversions of starting compounds and a 95% yield of 5,7-diazaspiro[2.5]octane-1,1-
dicarbonitrile 3a were obtained when the reaction was carried out in ethanol by the action of
bromine in the presence of 1.2 equivalents of EtONa (entry 3, Table 1). The increase in EtONa
quantity compared to 1.2 equivalents resulted in decrease of the reaction yield, which may be
connected with the activation of undesired base induced oligomerization processes of the starting
benzylidenemalononitile.21

ACCEPTED MANUSCRIPT
4
Under the optimal conditions found (bromine as active halogen compound, 1.2 equivalents of
EtONa as base, and ethanol as solvent), substituted benzylidenemalononitriles 1a-i and N,N′-
dialkylbarbituric acids 2a,b were transformed into the corresponding substituted 2-aryl-4,6,8-
trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitriles 3a-k in 75-95% yields (Table 2).
Table 2 Direct transformation of substituted benzylidenemalononitriles 1a-i and
N,N′-dialkylbarbituric acids 2a,b into substituted 2-aryl-4,6,8-trioxo-5,7-
diazaspiro[2.5]octane-1,1-dicarbonitriles 3a-k by the action of bromine a
Benzylidene-
malononitrile
Barbituric
acid
R1
R2
Product, yield b (%)
H
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
3a, 95
3b, 93
3c, 81
3d, 80
3e, 85
3f, 83
3g, 87
3h, 95
3i, 75
3j, 77
3k, 81
4-Me
2-MeO
4-t-Bu
2-Cl
3-Cl
3-Br
4-NO2
H
1g
1h
1a
1b
1i
4-Me
Et
4-Cl
Et
a 10 mmol of benzylidenemalononitrile, 10 mmol of barbituric acid, 20 mL of EtOH, 12 mmol of EtONa,
10 mmol of bromine, time of the reaction – 3 hours.
b Isolated yields (isolation by filtration of the reaction mixture).
But the reaction of benzylidenemalononitrile 1a and unsubstituted barbituric acid (2c R2=H)
under conditions of Method A resulted in the formation of 2-phenyl-4,6,8-trioxo-5,7-
diazaspiro[2.5]octane-1,1-dicarbonitrile 4a in the only 45% yield.
Recently we have also used direct action of the only bromine (Method B) for transformation
alkylidenemalononitriles and malononitrile into tetracyanosubstituted cyclopropanes
(Scheme 3).22
R1
2
R
CN
CN
1
Br2, (H2O)
NC
NC
CN
CN
R
CN
CN
+
C C
R2
o
EtOH, 40 C
Method B
Scheme 3. Cascade transformation of alkylidenemalononitriles and malononitrile into
tetracyanosubstituted cyclopropanes. (Method B).

ACCEPTED MANUSCRIPT
5
The reaction of benzylidenemalononitrile 1a and unsubstituted barbituric acid 2c under the
conditions of Method В resulted in formation of the corresponding spirocyclopropane 4a in
excellent 86% yield.
Under conditions of the Method B i.e. bromine as active halogen compound, and ethanol as
solvent substituted benzylidenemalononitriles 1a-g and barbituric acids 2c were transformed into
the corresponding spirocyclopropanes 4a-g in 84-93% yields (Scheme 4, Table 3).
R1
O
O
CN
Br2 (H2O)
EtOH, 40 oC
Method B
H
O
H
O
H
O
NC
NC
R1
N
N
N
+
CN
O
N
H
1a-g
2c
4a-g
a R1 = H, b R1 = 4-Me, c R1 = 2-MeO,
d R1 = 4-t-Bu, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 3-Br
a R1 = H, b R1 = 4-Me, c R1 = 2-MeO,
d R1 = 4-t-Bu, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 3-Br
Scheme 4. Cascade transformation of benzylidenmalononitriles 1 and barbituric acid 2c into
spirocyclopropylbarbiturates 4 (Method B).
Table 3 Direct transformation of substituted benzylidenemalononitriles 1a-g and
barbituric acid 2c into spirocyclopropanes 4a-g with the only bromine action
(Method B) a
Benzylidene-
malononitrile
Barbituric
acid
R1
R2
Product, yield b (%)
H
H
H
H
H
H
H
H
4a, 86
4b, 93
4c, 90
4d, 85
4e, 89
4f, 87
4g, 84
1a
1b
1c
1d
1e
1f
2c
2c
2c
2c
2c
2c
2c
4-Me
2-MeO
4-t-Bu
2-Cl
3-Cl
3-Br
1g
a
10 mmol of benzylidenemalononitrile, 10 mmol of barbituric acid, 20 mL of EtOH, 10 mmol of
bromine, time of the reaction – 3 hours.
b Isolated yields (isolation by filtration of the reaction mixture).
In the next stage of our investigation we sought to accomplish the multicomponent
transformation
of
benzaldehyde,
malononitrile
and
barbituric
acid
2a
into
spirocyclopropylbarbiturate 3a.

ACCEPTED MANUSCRIPT
6
In typical procedure benzaldehyde and malonitrile were stirred in ethanol in the presence of 0.3
equivalent of NaOAc for 30 min, then barbituric acid was added and either procedure Method A
or Method B was used. In both cases a complex mixture of compounds was found in the end of
the reaction (NMR-data). In the procedure with the Method A the mixture of
spirocyclopropylbarbiturate 3a (53%), together with 3-phenyl-1,1,2,2-tetracyanocyclopropane 5
(8%) and 1,1',3,3'-tetramethyl-5-phenyl-1,5-dihydro-2H,2'H-spiro[furo[2,3-d]pyrimidine-6,5'-
pyrimidine]-2,2',4,4',6'(1'H,3H,3'H)-pentone 6 (21%) was isolated in the end of the reaction.
When Method B was used the mixture of spirocyclopropylbarbiturate 3a (51%), 3-phenyl-
1,1,2,2-tetracyanocyclopropane 5 (10%) and 1,1',3,3'-tetramethyl-5-phenyl-1,5-dihydro-2H,2'H-
spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]-2,2',4,4',6'(1'H,3H,-3'H)-pentone
obtained.
6
(18%) was
Recently we have accomplished the combined electrolysis of benzylidenemalononitriles and
barbituric acids in methanol in an undivided cell in the presence of catalytic amounts of sodium
bromide as mediator which also results in efficient MHIRC formation of the corresponding
spirocyclopropylbarbiturates in 55–93% substance yield.23
R1
O
O
R2
O
R2
O
R2
O
CN
CN
NC
NC
electrolysis, 2 F/mol
R3OH, NaBr
N
N
R1
N
+
O
N
R2
Scheme 4. Electrocatalytic transformation of benzylidenmalononitriles and barbituric acids into
spirocyclopropylbarbiturates.
This electrocatalytic reaction smoothly proceeds under neutral and mild conditions without any
heating with benzylidenemalonotitriles bearing both electron-donating and electron-withdrawing
groups. The application of electrocatalysis in the MHIRC reaction strategy allowed the
combination of the synthetic virtues of both methods and accounted for an efficient approach to
medicinally relevant spirocyclopropylbarbiturates avoiding inconvenient direct use of molecular
halogen or halogenated substrates in accordance with concepts of green chemistry.23
Thus, on the next step of our research we used electrocatalytic methodology to realize
multicomponent transformation of benzaldehydes 7, malononitrile and barbituric acids 2 into
spirocyclopropylbarbiturates 3 (Scheme 5, Table 4).

ACCEPTED MANUSCRIPT
7
R1
O
O
O
R2
O
R2
O
R2
O
NC
NC
CN
CN
electrolysis, 2 F/mol
R3OH, NaOAc- NaBr
N
N
N
R1
+
+
O
N
R2
7a-i
2a,b
a R = Me, b R=Et
3a-k
a R1 = H, b R1 = 4-Me, c R1 = 2-MeO,
d R1 = 4-t-Bu, e R1 = 2-Cl, f R1 = 3-Cl,
g R1 = 3-Br, h R1 = 4-NO2, i R1 = 4-Cl
a R1 = H, R2 = Me; b R1 =4-Me, R2 = Me; c R1 = 2-MeO, R2 = Me;
d R1 =4-t-Bu, R2 = Me; e R1 = 2-Cl, R2 = Me; f R1 = 3-Cl, R2 = Me;
g R1 =3-Br, R2 = Me; hR1 = 4-NO2, R2 = Me; i R1 = H, R2 = Et;
j R1 =4-Me, R2 = Et; k R1 = 4-Cl, R2 = Et
Scheme 5. Electrocatalytic multicomponent transformation of benzaldehydes 7, malononitrile and
barbituric acids 2 into spirocyclopropylbarbiturates 3.
Table 4 Electrocatalytic multicomponent transformation of benzaldehydes 7a-i, malononitrile
and barbituric acids 2a,b into spirocyclopropylbarbiturates 3a-k a
Barbituric
acid
R1
R2
Product, yield b (%)
Aldehyde
H
7a
7b
7c
7d
7e
7f
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
3a, 62
3b, 65
3c, 51
3d, 63
3e, 57
3f, 56
3g, 52
3h, 50
3i, 57
3j, 59
3k, 53
4-Me
2-MeO
4-t-Bu
2-Cl
3-Cl
3-Br
4-NO2
H
7g
7h
7a
7b
7i
4-Me
4-Cl
Et
Et
a 5 mmol of aldehyde 7, 5 mmol of malononitrile, 5 mmol of barbituric acid 2, 3 mmol of NaOAc, 3 mmol
of NaBr, 20 mL of MeOH, Fe-cathode (5 cm2), C anode (5 cm2), 2 F/mol, 10 ºC.
b Isolated yields (isolation by filtration of the reaction mixture).
In typical electrocatalytic procedure a solution of aldehyde, and malononitrile in the presence
of NaOAc-NaBr mediatory system was stirred at room temperature for 30 min. Then, barbituric
acid was added and the reaction was electrolyzed in an undivided cell under constant current
density 100 mA/cm2 (I = 500 mA, electrodes square 5 cm2) at 10 ºC temperature
until 2 F/mol of electricity was passed (process time 32 min). Under these conditions in the all
experiments excellent conversion was found for all starting compounds. Increasing the

ACCEPTED MANUSCRIPT
8
temperature of the electrolysis to 20 ºC resulted in a slight decrease in the yields of the
spirocyclopropylbarbiturates 3. Under optimal conditions thus found spirocyclopropylbarbiturates
3 were isolated in 50-65% yields by the evaporation of reaction mixture to one fifth of the initial
volume and filtration.
Taking into consideration all results obtained and our previous results on the transformation of
benzylidenemalononitriles and malononitrile into substituted tetracyanocyclopropanes,18 the
following mechanism is proposed for chemical transformation of benzylidenemalononitriles 1 and
N,N′-dialkylbarbituric acids 2 into spirocyclopropylbarbiturates 3 by the action of bromine in
ethanol in the presence of EtONa (Method A) (Scheme 6).
O
R2
O
R2
N
N
O
_
R2
O
R2
O
CN
CN
O
B, -BH
R1
N
N
CN
+
EtOH
_
R1
CN
Br2
1
2
A
O
R1
R2
O
R2
N
N
O
R2
O
O
-HBr
NC
NC
N
EtOH
CN
Br
R1
O
N
R2
CN
3
8
Scheme 6. Mechanism of cascade transformation of benzylidenmalononitriles 1 and barbituric acids 2 into
spirocyclopropylbarbiturates 3 (Method A).
The first step involves Michael addition of N,N′-dialkylbarbituric acids 2 to the
benzylidenemalononitriles 1 in the presence of the EtONa to give anion A. Next, bromination of
anion A leads to substituted 2-aryl-1-bromo-2-(1,3-dialkyl-2,4,6-trioxohexahydropyrimidin-5-
yl)ethane-1,1-dicarbonitrile 8. Then, cyclization of 8 into substituted spirocyclopropylbarbiturate
3 in alcoholic solutions takes place in accordance with the earlier reported data (Scheme 4).18, 24 It
should be mentioned that the final step of the mechanism (Scheme 4) is similar to the final stage

ACCEPTED MANUSCRIPT
9
for the synthesis of 3-substituted tetracyanocyclopropanes synthesis reported by Mariella and
Roth.24
In the case of chemical transformation of benzylidenemalononitriles 1 and unsubstituted
barbituric acid 2c into spirocyclopropylbarbiturates 4 by the direct action of the bromine in
ethanol (Method B) another reaction mechanism takes place (Scheme 7).
O
O
H
O
H
O
H
O
H
O
N
N
N
N
Br2
+
Br
2c
9
R1
O
O
CN
H
H
O
N
N
R1
H
O
NC
NC
+
N
CN
O
O
N
H
1
Br
9
4
Scheme 7. Mechanism of cascade transformation of benzylidenmalononitriles 1 and barbituric acids 2c
into spirocyclopropylbarbiturates 4 (Method B).
In the absence of base (Method B), first bromination of barbituric acid 2c takes place leading
to the formation of 5-bromobarbituric acids 9 (Scheme 7). The bromobarbituric acid 9 is a
reasonably strong acid which could, by the analogy with bromomalononitrile,24-26 furnish a
sufficient
concentration
of
bromobarbituric
carbanions
for
the
addition
to
benzylidenemalononitrile 1 to form spirocyclopropylbarbiturate 4 by further cyclization.
The mechanism of the electrocalytic multicompanent transformation of aromatic
benzaldehydes 7, malononitrile and barbituric acids 2a,b into spirocyclopropylbarbiturates 3 in
alcohol in an undivided cell in the presence of the NaOAc-NaBr mediatory system is shown on
the Scheme 8.

ACCEPTED MANUSCRIPT
10
CN
CN
R1
O
NaOAc
R1
+
CN
CN
1
_
_
Br2
2 MeO
anode: 2 Br
2e
_
+ H2
cathode: 2 MeOH + 2e
O
O
R2
O
R2
R2
O
R2
_
MeO
N
N
N
N
+
+ MeOH
_
O
O
2
O
R2
O
R2
N
N
O
R2
O
R2
O
CN
O
N
N
R1
+
CN
CN
_
_
R1
1
CN
A
Br2
O
R1
R2
O
R2
N
N
O
R2
O
-HBr
NC
NC
N
EtOH
CN
Br
R1
O
N
R2
O
CN
3
Scheme 8. Mechanism of electrocatalytic multicomponent transformation of aldehydes, malononitrile and
barbituric acids 2 into spirocyclopropylbarbiturates 3.
In the first step the Knoevenagel condensation of malononitrile and aldehyde leading to the
formation of benzylidenemalononitrile 1 is catalyzed by NaOAc (Scheme 8). The formation of
bromine at the anode is a well-known process and the corresponding halogen colour was observed
at the anode when the electrolysis was conducted without stirring the reaction mixture. The

ACCEPTED MANUSCRIPT
11
deprotonation of methanol at the cathode as a result of the cathode process leads to the formation
of methoxide anion. The evolution of hydrogen at the cathode is observed, especially when
electrolysis is conducted without stirring of the reaction mixture. Reaction in solution between a
methoxide ion and barbituric acid 2 leads to the formation of a barbituric acid anion. Then,
addidition of anion of barbituric acid to benzylidenemalononitrile 1 results in formation of an
anion A. The following bromination of the anion A by the bromine generated at the anode and
final cyclization afford the formation of the spirocyclopropyl barbiturate 3.
3. Conclusion
In conclusion, the simple electrocatalytic system can produce under mild conditions direct
“one-pot” transformation of aldehydes, malononitrile, and barbituric acids into
spirocyclopropylbarbiturates in good yields as a result of a complex multicomponent process. The
electrocatalytic multicomponent and chemical cascade processes smoothly proceed with aromatic
aldehydes bearing both electron-donating and electron-withdrawing groups, and allow for the
selective and efficient one-step formation of spirocyclopropylbarbiturates which are a perspective
class of compounds with prominent pharmacological and physiological activity. This novel
process offers a facile and convenient way to create diversely substituted privileged
spirocyclopropylbarbiturates – the approved basis for the generation of small-molecule ligands
with different biomedical properties including pronounced neuropharmacological effect and
inhibition of dihydroorotate dehydrogenase (DHODase) and matrix metalloproteinases (MMP). In
the electrocatalytic process the necessity of bromine using in stochiometric quantities, which is
typical for these new chemical cascade processes, was changed for using catalytic quantities of
sodium bromide as mediator and the source of generated at anode bromine. The application of the
effective electrocatalytic multicomponent method to the formation of medicinally relevant
spirocyclopropylbarbiturates is also beneficial from the viewpoint of diversity-oriented large-scale
processes and represents novel, facile and environmentally benign synthetic concept for
multicomponent reaction strategy. The electrocatalytic procedure utilizes facile equipment, an
undivided cell, and requires simple and reasonable starting materials. It is easily carried out, and
the reaction products are directly crystallized from the reaction mixture. Therefore, this novel type
of cascade process brings us a step closer to the notion of “ideal synthesis”.27

ACCEPTED MANUSCRIPT
12
4. Experimental
4.1. General
All melting points were measured with a Gallenkamp melting point apparatus and are
uncorrected. 1H- and 13C NMR spectra were recorded with Bruker Avance II 300 spectrometers at
ambient temperature. Chemical shifts values are relative to Me4Si for DMSO-d6 and CDCl3
solutions. IR spectra were registered with a SPECORD M82 spectrometer in KBr pellets. Mass-
spectra (EI = 70 eV) were obtained directly with a Finningan MAT INCOS 50 spectrometer.
Aromatic aldehydes, barbituric acid and malononitrile were obtained from commercial sources
and were used without further purification. Benzylidenemalononitriles were obtained as follows:
to a 30 mL ethanol solution of aromatic aldehyde (0.1 mol) and malononitrile (6.6 g, 0.1 mol) in
50 mL flask, 0.41 g (0.005 mol) of NaOAc was added. The mixture was refluxed for 30 min.
Then 15 mL of ethanol was evaporated under reduce pressure and the residue was frozen at
−10 °C for 30 min. The solid phase was filtered, washed with 10 mL of cold ethanol and dried to
isolate benzylidenemalononitriles 1 in 85-95% yields.
4.2. Typical procedures for cascade transformation of benzylidenemalononitriles and
barbituric acids
4.2.1. Method A. Elemental bromine, sodium ethoxide
To a 10 mL ethanol suspension of benzylidenemalononitrile 1 (10 mmol) and barbituric acid
2 (10 mmol) in a 50 ml beaker, 0.82 g (12 mmol) of sodium ethoxide in 10 mL of ethanol was
added over 1 min. Then 10 mmol (0.51 mL) of bromine was added over 1 min without external
cooling. The mixture was magnetically stirred for 3 h, then cooled at −10 °C for 30 min and the
solid phase was filtered, washed with cold ethanol and dried to afford pure
spirocyclopropylbarbiturate.
4.2.2. Method B. Bromine water
To suspension of benzylidenemalononitrile 1 (5 mmol) and barbituric acid 2c (5 mmol) in
ethanol (15 mL) in a 50 ml three-necked flask, bromine in water (5 mmol, 25 mL, 0.2 M) was
added during 1 min. The mixture was magnetically stirred at 40 ºC for 1 h, then cooled to 0 °C for
1 h and the solid phase was filtered off, washed with cold ethanol and dried to isolate pure
spirocyclopropylbarbiturate.

ACCEPTED MANUSCRIPT
13
4.3. Typical procedure for multicomponent cascade transformation of aromatic aldehydes
malononitrile and barbituric acids
4.3.1. Method A. Elemental bromine, sodium ethoxide
A solution of benzaldehyde 7 (1.06 g, 10 mmol), malononitrile (0.66 g, 10 mmol) and sodium
acetate (0.25 g, 3 mmol) in ethanol (10 mL) was stirred for 30 minutes in a 50 mL beaker at
ambient temperature. Then barbituric acid 2 (10 mmol) was added. Later 0.82 g (12 mmol) of
sodium ethoxide in 10 mL of ethanol was added over 1 min. Subsequently 10 mmol (0.51 mL) of
bromine was added over 1 min without external cooling. The mixture was magnetically stirred for
3 h, then cooled at −10 °C for 30 min and the solid phase was filtered, washed with cold ethanol,
dried and analyzed by NMR-spectroscopy.
4.3.2. Method B. Bromine water
A solution of benzaldehyde 7 (0.53 g, 5 mmol), malononitrile (0.33 g, 5 mmol) and sodium
acetate (0.25 g, 3 mmol) in ethanol (15 mL) was stirred in 50 mL three-necked flask at ambient
temperature. Then barbituric acid 2 (5 mmol) was added. Subsequently (0.80 g, 5 mmol, 25 ml of
0.2 M bromine in water) were added during 1 min. The mixture was magnetically stirred at
40 ºC for 1 h, and then cooled at 0 °C for 1 h and the solid phase was filtered off, washed with
cold ethanol, dried and analyzed by NMR-spectroscopy.
4.3.3. Method C. Electrolysis procedure
A solution of aromatic aldehyde 7 (5 mmol), malonotitrile (0.33 g, 5 mmol), sodium acetate
(0.25 g, 3 mmol) and sodium bromide (0.31 g, 3 mmol) in 20 mL of methanol was stirred for 30
minutes. After this time, the reaction mixture was cooled to 10 oC and barbituric acid 2 (5 mmol)
was added. The reaction mixture was electrolyzed in an undivided cell equipped with a magnetic
stirrer, a graphite anode and an iron cathode at 10 ºC under a constant current density of
100 mA/cm2 (I = 500 mA, electrodes square 5 cm2) until 2 F /mol of electricity was passed
(process time 32 min). After the electrolysis was finished, the reaction mixture was gently
concentrated to one fifth of initial volume (ca. 4 mL) to crystallize the solid product, which was
then filtered, rinsed with an ice-cold methanol (2 × 2 mL), and dried under reduced pressure to
isolate pure spirocyclopropylbarbiturate.
4.4. 5,7-Dimethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3a). White
solid; mp: 259-260 °C (lit.20 mp: 259-260 °C); δH (300 MHz, DMSO-d6) 3.12 (s, 3H, CH3), 3.28
(s, 3H, CH3), 4.36 (s, 1H, CH), 7.32-7.40 (m, 3H, Ph), 7.44-7.50 (m, 2H, Ph).

ACCEPTED MANUSCRIPT
14
4.5. 5,7-Dimethyl-2-(4-methylphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3b). White solid; mp: 203-204 °C (lit.23 mp: 203-204 °C); δH (300 MHz, DMSO-d6) 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).
4.6. 2-(2-Methoxyphenyl)-5,7-Dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3c). White solid; mp: 229-230 °C (lit.20 mp: 229-230 °C); δH (300 MHz, DMSO-d6) 3.14 (s, 3H,
CH3), 3.30 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.01 (s, 1H, CH), 6.96-7.08 (m, 2H, Ar), 7.36-7.42
(m, 2H, Ar).
4.7. 2-(4-tert-Butylphenyl)-5,7-Dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonit-
rile (3d). White solid; mp: 218-219 °C (lit.23 mp: 218-219 °C); δH (300 MHz, DMSO-d6) 1.28 (s,
9H, CH3), 3.12 (s, 3H, CH3), 3.26 (s, 3H, CH3), 4.28 (s, 1H, CH), 7.17 (d, J 7.8 Hz, 2H, Ar), 7.40
(d, J 7.8 Hz, 2H, Ar).
4.8. 2-(2-Chlorophenyl)-5,7-Dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3e). White solid; mp: 255-256 °C (lit.23 mp: 255-256 °C); δH (300 MHz, DMSO-d6) 3.15 (s, 3H,
CH3), 3.38 (s, 3H, CH3), 4.32 (s, 1H, CH), 7.36-7.45 (m, 2H, Ar), 7.52-7.58 (m, 2H, Ar).
4.9. 2-(3-Chlorophenyl)-5,7-Dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3f). White solid; mp: 201-203 °C; [Found C 55.91, H 3.27, Cl 10.23, N 16.29; C16H11ClN4O3
requires C 56.07, H 3.23, Cl 10.34, N 16.35]; νmax (KBr): 2248, 1704, 1680, 1456, 1424, 1384,
1300, 756 cm-1; MS, m/z (%): 344 (2, M+, C137), 342 (6, M+, C135), 307 (10), 228 (28), 200 (32),
193 (16), 165 (100), 138 (22), 75 (28), 56 (77); δH (300 MHz, DMSO-d6) 3.15 (s, 3H, CH3), 3.38
(s, 3H, CH3), 4.39 (s, 1H, CH), 7.38-7.44 (m, 2H, Ar), 7.46-7.54 (m, 1H, Ar), 7.64-7.66 (m, 1H,
Ar); δC (75 MHz, DMSO-d6) 23.6, 28.6, 29.0, 41.3, 42.6, 110.6, 112.1, 127.9, 128.2, 129.2, 129.9,
131.0, 132.7, 150.9, 160.5, 162.7.
4.10. 2-(3-Bromophenyl)-5,7-Dimethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3g). White solid; mp: 220-222 °C (lit.23 mp: 220-222 °C); δH (300 MHz, DMSO-d6) 3.12 (s, 3H,
CH3), 3.28 (s, 3H, CH3), 4.39 (s, 1H, CH), 7.35 (t, 1H, J 7.9 Hz, Ar), 7.50-7.57 (m, 2H, Ar), 7.77-
7.79 (m, 1H, Ar).
4.11. 5,7-Dimethyl-2-(4-nitrophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3h). Yellow solid; mp: 219-221 °C (lit.23 mp: 219-221 °C); δH (300 MHz, 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).

ACCEPTED MANUSCRIPT
15
4.12. 5,7-Diethyl-4,6,8-trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (3i). White
solid; mp: 186-188 °C (lit.20 mp: 186-188°C); δH (300 MHz, DMSO-d6) 1.18 (t, J 7.0 Hz, 3H,
CH3), 1.33 (t, J 7.0 Hz, 3H, CH3), 3.95 (dq, J1 7.1 Hz, J2 1.3 Hz, 2H, CH2), 4.10 (q, J 7.0 Hz, 2H,
CH2), 4.29 (s, 1H, CH), 7.22-7.32 (m, 2H, Ar), 7.36-7.46 (m, 3H, Ar).
4.13. 5,7-diethyl-2-(4-methylphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3j). White solid; mp: 196-198 °C; [Found C 65.01, H 5.25, N 15.83; C19H18N4O3 requires C
65.13, H 5.18, N 15.99]; νmax (KBr): 2248, 1704, 1684, 1456, 1444, 1416, 1376 cm-1; MS, m/z
(%): 279 (4, M+ - O=C-N-Et), 251 (10), 208 (78), 180 (100), 165 (58), 153 (39), 140 (28), 115
(36), 91 (30), 70 (93); δH (300 MHz, CDCl3) 1.18 (t, J 7.2 Hz, 3H, CH3), 1.34 (t, J 7.2 Hz, 3H,
CH3), 2.38 (s, 3H, CH3), 3.95 (dq, J1 7.2 Hz, J2 1.3 Hz, 2H, CH2), 4.10 (q, J 7.2 Hz, 2H, CH2),
4.25 (s, 1H, CH), 7.18 (d, J 7.9 Hz, 2H, Ar), 7.28 (d, J 7.9 Hz, 2H, Ar); δC (75 MHz, DMSO-d6)
12.5, 12.6, 20.7, 23.4, 36.9, 37.5, 41.4, 43.8, 110.9, 112.4, 125.5, 128.7 (2C), 129.1 (2C), 137.6,
149.9, 160.1, 162.5.
4.14. 2-(4-Chlorophenyl)-5,7-diethyl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile
(3k). White solid, mp: 209-210 °C (lit.23 mp: 209-210 °C); δH (300 MHz, DMSO-d6) 1.19 (t, J 7.1
Hz, 3H, CH3), 1.32 (t, J 7.1 Hz, 3H, CH3), 3.96 (q, J 7.1 Hz, 2H, CH2), 4.05-4.15 (m, 2H, CH2),
4.25 (s, 1H, CH), 7.25 (d, J 7.3 Hz, 2H, Ar), 7.41 (d, J 7.3 Hz, 2H, Ar).
4.15. 4,6,8-Trioxo-2-phenyl-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4a). White solid; mp:
274-276 °C (lit.23 mp: 274-276 °C); δH (300 MHz, DMSO-d6) 4.23 (s, 1H, CH), 7.34-7.46 (m, 5H,
Ph), 11.66 (s, 1H, NH), 11.88 (s, 1H, NH).
4.16. 2-(4-methylphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4b). White
solid; mp: 278-279 °C; [Found C 61.09, H 3.51, N 18.87; C15H10N4O3 requires C 61.22, H 3.43, N
19.04]; νmax (KBr): 3264, 2256, 1736, 1704, 1684, 1404, 1368 cm-1; MS, m/z (%): 294 (100, M+),
277 (13), 249 (9), 208 (8), 181 (11), 165 (37), 139 (17), 104 (18), 91 (40), 57 (20); δH (300 MHz,
DMSO-d6) 2.30 (s, 3H, CH3), 4.16 (s, 1H, CH), 7.16 (d, J 8.0 Hz, 2H, Ar), 7.33 (d, J 8.0 Hz, 2H,
Ar), 11.66 (s, 1H, NH), 11.88 (s, 1H, NH); δC (75 MHz, DMSO-d6) 20.9, 22.5, 40.7, 43.2, 111.1,
112.6, 125.6, 128.9 (2C), 129.3 (2C), 137.8, 150.3, 161.9, 164.4.
4.17. 2-(2-Methoxyphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4c). White
solid; mp: 268-269 °C (lit.23 mp: 269 °C); δH (300 MHz, DMSO-d6) 3.72 (s, 3H, CH3), 3.86 (s,
1H, CH), 6.95-7.05 (m, 2H, Ar), 7.33-7.40 (m, 2H, Ar), 11.83 (br s, 2H, NH).
4.18. 2-(4-tert-Butylphenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4d). White
solid; mp: 286-288 °C; [Found C 64.13, H 4.68, N 16.49; C18H16N4O3 requires C 64.28, H 4.79, N
16.66]; νmax (KBr): 3264, 2256, 1736, 1704, 1684, 1404, 1368 cm-1; MS, m/z (%): 336 (31, M+),

ACCEPTED MANUSCRIPT
16
321 (79), 272 (37), 257 (100), 215 (19), 195 (76), 128 (38), 91 (64), 66 (63), 57 (80); δH (300
MHz, DMSO-d6) 1.28 (s, 9H, CH3), 4.17 (s, 1H, CH), 7.26 (d, J 7.8 Hz, 2H, Ar), 7.33 (d, J 7.8
Hz, 2H, Ar), 11.66 (s, 1H, NH), 11.89 (s, 1H, NH); δC (75 MHz, DMSO-d6) 22.3, 31.1 (3C), 34.3,
40.6, 43.0, 111.0, 112.5, 125.0 (2C), 125.7, 129.0 (2C), 150.1, 150.6, 161.8, 164.3.
4.19. 2-(2-Chlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4e). White
solid; mp: 266-267 °C (lit.23 mp: 266-267 °C); δH (300 MHz, DMSO-d6) 4.17 (s, 1H, CH), 7.36-
7.44 (m, 2H, Ar), 7.50-7.62 (m, 2H, Ar), 11.84 (s, 1H, NH), 12.08 (s, 1H, NH).
4.20. 2-(3-Chlorophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4f). White
solid; mp: 274-275 °C; [Found C 53.31, H 2.28, Cl 11.09, N 17.67; C14H7ClN4O3 requires C
53.43, H 2.24, Cl 11.27, N 17.80]; νmax (KBr): 3264, 2256, 1736, 1704, 1684, 1404, 1368 cm-1;
MS, m/z (%): 316 (8, M+, Cl37), 314 (25, M+, Cl35), 280 (8), 273 (8), 271 (8), 250 (20), 200 (30),
165 (100), 138 (27), 89 (17), 75 (26); δH (300 MHz, DMSO-d6) 4.25 (s, 1H, CH), 7.36-7.55 (m,
3H, Ar), 7.68 (br s, 1H, Ar), 11.71 (s, 1H, NH), 11.89 (s, 1H, NH); δC (75 MHz, DMSO-d6) 22.7,
40.6, 41.7, 110.8, 112.3, 128.1, 128.3, 129.5, 130.0, 131.2, 132.7, 150.3, 162.0, 164.1.
4.21. 2-(3-Bromophenyl)-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-dicarbonitrile (4g). White
solid; mp: 251-252 °C (lit.23 mp: 252 °C); δH (300 MHz, DMSO-d6) 4.24 (s, 1H, CH), 7.33 (t, J
7.8 Hz, 1H, Ar), 7.51-7.54 (m, 2H, Ar), 7.80 (s, 1H, Ar), 12.70 (br s, 2H, NH).
Acknowledgments
This work was supported by the Presidential Scholarship Program for the State Support of young
Russian scientists – PhD (project no. MK-387.2012.3).
References and Notes
1
(a) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324–337; (b) Nefzi, A.; Ostresh, J.
M.; Houghten, R. A. Chem. Rev. 1997, 97, 449–472.
2.
(a) Yanovskaya, L. A.; Dombrovsky, V. A.; Khusid A. Kh. Tsiklopropani s funktsionalnimi
gruppami. Sintez i primenenie. (Cyclopropanes with Functional Groups. Synthesis and
Application), Nauka, Moscow, 1980; (b) Tsuji, T; Nishida, S. The Chemistry of the
Cyclopropyl Group; ed. Wiley and Sons: New York, 1987; (c) Boche, G.; Walbirsky, H. M.
Cyclopropane Derived Intermediates, John Wiley and Sons: New York, 1990; (d)
Rappoport, Z. The Chemistry of the Cyclopropyl Group; Wiley and Sons: New York, 1996.
3.
(a) Graham, D. W.; Ashton, W. T.; Barash, L.; Brown, J. E.; Brown R. D.; Canning, L. F.;
Chen, A.; Springer, J. P.; Rogers, E. F. J. Med. Chem. 1987, 30, 1074–1090; (b) Salaun, J.;
Baird, M. S. Curr. Med. Chem. 1995, 2, 511–519; (c) Baba, Y.; Saha, G.; Nakao, S.; Iwata,
C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81–88; (d)
Boger, D. L.; Hughes, T. V.; Hedrick M. P. J. Org. Chem. 2001, 66, 2207–2216; (e)
Yoshida, S.; Rosen, T. C.; Meyer O. G. J.; Sloan M. J.; Ye, S.; Haufe, G.; Kirk, K. L.

ACCEPTED MANUSCRIPT
17
Bioorg. Med. Chem. 2004, 12, 2645-2652; (f) Yamaguchi, K.; Kazuta, Y.; Hirano, K.;
Yamada, S.; Matsuda, A.; Shuto, S. Bioorg. Med. Chem. 2008, 16, 8875-8881.
4.
5.
For reviews see: (a) Faust, R. Angew. Chem., Int. Ed. 2001, 40, 2251-2253; (b) Donaldson,
W. A. Tetrahedron 2001, 57, 8589–8627; (c) Reissig, H. U.; Zimmer, R. Chem. Rev. 2003,
10, 1151-1150; (d) Brandt, W.; Thiemann, T. Chem. Rev. 2003, 103, 1625-1647.
(a) Mokrosz, J. L. Pharmazie 1985, 40, 359-360; (b) Kinder, F. R.; Wang, R.; Bauta, W. E.;
Bair, K. W. Bioorg. Med. Chem. Lett. 1996, 6, 1029-1032; (c) Sandanyaka, V. P.; Prashad,
A. S.; Yang, Y.; Williamson, R. T.; Lin, Y.; Mansour, T. S. J. Med. Chem. 2003, 46, 2569-
2571; (d) Dundee, J. W.; Mcilroy, P. D. A. Anaestesia 2007, 37, 726-734; (e) Lomlin, L.;
Einsiedel, J.; Heinemann, F. W.; Meyer, K.; Gmeiner, P. J. Org. Chem. 2008, 73, 3608-
3611.
6
7
(a) Brunton, L. L.; Lazo, J. S.; Lazo, P.; Keith, L. Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 11th Edition, McGraw–Hill, 2006. (b) Johns, M.
W. Drugs, 1975, 9, 448-78; (c) Naguib, F. N. M.; Levesque, D. L.; Wang, E.-C.; Panzica P.
P.; El Kouni, M. H.; Biochem. Pharmacol. 1993, 46, 1273-1278; (d) Grams, F.;
Brandstetter, H.; D’Alo, S.; Gepperd D.; Krel H.-W.; Leinert, H.; Livi V.; Menta, E.; Oliva,
A.; Zimmermann G. Biol. Chem. 2001, 382, 1277-1275; (e) Uhlmann, C.; Froscher, W.
CNS Neurosci. Therapeutics 2009, 15, 24-31.
(a) Maquoi, E.; Sounni, N. E.; Devy, L.; Olivier, F.; Frankenne, F.; Krell, H.-W.; Grams,
F.; Foidart, J.-M.; Noel, A Clinical Cancer Research 2004, 10, 4038-4047; (b) Breyholz,
H.-J.; Wagner, S.; Faust, A.; Riemann, B.; Hoeltke, C.; Hermann, S.; Schober, O.; Schafers,
M.; Kopka K. Chem. Med. Chem. 2010, 5, 777-789; (c) Bartsch, P.; Cataldo, D.; Endele,
R.; Evrard, B.; Foidart, J.-M.; Krell, H.-W.; Zimmermann, G. Int. Appl. No. PCT EP, 2005,
003348.
8.
9
(a) King, S. B.; Stratford, E. S.; Craig, C. R.; Fifer, E. K. Pharmaceutical Research 1995,
12, 1240-1243; (b) Prankerd, R. J.; Mckeown, R. H. Int. J. Pharm. 1992, 83, 39-45.
Galati, E. M.; Monforte, M. T.; Miceli, N.; RaneriIl, E Farmaco 2001, 56, 459-461.
10 Kim, S.-H.; Pudzianowski, A. T.; Leavitt, K. J.; Barbosa, J.; McDonnell, P. A.; Metzler, W.
J.; Rankin, B. M.; Liu, R.; Vaccaro, W.; Pitts, W. Bioorg. Med. Chem. Lett., 2005, 15,
1101-1106.
11 Fraser, W.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc. Perkin Trans. 1, 1990, 3137-
3144.
12 Duan, J.; Jiang, B.; Chen, L.; Lu, Z.; Barbosa, J.; Pitts, W. J. US Pat. Appl. 2003, 0229084.
13. Elinson, M. N.; Feducovich, S. K.; Lizunova, T. L.; Nikishin, G. I. Elektrokhimiya 1996, 32,
42-52.
14. (a) Nikishin, G. I; Elinson, M. N.; Feducovich, S. K. Izv. Akad. Nauk SSSR Ser. Khim. 1986,
1919–1920; (b) Elinson, M. N.; Lizunova, T. L.; Dekaprilevich, M. O; Struchkov, Yu. T.;
Nikishin, G. I. Mendeleev Commun. 1993, 192–193; (c) Feducovich, S. K.; Elinson, M. N.;
Nikishin, G. I. Izv. Akad. Nauk Ser. Khim. 1994, 1835-1836.
15. (a) Elinson, M. N.; Feducovich, S. K.; Zakharenkov, A. A.; Bushuev, S. G.; Pashchenko,
D. V.; Nikishin, G. I. Mendeleev Commun. 1998, 15–17; (b) Elinson, M. N.; Feducovich, S.
K.; Starikova, Z. A.; Olessova, O. S.; Vereshchagin, A. N.; Nikishin, G. I. Tetrahedron Lett.
2000, 41, 4937-4941; (c) Elinson, M. N.; Feducovich, S. K.; Starikova, Z. A.; Vereshchagin,
A. N.; Gorbunov, S. V.; Nikishin, G. I. Tetrahedron Lett. 2005, 46, 6389–6393; (d) Elinson,
M. N.; Feducovich, S. K.; Starikova, Z. A.; Vereshchagin, A. N.; Belyakov, P. A.; Nikishin,
G. I. Tetrahedron, 2006, 62, 3989-3996.
16. (a) Elinson, M. N.; Feducovich, S. K.; Lizunova, T. L.; Nikishin, G. I. Tetrahedron 2000,
56, 3063–3069; (b) Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.; Vereshchagin,

ACCEPTED MANUSCRIPT
18
A. N.; Nikishin, G. I. Izv. Akad. Nauk Ser. Khim. 2005, 663–667; (c) Vereshchagin, A. N.;
Elinson, M. N.; Zaimovskaya, T. A.; Nikishin, G. I. Tetrahedron 2008, 64, 9766-9770.
17. Elinson, M. N.; Feducovich, S. K.; Vereshchagin, A. N.; Gorbunov, S. V.; Belyakov, P. A.;
Nikishin, G. I Tetrahedron Lett. 2006, 47, 9129-9133.
18. Elinson, M. N.; Feducovich, S. K.; Stepanov, N. O.; Vereshchagin, A. N.; Nikishin, G. I.
Tetrahedron 2008, 64, 708-713.
19. (a) Little, R. D.; Dawson, J. R. J. Am. Chem. Soc. 1978, 100, 4607-4609; (b) Little, R. D.;
Dawson, J. R. Tetrahedron Lett. 1980, 21, 2609-2612. For review see: (c) Zwannenburg, B.;
De Kimpe, N. In Methods of Organic Chemistry (Houben–Weyl), Vol. E.17A Carbocyclic
Three-Membered Ring Compounds (Ed. de Meijere, A.), 4th ed., Thieme: Stuttgart, 1997,
45–105; d) Caine, D. Tetrahedron 2001, 57, 2643-2684.
20. Elinson, M. N.; Vereshchagin, A. N.; Stepanov, N. O.; Belyakov, P. A.; Nikishin, G. I.
Tetrahedron Lett. 2010, 51, 6598-6601.
21. (a) Freeman, F. Chem. Rev. 1969, 69, 591-624; (b) Fatiadi, A. J. Synthesis 1978, 165-204.
22. Vereshchagin, A. N.; Elinson, M. N.; Stepanov N. O.; Nikishin G. I. Mendeleev Commun.
2009, 19, 324-325.
23. 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 Advances, 2012, 4444-4452.
24. Mariella, R. P.; Roth, A. J. J. Org. Chem. 1957, 22, 1130-1133.
25. Pearson, R. G.; Dillon, R. L. J. Amer. Chem. Soc. 1953, 75, 2439-2443.
26. Hart, H.; Kim, Y. C. J. Org. Chem. 1966, 31, 2784-2789.
27. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. (London) 1997, 765-769.

ACCEPTED MANUSCRIPT
19
Electroсatalytic and chemical methods in
MHIRC reactions: the first example of the
multicomponent assembly of medicinally
relevant spirocyclopropylbarbiturates from
three different molecules
Anatolii N. Vereschagin, Michail N. Elinson, Evgeniya O. Dorofeeva, Nikita O. Stepanov,
Tatiana A. Zaimovskaya, Gennady I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Leninsky pr. 47, 119991 Moscow, Russia
R1
O
O
O
R2
O
R2
O
R2
O
CN
CN
N
N
NC
NC
R1
+
+
N
O
N
R2
55-65%