Electrochemical oxidation of catechols (=benzene-1,2-diols) in the presence of benzoylacetonitrile: Synthesis of new derivatives of 5,6-dihydroxybenzofuran

Article abstract of DOI:10.1002/hlca.201200029

The electrochemical oxidation of catechol (=benzene-1,2-diol; 1a) and some of its derivatives in H₂O/MeCN 1: 1 containing benzoylacetonitrile (=β-oxobenzenepropanenitrile; 3) as a nucleophile was studied by cyclic voltammetry and controlled-potential coulometry. The voltammetric data showed that electrochemically generated o-benzoquinones (=cyclohexa-3,5-diene-1,2- diones) from catechol (1a) and 3-methylcatechol (1b) participate in a Michael-addition reaction with 3 to form the corresponding 5,6- dihydroxybenzofuran-3-carbonitrile 8 (Scheme1). In this work, we report an efficient one-pot method with high atom economy for the synthesis of new substituted 5,6-dihydroxybenzofuran-3-carbonitriles in an undivided cell under ambient conditions.

Full text of DOI:10.1002/hlca.201200029

Helvetica Chimica Acta – Vol. 95 (2012)
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Electrochemical Oxidation of Catechols (¼ Benzene-1,2-diols) in the Presence
of Benzoylacetonitrile: Synthesis of New Derivatives of 5,6-
Dihydroxybenzofuran
by Davood Nematollahi*, Ali Reza Atlasi-Pak, and Roya Esmaili
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Zip Code 65178-38683, Iran
(phone: þ 98-811-8380647; fax: þ 98-811-8380709; e-mail: nemat@basu.ac.ir)
The electrochemical oxidation of catechol (¼ benzene-1,2-diol; 1a) and some of its derivatives in
H2O/MeCN 1:1 containing benzoylacetonitrile (¼ b-oxobenzenepropanenitrile; 3) as a nucleophile was
studied by cyclic voltammetry and controlled-potential coulometry. The voltammetric data showed that
electrochemically generated o-benzoquinones (¼cyclohexa-3,5-diene-1,2-diones) from catechol (1a) and
3-methylcatechol (1b) participate in a Michael-addition reaction with 3 to form the corresponding 5,6-
dihydroxybenzofuran-3-carbonitrile 8 (Scheme 1). In this work, we report an efficient one-pot method
with high atom economy for the synthesis of new substituted 5,6-dihydroxybenzofuran-3-carbonitriles in
an undivided cell under ambient conditions.
Introduction. – Catechol (¼ benzene-1,2-diol; 1a) and its mono-substituted
derivatives are active in part against Pseudomonas. Also, many flavonoids and catechol
derivatives turned out to be antimicrobial agents [1]. On the other hand, many
compounds having a dihydroxybenzofuran moiety as the core structure show
interesting pharmacological activities [2 – 5]. For example, a series of (2Z)-2-
benzylidene-6,7-dihydroxybenzofuran-3(2H)-ones (cf. Fig. 1) were identified as potent
inhibitors of bacterial chorismate synthase [2].
Fig. 1. Synthase inhibitor (2Z)-2-benzylidene-6,7-dihydroxybenzofuran-3(2H)-one (A) and synthesized
5,6-dihydroxybenzofuran-3-carbonitrile derivatives B
The importance of dihydroxybenzofuran compounds has prompted us to synthesize
a number of these compounds by electrochemical oxidation of catechols in the
presence of some nucleophiles derived from CH-acids such as acetylacetone [6],
dimedone [7], 3-hydroxy-1H-phenalen-1-one [8], and cyanoacetone [9]. In the present
work, in order to extend the above-mentioned strategy, we describe the preparation of
some other new dihydroxybenzofurans using the electrochemical oxidation of catechol
(1a) and 3-methylcatechol (1b) in the presence of benzoylacetonitrile (¼ b-oxobenze-
nepropanenitrile; 3). The present work led to the development of a facile and
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

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reagentless method with high atom economy for the synthesis of some new 5,6-
dihydroxybenzofuran derivatives under ambient conditions in an undivided cell
equipped with a carbon electrode.
Results and Discussion. – Electrochemical Oxidation of Catechol (1a; R ¼ H) and 3-
Methylcatechol (1b; R ¼ Me) in the Presence of Benzoylacetonitrile (3). The cyclic
voltammogram of a 1.0 mm solution of catechol (1a) in H2O/MeCN 1:1 containing
0.20m phosphate buffer (pH 7.0) showed one anodic (A1) and corresponding cathodic
peak (C1) (Fig. 2), which correspond to the transformation of catechol (1a) to o-
benzoquinone (¼cyclohexa-3,5-diene-1,2-dione; 2a) and vice versa within a quasi-
reversible two-electron process [10] (Scheme 1, Eqn. 1). A peak-current ratio (IpC /IpA
)
1
1
of near unity can be considered as a criterion for the stability of o-benzoquinone (2a)
produced at the surface of the electrode under the experimental conditions. In other
words, any other reactions such as hydroxylation [11][12], dimerization [13 – 15], or
oxidative ring cleavage [16][17] of electrochemically generated 2a were too slow to be
observed at the time scale of cyclic voltammetry.
Fig. 2. Cyclic voltammograms of 1.0 mm catechol (1a): a) in the absence of benzoylacetonitrile (3), b) and
c) first and second scan in the presence of 1.0 mm 3, and d) in the presence of 1.0 mm 3 but in the absence of
1a, all at a glassy carbon electrode in H2O/MeCN 1:1 containing 0.2m phosphate buffer (pH 7.0). Scan
rate 100 mV sꢀ1. T 25 ꢁ 18.
The oxidation of 1a in the presence of benzoylacetonitrile (3) as a nucleophile was
studied in some detail. The cyclic voltammogram obtained for a 1.0 mm solution of 1a
in the presence of 1.0 mm 3 (Fig. 2, Curve b) exhibited a remarkable decrease in the
current of peak C1 due to the chemical reaction of 2a with 3 [10]. The second-cycle
voltammogram of 1a in the presence of 3 (Curve c) showed that concomitantly to the
shift of the peak A1 in a positive direction and peak C1 in negative direction, a new
anodic peak (A0) appeared at a less positive potential (Fig. 2, Curve c). This new peak
suggested the presence of a relatively stable intermediate in the electrochemical

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Scheme 1. Electrochemical Oxidation of Catechol (1a; R ¼ H) and 3-Methylcatechol (1b; R ¼ Me) in the
Presence of Benzoylacetonitrile (3)
oxidation of 1a in the presence of 3. The shift of the peaks A1 and C1 in the presence of
3 was due to the formation of a thin film of product at the surface of the electrode,
inhibiting to a certain extent the performance of the electrode process. The voltammo-
gram of 3 (Fig. 2, Curve d) is established a totally irreversible electron-transfer process.
Additionally, proportional to the increase of the potential scan rate, the peak-current
ratio IpC /IpA increased (Fig. 3). A plot of the peak current ratio IpC =IpA vs. the scan
1
1
1
1
rate for a mixture of 1a and 3 confirmed the reactivity of o-benzoquinone 2a towards 3.

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Fig. 3. a) – e) Cyclic voltammograms of 1.0 mm catechol (1a) in the presence of 1.0 mm benzoylacetoni-
trile (3) at a glassy carbon electrode in H2O/MeCN 1:1 containing 0.2m phosphate buffer (pH 7.0), with
the scan rates 25, 50, 100, 200, and 300 mV sꢀ1 from a) to e), resp. f) Variation of peak current ratio
ðIpC =IpA Þ vs. scan rate. T 25 ꢁ 18.
1
1
Controlled-potential coulometry was employed for determining the number of
transferred electrons (n) during the electrode process. In this work, controlled-
potential coulometry of 1a (0.15 mmol) in the presence of 3 (0.15 mmol) at 0.30 V vs.
SCE in H2O/MeCN 1:1 verified the transfer of four electrons per molecule of 1a.
Diagnostic criteria of cyclic voltammetry, including decreasing of peak C1 during
the reverse scan in cyclic voltammetry of 1a in the presence of 3 (Fig. 2) and
reappearance of it with increasing scan rate (Fig. 3) on the one hand, and controlled-
potential coulometry (consumption of ca. 4 eꢀ) on the other hand, accompanied by the
1
IR and H- and 13C-NMR data (see Exper. Part) and a molecular mass of 251 of the
final product, indicated that the reaction mechanism of electrochemical oxidation of 1a
and 1b in the presence of 3 is of the type ECEC (electron transfer, chemical reaction,
electron transfer, and then chemical reaction). According to our data, the intermo-
lecular Michael-addition reaction of the anion 3a of benzoylacetonitrile (enolate) to o-
benzoquinone (2a) leads via 4a to the intermediate 5a. In the next step, 5a, via another
two-electron oxidation process is converted into o-benzoquinone 6a. In the final step,
an intramolecular Michael-addition reaction and aromatization converts 6a via 7a into
8a as the final product. Consequently, the anodic peak A1 pertained to the oxidation of
1a to 2a, peak C1 corresponded to the reduction of 2a, and the new anodic peak A0 was
related to the oxidation of 5a to o-benzoquinone 6a.
The electrochemical oxidation of 3-methlycatechol (1b) in the presence of
benzoylacetonitrile (3) in phosphate buffer solution (pH 7.0, 0.2m) proceeded in a
similar way to that of 1a. But, the presence of the Me group at C(3) of 1b may cause the
Michael acceptor 2b to be attacked by 3 at C(4) (Path A) and/or C(5) (Path B) to yield

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Scheme 2. Possible Products of the Electrochemical Oxidation of 3-Methylcatechol (1b) in the Presence
of Benzoylacetonitrile (3)
two types of products (Scheme 2). The experimental and calculated 13C-NMR chemical
shift [18] of the Me group for the obtained product 8b and the second possible structure
9b in the Table suggested that o-benzoquinone 2b was attacked at C(5) (Path B) by 3
leading to the formation of the product 8b.
Table 1. Experimental and Calculated 13C-NMR Data for the Me Group of the Product from 1b and 3 (cf.
Scheme 2)
d(C) of Me
Experimentala)
Calculated for 8b
Calculated for 9b
9.7
8.6
12.1
a) Experimental data obtained for the filtered product without any purification.
Electrochemical Oxidation of 4-Methylcatechol (1c) in the Presence of Benzoyla-
cetonitrile (3). The voltammetric responses and coulometry results of the electro-
chemical oxidation of 4-methylcatechol (1c) in the presence of 3 showed a similar
behavior to that of 1a. But contrary to these data, the 1H-NMR spectrum of the isolated
product exhibited a different pattern from that observed for 8a and 8b: a single peak
appeared at d(H) 4.77 which was assigned to the H-atom of the C(O)CHCN moiety of
5c (Scheme 3). These observations allowed us to propose the pathway illustrated in
Scheme 3 for the electrochemical oxidation of 1c in the presence of 3.
The presence of substituents at the catechol 1 is important for the type of the final
product of the reaction of the electrochemically generated o-benzoquinone 2 with
nucleophiles. The presence of the Me group at one of the reaction sites of catechol 1
prevented the oxidative cyclization of intermediate 4c into a benzofuran derivative (see
Scheme 1, Eqn. 4) and caused the formation of the substituted o-benzoquinone 5c as
the final product. The 13C-NMR spectrum of 5c, surprisingly showed two peaks at d(C)
19.6 and 22.3 (instead of one peak) and an unexpected peak at d(C) 87.7, which were
not consistent with the structure 5c. These results established that 5c was in equilibrium
with its tautomeric form 6c (Scheme 4).

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Scheme 3. Electrochemical Oxidation of 4-Methylcatechol (1c) in the Presence of Benzoylacetonitrile (3)
Scheme 4. Tautomerization Equilibrium 5c > 6c
Conclusions. – The mechanism of the reaction of electrochemically generated o-
benzoquinones 2 with benzoylacetonitrile (3) was investigated, and a method of
general applicability for their high-yield transformation under mild experimental
conditions was provided. We observed an interesting diversity in the mechanism of the
electrochemical oxidation of catechols 1a – 1c in the presence of 3. In the case of 3-
methylcatechol (1b) (and of catechol (1a)), the final product, a dihydroxybenzofuran,
was obtained after intermolecular and intramolecular Michael-addition reactions,
whereas in the case of 4-methylcatechol (1c), the final product was the o-benzoquinone
5c that was obtained after the intermolecular Michael-addition reaction. The different
results of the electrochemical oxidation of 3-methylcatechol (1b) and 4-methylcatechol
(1c) in the presence of 3 was attributed to the blocking of one of the reaction sites of
the catechol by a Me group in 4-methylcatechol (1c). In conclusion, we can state that
the addition of benzoylacetonitrile to catechol derivatives 1 is an interesting reaction
that provides direct access to new 5,6-dihydroxybenzofuran and o-benzoquinone
derivatives.

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We acknowledge the Bu-Ali Sina University Research Council and the Center of Excellence in
Development of Chemical Methods (CEDCM) for their support of this work.
Experimental Part
General. Catechols and benzoylacetonitrile were from Aldrich and Fluka, MeCN, H3PO4
(phosphoric acid) and phosphate salts were of pro-analysis grade from E. Merck. These chemicals
were used without further purification. Cyclic voltammetry: Sama-500 instrument. Controlled-potential
coulometry and prep. electrolysis: Behpajoh-BHP-2050 potentiostat/galvanostat. The working electrode
used in the voltammetry experiments was a glassy carbon disc (1.8 mm2 area), and Pt-wire was used as a
counter electrode. The working electrode used in the controlled-potential coulometry and macroscale
electrolysis was an assembly of four graphite rods, and a large stainless-steel gauze constituted the
counter electrode. The working electrode potentials were measured vs. SCE (all electrodes from Azar
Electrode Co., Iran).
Electrochemical Synthesis of 8a, 8b, and 5c: General Procedure. A soln. (ca. 80 ml) of 0.2m
phosphate buffer (pH 7.0) in H2O/MeCN 1:1 containing 1.0 mmol of a catechol 1 and 1.0 mmol of
benzoylacetonitrile (3) was electrolyzed at a potential of 0.40 V in the case of 1a and 0.30 V in the cases
of 1b and 1c, in an undivided cell equipped with a carbon anode and a large stainless-steel gauze as
cathode, at 258. The electrolysis was terminated when the current decayed to 5% of its original value. The
process was interrupted during the electrolysis, and the carbon anode was washed in acetone to reactivate
it. At the end of the electrolysis, the cell was placed in a refrigerator overnight. The solid precipitated was
collected by filtration and washed several times with H2O. The product was purified by column
chromatography. The yields of isolated 8a, 8b, and 5c were 78, 73, and 82%, resp.
5,6-Dihydroxy-2-phenylbenzofuran-3-carbonitrile (8a): Black solid. M.p. 213 – 2158. IR (KBr): 3477
(OH), 2231 (CN), 1622, 1466, 1320, 1217, 1144, 838, 763, 682, 626. 1H-NMR ((D6)DMSO, 500 MHz): 6.97
(s, 1 H); 7.13 (s, 1 H); 7.54 (m, 3 H); 8.0 (d, J ¼ 8.1, 2 H); 9.54 (br., OH, ca. 2 H). 13C-NMR ((D6)DMSO,
125 MHz): 88.0; 99.4; 103.9; 115.3; 118.6; 126.2; 128.6; 130.3; 131.6; 145.8; 147.6; 148.3; 160.0. EI-MS: 251
(100, Mþ), 177 (15), 105 (40), 77 (30), 51 (15).
5,6-Dihydroxy-7-methyl-2-phenylbenzofuran-3-carbonitrile (8b): Dark brown solid. M.p. 223 – 2258.
1
IR (KBr): 3400 (OH), 3300 (OH), 2227 (CN), 1627, 1452, 1301, 1234, 1101, 1008, 769, 690. H-NMR
((D6)DMSO, 500 MHz): 2.35 (s, 3 H); 6.85 (s, 1 H); 7.54 (m, 3 H); 8.03 (d, J ¼ 7.3, 2 H); 8.92 (br., OH);
9.81 (br., OH). 13C-NMR ((D6)DMSO, 125 MHz): 9.7; 88.1; 100.8; 109.2; 115.4; 117.8; 126.2; 128.8;
130.3; 131.4; 145.2; 145.3; 147.9; 159.8. EI-MS: 265 (100, Mþ. ), 190 (15), 105 (30), 77 (25).
2-(6-Methyl-3,4-dioxocyclohexa-1,5-dienyl)-3-oxo-3-phenylpropanenitrile (¼a-(6-Methyl-3,4-dioxo-
cyclohexa-1,5-dien-1-yl)-b-oxobenzenepropanenitrile; 5c) and (2E)-3-Hydroxy-2-(6-methyl-3,4-dioxocy-
clohexa-1,5-dienyl)-3-phenylprop-2-enenitrile (¼(aE)-a-(Hydroxyphenylmethylene)-6-methyl-3,4-diox-
ocyclohexa-1,5-diene-1-acetonitrile; 6c): Brown solid. M.p. 105 – 1078. IR (KBr): 3442 (OH), 2922
1
(CH), 2229 (CN), 1631, 1469, 1333, 1219, 1150, 1025, 893, 841, 810, 765, 681. H-NMR ((D6)DMSO,
500 MHz): 1.70 (s, 3 H); 4.77 (s, 1 H); 6,78 (s, 1 H); 6.97 (s, 1 H); 7.35 – 7.53 (m, 4 H); 8.00 (d, J ¼ 5.3,
1 H). 13C-NMR ((D6)DMSO, 125 MHz): 19.5; 22.5; 51.5; 87.7; 109.5; 114.4; 118.3; 129.1; 129.2; 129.3;
129.7; 130.1; 130.4; 130.9; 136.4; 143.9; 146.1; 167.5; 182.1; 190.4. EI-MS: 256 (3, Mþ), 236 (15), 237 (6),
209 (4), 108 (4), 105 (87), 77 (100).
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Received January 22, 2012