Electrocatalytic and chemical assembling of N,N′-dialkylbarbituric acids and aldehydes: Efficient cascade approach to the spiro-[furo[2,3-d] pyrimidine-6,5′-pyrimidine]-2,2′,4,4′,6′-(1′H,3H, 3′H)-pentone framework

Article abstract of DOI:10.1016/j.tet.2011.11.057

Electrocatalytic assembling of aldehydes and N,N′-dialkylbarbituric acids leads to selective and efficient formation of substituted 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)-pentones in 70-85% yields as a r

Full text of DOI:10.1016/j.tet.2011.11.057

Tetrahedron 68 (2012) 1198e1206
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electrocatalytic and chemical assembling of N,N0-dialkylbarbituric acids
and aldehydes: efficient cascade approach to the spiro-[furo[2,3-d]pyrimidine-6,
50-pyrimidine]-2,20,4,40,60-(10H,3H,30H)-pentone framework
,
a
b
Anatolii N. Vereshchagin a, Michail N. Elinson a , Evgeniya O. Dorofeeva , Tatiana A. Zaimovskaya ,
*
Nikita O. Stepanov a, Sergey V. Gorbunov a, Pavel A. Belyakov a, Gennady I. Nikishin a
a N. D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect 47, 119991 Moscow, Russia
b A. V. Topchiev Institute of Petrochemical Synthesis, Leninsky Prospect 29, 119991 Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Electrocatalytic assembling of aldehydes and N,N0-dialkylbarbituric acids leads to selective and efficient
formation of substituted 1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-
(10H,3H,30H)-pentones in 70e85% yields as a result of the complex cascade process. The electrocatalytic
process smoothly proceeds with aromatic aldehydes bearing both electron-donating and electron-
withdrawing groups, and allows for the selective and efficient one-step formation of spirobarbiturates
containing furo[2,3-d]pyrimidine scaffold, which are a perspective class of compounds with prominent
pharmacological and physiological activity. The application of the effective electrocatalytic cascade
method to the formation of medicinally relevant spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-
2,20,4,40,60-(10H,3H,30H)-pentones is also beneficial from the viewpoint of diversity-oriented large-scale
processes and represents a novel, facile and environmentally benign synthetic concept for electro-
catalytic cascade reaction strategy.
Article history:
Received 4 October 2011
Received in revised form 3 November 2011
Accepted 21 November 2011
Available online 26 November 2011
Keywords:
Cascade reactions
Electrocatalysis
Barbiturates
Aldehydes
Spirofuropyrimidines
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The discovery of novel synthetic methodologies to facilitate the
preparation of compound libraries is a pivotal focal point of re-
In recent years the concept of ‘privileged medicinal structures or
scaffolds’1 has emerged as one of the guiding principles in the drug
discovery process.2 It involves the use of molecular frameworks
with inherent potential for biological activity. Through appropriate
functional group modifications, these scaffolds are capable of pro-
viding ligands for a number of functionally and structurally discrete
biological receptors. Moreover, compound libraries designed on the
basis of such frameworks exhibit enhanced biological properties
and result in high-quality leads.
The recent structural analysis of more than 5000 commer-
cially available drugs revealed that the half of them incorporated
only 32 of the most frequently occurring molecular frameworks.3
These privileged scaffolds commonly consist of a rigid hetero ring
system that assigns well-defined orientation of appended func-
tionalities for target recognition. Thus, the accessibility of con-
venient methods for the diversification of privileged scaffold
functionalities impacts on the success of a search for potential
drugs.
search activity in the field of modern medicinal and combinatorial
chemistry.4 The continual upsurge in molecular complexity and
diversity in the natural and biologically relevant systems urges
chemists to increase the tools of their arsenal.
One powerful approach towards this goal involves combination
of two or more distinct reactions into a single transformation,
thereby producing cascade reactions as a sequential reaction pro-
cess. Cascade reactions have been utilized as powerful method to
construct molecular complexity from readily available starting
materials by combining two or more reactions into single trans-
formation.5 Thus, cascade reactions are of increasing importance in
modern organic chemistry. This is not only due to a need for more
efficient and less labour-intensive methodologies for the synthesis
of organic compounds, but also because of the increasing envi-
ronmental concerns. Thereby, cascade reactions have significant
economical and ecological benefits, when one performs several
synthetic steps in one operation without isolating the reaction in-
termediates. In addition to the intrinsic economy and selectivity
underlying such reactions, the cascade strategy offers significant
advantages over conventional linear-type synthesis due to its
flexible and convergent nature.6 The rapid assembly of molecular
diversity utilizing cascade reactions has received a great deal of
* Corresponding author. Tel.: þ7 499 137 38 42; fax: þ7 499 135 53 28; e-mail
address: elinson@ioc.ac.ru (M.N. Elinson).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.057

A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
1199
attention, especially for the design and construction of elaborate
heterocyclic frameworks possessing enhanced ‘drug-like’ proper-
ties.7 For example, Hantzsch,7c Ugi,7e,f and Biginelli8 cascade re-
actions are methods to prepare functionalized 1,4-dihydropyridine,
benzodiazepinedione and dihydropyrimidine privileged scaffolds,
respectively. Thus, the success of combinatorial chemistry in drug
discovery is considerably dependent on further advancement in
heterocyclic methodology and, according to current synthetic re-
quirements, environmentally benign cascade procedures that lead
to diversely functionalized heterocyclic privileged scaffolds are
particularly welcome.
The pyrimidinone moiety often appears as an important struc-
tural component in both biologically active and natural com-
pounds. Many pyrimidinone derivatives possess promising
therapeutic properties including anticancer, antiviral, central
stimulant and calcium antagonist activity.9
abbreviation of this type of the cyclopropane formation reaction
should be MHIRCdMichael Halogenation Initiated Ring Closure
reaction by the analogy with MIRCdMichael Initiated Ring Closure
reaction21 (Scheme 1).
R1
R1
R2
CN
CN
XHal
NC
NC
CN
CN
CN
+
R2
EtOH, B
CN
Hal = I, Br
X = I, Br,
O
N
O
Scheme 1. Cascade transformation of alkylidenemalononitriles and malononitrile into
tetracyanosubstituted cyclopropanes.
The 2,4,6(1H,3H,5H)-pyrimidinetriones, also called barbiturates
(derivatives of barbituric acid), are the famous 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.10 They are also effective as anxiolytics and as anti-
convulsants.10a,11 Phenobarbital is the most widely used anticon-
vulsant and the oldest still in use.12 The current interest in
barbiturates arises from their pharmacological potential as ana-
leptics, immunomodulating and anti-AIDS agents, as well as anti-
cancer remedies.13
Recently we have found the first example of the cascade as-
sembling of a spirocyclopropane structure: direct transformation of
benzylidenemalononitriles and N,N0-dialkylbarbituric acids into
substituted
2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitriles22 (Scheme 2).
R1
O
O
R2
R1
N
N
O
CN
Br2
Among 2,4,6(1H,3H,5H)-pyrimidinetriones, spirobarbiturates
are a perspective class of compounds with pronounced pharma-
cological and physiological activity.14
+
O
NC
NC
R2
O
EtONa/ EtOH
N
CN
R2
O
N
R2
2. Results and discussion
Scheme 2. Cascade transformation of benzylidenemalononitriles and N,N0-dia-
lkylbarbituric acids into substituted 2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitriles.
During the course of our studies into cascade and multicom-
ponent reactions, we suggested a new strategy to the cyclopropane
ring structure by the chemical and electrocatalytic construction of
the functionally substituted cyclopropane ring15 from only CH-
acids,16 activated olefins and CH-acids,17 carbonyl compounds and
CH-acids.18 The first synthesis of the cyclopropane structure from
three different molecules was also achieved by us as multicompo-
nent cascade process in an electrocatalytic manner.19
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).20 In this type of the reaction halogenation of the
CH-acid was followed by a Michael addition step, thus the
In the present study we report our results on the cascade re-
action of benzylidenebarbituric acids 1aem and N,N0-dia-
lkylbarbituric acids 2a,b. This process results in formation of 1,5-
dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-
2,20,4,40,60(10H,3H,30H)-pentones 3aem (Scheme 3, Tables 1 and 2).
First, toevaluatethesyntheticpotentialoftheprocedureproposed,
and to optimize the general conditions, the cascade transformation of
benzylidene[N,N0-dimethylbarbituric acid] 1a and N,N0-dime-
thylbarbituric acid 2a into the corresponding 1,10,3,30-tetramethyl-5-
phenyl-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimi-
dine]-2,20,4,40,60(10H,3H,30H)-pentone 3a was studied by the action of
bromine in ethanol in the presence of EtONa as base (Table 1).
R1
O
O
O
R2
O
R1
R2
R2
O
N
O
R2
Method A or B
N
N
+
O
N
N
O
O
N
N
O
O
R2
N
R2
R2
O
2 a,b
R2
a R2 = Me, b R2 = Et
1 a-m
3 a-m
a R1 = H, R2 = Me; b R1 = Me, R2 = Me; c R1 = 4-t-Bu, R2 = Me; d R1 = 2-MeO, R2 = Me; e R1 = 4-MeO, R2 = Me; f R1 = 2-Cl, R2 = Me;
g R1 = 3-Cl, R2 = Me; h R1 = 4-Cl, R2 = Me; i R1 = 3-Br, R2 = Me; j R1 = 4-NO2, R2 = Me; k R1 = H, R2 = Et; l R1 = 4-Me, R2 = Et;
m R1 = 4-NO2, R2 = Et
Method A: 1. EtONa / EtOH; 2. Br2; 3 h, r.t.
Method B: 0.2 M Br2 in water, EtOH; 1 h, 40oC
Scheme 3. Cascade transformation of benzylidenebarbituric acids 1aem and N,N0-dialkylbarbituric acids 2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pen-
tones 3aem.

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A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones 3aem in
82e95% yields (method A Table 2).
Table 1
Cascade transformation of benzylidene[N,N0-dimethylbarbituric acid] 1a, and N,N0-
dimethylbarbituric acid 2a into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pen-
tone 3aa
Recently we have found a new type of conditions that exclude
a use of base (EtONa) in the cascade synthesis of tetracyanocyclo-
propanes from benzylidenemalononitriles and malononitrile.23 This
process was accomplished byonly bromine direct action.23 Thus, the
next step of our research was the investigation of spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]pentones 3aem formation from ben-
zylidenebarbituric acids 1aem and N,N0-dialkylbarbituric acids 2a,b
by the only bromine direct action (method B, Scheme 3; Table 2). The
yields of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones
3aem in the procedure under the conditions of the method B were
generally slightly lower, namely in the range of 73e90%.
Entry
Quantity of EtONa (equiv)
Yield of 3ab (%)
1
2
3
4
5
0.5
1.0
1.2
1.5
2.0
67
83
95
85
73
a
Benzylidene[N,N0-dimethylbarbituric acid] 1a (10 mmol), 10 mmol of N,N0-
dimethylbarbituric acid 2a, 10 mmol of bromine, 20 mL of ethanol, time of the
reactiond3 h.
b
Isolated yield (isolation by filtration of the reaction mixture).
Nevertheless, it is known that the reaction of aldehydes with
N,N0-dialkylbarbituric acids 2 results in benzylidenebarbituric acids
1 formation under mild conditions in high yields.24 Taken these
results into consideration, the best route to the substituted spiro
[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentone 3a could be the
‘one-pot’ more complicated chemical cascade process starting di-
rectly from aromatic aldehydes 4 and N,N0-dialkylbarbituric acids 2
(Scheme 4, Table 3); for preliminary communication see Ref. 25.
Under the conditions of method A (bromine as active halogen
compound, 1.2 equiv of EtONa as base, and ethanol as solvent), al-
dehydes 4aej and N,N0-dialkylbarbituric acids 2a,b were trans-
formed into the corresponding substituted spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]pentones 3aem in 75e88% yields
(Table 3). These yields are lower than those for the conversion of
benzylidenebarbituric acids 1aem and N,N0-dialkylbarbituric acids
2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones
3aem (82e95%); but are sufficiently high, especially taken into
consideration that these conditions are more simple because it is not
necessary in the first stage to prepare benzylidenebarbituric acids 1.
The following step of the research was devoted to the synthesis
of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones 3 directly
from aldehydes 4 and N,N0-dialkylbarbituric acids 2a,b by the only
bromine action (method B, Scheme 4; Table 3). It was not obvious,
but Knoevenagel condensation of aldehydes 4aej with N,N0-dia-
lkylbarbituric acids 2a,b took place efficiently also under the con-
ditions of the method B in the absence of any base; the yields of
Table 2
Cascade transformation of benzylidenebarbituric acids 1aem, and N,N0-dia-
lkylbarbituric acids 2a,b into the spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pen-
tones 3aema
Entry Benzylidenebarbituric Barbituric R1
R2
Spiro[furo[2,3-d]
pyrimidine-6,50
-pyrimidine]
acid
acid
pentone, method,
yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
H
4-Me
Me 3a, A 95; B 90
Me 3b, A 93; B 85
4-t-Bu Me 3c, A 84; B 75
2-MeO Me 3d, A 83; B 76
4-MeO Me 3e, A 88; B 73
2-Cl
3-Cl
Me 3f, A 93; B 87
Me 3g, A 95; B 89
Me 3h, A 92; B 86
Me 3i, A 93, B 82
Me 3j, A 87; B 80
4-Cl
9
3-Br
4-NO2
H
4-Me
4-NO2
10
11
12
13
1j
1k
1l
Et
Et
Et
3k, A 82; B 76
3l, A 86, B 79
3m, A 92, B, 86
1m
a
Method A: 10 mmol of benzylidenebarbituric acid 1, 10 mmol of N,N0-dia-
lkylbarbituric acid 2, 12 mmol of EtONa, 10 mmol of bromine, 20 mL of EtOH,
without heating, time of the reactiond3 h. Method B: 10 mmol of benzylidene-
barbituric acid 1, 10 mmol of N,N0-dialkylbarbituric acid 2, 10 mmol of bromine in
50 mL of H2O, 20 mL of EtOH, 40 ꢀC, time of the reactiond1 h.
b
Isolated yield (isolation by filtration of the reaction mixture).
The best yield of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]
pentone 3a (95%) was obtained when 1.2 equiv of EtONa was used
(entry 3, Table 1). An increase in EtONa (entries 4 and 5, Table 1)
resulted in a decrease of the reaction yield, that may be connected
with the activation of undesired base induced oligomerization
processes.
Under the optimal conditions thus found, i.e., bromine as active
halogen compound, 1.2 equiv of EtONa as base, and ethanol as
solvent, benzylidenebarbituric acids 1aem and N,N0-dia-
lkylbarbituric acids 2a,b were transformed into the substituted
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones
case were generally somewhat lower than in method A.
3 in this
The advances in electrosynthesis in the last few decades have
provided organic chemists with a new versatile synthetic device of
great promise.26 Despite the significant synthetic potential and
ecological advantages of electrochemical methods, the practical us-
age of electrochemical procedure is often limited on account of its
technical complexity and generally long processing times. In the
course of our study on the electrochemical transformation of organic
compounds, we have found
a
new type of electrochemical
R1
O
R2
O
R2
R1
O
R2
N
N
N
N
N
O
O
R2
Method A or B
+
+
O
O
N
O
N
R2
O
R2
O
O
O
N
R2
4 a-j
2 a,b
O
R2
a R1 = H, b R1 = Me, c R1 = 4-t-Bu,
d R1 = 2-MeO, e R1 = 4-MeO,
f R1 = 2-Cl, g R1 = 3-Cl, h R1 = 4-Cl,
i R1 = 3-Br, j R1 = 4-NO2.
a R2 = Me; b R2 = Et
3 a-m
(Codes are interpreted in Table 3)
Method A: 1. EtONa / EtOH; 2. Br2; 3 h, r.t.
Method B: 1. EtOH; 2. 0.2 M Br2 in water; 1 h, 40oC
Scheme 4. Cascade transformation of aldehydes 4aej and N,N0-dialkylbarbituric acids 2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentones 3aem.

A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
1201
Table 3
Table 4
Cascade one-pot transformation of aldehydes 4aej and N,N0-dialkylbarbituric acids
2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones 3aema
Electrocatalytic cascade one-pot transformation of benzaldehyde 4a and N,N0-di-
methylbarbituric acid 2a into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentone
3aa
Entry Aldehydes Barbituric R1
acid
R2
Spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]
-pentone, method, yield (%)b
Entry Mediator
Electricity
Time of
Yield of 3a (%)c
passed [F/mol]b electrolysis [min]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
H
4-Me
4-t-Bu
Me 3a, A 88; B 83
Me 3b, A 86, B 81
Me 3c, A 85
1
NaBr
1.0
32
32
40
48
40
45
73
85
82
74
2d
3d
4d
5d
NaBreNaOAc 1.0
NaBreNaOAc 1.2
NaBreNaOAc 1.5
2-MeO Me 3d, A 77
4-MeO Me 3e, A 82; B 70
2-Cl
3-Cl
NaIeNaOAc
1.2
Me 3f, A 85, B 79
Me 3g, A 88
Me 3h, A 82
Me 3i, A 86, B 80
Me 3j, A 79; B 75
a
Benzaldehyde 4a (5 mmol), 10 mmol of N,N0-dimethylbarbituric acid 2a, 2 mmol
of NaBr, 2 mmol of NaOAc, 50 mL of MeOH, Fe-cathode, C-anode, current density
100 mAcmꢁ2, 20 ꢀC.
4-Cl
9
3-Br
4-NO2
H
4-Me
4-NO2
b
Calculated for N,N0-dimethylbarbituric acid 2a.
Isolated yield (isolation by filtration of the reaction mixture).
Stirring before electrolysis 30 min.
10
11
12
13
4j
c
4a
4b
4j
Et
Et
Et
3k, A 75
3l, A 82; B 74
3m, A 85; B 79
d
a
Method A: 10 mmol of aldehyde 4, 20 mmol of N,N0-dialkylbarbituric acid 2,
12 mmol of EtONa, 10 mmol of bromine, 20 mL of EtOH, without heating, time of the
reactiond3 h. Method B:10 mmol of aldehyde 4, 20 mmol of N,N0-dialkylbarbituric
acids 2, 10 mmol of bromine in 50 mL of H2O, 20 mL of EtOH, 40 ꢀC, time of the
reactiond1 h.
Table 5
Electrocatalytic cascade one-pot transformation of aldehydes 4aej and N,N0-dia-
lkylbarbituric acid 2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones
3aema
b
Isolated yield (isolation by filtration of the reaction mixture).
Entry
Aldehyde
Barbituric
acid
R1
R2
Spiro[furo[2,3-d]
pyrimidine-6,50
-pyrimidine]
transformation, namely electrocatalytic constructing of functionally
substituted cyclopropane rings from activated olefins or carbonyl
compounds and CH-acids in the presence of mediatorsdhalide
ions.17a,d,27 These unique electrochemical processes afford excellent
yields of the products, utilize a simple undivided cell, reasonable
processing times and are advantageous over classical organic
chemistry because of its mild catalytic nature and the use of a cheap
and environmentally responsible chemical reagentdelectricity.28
The following improvement of the cascade synthesis of spiro[furo
[2,3-d]pyrimidine-6,50-pyrimidine]pentones 3 was accomplished
using the electrocatalytic mediatordbromide iondas catalyst in-
stead of equivalent quantity of bromine (Scheme 5, Tables 4 and 5).
On the first stage of this research, we optimized the conditions
of the electrolysis of benzaldehyde 4a, and N,N0-dimethylbarbituric
acid 2a in methanol in the presence of sodium bromide in an un-
divided cell with the formation of 1,10,3,30-tetramethyl-5-phenyl-
1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]
2,20,4,40,60-(10H,3H,30H)-pentone 3a (Scheme 5, Table 4).
-pentone, yield (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a, 85
3b, 75
3c, 83
3d, 75
3e, 78
3f, 73
3g, 75
3h, 72
3i, 77
3j, 71
3k, 74
3l, 70
3m, 73
4-Me
4-t-Bu
2-MeO
4-MeO
2-Cl
3-Cl
4-Cl
3-Br
4-NO2
H
9
10
11
12
13
4j
4a
4b
4j
4-Me
4-NO2
Et
Et
a
Benzaldehyde 4 (5 mmol), 10 mmol of N,N0-dialkylbarbituric acid 2, 2 mmol of
NaBr, 2 mmol of NaOAc, 50 mL of MeOH, Fe-cathode, C-anode, current density
100 mAcmꢁ2 1.2 F/mol electricity passed at 20 ꢀC, stirring before electrolysis 30 min;
time of electrolysis 40 min.
b
Isolated yield (isolation by filtration of the reaction mixture).
The best yield of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]
pentone 3a (85%) was achieved using NaBreNaOAc mediator pair in
the procedure with preliminary stirring when 1.2 F/mol of elec-
tricity was passed (entry 3, Table 4). An increase in electricity
passed compared to 1.2 F/mol (entry 4, Table 4) did not sufficiently
influence on the yield of 3a.
electricity was passed, and methanol as solvent, aldehydes 4aej
and N,N0-dialkylbarbituric acids 2a,b were transformed into the
substituted spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones
3aem in 70e85% yields (Table 5).
Under the optimal conditions thus found, i.e., the procedure
with preliminary stirring, mediator pair NaBreNaOAc, 1.2 F/mol of
With the above results taken into consideration and the
mechanistic data on the cascade chemical transformation of
Scheme 5. Electrocatalytic cascade one-pot transformation of aldehydes 4aej and N,N0-dialkylbarbituric acid 2a,b into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-
pentones 3aem.

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A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
alkylidenemalononitriles and malononitrile into tetracyanosub-
stituted cyclopropanes and also the cascade transformation of
benzylidenemalononitriles and N,N0-dialkylbarbituric acids into
on Scheme 3. In method A (Scheme 4) action of EtONa results
in the anion A (Scheme 6) formation directly from aldehyde 4
and two molecules of N,N0-dialkylbarbituric acids 2 as a result
of successive Knoevenagel and Michael reactions. Further
formation of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pen-
tones 3 takes place in the same way as shown for anion A on
Scheme 6.
substituted
2-aryl-4,6,8-trioxo-5,7-diazaspiro[2.5]octane-1,1-
dicarbonitriles realized under the action of active halogen con-
taining compounds in ethanol in the presence of bases (Schemes 1
and 2)21,22 the following mechanism for the cascade transformation
of benzylidenebarbituric acids 1aem, and barbituric acids 2a,b into
the spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentones 3aem
in the presence of EtONa is proposed (method A, Scheme 6).
More interesting is spiro[furo[2,3-d]pyrimidine-6,50-pyrimi-
dine]pentone 3 formation directly from aldehydes 4 and N,N0-dia-
lkylbarbituric acids 2 in the case of only bromine action (method B,
Scheme 6. Cascade transformation of benzylidenebarbituric acids 1 and N,N0-dialkylbarbituric acids 2 into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentones 3 in
the presence of EtONa (method A).
The Michael addition of N,N0-dialkylbarbituric acid 2 to benzy-
lidenebarbituric acid 1 in the presence of EtONa results in the anion
A formation. Then, bromination of anion A leads to the substituted
bromoadduct 5, which is further cyclized into spiro[furo[2,3-d]py-
rimidine-6,50-pyrimidine]pentone 3.
In the absence of base (method B), more probably, on the first
stage bromination of N,N0-dialkylbarbituric acids 2 takes place with
the formation of N,N0-dialkyl-5-bromobarbituric acids 6 (Scheme 7).
The bromobarbituric acids 6 are reasonably strong acids, which
could, by the analogy with bromomalononitrile,23,29,30 furnish
a sufficient concentration of bromobarbituric carbanions for the
addition to benzylidenebarbituric acids 1 to form spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]pentones 3 by further cyclization.
The cascade process starting from aldehydes 4 and N,N0-
dialkylbarbituric acids 2 (Scheme 4) is very similar to those
Scheme 4). In this case, rapid Knoevenagel condensation of alde-
hydes 4 with N,N0-dialkylbarbituric acids 2 takes place even in the
absence of base as was reported earlier24a simultaneously with
bromination of N,N0-dialkylbarbituric acids 2. The following addi-
tion of bromobarbituric acids 6 just formed to benzylidenebarbi-
turic acids 1 (Knoevenagel product) results in spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]pentones 3 formation in the same way
as in method B (Scheme 7).
The electrocatalytic variant of the reaction is more complicated.
In this case in solution NaOAc catalyzes Knoevenagel condensation
of the aldehydes 4 and barbituric acids 2 before the electrolysis takes
place. This condensation is also partly catalyzed by the methoxide
anion formed at cathode during the electrolysis (Scheme 8).
The evolution of hydrogen at the cathode is observed, especially
when electrolysis is conducted without stirring of the reaction
O
R2
O
O
R2
N
N
N
N
Br
O
Br2
+
O
O
R2
R2
2
6
R1
O
O
O
R2
O
O
R2
R1
N
N
R2
O
R2
N
N
+
Br
O
N
O
N
O
N
R2
O
O
N
R2
R2
O
R2
1
6
3
Scheme 7. Cascade transformation of benzylidenebarbituric acids 1 and N,N0-dialkylbarbituric acids 2 into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentones 3 by
the bromine only action (method B).

A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
1203
O
O
O
R2
R1
R2
O
R1
N
N
N
NaOAc
O
+
O
O
N
R2
R2
4
2
1
-
2Br
2e
Br2
-
anode:
2 MeOH
2e
2 MeO
H2
cathode:
O
R2
O
O
R2
N
N
N
-
+
MeO
O
+
MeOH
O
N
O
R2
R2
R1
O
O
O
R2
R1
O
O
R2
O
N
Br2
N
R2
R2
O
-
+
O
_Br
N
N
N
O
N
R2
O
N
N
R2
O O
1
R2
R2
A
R1
Br
R1
R1
O
O
O
O
O
O
R2
Br
R2
R2
R2
R2
O
R2
-
-
_Br
N
MeO
MeOH
N
N
N
N
N
O
N
O
O
O
N
N
O
N
N
O
N
O O
O O
R2
R2
R2
O
R2
R2
R2
5
3
B
Scheme 8. The electrocatalytic cascade transformation of aldehydes 4 and N,N0-dialkylbarbituric acids 2 into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentones 3.
mixture. 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. Reaction in solution between a methoxide ion
and N,N0-dialkylbarbituric acid 2 leads to the formation of a N,N0-
pyrimidine]-2,20,4,40,60-(10H,3H,30H)-pentones in 70e95% yields as
a result of complex cascade processes. The electrocatalytic and
chemical 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
spirobarbiturates containing the furo[2,3-d]pyrimidine framework,
which are a class of compounds with prominent pharmacological
and physiological activity. Thus, thirteen previously inaccessible
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidines have been obtained.
This novel process offers a facile and convenient way to create di-
versely substituted privileged spirobarbituratesdthe approved
basis for the generation of small-molecule ligands with different
biomedical properties including pronounced anticancer and anti-
AIDS activities. In the electrocatalytic process the necessity of
bromine using in stoichiometric 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 cascade method to the formation of medicinally
relevant spiro[furo[2,3-d]pyrimidine-6,50-pyrimidines is also ben-
eficial from the viewpoint of diversity-oriented large-scale pro-
cesses and represents novel, facile and environmentally benign
synthetic concept for cascade reaction strategy. The developed
electrocatalytic cascade procedure utilizes facile equipment, an
undivided cell, and requires simple and reasonable starting
dialkylbarbituric acid anion. The addition of
a
N,N0-dia-
lkylbarbituric acid anion to benzylidenebarbituric acid 1 results in
anion A formation. Then bromination of anion A takes place with
the following formation of anion B by the action of the next
methoxide anion, and finally cyclization leads to spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentone 3 formation.
The alternative electrocatalytic mechanism of spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine]-2,20,4,40,60-pentone 3 formation could
include the bromination of the N,N0-dialkylbarbituric acid anion by
the bromine generated at the anode, then formation of the N,N0-
dialkyl bromobarbituric acid anion, followed by the addition to the
benzylidenebarbituric acid 1 (Knoevenagel product) and then cy-
clization into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]pentone
3 (Scheme 9).
3. Conclusion
The new electrocatalytic and chemical assembling of barbituric
acids and aldehydes leads to the selective and efficient formation of
substituted 1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-

1204
A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
Scheme 9. Alternative mechanism of electrocatalytic cascade transformation of aldehydes 4 and N,N0-dialkylbarbituric acids 2 into spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-
2,20,4,40,60-pentones 3.
materials. It is easily carried out, and the reaction products are di-
rectly crystallized from the reaction mixture. Therefore, this novel
type of cascade process brings us a step closer to the notion of ‘ideal
synthesis’.31
Method B: To a 20 mL of ethanolic suspension of benzylidene-
barbituric acid 1 (10 mmol) and barbituric acid 2 (10 mmol) in
a 100 mL three-necked flask, 0.2 M bromine in water (50 mL,
10 mmol) was added over 5 min. The mixture was magnetically
stirred at 40 ꢀC for 1 h. Then solid phase was filtered off, washed with
water and dried in desiccator over P2O5 to isolate pure product 3.
4. Experimental section
4.1. General remarks
4.3. Typical procedure for cascade transformation of
aromatic aldehydes and barbituric acids
All melting points were measured with a Gallenkamp melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded with Bruker AC-300 and Bruker Avance II 300 spectrom-
eters 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
(EI¼70 eV) were obtained directly with a Finningan MAT INCOS 50
spectrometer. All starting materials were obtained from commercial
sources and were used without further purification.
Method A: To a 10 mL of ethanolic suspension of aromatic al-
dehyde 4 (10 mmol) and barbituric acid 2 (20 mmol) in a 50 mL
beaker, sodium ethoxide (12 mmol) in ethanol (10 mmol) was
added over 1 min. Then of bromine (10 mmol) was added during
1 min without external cooling. The mixture was magnetically
stirred at room temperature for 3 h. Then solid phase was filtered
off, washed with water and dried in desiccator over P2O5 to isolate
pure product 3.
Method B: An ethanolic solution (20 mL) of aromatic aldehyde 4
(10 mmol) and barbituric acid 2 (20 mmol) in a 100 mL three-
necked flask, 0.2 M bromine in water (50 mL, 10 mmol) was
added over 5 min. The mixture was magnetically stirred at 40 ꢀC for
1 h. Then solid phase was filtered off, washed with water and dried
in desiccator over P2O5 to isolate pure product 3.
4.2. Typical procedure for cascade transformation of
benzylidenebarbituric acids and barbituric acids
Method A: To a 10 mL of ethanolic suspension of benzylidene-
barbituric acid 1 (10 mmol) and barbituric acid 2 (10 mmol) in
a 50 mL beaker, sodium ethoxide (12 mmol), in ethanol (10 mL) was
added over 1 min. Then of bromine (10 mmol) was added over
1 min without external cooling. The mixture was magnetically
stirred at room temperature for 3 h. Then solid phase was filtered
off, washed with water and dried in desiccator over P2O5 to isolate
pure product 3.
4.4. Typical electrolysis procedure
A solution of aromatic aldehyde 4 (5 mmol), barbituric acid 2
(10 mmol), sodium acetate (2 mmol) and sodium bromide (2 mmol)
in methanol (50 mL) was stirred in an undivided cell equipped with

A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
1205
a graphite anode and an iron cathode at room temperature for
30 min. The mixture was electrolyzed at 20 ꢀC under a constant
current density of 100 mAcmꢁ2 (I¼500 mA, electrode squares
5 cm2) until the quantity of electricity 1.2 F/mol was passed. After
the electrolysis was finished (40 min), solid product was filtered out
and dried under reduced pressure. An additional amount of product
3 was isolated as follows. The reaction mixture was concentrated to
10 mL and cooled to ꢁ10 ꢀC overnight. Additional portion of 3 was
filtered out and crystallized from an acetoneehexane.
pentone (3f). White solid; mp: 264e266 ꢀC (lit.25 mp:
264e266 ꢀC); dH (300 MHz, CDCl3) 2.69 (s, 3H; CH3), 3.30 (s, 3H;
CH3), 3.38 (s, 3H; CH3), 3.50 (s, 3H; CH3), 5.56 (s, 1H; CH), 7.10e7.18
(m, 1H, CH, Ar), 7.21e7.31 (m, 2H, CH, Ar), 7.33e7.41 (m, 1H, CH, Ar).
4.4.7. 5-(3-Chlorophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3g). White solid; mp: 222e224 ꢀC; [Found (%): C 52.64, H
4.06, Cl 8.11, N 12.81; C19H17ClN4O6 requires C 52.73, H 3.96, Cl 8.19,
N 12.94]; nmax (KBr) 1716, 1696, 1684, 1672, 1648, 1520, 1436, 1420,
1368,1032 cmꢁ1; MS, m/z (%): 434 (0.5) [Mþ, Cl37], 432 (1) [Mþ, Cl35],
345 (3), 277 (4), 176 (11), 136 (14), 113 (6), 75 (17), 66 (24), 58 (100),
56 (74); dH (300 MHz, DMSO-d6) 2.69 (s, 3H; CH3), 3.30 (s, 3H; CH3),
3.38 (s, 3H; CH3), 3.50 (s, 3H; CH3), 5.56 (s,1H; CH), 7.10e7.18 (m,1H,
CH, Ar), 7.21e7.31 (m, 2H, CH, Ar), 7.33e7.41 (m, 1H, CH, Ar); dC
(75 MHz, CDCl3) 28.2, 28.5, 29.5, 29.9, 58.3, 85.1, 89.9, 126.5, 128.4,
129.6, 130.0, 134.9, 135.1, 149.4, 151.0, 158.5, 162.6, 162.8, 165.2.
4.4.1. 1,10,3,30-Tetramethyl-5-phenyl-1,5-dihydro-2H,20H-spiro[furo
[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone
(3a). White solid; mp: 256e258 ꢀC (lit.25 mp: 256e258 ꢀC); dH
(300 MHz, CDCl3) 2.40 (s, 3H; CH3), 3.12 (s, 3H; CH3), 3.22 (s, 3H;
CH3), 3.40 (s, 3H; CH3), 5.11 (s, 1H; CH), 7.11e7.18 (m, 2H, Ph),
7.25e7.35 (m, 3H, Ph).
4.4.2. 1,10,3,30-Tetramethyl-5-(4-methylphenyl)-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3b). White solid; mp: 219e221 ꢀC; [Found: C 58.02, H
5.01, N 13.43; C20H20N4O6 requires C 58.25, H 4.89, N 13.59]; nmax
(KBr) 1724, 1712, 1688, 1676, 1660, 1520, 1440, 1420, 1380,
1036 cmꢁ1; MS, m/z (%): 412 (56) [Mþ], 384 (9), 325 (26), 297 (17),
270 (14), 257 (100), 211 (36), 200 (18), 156 (53), 115 (42); dH
(300 MHz, CDCl3) 2.31 (s, 3H; CH3), 2.58 (s, 3H; CH3), 3.29 (s, 3H;
CH3), 3.42 (s, 3H; CH3), 3.52 (s, 3H; CH3), 4.88 (s, 1H; CH), 6.93 (d, J
8.1 Hz, 2H; CH, Ar), 7.12 (d, J 8.1 Hz, 2H; CH, Ar); dC (75 MHz, CDCl3)
20.9, 27.9, 28.2, 29.3, 29.8, 58.8, 85.5, 90.2, 127.9, 129.4, 129.5, 139.2,
149.5, 151.1, 158.5, 162.4, 162.9, 165.4.
4.4.8. 5-(4-Chlorophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3h). White solid; mp: 257e259 ꢀC; [Found (%): C 52.63, H
3.88, Cl 8.01, N 12.81; C19H17ClN4O6 requires C 52.73, H 3.96, Cl 8.19,
N 12.94]; nmax (KBr) 1716, 1700, 1676, 1656, 1516, 1440, 1428, 1396,
1376, 1032 cmꢁ1; MS, m/z 434 (0.5) [Mþ, Cl37], 432 (1) [Mþ, Cl35],
345 (4), 277 (5), 176 (13), 136 (21), 113 (9), 75 (19), 66 (32), 58 (100),
56 (80); dH (300 MHz, CDCl3) 2.64 (s, 3H; CH3), 3.28 (s, 3H; CH3),
3.40 (s, 3H; CH3), 3.50 (s, 3H; CH3), 4.87 (s, 1H; CH), 7.00 (d, J 8.5 Hz,
2H; CH, Ar), 7.30 (d, J 8.5 Hz, 2H; CH, Ar); dC (75 MHz, CDCl3) 28.2,
28.5, 29.5, 30.0, 58.4, 85.3, 89.9, 129.2, 129.7, 131.5, 135.6, 149.5,
151.2, 158.6, 162.8, 162.9, 165.3.
4.4.3. 5-(4-tert-Butylphenyl)-1,10,3,30-tetramethyl-1,5-dihydro-
2H, 20H-spiro[furo[2, 3-d]pyrimidine-6, 50-pyrimidine]-
2,20,4,40,60(10H,3H,30H)-pentone (3c). White solid; mp: 228e230 ꢀC
(lit.25 mp: 228e230ꢀC);dH (300 MHz, DMSO-d6)1.25(s,9H;CH3), 2.33
(s, 3H; CH3), 3.12 (s, 3H; CH3), 3.22 (s, 3H; CH3), 3.40 (s, 3H; CH3), 5.06
(s, 1H; CH), 7.05 (d, J 8.3 Hz, 2H; CH, Ar), 7.29 (d, J 8.3 Hz, 2H; CH, Ar).
4.4.9. 5-(3-Bromophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3i). White solid; mp: 236e238 ꢀC; [Found (%): C 47.72, H
3.63, Br 16.65, N 11.58; C19H17BrN4O6 requires C 47.81, H 3.59, Br
16.74, N 11.74]; nmax (KBr) 1720, 1696, 1684, 1672, 1652, 1516, 1432,
1420, 1364, 1032 cmꢁ1; MS, m/z (%): 478 (0.5) [Mþ, Br81], 476 (0.5)
[Mþ, Br79], 391 (0.5), 389 (0.5), 323 (3), 321 (3), 277 (4), 222 (19),
220 (20), 182 (20), 180 (20), 127 (24), 101 (31), 66 (49), 58 (100); dH
(300 MHz, DMSO-d6) 2.49 (s, 3H; CH3), 3.12 (s, 3H; CH3), 3.20 (s, 3H;
CH3), 3.39 (s, 3H; CH3), 5.15 (s, 1H; CH), 7.12e7.30 (m, 2H, CH, Ar),
7.38e7.54 (m, 2H, CH, Ar); dC (75 MHz, DMSO-d6) 28.1, 28.2, 29.5,
30.2, 55.3, 85.5, 90.3, 121.9, 128.4, 130.5, 131.8, 131.8, 137.9, 150.4,
151.3, 158.6, 163.0, 163.4, 165.7.
4.4.4. 5-(2-Methoxyphenyl)-1,10,3,30-tetramethyl-1,5-dihydro-
2H, 20H-spiro[furo[2, 3-d]pyrimidine-6, 50-pyrimidine]-
2,20,4,40,60(10H,3H,30H)-pentone
(3d). Yellow
solid;
mp:
258e260 ꢀC; [Found (%): C 55.94, H 4.83, N 12.91; C20H20N4O7 re-
quires C 56.07, H 4.71, N 13.08]; nmax (KBr) 1722, 1704, 1688, 1676,
1664,1512,1492, 1444,1380,1032 cmꢁ1; MS, m/z (%): 428 (15) [Mþ],
397 (91), 340 (8), 283 (100), 243 (39), 186 (30), 172 (29), 157 (41),
131 (57), 58 (64); dH (300 MHz, DMSO-d6) 2.48 (s, 3H; CH3), 3.13 (s,
3H; CH3), 3.26 (s, 3H; CH3), 3.39 (s, 3H; CH3), 3.69 (s, 3H; OCH3), 5.17
(s, 1H; CH), 6.80e6.90 (m, 1H, CH, Ar), 6.92e7.04 (m, 2H, CH, Ar),
7.23e7.33 (m, 1H, CH, Ar); dC (75 MHz, DMSO-d6) 27.6, 27.7, 28.6,
29.6, 49.9, 55.7, 84.4, 88.94, 109.8, 120.2, 121.5, 129.8, 129.9, 150.3,
150.8, 156.3, 158.1, 162.3, 163.2, 166.0.
4.4.10. 5-(4-Nitrophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3j). White solid; mp: 221e223 ꢀC; [Found (%): C 51.31, H
3.98, N 15.62; C19H17N5O8 requires C 51.47, H 3.86, N 15.80]; nmax
(KBr) 1720, 1706, 1696, 1672, 1520, 1440, 1392, 1380, 1348,
1044 cmꢁ1; MS, m/z 443 (3) [Mþ], 356 (6), 288 (5),187 (12),141 (19),
113 (9), 75 (20), 66 (33), 58 (100), 56 (80); dH (300 MHz, DMSO-d6)
2.47 (s, 3H; CH3), 3.12 (s, 3H; CH3), 3.22 (s, 3H; CH3), 3.41 (s, 3H;
CH3), 5.36 (s, 1H; CH), 7.52 (d, J 8.8 Hz, 2H; CH, Ar), 8.16 (d, J 8.8 Hz,
2H; CH, Ar); dC (75 MHz, DMSO-d6) 27.8, 27.9, 29.1, 29.8, 54.5, 85.3,
89.6, 123.0, 130.3, 142.4, 147.6, 149.9, 150.9, 158.2, 162.7, 162.9, 165.1.
4.4.5. 5-(4-Methoxyphenyl)-1,10,3,30-tetramethyl-1,5-dihydro-
2H, 20H-spiro[furo[2, 3-d]pyrimidine-6, 50-pyrimidine]-
2,20,4,40,60(10H,3H,30H)-pentone (3e). Yellow solid; mp: 206e208 ꢀC;
[Found (%): C 56.01, H 4.79, N 12.87; C20H20N4O7 requires C 56.07, H
4.71, N 13.08]; nmax (KBr) 1716, 1706, 1692, 1676, 1656, 1516, 1440,
1424, 1372, 1032 cmꢁ1; MS, m/z (%): 428 (27) [Mþ], 341 (23), 305
(26), 273 (65), 227 (41), 172 (73), 157 (72), 135 (72), 132 (73), 58
(100); dH (300 MHz, DMSO-d6) 2.46 (s, 3H; CH3), 3.12 (s, 3H; CH3),
3.21 (s, 3H; CH3), 3.40 (s, 3H; CH3), 3.73 (s, 3H; OCH3), 5.05 (s, 1H;
CH), 6.83 (d, J 8.4 Hz, 2H; CH, Ar), 7.07 (d, J 8.4 Hz, 2H; CH, Ar); dC
(75 MHz, DMSO-d6) 27.7, 27.8, 28.9, 29.7, 55.2, 55.6, 85.6, 90.2,113.4,
126.3, 129.9, 150.1, 150.8, 158.1, 159.4, 162.2, 163.2, 165.6.
4.4.11. 1,10,3,30-Tetraethyl-5-phenyl-1,5-dihydro-2H,20H-spiro[furo
[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone
(3k). White solid; mp: 173e175 ꢀC; [Found (%): C 60.62, H 5.83, N
12.15; C23H26N4O6 requires C 60.78, H 5.77, N 12.33]; nmax (KBr)
1720, 1704, 1688, 1676, 1624,1520, 1480, 1436,1396, 1036 cmꢁ1; MS,
m/z (%): 454 (14) [Mþ], 339 (40), 284 (31), 271 (100), 197 (44), 156
(50),128 (67),102 (77), 70 (70), 44 (76); dH (300 MHz, CDCl3) 0.68 (t,
J 7.1 Hz, 3H; CH3), 1.20 (t, J 7.1 Hz, 3H; CH3), 1.35 (t, J 7.3 Hz, 3H; CH3),
1.44 (t, J 7.1 Hz, 3H; CH3), 2.98e3.16 (m, 1H), 3.24e3.44 (m, 1H),
4.4.6. 5-(2-Chlorophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-

1206
A.N. Vereshchagin et al. / Tetrahedron 68 (2012) 1198e1206
Opgenorth, T. J.; Kerkman, D. J.; Debernardis, J. F. Pharmacology 1993, 47,
176e187.
3.88e4.20 (m, 6H), 4.88 (s, 1H; CH), 7.02e7.16 (m, 2H, Ph),
7.26e7.36 (m, 3H, Ph); dC (75 MHz, CDCl3) 12.2, 12.9, 13.1, 13.6, 36.5,
37.7, 38.0, 38.9, 58.9, 85.8, 89.5, 128.4, 128.8, 129.2, 132.8, 148.7,
150.2, 158.2, 162.3, 162.6, 165.3.
10. (a) Brunton, L. L.; Lazo, J. S.; Keith, L. P. Goodman & Gilman’s the Pharmacological
Basis of Therapeutics, 11th ed.; The McGraweHill Companies: New York, NY,
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Zabel, M. Eur. J. Org. Chem. 2003, 855e862.
4.4.12. 1,10,3,30-Tetraethyl-5-(4-methylphenyl)-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3l). White solid; mp: 160e162 ꢀC (lit.25 mp: 160e162 ꢀC);
dH (300 MHz, CDCl3) 0.69 (t, J 7.3 Hz, 3H; CH3), 1.20 (t, J 7.1 Hz, 3H;
CH3), 1.35 (t, J 7.1 Hz, 3H; CH3), 1.44 (t, J 7.1 Hz, 3H; CH3), 2.31 (s, 3H,
CH3), 3.02e3.18 (m,1H), 3.28e3.44 (m,1H), 3.88e4.20 (m, 6H), 4.85
(s, 1H; CH), 6.97 (d, J 8.1 Hz, 2H; CH, Ar), 7.12 (d, J 8.1 Hz, 2H; CH, Ar).
11. Lyons, K. E.; Pahwa, R. CNS Drugs 2008, 22, 1037e1045.
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633e638.
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4.4.13. 1,10,3,30-Tetraethyl-5-(4-nitrophenyl)-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3m). White solid; mp: 221e223 ꢀC; [Found (%): C 55.21, H
5.16, N 13.84; C23H25N5O8 requires C 55.31, H 5.05, N 14.02]; nmax
(KBr) 1710, 1696, 1680, 1660, 1504, 1440, 1408, 1348, 1176,
1064 cmꢁ1; MS, m/z (%): 499 (95) [Mþ], 471 (11), 384 (85), 329 (63),
316 (100), 285 (58), 258 (46), 230 (98), 201 (36), 127 (16); dH
(300 MHz, DMSO-d6) 0.54 (t, J 7.2 Hz, 3H; CH3), 1.07 (t, J 7.0 Hz, 3H;
CH3), 1.19 (t, J 7.0 Hz, 3H; CH3), 1.33 (t, J 7.0 Hz, 3H; CH3), 2.85e3.03
(m, 1H), 3.16e3.34 (m, 1H), 3.68e4.08 (m, 6H), 5.25 (s, 1H; CH), 7.47
(d, J 8.6 Hz, 2H; CH, Ar), 8.17 (d, J 8.6 Hz, 2H; CH, Ar); dC (75 MHz,
DMSO-d6) 11.8, 12.6, 12.8, 13.4, 35.8, 36.8, 37.8, 386, 54.9, 85.7, 89.1,
123.2, 130.5, 142.0, 147.6, 149.1, 149.9, 157.7, 162.4, 162.5, 165.1.
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1996, 32, 42e52.
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1986, 1919e1920; (b) Elinson, M. N.; Lizunova, T. L.; Dekaprilevich, M. O.;
Struchkov, Y. T.; Nikishin, G. I. Mendeleev Commun. 1993, 192e193; (c) Fedu-
covich, S. K.; Elinson, M. N.; Nikishin, G. I. Izv. Akad. Nauk, Ser. Khim. 1994,
1835e1836.
17. (a) Elinson, M. N.; Feducovich, S. K.; Zakharenkov, A. A.; Bushuev, S. G.; Pash-
chenko, D. V.; Nikishin, G. I. Mendeleev Commun. 1998, 15e17; (b) Elinson, M. N.;
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3989e3996.
Acknowledgements
The authors gratefully acknowledge the financial support of the
Russian Foundation for Basic Research (Project No. 09-03-00003).
18. (a) Elinson, M. N.; Feducovich, S. K.; Lizunova, T. L.; Nikishin, G. I. Tetrahedron
2000, 56, 3063e3069; (b) Elinson, M. N.; Feducovich, S. K.; Zaimovskaya, T. A.;
Vereshchagin, A. N.; Nikishin, G. I. Izv. Akad. Nauk, Ser. Khim. 2005, 663e667; (c)
Vereshchagin, A. N.; Elinson, M. N.; Zaimovskaya, T. A.; Nikishin, G. I. Tetrahe-
dron 2008, 64, 9766e9770.
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