Direct electrosynthesis of a series of novel caffeic acid analogues through a clean and serendipitous domino oxidation/thia-Michael reaction

Article abstract of DOI:10.1039/c4ra02046d

A series of novel caffeic acid analogues have been synthesized in an experimentally simple electrochemical procedure employing electrons as the only reagents in aqueous solution without introducing any catalyst or oxidant. It has been shown that the react

Full text of DOI:10.1039/c4ra02046d

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Page 1 of 17
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Direct electrosynthesis of a series of novel caffeic acid analogues
View Article Online
DOI: 10.1039/C4RA02046D
through a clean and serendipitous domino oxidation/thia-Michael
reaction
A. Alizadeh*a,b, M. M. Khodaei*a, M. Fakharia and M. Shamsuddinb
a Department of Organic Chemistry, Faculty of Chemistry and Nanoscience & Nanotechnology Research
Center (NNRC), Razi University, Kermanshah, 67149 Iran; Phone: (98) 831 4274562 (Ext. 300); Fax: (98)
831 4274559; Email: ahalizadeh2@hotmail.com;
b Ibnu Sina Institute for Fundamental Science Studies, Universiti Teknologi Malaysia, 81310 UTM, Johor
Baharu, Johor, Malaysia
ABSTRACT
A series of novel caffeic acid analogues have been synthesized in an experimentally simple
electrochemical procedure employing electrons as the only reagents in aqueous solution without
introducing any catalyst or oxidant. It has been shown that the reactions proceed via a domino of
electrochemical and chemical events (EC mechanism) with an interesting regioselectivity in the
formation of arylsulfonyl-functionalized N-caffeoyl amides and caffeate esters. All products were
purely obtained at the surface of anode (carbon rods) in excellent yields and no extra purification
was needed. Structural characterization of these novel compounds was also performed using
various spectroscopic techniques: FT-IR, 1HNMR, 13CNMR and HR-Mass.
Introduction

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Caffeic acid and its naturally occurring derivatives are the main representatives of the
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DOI: 10.1039/C4RA02046D
hydroxycinnamic and phenolic acids and widely distributed in plants, vegetables, and propolis as
simple derivatives such as esters, amides, glycosides, and sugar esters.1 The physiological
functionality of caffeic acid and its analogues has attracted a great deal of attention in recent years.
They are known to have many biological activities like antibacterial,2, 3 antifungal,4, 5 antiviral,6
anti-oxidative,7-10 and proteins cross-linker properties.11 On the other hand, sulfone fragments are
important building blocks in medicinal chemistry12 and also useful intermediates in a wide range of
fields such as polymers13 and organic synthesis.14-16 By considering the unique synthetic and
biomedical potential of caffeic acids and sulfones, we envisioned that cross-combination of these
moieties through biocompatible approaches might lead to the formation of novel compounds
possessing dual synthetic and biological potential functionalities. A literature survey revealed that
despite their promising biological features, the synthesis of polyfunctional adducts bearing caffoeyl
and arylsulfonyl groups have not been subjected to detailed investigations and only one study of
Zeng and co-workers in 2007 has reported the electrochemical synthesis of two caffeic acid
derivatives.17
The advances in electrochemical-induced synthesis in the last few years have provided
organic chemists with a clean and convenient synthetic device of great promise.18-22
Electrochemical reaction works based on the electron transfer in the Helmholtz layer at the
electrode-solution interface23. Several features of electron-transfer reactions between ions and
molecules in solution have been widely explored in chemical and electrochemical systems24. For
example, many rate constants of electron transfer reactions in solution and at electrodes have been
measured and some quantitative comparisons of the data in these two fields have been performed25,
26. Furthermore, many experimental and theoritical efforts have been made to develop various
aspects of electron-transfer processes27, 28. Through these chemical and electrochemical processes,
highly reactive intermediates (i.e., cation-radicals, anione-radicals etc.) can be generated under very
mild conditions, such as ambient temperatures, normal pressure, and often in non-halogenated

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solvents. Electrochemical oxidation reactions of organic compounds such as catechol,
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DOI: 10.1039/C4RA02046D
hydroquinone, phenols and aminophenols in aqueous solution are biocompatible and similar to
enzymatic oxidation in biological systems29, 30. Since the basic of electrochemical reactions and
principal biological function of cytochromes P450 is electron transfer31, they often parallel the
cytochrome P450-catalyzed oxidation in liver microsomes32. Direct electrochemical
oxidation/reduction of substrates utilizes practically electrons as the only reagents in synthetic
organic reactions. For instance, the concept of electrochemical oxidation of catechols and
subsequent trapping of their nascent o-benzoquinones with nucleophiles goes back at least as far as
1976 when, for the first time, Tabakovic and co-workers reported that electrochemically-generated
o-benzoquinones could simply undergo 1,4-Michael addition reactions with a varieaty of
nucleophiles33. In this sense, electrochemistry is frequently referred to as one of the prototypical
simple and green procedures for synthesizing various organic molecules and structures.34
Therefore, the electrochemical feasible approach to functionalized novel caffeic acid analogues
seems to be a highly attractive approach from a mechanistic and synthetic point of view as it allows
the combination of the synthetic virtues of a mild electrooxidation protocol with the benefits and
convenience of green chemistry.
Inspired by the above facts and in continuation of our ongoing research program in the field
of chemical and electrochemical domino reactions,35-38 herein we report an experimentally simple
and clean method for the synthesis of a series of amides and esters analogues of caffeic acid
bearing arylsulfonyl moiety with pharmaceutical applications. All reactions occur in a domino of
electrochemical and chemical events in aqueous solution and ambient conditions with high atom
economy and excellent current efficiencies.
Results and discussion

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The starting N-caffeoyl amides (1a, 1b) and alkyl caffeate esters (1c-e) were simply synthesized
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DOI: 10.1039/C4RA02046D
following the previously reported procedures9, 39 (Scheme 1) and then used in our further
electrochemical investigations and in final preparative electrolyses as electroactive starting
materials.
CH3
NH
N
O
1o or 2o amine
O
BOP/Et3N
DMF/CH2Cl2
OH
O
HO
OH
1a
HO
OH
1b
HO
OH
CH3
O
CH3
O
H3C
O
H3C
caffeic acid
O
O
O
1o or 2o ROH
SOCl2, DMF
HO
OH
HO
OH
HO
OH
1c
1d
1e
Scheme 1 Procedures for the synthesis of starting N-caffeoyl amides and caffeate esters.
Cyclic voltammogram of a 1 mM solution of N-caffeoyl piperidine (1a) in water/acetonitrile
(80/20) solution containing sodium phosphate (0.2 M, pH = 7) shows one anodic peak (A1) and a
corresponding cathodic peak (C1), which correspond to the transformation of 1a to its
corresponding o-benzoquinone (2a) (Scheme 2) and vice versa through a quasi-reversible two-
electron process (Fig. 1, curve a). A peak current ratio (IpC1/IpA1) of nearly unity can be
considered as a criterion for the stability of o-benzoquinone produced at the surface of electrode,
under the experimental conditions. In other words, any side reactions such as hydroxylation and/or
dimerization reactions are too slow to be observed at the time scale of cyclic voltammetry. To get
further support on the electrochemical oxidation of 1a, it was studied in the presence of sodium p-

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toluenesulfinate (3). Although o-benzoquinones are extremely reactive and often difficult to isolate,
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DOI: 10.1039/C4RA02046D
they can be easily generated in situ by oxidation of their corresponding catechols and then trapped
by sulfur nucleophiles.38, 40, 41 Fig. 1, curve b, shows the cyclic voltammogram obtained for a 1 mM
solution of 1a in the presence of 1 mM of 3. As seen, the voltammogram exhibits two anodic (A1)
and (A2) and one cathodic (C1) peaks. The new anodic (A2) peak is attributed to the
electrooxidation of product which is formed at the surface of electrode. Also notably, comparison
of the cathodic part of curves a and b shows a complete decrease in the current density for curve b.
This clearly reveals that, compared to the back-reduction of 2a to 1a, the intermolecular Michael-
type addition of 3 to 2a is dominant and fast process and as result cathodic part of curve b is
completely disappeared. These facts are in a good agreement with the high reactivity of
electrogenerated o-benzoquinone 2a toward 3 and the formation of Michael adduct through an
12
A2
A1
8
b
4
c
0
a
-4
C1
-8
-0.6
-0.3
0 0.3
E/V vs. SCE
0.6
0.9
Fig. 1 Cyclic voltammograms of 1 mM of 1a: (a) in the absence; (b) in the presence of 1 mM of 3; and (c) 1 mM of 3
in the absence of 1a at a glassy carbon electrode in sodium phosphate solution (0.2 M, pH = 7); scan rate: 100 mV s-1;
T = 25 1° C.
interfacial reaction at the electrode surface. The cyclic voltammogram of a 1 mM solution of 3 is
shown in Fig. 1, curve c, for comparison.

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Furthermore, our investigations on the preparative electrolysis of 1a in the presence of 3,
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DOI: 10.1039/C4RA02046D
began with the optimization of the reaction conditions. According to the aforementioned cyclic
voltammetry studies, we found that the optimum conditions required a graphite anode,
water/acetonitrile (80/20 v/v) as the solvent, and sodium phosphate solution (0.2 M, pH = 7) as the
supporting electrolyte. In addition, 0.5 equivalent of 1a and 0.5 equivalent of nucleophile 3 were a
good reagent combination for this reaction. In the meantime, the anode potential was maintained at
+0.21 V vs SCE, which is at a potential for which 1a could be oxidized to the corresponding o-
benzoquinone form and vice- versa within a reversible two-electron process. The continuously low
concentration of the electrogenerated ortho-benzoquinone 2a, together with the large excess of 3,
promotes the Michael-type reaction at the expense of other side reactions and this intermolecular
event seems to be much faster than the other side reactions.
70
50
a
f
30
10
e
-10
-0.6
-0.3
0
0.3
E/V vs. SCE
0.6
0.9
Fig. 2 Cyclic voltammograms of 0.5 mmol amide 1a in the presence of 0.5 mmol of nucleophile 3, at a glassy carbon
electrode during controlled potential coulometry at 0.21 V vs. SCE. After consumption of: (a) 0, (b) 25, (c) 40, (d), 65
and (e) 80 C. Scan rate 100 mV s−1; T = 25 1 °C; (f) Variation of peak current (IpA1) versus charge consumed.

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As seen in Fig. 2, the electrolysis progress was simply monitored using cyclic voltammetry,
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DOI: 10.1039/C4RA02046D
and it was found that proportional to the advancement of coulometry, the anodic peak decreases
and disappears when the charge consumption becomes about 2e- per molecule of 1a.
In addition to the above-mentioned electrochemical observations, some additional
experimental tests were performed to allow us to understand more about the mechanism and the
rate-determining step (RDS) of this reaction. The mechanism and RDS of the sequential
oxidation/Michael addition reactions of o-benzoquinones with N- and S-nucleophiles have been
previously investigated in details by Mavri’s group using computational calculations employing
modern quantum chemical methods42, 43. Their calculations nicely demonstrated that RDS of these
sequential reactions is Michael addition between quinones and nucleophiles43. Having this in mind,
we assumed that in the present study, among three steps shown in scheme 2: i) anodic oxidation of
1a to 2a, ii) nucleophilic Michael addition of 3 to 2a and iii) rearomatization of 4a to 5a, the rate-
limiting step is the Michael addition of 3 to 2a. The accuracy of this assumption was evaluated
experimentally by varying the ratio of starting materials (1a:3). According to the basic principals of
chemical kinetic44, it was expected that, if the Michael nucleophilic addition of 3 to 2a is the RDS,
then any change made in the concentration of 3 should directly affect the overall rate of the reaction
and total time of the electrolysis. To explore this, we carried out the elctrolysis of 1a in the
presence of 3 using two different ratio (1:1and 1:5) under the potential-controlled condition. It was
found that, proportional to the increasing of 3 to 1a concentration ratio, the elctrolysis was
completed in much shorter time indicating the dependence of the overal rate of reaction to the
concentration of nucleophile 3. On the other hand, changing the starting material from 1a to 1b had
no remarkable effect on the time of electrolysis, confirming that the overall rate is independent of
the concentration of 1a. All together, these experimental evidences clearly proved that the rate-
limiting step of the three-step sequential reaction between 1a and 3 was nucleophilic Michael
addition rather than anodic oxidation or rearomatization steps and the overall rate of reaction was
therefore more or less equal to the rate of the nucleophilic Michael addition step. Therefore, this

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three-step one-pot coupling reaction was considered as a sequential reaction composed of at least
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DOI: 10.1039/C4RA02046D
one electron transfer step (E) at the electrode and a preceding and follow-up C-S bond forming step
(C) (Scheme 2). The irreversible bond formation is the most common following coupled chemical
reaction in EC mechanism45.
The overoxidation of 5a was circumvented during the preparative reaction (anode potential
maintained at +0.28 V), since its oxidation seems to be more difficult than the parent starting
molecule 1a, by virtue of the presence of tolylsulfonyl group with electron-withdrawing character
on the dihydroxybenzene ring. The electrochemical efficiency (current efficiency) of this
controlled-potential coulometry was simply calculated using the Faraday’s law and found to be >
95% (EC mechanism needs at least two electrons, n=2 and 2F charge consumption per each mol of
1a). Under these reaction conditions, a highly functionalized caffeic acid analogue 5a bearing an
aryl sulfonyl moiety was purely obtained in excellent yield and no extra purification was needed.
The product was characterized by various spectroscopic techniques: FT-IR, 1HNMR, 13CNMR and
HRMS.
From the mechanistic point of view, it is worthy to mention that the existence of an unsaturated
substituent at C-4 position of 2a would probably cause this Michael acceptor to be attacked by 3 at
one of the four possible electrophilic sites (C-3, C-5, C-6, or C-8, Scheme 2) and formation of four
regioisomers (5a-8a). Since the substituent at C-4 position has an electron-withdrawing character,
we suggest 2a to be more electropositive at C-5 position and selectively attacked from this site by 3
leading to the formation of regioisomer 5a. The accuracy of this suggestion was proved by means
1
of theoretical46 and experimental H NMR studies. Addition of 3 to C-3 position in generation of
6a, once ortho hydrogens would couple, may result in two doublets with a coupling constant of
1
about 7-8 Hz in H NMR spectrum, however, addition of 3 to the C-6 position may lead to the
formation of 7a with two doublets with a coupling constant of about 3-4 Hz. Also, addition of 3 to
C-8 position gives a complex signal pattern with various possible coupling in product 8a (Table 1).

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O
O
O
Anodic oxidation
-
+ 2H+
+
2e
View Article Online
(1)
HO
HO
O
O
E
N
N
N
O
DOI: 10.1039/C4RA02046D
1a
3
2a
NaO2S
O
N
H+
O
O
+
8
O
(2)
Michael addition
C
5
HO
S
6
H
CH3
O
4a
3
2a
CH3
O
O
H
H
O
O
SO2-Tol
(3)
HO
HO
HO
HO
8
N
HO
HO
HO
HO
3
O
5
6
SO2-Tol
S
SO2-Tol
O
6a
7a
8a
5a
CH3
Scheme 2 Proposed mechanism for the electrochemical oxidation of N-caffeoyl piperidine in the presence of sodium p-
toluenesulfinate.
1
On the other hand, H NMR spectrum of the obtained product (Fig. 3) shows two singlets
appeared at 7.21 and 7.49 ppm which is in a good agreement with two aromatic protons in para
position47 and formation of the single regioisomer 5a.
Table 1 Experimental and theoretical 1H NMR data for possible structures 5a-8a
Structure
Experimental
Theoretical
J (Hz)/(multiplicity)
δ (ppm)
J (Hz)/(multiplicity)
δ (ppm)
7.21, 7.49
0.0 / (s)
6.9-7.6
7.2-8.1
7.0-8.0
3J = 7.5-8 (d)
4J = 2-3 (d)
6a
7a
8a
3J = 7.5-8 (d)
4J = 2-3 (d)
5J = <1 or (s)
7.3-7.5
5J = <1 or (s)
5a

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View Article Online
DOI: 10.1039/C4RA02046D
Fig. 3 Experimental 1HNMR spectrum of 5a in DMSO-d6 (expanded 5-10 ppm)
With a reliable set of conditions in hand, and in examining the scope and generality of the
developed protocol as well as the influence of structural variation of caffeic acid amides and esters
on their reactivity toward 3, we studied the reaction of other caffeic acid derivatives (1b-1e) with 3.
It was found that the electro-oxidation of these caffeic acid derivatives in the presence of 3 proceed
in a way similar to that of 1a. For instance, Fig. 4, curve b, shows the cyclic voltammogram
obtained for a 1 mM solution of isopropyl caffeate (1e) in the presence of 1 mM of 3. As it is seen,
20
A2
A1
15
10
b
5
a
0
c
-5
C1
-10
-0.5
-0.3
-0.1
0.1 0.3
E /V vs. SCE
0.5
0.7
0.9
Fig. 4 Cyclic voltammograms of 1 mM of 1e: (a) in the absence; (b) in the presence of 1 mM of 3; and (c) 1 mM of 3 in
the absence of 1e at a glassy carbon electrode in sodium phosphate solution (0.2 M, pH = 7); Scan rate: 100 mV s−1; T=
25 1° C.

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Table 2 Electroanalytical and preparative electrolysis data for preparation of 5a-e a
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Starting
Peak
Peak potentials (V)c
Applied
potential at
carbon rodsd
Product
C.E.e/
DOI: 10.1039/C4RA02046D
material potentials (V)b
Yieldf
(%)
Epox
0.24
Epred
0.16
Epox1
0.24
Epox2
0.41
Epred1
-
O
+ 0.21
1a
N
HO
HO
96/78
O
S
O
CH3
CH3
5a
O
0.26
0.11
0.25
0.40
-
+ 0.24
1b
N
H
HO
HO
O
S
93/89
O
CH3
5b
O
0.28
0.22
0.29
0.44
-
+ 0.25
1c
CH3
O
HO
HO
O
S
98/90
O
CH3
CH3
5c
O
0.29
0.22
0.30
0.49
-
+ 0.28
1d
O
HO
HO
96/92
O
S
O
CH3
5d
O
CH3
0.25
0.15
0.24
0.40
-
+ 0.24
1e
O
CH3
CH3
HO
HO
96/78
O
S
O
5e
a
Cyclic voltammetry measurements were performed in 4:1 (V:V) of 0.2 M phosphate buffer solution (pH = 7) and
b
CH3CN, glassy carbon (GC) working electrode; scan rate 100 mV/s. Reference electrode: SCE. 1 mM 1 in the
c
absence and, in the presence of 1 mM 3. d Controlled-potential coulometries were carried out in 0.2 M phosphate
buffer solution, at carbon rods; reference electrode: SCE, e Calculated using the Faraday’s law, f Isolated yields.
similar to that of 1a, the voltammogram exhibits two anodic (A1) and (A2) peaks and a cathodic
peak (C1). Comparison of the cathodic part of curves a and b shows a considerable decrease in the
case of curve b which is in a good agreement with the electrooxidation of 1e to its relevant o-

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benzoquinone, interfacial Michael addition of 3 to the intermediate 2e, followed by a re-
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aromatization process to form the Michael adduct 5e at the electrode surface through an EC
mechanism. Furthermore, the electrochemical investigation of the other starting materials (1b, 1c,
1d) in the presence of 3 was pursued in more details and the results are summarized in Table 2.
From mechanistic points of view, it was also found that changing the functionalities on the
starting materials has no subtle electronic and steric effects on the reactivity of their relevant o-
bezoquinones and almost similar current efficiencies and mechanistic pathways (EC) can be
considered for these structures. Also, in preparative electrolysis, four novel and highly
functionalized caffeic acid analogues 5b-e were purely obtained in excellent yields via the EC
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.
Experimental
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 a large platinum gauze
constituted the counter electrode. The working electrode potentials were measured versus SCE.
1H and 13C NMR spectra were recorded on a spectrometer operating at 200 MHz and 50 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 MAT 8200 Finnigan (EI, 70 eV) high resolution mass spectrometer; the latter employed a

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mass of 12.0000 for carbon and the data are listed as follows: mass-to charge ratio (m/z). Infrared
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spectra were recorded neat and are reported in wavenumbers (cm-1). All chemicals were reagent-
grade materials and solvents and reagents were of pro-analysis grade. These chemicals were used
without further purification.
Typical electrolysis procedure
In a typical experiment, controlled potential electrolysis (CPE) was carried to a 100 mL of suitable
buffer solution in water/acetonitrile mixture containing 0.5 mmol of caffeic acid derivatives (1a-e)
and 0.5 mmol of sodium p-toluenesulfinate (3), 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 (V) vs. SCE (see Table 2) at ambient condition. In order to minimize the ohmic
drop, the reference electrode was kept in close proximity to the working electrodes.
The progress of electrolysis was followed by recording periodically the decreases in current
with time and eventually, the electrolysis was terminated when the current decreased by more than
95% (also monitored by TLC). 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. The
precipitated solid was collected by filtration and washed copiously with distilled water and with no
extra purification process this protocol led to the desired Michael adducts 5a-e.
3-[4,5-Dihydroxy-2-(toluene-4-sulfonyl)-phenyl]-1-piperidin-1-yl-propenone (5a)
1
The product was isolated as a pale white solid in 78% yield (156.44 mg): mp = 207°C; H NMR
(200 MHz, DMSO-d6) δ 1.42 (m, 4H), 1.55 (m, 2H), 2.31 (s, 3H), 3.47 (m, 4H), 4.22-4.30 (br,
OH), 6.77 (d, J = 15 Hz, 1H), 7.21 (s, 1H), 7.32 (d, J = 8 Hz, 2H), 7.49 (s, 1H), 7.62 (d, J = 8
Hz),8.05 (d, J = 15 Hz, 1H); 13C NMR (50 MHz, DMSO-d6) δ (ppm) 21.4, 24.6, 32.1, 48.2, 115.7,
116.4, 120.3, 126.9, 127.4, 129.5, 130.2, 137.1, 139.7, 144.1, 147.2, 151.2, 164.4; IR (neat) ν 3319,

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3105, 2947, 1637, 1572, 1446, 1335 (SO2), 1290, 1146 (SO2), 1088 cm-1; HRMS (EI): m/z calcd
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DOI: 10.1039/C4RA02046D
for C21H23NO5S: 401.1296; found: 401.1173.
3-[4,5-Dihydroxy-2-(toluene-4-sulfonyl)-phenyl]-N-ethyl-acrylamide (5b)
1
The product was isolated as a white solid in 89% yield (160.69 mg): mp = 214°C; H NMR (200
MHz, DMSO-d6) δ 1.03 (t, J = 7 Hz, 3H), 2.31(s, 3H ), 3.15 (m, 2H), 6.16 (d, J = 15 Hz, 1H), 6.96
(s, 1H), 7.34 (d, J = 8 Hz, 2H), 7.52 (s, 1H), 7.62 (d, J = 8 Hz, 2H), 8.01 (d, J = 15 Hz, 1H); IR
(neat) ν 3394 (NH), 3313, 33086, 2978, 1660, 1587, 1330 (SO2), 1140 (SO2), 1086 cm-1; HRMS
(EI): m/z calcd for C18H19NO5S: 361.0983; found: 361.0914.
3-[4,5-Dihydroxy-2-(toluene-4-sulfonyl)-phenyl]-acrylic acid methyl ester (5c)
1
The product was isolated as a white solid in 90% yield (156.63 mg): mp = 240-242°C; H NMR
(200 MHz, DMSO-d6) δ 2.35 (s, 3H), 3.72 (s, 3H), 6.21 (d, J = 15.7 Hz, 1H), 7.18 (s, 1H), 7.4 (d, J
13
= 8 Hz, 2H), 7.55 (s, 1H), 7.65 (d, J = 8 Hz, 2H), 8.28 (d, J = 15.7 Hz, 1H); C NMR (50 MHz,
DMSO-d6) δ (ppm) 20.0, 52.0, 114.0, 116.0, 118.0, 124.0, 127.0, 129.0, 130.0, 140.0, 140.0, 143.0,
149.0, 152.0, 166.0; IR (neat) ν 3292, 2949, 1709, 1581, 1442, 1308, 1132, 1086 cm-1; HRMS (EI):
m/z calcd for C17H16O6S: 348.0667; found: 348.0612.
3-[4,5-Dihydroxy-2-(toluene-4-sulfonyl)-phenyl]-acrylic acid ethyl ester (5d)
1
The product was isolated as a light brown solid in 92% yield (166.56 mg): mp = 214-216°C; H
NMR (200 MHz, CO(CD3)2) δ 1.29 (t, J = 7 Hz, 3H), 2.35 (s, 3H), 4.19 (q, J = 7 Hz, 2H), 5.50 (br,
OH), 6.09 (d, J = 15.7 Hz, 1H), 7.16 (s, 1H), 7.32 (d, J = 8 Hz, 2H), 7.63 (s, 1H), 7.72 (d, J = 8 Hz,
2H), 8.5 (d, J = 15.7 Hz, 1H);13C NMR (50 MHz, CO(CD3)2) δ (ppm) 13.8, 20.5, 59.9, 114.2,
116.3, 118.2, 124.8, 127.2, 129.6, 130.4, 140.3, 140.6, 143.6, 149.4,152.1, 166.0; IR (neat) ν 3330,
3007, 2983, 1697, 1587, 1473, 1315, 1136, 1086 cm-1; HRMS (EI): m/z calcd for C18H18O6S:
٣٦٢.٠٨٢٤; found: 362.0911.

Page 15 of 17
RSC Advances
3-[4,5-Dihydroxy-2-(toluene-4-sulfonyl)-phenyl]-acrylic acid isopropyl ester (5e)
View Article Online
DOI: 10.1039/C4RA02046D
1
The product was isolated as a white solid in 90% yield (169.92mg): mp = 193-195°C; H NMR
(200 MHz, DMSO-d6) δ 1.26 (d, J = 6 Hz, 6H), 2.35(s, 3H), 4.99 (septet, J = 6 Hz, 1H), 6.11 (d, J
= 15.7 Hz, 1H), 7.16 (s, 1H), 7.38 (d, J = 8 Hz, 2H), 7.57 (s, 1H), 7.65 (d, J = 8 Hz, 2H), 8.25 (d, J
= 15.7 Hz, 1H);13C NMR (50 MHz, DMSO-d6) δ (ppm) 21.4, 22.1, 68, 115.2, 116.6, 119.7, 125,
127.2, 130.2, 130.4, 139.4, 139.8, 139.9, 144.5, 148, 151.1, 165.8; IR (neat) ν 3373, 3280, 3011,
2981, 1655, 1577, 1448, 1350, 1136, 1086 cm-1; HRMS (EI): m/z calcd for C19H20O6S: 376.0980;
found: 376.0920.
Conclusion
In summary, we have established a successful use of electric current as a clean tool in oxidation of
amides and esters derivatives of caffeic acid to produce a series of highly substituted novel caffeic
acid analogues. The developed synthetic protocol is based on a feasible and clean approach
employing electrons as the only reagents in aqueous solution without introducing any catalyst or
oxidant. We think that this simple electrooxidative coupling protocol with its advantages of
complementary reactivity, and especially dramatically technical feasibility may find potential
applications in synthetic organic chemistry. In addition, we hope that because of the diversity of
this procedure and the possibility of introducing variations in both Michael-addition partners, it can
be adopted in bioorganic chemistry to synthesize and screen libraries of related biologically
important structures.
Acknowledgments
The authors are grateful to Razi University and Universiti Teknologi Malaysia for their financial
support for accomplishment of the work and for providing necessary facilities.

RSC Advances
Page 16 of 17
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