An environmentally friendly electrochemical method for synthesis of benzofuranoquinone derivatives

Article abstract of DOI:10.1248/cpb.55.1198

Electrochemical oxidation of catechols (1a-c) has been studied in the presence of 2-hydroxy-1,4-naphtoquinone (3b) in aqueous solutions, using cyclic voltammetry and controlled-potential coulometry. The results indicated that the electrochemically generated o-benzoquinones (2a-c) participate in Michael addition reaction with 3b to the corresponding benzofuranoquinones (8a-c, 10a-c). The electrochemical synthesis of these compounds has been successfully preformed at a carbon rod electrode with good yields using an environmentally friendly method.

Full text of DOI:10.1248/cpb.55.1198

1198
Chem. Pharm. Bull. 55(8) 1198—1202 (2007)
Vol. 55, No. 8
An Environmentally Friendly Electrochemical Method for Synthesis of
Benzofuranoquinone Derivatives
Saied Saeed HOSSEINY DAVARANI,*,a Mojtaba SHAMSIPUR,b Davood NEMATOLLAHI,*,c
a
Somayyeh RAMYAR,a and Leila MASOUMI
a Department of Chemistry, Faculty of Science, Shahid Beheshti University; Tehran 1983963113, Iran: b Department of
Chemistry, Faculty of Science, Razi University; Kermanshah 67149, Iran: and c Faculty of Chemistry, Bu-Ali Sina
University; Hamadan 65174, Iran. Received March 28, 2007; accepted May 27, 2007
Electrochemical oxidation of catechols (1a—c) has been studied in the presence of 2-hydroxy-1,4-naphto-
quinone (3b) in aqueous solutions, using cyclic voltammetry and controlled-potential coulometry. The results
indicated that the electrochemically generated o-benzoquinones (2a—c) participate in Michael addition reaction
with 3b to the corresponding benzofuranoquinones (8a—c, 10a—c). The electrochemical synthesis of these com-
pounds has been successfully preformed at a carbon rod electrode with good yields using an environmentally
friendly method.
Key words Michael addition reaction; electrochemical synthesis; cyclic voltammetry; catechol; 2-hydroxy-1,4-naphtoquinone;
benzofuranoquinone
Catechol derivatives are a promising group of compounds and antimalarial activities12) and many of them are also in-
worthwhile for further investigation, which may lead to volved in enzyme inhibition and DNA cross-linking.13) With
the discovery of selective acting, biodegradable agrochemi- due attention to our experiences on electrochemical synthesis
cals having high human, animal and plant compatibility.1) of organic compounds,14—22) we thought that synthesis of a
Catechol itself and mono-substituted catechols (–OH, –CH3, new organic compounds (8a—c, 10a—c) with triad struc-
–OCH3, –CHO, –COOH) are active in part against Pseudo- tures of catechol, benzofuran and quinone would be useful
monas, Bacillus, but not Penicillium species. Caffeic acid is from the point of view of pharmaceutical properties.
inhibitory to soil bacteria and fungi, but species differences
This idea prompted us to investigate the electrochemical
exist, while its methyl ester has more pronounced activity oxidation of catechols 1a—c in the presence of 2-hydroxy-
against Bacillus and Pseudomonas species. Hydroxychavicol 1,4-naphtoquinone (3b) as a nucleophile and represent a
inhibits a greater number of microorganisms including facile and one-pot electrochemical method for the synthesis
Pseudomonas, Cladosporium and Pythium species. Many of of some new organic compounds (8a—c, 10a—c) in high
flavonoids and catechol derivatives turned out to be as yield using an environmentally friendly method.
antimicrobial agents.2) Also, in recent years, medicinal prop-
erties of benzofuran derivatives have been investigated Results and Discussion
widely and were shown to be effective as antitumor,3) anti-
Electrochemical Study Cyclic voltammetry of 2 mM of
depressant,4) antifungal,5) anti-hypertensive, and cytotoxic.6) catechol (1a) in aqueous solution containing 0.2 M acetate
They are also potent and selective oxytocin antagonists,7) buffer (pHꢀ5.0) shows one anodic (A1) and the correspond-
PDE5 inhibitor for treatment of erectile dysfunction,8) and H3 ing cathodic peak (C1) which corresponds to the transforma-
receptor antagonists.9) On the other hand, quinones are of tion of 1a to o-benzoquinone (2a) and vice-versa within a
considerable interest because many drugs such as doxoru- quasi-reversible two-electron process (Fig. 1, curve a). Figure
bicin, daunorubicin and mitomycin C in cancer chemother- 1, curve b, shows cyclic voltammogram of 2 mM of 2-hy-
apy contain quinones,10) whereas various other quinones have droxy-1,4-naphtoquinone (3b) in aqueous solution contain-
found use in industry.11) Some of them also exhibit antitumor ing 0.2 M acetate buffer (pHꢀ5.0). Cyclic voltammogram ex-
Fig. 1. (a) Cyclic Voltammogram of 2 mM Catechol (1a), (b) Cyclic Voltammogram of 2 mM 2-Hydroxy-1,4-naphtoquinone (3b), (c) Cyclic Voltammo-
gram of 2 mM 1a in the Presence of 2 mM 3b, at a Glassy Carbon Electrode, in Aqueous Solution Containing 0.2 M Acetate Buffer (pHꢀ5.0)
Scan rate: 100 mV sꢁ1. tꢀ25ꢂ1 °C.
∗ To whom correspondence should be addressed. e-mail: nemat@basu.ac.ir
© 2007 Pharmaceutical Society of Japan

August 2007
1199
hibits one anodic (A2) and the corresponding cathodic peak was studied in some detail. Figure 1, (curve c) shows the
(C2) which corresponds to the transformation of naphthalene- cyclic voltammogram obtained for a 2 mM solution of 1a in
1,2,4-triol (3a) to 3b (Chart 1).23)
the presence of 2 mM 3b. The voltammogram exhibits two
The oxidation of 1a in the presence of 3b as a nucleophile anodic (A1 and A2) and two corresponding cathodic peaks
(C1 and C2). Comparison of voltammogram c with a reveals
that the peak C1 which corresponds to the reduction of o-
benzoquinone (2a) decreased. Furthermore, it is seen that
proportional to the augmentation of potential sweep rate, the
height of the C1 peak increases (Fig. 2). A similar situation is
observed when the 3b to 1a concentration ratio is decreased.
A plot of peak current ratio (IpC1/IpA1) versus scan rate, for a
Chart
1
Fig. 2. Typical Cyclic Voltammograms of 2 mM Catechol (1a) in the Presence of 2 mM 2-Hydroxy-1,4-naphtoquinone (3b), at a Glassy Carbon Electrode,
in Aqueous Solution Containing 0.2 M Acetate Buffer (pHꢀ5.0)
Scan rates from (a) to (e) are: 100, 200, 400, 800, 1600 mV sꢁ1, respectively. (f) Variation of peak current ratio (IpC1/IpA1) versus scan rate. (g) Variation of peak current function
(IpA1/n1/2) versus scan rate.
Chart
2

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Vol. 55, No. 8
Fig. 3. The Possible Products of Electrochemical Oxidation of 3-Methylcatechol (1b) in the Presence of 2-Hydroxy-1,4-naphtoquinone (3b)
Table 1. Experimental and Calculated 13C-NMR Data for Methyl Carbons
mixture of 1a and 3b confirms the reactivity of o-benzo-
quinone (2a) towards 3b, appearing as an increase in the
height of the cathodic peak C1 at higher scan rates (Fig. 2,
curve f). On the other hand, the current function for the A1
peak, (IpA1/n1/2), decreases on increasing the scan rate (Fig. 2,
curve g). Controlled-potential coulometry was performed in
aqueous solution containing 0.25 mmol of 1a and 0.25 mmol
of 3b at 0.5 V versus 3 M Ag/AgCl. Cyclic voltammetric
analysis carried out during the electrolysis shows the pro-
gressive disappearance of A1 peak. All anodic and cathodic
Type
13C-NMR data (ppm)
Experimental
9.2 and 9.3
8.6
8.6
12.6
12.6
Calculated for 8b
Calculated for 10b
Calculated for 11b
Calculated for 12b
peaks disappear when the charge consumption becomes increases with decreasing pH. This can be related to protona-
about 4eꢁ per molecule of 1a. These behavior is adopted as tion of anion 3b and inactivation of it towards Michael addi-
indicative of an ECEC mechanism.24) According to our re- tion reaction with 2a that enhanced by decreasing pH. The
sults, it seems that the Michael addition reaction of anion 3b ratio of “peak current ratio” in the absence and in the pres-
to o-benzoquinone (2a) (Eq. 2) is faster than other secondary ence of 3b [(IpA1/IpC1) )
absence/(IpA1/IpC1 presence] versus pH has
reactions, leading to the intermediates 5a and 6a. The oxida- been shown in Fig. 4. This curve has a maximum in pH 7.0.
tion of these compounds (5a, 6a) is easier than the oxidation Therefore, in this study, solution containing phosphate buffer
of the parent-starting molecule (1a) by virtue of the presence (pH 7.0, 0.2 M) has been selected as more suitable medium
of an electron-donating group. The intramolecular reaction for electrochemical synthesis of compounds 8a—c and
was performed via 1,4-(Michael) addition reaction (Eqs. 4 10a—c.
and 5). The over-oxidation of 8a and 10a was circumvented
during the preparative reaction because of the more difficult
oxidation of formed dihydroxybenzofuranes14) as well as the
insolubility of the products in sodium acetate solution
medium.
Experimental
Reaction equipments are described in an earlier paper.15) All chemicals
(catechols and 2-hydroxy-1,4-naphtoquinone) were reagent-grade materials.
Sodium acetate, phosphate salts and other acids and bases were of pro-
analysis grade. These chemicals were used without further purification.
Electrochemical Synthesis of 8a—c and 10a—c In a typical proce-
dure, 100 ml 0.2 M sodium aqueous acetate solution (or phosphate buffer, pH
7.0, 0.2 M) was pre-electrolyzed at the chosen potential (see Table 2), in a
two compartment cell. Then, 2.0 mmol of catechols (1a—c) and 2-hydroxy-
1,4-naphtoquinone (3b) were added to the cell. The electrolysis was termi-
nated when the decay of the current became more than 95%. Due to the for-
mation of a thin film of product at the surface of the electrode, 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, few drops of
acetic acid were added to the solution and the cell was placed in a refrigera-
tor overnight. The precipitated solids were collected by filtration and washed
with distilled water. After drying, the products were characterized using IR,
1H-NMR, 13C-NMR and MS. The 1H- and 13C-NMR data showed that, in
The electro-oxidation of 3-methylcatechol (1b) in the pres-
ence of 3b is considered to involve the Michael acceptor 2b
as an intermediate that could be attacked at positions C-5 or
C-4 to yield (8b, 10b) and (11b, 12b) respectively (Fig. 3).
The experimental and calculated25) 13C-NMR results for the
methyl carbon in the catechol ring of the products and for the
suggested possible structures are shown in Table 1. Accord-
ing to the 13C-NMR results, we suggest that o-benzoquinone
2b is attacked in all possibilities only in the C-5 position by
3b leading to the formation of the products 8b and 10b. The
same results obtained for 3-methoxycatechol (1c).
The Effect of pH Cyclic voltammogrames of 2 mM solu- each case two isomers were obtained as final products (Chart 2) and column
chromatography attempts for separation of these products were unsuccessful.
tion of 1a in aqueous solutions in pH 2.0—9.0 have been
shown in Fig. 4, curves a. As shown, cyclic voltammograms
show one anodic (A1) and a corresponding cathodic peak
Data for 8a and 10a (C16H8O5): IR (KBr) cmꢁ1: 3510, 3439, 3200, 1646,
1584, 1558, 1472, 1322, 1272, 1202, 1070, 1001, 911, 718. 1H-NMR,
(300 MHz, DMSO-d6) d: 7.10 (1H, s, aromatic in catechol ring), 7.16 (1H, s,
(C1). Furthermore, it is seen that proportional to the increas-
ing of pH, the height of the C1 peak decreases. On the other
hand, in basic solutions, the peak current ratio (IpC1/IpA1) is
less than unity and increases with decreasing pH as well as
by increasing the potential sweep rate. These observation can
be related to the coupling of anionic or dianionic forms of 1a
with o-benzoquinone (2a) (dimerization reaction).26,27) The
oxidation of 1a in the presence of 3b was studied in some de-
tail. Figure 4, (curves b) shows the cyclic voltammogram ob-
tained for a 2 mM solution of 1a in the presence of 2 mM 3b
aromatic in catechol ring), 7.26 (1H, s, aromatic in catechol ring), and 7.43
(1H, s, aromatic in catechol ring), 7.53—8.05 (8H, m, aromatic), 9.49 (1H,
s, hydroxyl), 9.58 (1H, s, hydroxyl), 9.83 (1H, s, hydroxyl), 10.17 (1H, s, hy-
droxyl) (the peaks 9.49, 9.58, 9.83 and 10.17 will have removed in the pres-
ence of a few drops of D2O). 13C-NMR, (75 MHz, DMSO-d6) d: 99.0, 99.3,
105.8, 106.0, 114.2, 115.3, 122.7, 124.4, 126.5, 126.6, 128.4, 129.8, 130.1,
130.8, 132.8, 133.1, 134.4, 134.5, 135.4, 145.5, 146.8, 146.9, 149.7, 150.4,
151.8, 152.2, 160.7, 173.9, 175.2, 179.9, 182.0. MS (EI): m/z (relative inten-
sity): 280 (100), 252 (30), 150 (25), 139 (35), 126 (20), 69 (35), 50 (30).
Data for 8b and 10b (C17H10O5): IR (KBr) cmꢁ1: 3535, 3224, 1643, 1555,
1481, 1326, 1271, 1070, 999, 867, 794, 671, 471. 1H-NMR, (300 MHz,
DMSO-d6) d: 2.32 (3H, s, methyl), 2.34 (ꢀ3H, s, exact valueꢀ2.70,
methyl), 7.16 (ꢀ1H, s, exact valueꢀ0.85, aromatic in catechol ring), 7.34
in pH 2.0—9.0. As it shown, the peak current ratio (IpC1/IpA1
)

August 2007
1201
Fig. 4. Cyclic Voltammograms of (a) 2 mM 1a in the Absence of 3b, (b) 2 mM 1a in the Presence of 2 mM 3b in Various pHs
XꢀIpA1/IpC1 in the absence of 3b. YꢀIpA1/IpC1 in the presence of 3b. Other conditions are the same as reported in Fig. 1.
Table 2. Electroanalytical and Preparative Data
ring), 7.54—8.08 (ꢀ7H, m, aromatic), 9.08 (ꢀ1H, s, exact valueꢀ0.76, hy-
droxyl), 9.62 and 9.66 (ꢀ2H, s, s, exact valueꢀ1.75, hydroxyl), 10.01 (1H,
s, hydroxyl). 13C-NMR, (75 MHz, DMSO-d6) d: 61.0, 61.1, 100.2, 100.8,
114.4, 115.7, 123.0, 124.4, 126.6, 126.7, 129.8, 130.1, 130.9, 132.8, 133.2,
133.6, 134.1, 134.5, 134.6, 135.4, 138.3, 141.9, 144.3, 146.6, 147.9, 152.5,
160.8, 174.0, 175.3, 179.9, 182.0. MS (EI): m/z (relative intensity): 310
(100), 294 (50), 266 (20), 183 (55), 152 (20), 139 (15), 126 (60), 76 (75), 69
(35), 50 (80).
Conversion
Applied potential Products ratioa) Product yield (%)
1a→8a and 10a
1b→8b and 10b
1c→8c and 10c
0.40
0.35
0.35
1 : 1
1 : 0.85
1 : 0.75
76
84
82
a) Based on the area of the corresponding 1H-NMR peaks.
Acknowledgment Financial support from the research affairs of Shahid
Beheshti University is gratefully acknowledged.
(1H, s, aromatic in catechol ring), 7.54—8.06 (ꢀ8H, m, aromatic), 8.88
(ꢀ1H, s, exact valueꢀ0.86, hydroxyl), 9.43 (ꢀ1H, s, exact valueꢀ0.85, hy-
droxyl), 9.77 (1H, s, hydroxyl), 10.19 (1H, s, hydroxyl). 13C-NMR,
(75 MHz, DMSO-d6) d: 9.2, 9.3, 102.8, 103.0, 108.5, 108.9, 113.4, 114.4,
117.1, 122.8, 126.4, 126.6, 128.5, 129.7, 130.0, 130.7, 132.8, 133.1, 134.3,
134.5, 135.4, 144.5, 145.0, 146.3, 147.9, 149.4, 151.4, 160.6, 173.8, 175.3,
180.0, 182.1. MS (EI): m/z (relative intensity): 294 (100), 266 (20), 163
(25), 152.25 (25), 139 (10), 126 (15), 76 (30), 69 (15), 50 (30).
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