Chemo and regioselective serendipitous electrochemically initiated spirocyclization of caffeic acid esters with barbituric acid derivatives

Article abstract of DOI:10.1016/j.electacta.2015.08.014

An interesting sequence of oxidation/Michael addition/oxidation/spirocyclization is observed in the electrolysis of caffeic acid esters in the presence of barbituric acid derivatives leading to the synthesis of a series of novel spirocycles. In an experim

Full text of DOI:10.1016/j.electacta.2015.08.014

Accepted Manuscript
Title: Chemo and regioselective serendipitous
electrochemically initiated spirocyclization of caffeic acid
esters with barbituric acid derivatives
Author: Abdolhamid Alizadeh Mohammad Mehdi Khodaei
Mitra Fakhari Gisya Abdi Sohrab Ghouzivand
PII:
S0013-4686(15)30264-4
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.electacta.2015.08.014
EA 25482
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Electrochimica Acta
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Accepted date:
20-4-2015
2-8-2015
4-8-2015
Please cite this article as: Abdolhamid Alizadeh, Mohammad Mehdi Khodaei, Mitra
Fakhari, Gisya Abdi, Sohrab Ghouzivand, Chemo and regioselective serendipitous
electrochemically initiated spirocyclization of caffeic acid esters with barbituric acid
derivatives, Electrochimica Acta http://dx.doi.org/10.1016/j.electacta.2015.08.014
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Chemo and regioselective serendipitous electrochemically initiated
spirocyclization of caffeic acid esters with barbituric acid derivatives
Abdolhamid Alizadeh*a,b,c, Mohammad Mehdi Khodaei*a, Mitra Fakharia, Gisya Abdia, Sohrab
Ghouzivanda
a Department of Organic Chemistry, Faculty of Chemistry, Razi University, Kermanshah, 6714967346
Iran
b Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Iran
c Nanoscience & Nanotechnology Research Center (NNRC), Razi University, Kermanshah, Iran
Phone: (98) 833 4274562 (Ext. 300); Fax: (98) 833 4274559; Email:ahalizadeh2@hotmail.com
Abstract
R
O
R
O
O
O
e
t
i
O
O
O
HO
HO
R
O
h
O
p
+
a
N
r
N
R1
R1
G
O
N R1
O
O
N
R1
OH
-
2H+, 2e
O
O
HO
6
I or II
R1 = H or CH3
1
2
R = Methyl or Ethyle or Isopropyl
An interesting sequence of oxidation/Michael addition/oxidation/spirocyclization is
observed in the electrolysis of caffeic acid esters in the presence of barbituric acid derivatives
leading to the synthesis of a series of novel spirocycles. In an experimentally simple and clean
procedure, the electrolyses proceed via a domino of electrochemical (E) and chemical (C) events
with employing electrons as the only reagents in aqueous solution without introducing any
catalyst or oxidant. From mechanistic point of view, a new type of domino mechanism (ECECi,

Ci=spirocyclization) is proven with a unique Ci phenomenon at final step. Also, in light of
experimental and theoretical NMR investigations, highly chemo and regioselectivities have been
detected in these synthetic electrolyses.
1. Introduction
First “spiran” structure was described by Bayer in 1900 as a bicyclic hydrocarbon connected by a
single carbon with a tetrahedral nature. Later on, the term “spirocyclanes” was used to describe
the family of such hydocarbons. Spirocyclic compounds occupy a key position in modern
synthetic organic chemistry and various useful synthetic methods for the synthesis of spiro cyclic
compounds have been developed [1-4].Moreover, phenolic compounds are secondary
metabolites and also the largest class of phytochemicals distributed in plants. In nature, they
usually participate in the defense role and exhibit antioxidant and other biological properties [5].
Phelligridin G 1 (Scheme 1) showed antioxidant activity inhibiting rat liver microsomal lipid
peroxidation and moderate selective cytotoxic[6] also Compounds 2 exhibit enhanced hydrogen
bonding capacity with diacetyldeoxyadenosine as compared to the reference
diacetylthymidine[7].
Caffeic acid and their analogues which are widely distributed in the plant kingdom, are potential
natural antioxidants with multiple mechanism involving free radical scavenging[8], metal ion
chelation[9], and inhibitory actions on specific enzymes that induce free radical and lipid
hydroperoxide formation[10, 11]. In addition, cyclic β-diketones such as barbituric acid
derivatives[12, 13] have been shown to exhibit various biological activities. Blizzard and
coworkers in 2002 reported a series 2-phenylspiroindenes such as 3 as estrogen receptor
ligands[14]. By considering all of the unique synthetic and biomedical potentials of caffeic acid
esters and pharmaceutically important barbituric acid derivatives, we anticipated that cross-

combination of these moieties through biocompatible approach might lead to the formation of
novel compounds possessing dual synthetic and biological potential functionalities.
Recent advances in electroorganic synthesis because of being green and simplicity of these
methods [15, 16].Through these electrochemical processes, highly reactive intermediates (i.e.,
cation-radicals, anion-radicals,…) can be generated under ambient temperatures, normal
pressure, and often in aqueous solvents. More importantly, in these protocols the electrons are
used as the only reagents in synthetic organic reactions[17]. Considering above facts and in
continuation of our research in the field of green electrochemical synthesis of organic
structures[18-21], herein we report an experimentally clean and feasible procedure for the
synthesis of a new series of spiro derivatives of various caffeates and barbituric acid derivatives.
All reactions were done in mild conditions with good yields as well as electrochemical
efficiencies.
2. Experimental
2.1.Apparatus and Reagents
All experiments were carried out in a conventional electrochemical cell using traditional three-
electrode system. The working electrode used in voltammetry experiments was a glassy carbon
disc (1.8 mm diameter) and platinum wire was used as the counter electrode. The working
electrode used in controlled-potential coulometry and bulk electrolysis (using an electronic
potentiostat) was an assembly of four rods, 6-mm diameter, and ~ 10-cm length and large
platinum gauze constituted the counter electrode. The working electrode potentials were
13
measured versus Ag/ AgCl. 1H and C NMR spectra were recorded on a spectrometer operating

at 400 MHz and 100 MHz for proton and carbon nuclei. Chemical shifts were recorded as δ
values in parts per million (ppm).
1H NMR spectra are reported as follows: chemical shift (δ) [multiplicity (where multiplicity is
defined as: br = broad; s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet), coupling
constant(s) J (Hz), relative integral, and assignment].Mass spectra and exact masses were
recorded on a 5973 Network Mass Selective Detector, Agilent Technology (HP), (EI, 70 eV)
high resolution mass spectrometer. Infrared spectra were recorded neat and are reported in wave
numbers (cm-1). All chemicals were reagent-grade materials and solvents and reagents were of
pro-analysis grade. These chemicals were used without further purification.
Cyclic voltammetric experiments were performed with a Voltametric Analyzer Model BHP2063
and controlled potential coulometry and preparative electrolysis were performed using a
coulometry BHP2050 potentiostat/galvanostat. A conventional three electrodes system was used
with a glassy carbon (GC) disc (1.8 mm diameter) as working electrode, a saturated Ag/AgCl as
reference electrode, and a platinum wire as the counter electrode. The working electrode used in
controlled potential coulometry and preparative electrolysis was an assembly of four carbon rods
(an assembly of four rods, 6-mm diameter, and 10 cm length) and large platinum gauze
constitute the counter electrode. The potential of working electrode was monitored vs. Ag/AgCl
reference electrode (from Azar electrode, Iran).
All chemicals (caffeic acid, barbituric acid, 1,3-dimethyl barbituric acid) were reagent-grade
materials., dihydrogene phosphate sodium, monohydrogene phosphate sodium acetic acid ,
acetate sodium, solvents and reagents were of pro-analysis. These chemicals were used without
further purification. Throughout all experiments distilled water was used and all experiments
were performed at room temperature.

2.2. General procedure for electrosynthesis of spirobarbiturates 6a-6f
In a typical procedure, 100 mL of suitable buffer solution in water/acetonitrile mixture
containing 0.5 mmol of caffeic acid derivatives (1a-c) and 0.5 mmol of C-H acid (barbitiric acid
derivatives) (Table 1), was electrolyzed in an undivided cell equipped with a carbon anode (an
assembly of four rods, 6-mm diameter, and 10-cm length) and a large platinum gauze at suitable
potential vs.Ag/AgCl (Table 1), at ambient condition. The electrolysis was terminated when the
current decreased by more than 95%. The process was interrupted during the electrolysis and the
graphite anode was washed in acetone in order to reactivate it. At the end of electrolysis, a few
drops of acetic acid were added to the solution and the cell was placed in a refrigerator overnight.
Then pure product was obtained from aqueous solution with ethylacetate extraction followed by
a recrystallization process using ethylacetate/n-hexane (1/2). The proper structure of the product
was confirmed by FT-IR, 1H NMR, 13C NMR and MS.
2.2.1. Methyl 5,6-dihydroxy-1',3'-dimethyl-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-spiro[indene-
1,5'-pyrimidine]-2-carboxylate (C16H14N2O7) (6a)
The product was isolated as an amorphous white solid, m.p: 265-267 ˚C; IR, ν (cm-1): 3460,
3200, 1691, 1440, 1581; 1H NMR, (DMSO-d6, 200 MHz), δ (ppm): 3.21 (s, 6H, 2CH3), 3.67 (s,
3H, CH3), 6.84 (s 1H, Har), 7.01 (s, 1H, Har), 7.86 (s, 1H, benzylic H), 9.54 (br, OH); 13C NMR

(DMSO-d6, 50 MHz), δ (ppm): 29.4, 52.4, 65.7, 110.3, 112.5, 133.7, 135.5, 137.6, 142, 147.2,
147.9, 151.4, 156.7, 163.3, 166.3, 170.9; MS (EI) m/z: 346 (M+), 232, 57, 43.
2.2.2. Ethyl 5,6-dihydroxy-1',3'-dimethyl-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-spiro[indene-
1,5'-pyrimidine]-2-carboxylate (C17H16N2O7)(6b)
The product was isolated as an amorphous white solid; m.p: 251-253 ˚C; 1H NMR, (DMSO-d6,
200 MHz), δ (ppm): 1.2 (t, 7 Hz, 3H, CH3), 3.24 (s, 6H, 2 CH3), 4.12 (q 7 Hz, 2H, CH2), 6.87 (s,
13
1H, Har), 7.04 (s, 1H, Har), 7.89 (s, 1H, benzylic H), 9.6 (br, OH); C NMR (DMSO-d6, 50
MHz), δ (ppm): 14.4, 29.4, 61.1, 65.5, 110.3, 112.5, 133.8, 136, 137.6, 147, 147.9, 151.4, 162.6,
166.4; MS (EI) m/z: 361, 360 (M+), 315, 218, 58, 116, 29.
2.2.3.
Isopropyl
5,6-dihydroxy-1',3'-dimethyl-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-
spiro[indene-1,5'-pyrimidine]-2-carboxylate (C18H18N2O7) (6c)
The product was isolated as an amorphous white solid; m.p: 236-239 ˚C; 1H NMR, (DMSO-d6,
200 MHz), δ (ppm): 1.12 (d, 6 Hz, 6H, 2 CH3), 3.23 (s, 6H, 2CH3), 4.89 (septet, 6 Hz, 1H, CH),
6.70 (s, 1H, Har), 6.93 (s, 1H, Har), 7.81 (s, 1H, benzylic H); MS (EI) m/z: 374 (M+), 287, 221,
57, 43.

2.2.4.
Methyl
5,6-dihydroxy-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-spiro[indene-1,5'-
pyrimidine]-2-carboxylate (C14H10N2O7) (6d)
1
The product was isolated as an amorphous light Yellow solid; m.p: 236-237 ˚C; H NMR,
(DMSO-d6, 200 MHz), δ (ppm): 3.71 (s, 3H, CH3), 6.80 (s, 1H, Har), 7.02 (s 1H, Har), 7.85 (s,
1H, benzylic H), 9.59 (br, OH), 11.33 (br, 2 NH); 13C NMR (DMSO-d6, 50 MHz), δ (ppm): 51.5,
65.3, 108.9, 112.2, 133.4, 134.9, 136.6, 146.6, 147.4, 150.3, 162.3, 167.4. MS (EI) m/z: 318
(M+), 287, 232, 148, 59, 15.
2.2.5.
Ethyl
5,6-dihydroxy-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-spiro[indene-1,5'-
pyrimidine]-2-carboxylate (C15H12N2O7)(6e)
The product was isolated as an amorphous light Yellow solid; m.p: 255-257 ˚C; IR, ν (cm-1):
3440, 3200, 3100, 1700, 1419, 1570; 1H NMR, (DMSO-d6, 200 MHz), 1.17 (t, 7 Hz, 3H, CH3),
4.11 (q, 7 Hz, 2H, CH2), 6.78(s, 1H, Har), 7 (s 1H, Har), 7.82 (s, 1H, benzylic H), 9.58 (br, 2 OH),

11.33 (br, 2 NH); 13C NMR (DMSO-d6, 50 MHz), δ (ppm): 14.5, .61, 65.7, 109.4, 112.6, 133.8,
135.4, 137.1, 147, 147.8, 150.7, 162.8, 167.8; MS (EI) m/z: 332 (M+), 287, 218, 29.
2.2.6.
Isopropyl
5,6-dihydroxy-2',4',6'-trioxo-1',3',4',6'-tetrahydro-2'H-spiro[indene-1,5'-
pyrimidine]-2-carboxylate (C16H14N2O7) (6f)
The product was isolated as an amorphous light Yellow solid; m.p: 244-246 ˚C; IR, ν (cm-1):
1
3440, 3200, 3100, 1750, 1430, 1570; H NMR, (DMSO-d6, 200 MHz), 1.16 (d, 6 Hz, 6H, 2
CH3), 4.92 (septet 6 Hz, 1H, CH), 6.77 (s, 1H, Har), 7 (s 1H, Har), 7.80 (s, 1H, benzylic H), 9.45
(br, OH), 9.63 (br, OH), 11.75(br NH). 13C NMR (DMSO-d6, 50 MHz), δ (ppm): 22, .65.6, 68.5,
109.3, 112.5 133.7, 133.9, 135.9, 137.0, 147, 147.8, 150.7, 162.1, 167.8, 168; MS (EI) m/z: 347
(M+), 346, 287, 218, 43.
3. Result and Discussion
3.1. Synthesis of caffeic acid esters 1a-c
This is necessary to mention caffeic acid and its analogues that we use them as electroactive
starting materials have several important biological activity[22-28] therefore according to these
facts in this study first we synthesized tree type of caffeates[29].

3.2. Electrochemical study for the synthesis of spirosystems6a-6f
To investigate electrochemically reactivity of these analogous, first we study these compounds
by cyclic voltammetry technique. Cyclic voltammogram of a 1 mM solution of methyl caffeate
(1a) in water/acetonitrile (95/5) solution containing phosphate buffer (pH = 7) shows one anodic
peak (A1) and a corresponding cathodic peak (C1), which correspond to the transformation of 1a
to o-benzoquinone 2a (Scheme 3) and vice versa through a reversible two electron process
(Figure 1, curve a).[30] To get further support on the electrochemical oxidation of 1a, it was
studied in the presence of 1,3-dimethyl barbituric acid (I) as a C-H nucleophile. The CH2 group
of barbituric acid is acidic enough so it seems that its ionic 1,4-addition to various quinones can
proceed in a quick and simple way. Figure 1 curve b shows the cyclic voltammogram obtained
for a 1 mM solution of 1 in the presence of 1 mM of I that shows a significant decrease of the
current density for cathodic peak (C1). This observation is in a good agreement with the
reactivity of the electrochemically derived active o-benzoquinone 2a toward barbituric acid[31].
Curve c shows the cyclic voltamogram of 1 mM solution of I.
Our investigations on the anodic controlled-potential electrolysis of various caffeates in the
presence of barbiturates began with the optimization of the reaction conditions. We found that
the optimum conditions required a graphite anode, water/acetonitrile as the solvent, and
phosaphate buffer (pH = 7) as the supporting electrolyte. For example 0.5 equivalent of various
caffeates and 0.5 equiv of nucleophile (barbituric acid derivatives) were a good reagent
combination for these reactions. In the meantime, the anode potential was maintained at
appropriate potential, V vs. Ag/AgCl, which is at a potential for which 1a could be oxidized to
the corresponding o-benzoquinone form 2a and vice-versa within a reversible two-electron
process.

The electrochemical synthesis was performed in controlled-potential condition through the
oxidation of 1a in the presence of I at appropriate potential on a graphite rode anode electrode in
an undivided cell. Monitoring of the electrolysis progress was carried out by cyclic voltammetry.
It is shown (Figure 2) that, proportional to the advancement of coulometery, anodic peak A1
decreases and disappears when the charge consumption becomes about 4e- per molecule of 1a.
1
13
The aforementioned coulometry data in addition to the HNMR, CNMR, Mass spectroscopies
results allow us to propose the pathways shown in scheme 3 for the electrooxidation of 1a in the
presence of I and synthesis of 6a. The shown one-pot coupling reaction is composed of at least
four electron transfer step (E) at the electrode as well as preceding and follow-up two C-C bond
forming steps [one intermolecular (C) and one intramolecular (Ci) chemical reactions].
Accordingly, molecule 1a is oxidized in a two-electron process to its related o-benzoquinone 2a
and in the next step, the electrochemically generated 2a, as a reactive Michael-acceptor
participates in a chemical reaction and a re-aromatization process gives intermediate 3a. As we
know, 3a possessing a β-diketone skeleton exists in a keto-enol tautomeric equilibrium and also,
an enol moiety has electron-donating character [32]. Therefore, the oxidation of enolic form 4a
should be much easier than the oxidation of the parent-starting molecule 1a; hence 4a is oxidized
to corresponding o-benzoquinone 5a. Then, this multifunctional and active molecule can form 6a
via an intramolcular spirocyclization process and unique ECECi mechanistic fashion as final
product in excellent yield and current efficiency (Scheme 3). Briefly, it seems that there is an
oxidative/ intermolecular Michael-type addition/oxidative/intramolecular Michael-type addition
sequence in this one-pot four-step coupling reaction of 1a with I leading to the formation of an
interesting novel spirosystem 6a as a final product.

3.3. Regioselectivity
Moreover, the pathways shown in scheme 2 represent an interesting regioselectivity in the
formation of 3a and subsequently the final product 6a. The existence of an unsaturated
substituent at C-4 position of 2 would probably cause this Michael acceptor to be attacked by I at
one of the four possible electrophilic sites (C-3, C-5, C-6, C-8, Scheme 4) and formation of four
regioisomers (Scheme 4, 6a-9a).
Since the substituent at C-4 position has an electron-withdrawing character, we suggest 2 to be
more electropositive at C-5 position and selectively attacked from this site by I leading to the
formation of regioisomer 3a.The accuracy of this suggestion was proved by means of
theoretical[32] and experimental 1H NMR studies. Theoretically, addition of I to C-3 position in
generation of 7a, once ortho hydrogenes in C-5 and C-6 would couple, may result in two
1
doublets with a coupling constant of about 7-8 Hz in H NMR spectrum, and two doublets for
hydrogens in C-7 and C-8, with a coupling constant of about 6-15 Hz for cis form and about 11-
18 Hz for trans form. However, coupling of I with 2 via C-6 position may lead to the formation
of 8a with two doublets for meta hydrogens in C-3 and C-5 with a coupling constant of about 3-4
Hz, and two doublets for hydrogens in C-7 and C-8, as mentioned earlier. With addition of I to
C-6 position, the final intramolecular cyclization step to produce spiro product is not possible.
Finally, addition of I to C-8 position gives a complex signal pattern for three hydrogens in ortho,
meta and para position of caffeate ring, with various possible coupling in product 9a, and one
1
singlet for the hydrogen in C-7 (Table 2). Considering all these, the experimentally obtained H
NMR spectrum for the final product shows two singlet appeared at 6.88 and 6.19 ppm which is
in a good agreement with two aromatic protons in para position [21] and formation of the single
regioisomer 6a.

3.4. Chemoselectivy
On the other hand, there is a chemoselective C- versus O-alkylation process in the final
cyclization step (5a→6a) of the reaction. It is clear to see that after tautomerization of keto 3a to
enol form 4a, and electrooxidation of 4a to 5a, there are three possibilities for 5a to be attacked
by nucleophilic species; i) an intermolecular attack of another molecule of I, ii) an
intramolecular Michael-type cyclization to form 6a with a unique spiro skeleton via a C-
alkylation process and iii) an intramolecular Michael-type cyclization to form 10a through an O-
alkylation process (Scheme 4). According to their structural features, there might be
distinguishable signals in the 1H and 13C NMR spectra of 6a and 10a.
We simply utilized an experimental and theoretical NMR investigation to clarify the claimed
13
chemoselectivity as well as proper structure of the final product. Theoretically, in C NMR the
chemical shifts of C9 in 6a and C10 in 10a are found to be at ~ 65 and 90 ppm, respectively[32].
1
In H NMR, the two methyl groups of 6a are equivalent and their signals should appear at the
same chemical shift (3.2 ppm), but in 10a, the methyl groups are not similar and their signals
should appear at two different chemical shifts (3.16 and 3.30 ppm) (Table 2). The experimentally
obtained 1H NMR spectrum for the final product of electrolysis showed only one singlet peak for
the methyl groups at 3.23 ppm. Meanwhile, as we know the chemical shifts of carbon atoms
highly depend on the hybridization state of carbon; sp3 hybridized carbon is more shielded than
sp2 and sp[32].Accordingly, the sp2 and sp3 carbons usually appears at 70-150 and 0-70 ppm,
13
respectively. CNMR of the final product showed a signal at 65 ppm which is presumably due
to the resonance of a sp3 carbon C9 in 6a. Briefly speaking, it seems that in a competition
between two intramolecular cyclization reactions, the formation of a five-membered ring

(spirosystem 6a) is dominant event and much faster than the formation of a seven-membered
ring (10a) and hence, these observations support the idea suggesting structure 6a as the final
product of the electrooxidation of 1a in the presence ofI under a clean and selective procedure.
4. Conclusions
In preparative electrolysis, five novel and highly functionalized caffeic acid spiro-analogues 6a-f
were purely obtained in excellent yields via the ECECi mechanistic fashions with high atom
economy and no extra purification was needed. In all cases, the reaction proceeds smoothly
under very mild conditions without introducing any acid, base, or metal catalyst.
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Table 1.Electroanalytical and preparative electrolysis data for preparation of 6a-fa
Nucleophil
Applied
potential at
carbon rods
Acetonitrile/Water
Product
Isolated Yields (%)
70
+ 0.28
+ 0.26
+ 0.30
10/90
I
6a
I
I
30/70
40/60
65
60
6b
6c

+ 0.33
+ 0.27
+ 0.32
5/95
20/80
30/70
78
70
65
II
II
II
6d
6e
6f
Cyclic voltammetry measurements were performed in 4:1 (V:V) of 0.2 M phosphate buffer solution (pH = 7) and
a
CH3CN. Controlled-potential coulometries were carried out in 0.2 M phosphate buffer solution, at carbon rods;
reference electrode: Ag/ AgCl.
Table 2. Experimental and theoretical 1H and 13C NMR data for CH3, C9 and C10 in 6a and 10a
1H NMR δ (ppm)
experimental calculated
13C NMR δ (ppm)
Structure
experimental
calculated
6a
CH3
3.23
3.2
C9
65.00
65.00
90.90
CH3
C10
3.16 and 3.30
10a

Scheme1. Structure of various spiro systems with biological activities.
OH
OH
N
O
H
N
O
O
O
O
OH
O
O
O
O
HO
NH
OH
HO
HO
O
OH
HO
HO
O
3
1
2

Scheme 2.Procedures for the synthesis of starting caffeates
CH3
O
CH3
O
H3C
H3C
OH
O
O
O
O
O
ROH
SOCl2 , DMF
OH
HO
OH
OH
HO
OH
HO
HO
1c
caffeic acid
1a
1b

Scheme 3.Proposed mechanism for the electrochemical oxidation of methyl caffeate (1a) in the presence of
barbituric acid derivatives (I)

Scheme 4. Proposed structures for the regioisomers formed from coupling of nucleophiles I-II with o-quinone 2 via
possible electrophilic sites (C-3, C-5, C-6, C-8) on 2.
O
3
O
O
R
O
8
5
R= Methyl or Ethyl or Isopropyl
2
6
I or II
5
3
6
8
O
O
O
O
HO
R1
R1
HO
HO
HO
HO
N
N
O
N
O
O
HO
O
O
O
O
HO
O
O
R1
O
N
R1
N
N
N
N
R1
R1
R1
6a
7a
8a
9a
O
R1
HO
O
R1= H or CH3

Scheme 5. Schematic presentation of chemoselective C- versus O-alkylation process in the final
cyclization step.
O
O
O
O
OH
O
N
N
5a
O
Intramolecular C-alkylation
Intramolecular O-alkylation
II
x
x
O
O
O
N
HO
N
O
O
HO
HO
O
N
O
HO
HO
O
O
O
HO
9
O
N
10
O
N
O
N
HO
OH
6a
O
10 a
O
N
N
O

20
15
10
5
b
a
c
0
-5
-10
-15
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
E/V vs.Ag/AgCl
Figure 1. Cyclic voltammograms of 1 mM methyl caffeate: (a) in the absence; (b) in the presence of 1Mm1,3-
dimethyl barbituric acid ; and (c) 1 mM 1,3-dimethyl barbituric acid in the absence of methyl caffeate, at a glassy
carbon electrode in phosphate buffer solution. (0.2 M, PH = 7); scan rate: 100 mV s−1; T=40±1 °C.

70
60
50
40
30
20
10
0
a
e
-10
-20
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
E/V vs. Ag/AgCl
Figure 2. Cyclic voltammograms of 0.5 mmol methyl caffeate in the presence of 0.5 mmol 1,3-dimethyl
barbituric acid, at a glassy carbon electrode during controlled potential coulometry at 0.33 V vs.
Ag/AgCl. After consumption of: (a) 0, (b) 140, (c) 230, (d), 240 and (e) 260 C. Scan rate 100 mV s−1; t =
40 ± 1 °C