An efficient electrochemical method for the atom economical synthesis of some benzoxazole derivatives

Article abstract of DOI:10.1039/c3gc40954f

Electrochemical synthesis of some 2-arylbenzoxazoles were directly carried out via the electrochemical oxidation of 3,5-di-tert-butylcatechol in the presence of benzylamines without using any catalyst under mild and green conditions. The results show that electrogenerated 3,5-di-tert-butyl-1,2- benzoquinone participates in the reaction with benzylamine derivatives and, via the ECCE mechanism electron transfer + chemical reaction (imine formation) + chemical reaction (cyclization) + electron transfer , converts to the corresponding benzoxazole derivatives. In this work, some benzoxazole derivatives with high yields in aqueous solutions, without toxic reagents and solvents at a carbon electrode using an environmentally friendly novel method, are provided.

Full text of DOI:10.1039/c3gc40954f

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An efficient electrochemical method for the atom
economical synthesis of some benzoxazole
Cite this: DOI: 10.1039/c3gc40954f
derivatives†
Hamid Salehzadeh, Davood Nematollahi* and Hooman Hesari
Electrochemical synthesis of some 2-arylbenzoxazoles were directly carried out via the electrochemical
oxidation of 3,5-di-tert-butylcatechol in the presence of benzylamines without using any catalyst under
mild and green conditions. The results show that electrogenerated 3,5-di-tert-butyl-1,2-benzoquinone
participates in the reaction with benzylamine derivatives and, via the ECCE mechanism “electron transfer
+ chemical reaction (imine formation) + chemical reaction (cyclization) + electron transfer”, converts to
the corresponding benzoxazole derivatives. In this work, some benzoxazole derivatives with high yields
in aqueous solutions, without toxic reagents and solvents at a carbon electrode using an environmentally
friendly novel method, are provided.
Received 21st May 2013,
Accepted 19th June 2013
DOI: 10.1039/c3gc40954f
www.rsc.org/greenchem
and 4-methoxy-TEMPO as an organic catalyst21 has recently
been reported. However, these reactions require the use of large
Introduction
Benzoxazole and its derivatives as heteroaromatic systems are amounts of the catalyst or excess base. In some of them the
important structural motifs in many biologically active natural yields were not satisfactory. Therefore, a more effective and
products and pharmaceutical compounds.1 These compounds environmentally friendly process is needed. The synthesis of
are used as cytotoxic agents,2 cathepsin S inhibitors,3 HIV molecules with desirable functional groups in the absence of
reverse transcriptase inhibitors,4 estrogen receptor agonists,5 catalysts and drastic conditions continues to be of great inter-
selective peroxisome proliferator activated receptor anta- est. The electroorganic synthesis, through the electron-transfer-
gonists,6 anticancer agents,7 and orexin-1 receptor antagonists.8 driven reactions, has been widely used,22 while the potential
They have also found application as herbicides and fluorescent applications have still not been fully utilized. Following our
whitening agent dyes.9 Due to the importance of these com- experience in electrochemical synthesis of organic compounds
pounds as components in pharmaceutical agents, a great deal under green conditions,23 herein we wish to describe a one-pot
of effort has been devoted to the synthesis of the benzoxazole and straightforward protocol for the synthesis of some benz-
derivatives. There are several common methods which have oxazole derivatives. This idea prompted us to investigate the
been used, including: (a) metal catalyzed cyclization of 2-halo- electrochemical oxidation of 3,5-di-tert-butylcatechol in the
N-acylanilines,10 (b) coupling of 2-aminophenols with carb- presence of benzylamine derivatives. This method represents a
oxylic acid derivatives, which is either catalyzed by strong facile and one-pot electrochemical process for the synthesis of
acids or microwave conditions,11 (c) the oxidative cyclization some benzoxazole derivatives with antimicrobial activities,24 in
of phenolic Schiff bases derived from the condensation of high yields and purities via electrochemical oxidation of 3,5-di-
2-aminophenols and aldehydes. In the latter reactions, various tert-butylcatechol in the presence of benzylamine derivatives
oxidants such as DDQ,12 Mn(OAc)3,13 PhI(OAc)2,14 ThClO4,15 under green conditions, without toxic reagents and solvents in
BaMnO4,16 NiO2,17 and Pb(OAc)418 have been used. In addition, a divided cell using an environmentally friendly method at a
catalytic oxidative reactions using oxygen as an oxidant have carbon electrode. This mild aqueous reaction expands the
received much attention because of their green and atom repertoire of aqueous chemistries available for small molecules.
economy chemistry. The aerobic catalytic synthesis of benz-
oxazoles promoted by activated carbon,19 copper nanoparticles20
Results and discussion
Mechanistic studies
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran, 65178-38683.
Cyclic voltammogram of a 0.1 mM solution of 3,5-di-tert-butyl-
E-mail: nemat@basu.ac.ir; Fax: +98-811-8257407
†Electronic supplementary information (ESI) available: FT-IR, 1H NMR,
13C NMR and MS spectra of compounds 6a–6e. See DOI: 10.1039/c3gc40954f
catechol (1) in a water–ethanol (70 : 30 v : v) solution contain-
ing 0.2 M phosphate buffer (pH 7.5) is shown in Fig. 1 (curve
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Fig. 1 Cyclic voltammograms of 0.1 mM 3,5-di-tert-butylcatechol (1): (a) in the
absence, (b) in the presence of 30 mM 4-methylbenzylamine (2b) and (c)
30 mM 2b in the absence of 1, at a glassy carbon electrode, in aqueous solution
containing 0.2 M phosphate buffer (c = 0.2 M, pH = 7.5). Scan rate: 2.5 mV s−1
t = 25 1 °C.
;
a). As can be seen, the anodic peak (A1) and the corresponding
cathodic peak (C1) were obtained, which corresponds to the
transformation of 1 to o-benzoquinone 1ox and vice versa
within a quasi-reversible two-electron process (Scheme 1).25
Under these conditions, the peak current ratio (IpC1/IpA1) of
nearly unity, particularly during the repetitive recycling of
potential, can be considered as a criterion for the stability
of o-benzoquinone 1ox produced at the surface of the elec-
trode. In other words, any side reactions are too slow to be
observed on the time scale of cyclic voltammetry. The oxidation
of 1 in the presence of 4-methylbenzylamine (2b) as a nucleo-
phile was studied in some detail. Fig. 1 (curve b) shows the
cyclic voltammogram of 3,5-di-tert-butylcatechol (1) in the pres-
ence of 4-methylbenzylamine (2b). As can be seen, the cathodic
peak C1 has decreased. The occurrence of a chemical reaction
after the electrochemical process is supported by the decrease
in the current of peak C1 during the reverse scan, which could
indicate that o-benzoquinone 1ox formed at the surface of the
electrode is consumed by a chemical reaction with 2b.25
Scheme 1
The current of peak C1 strongly depends on the potential
Diagnostic criteria of cyclic voltammetry and controlled
sweep rate (Fig. 2). At lower scan rates, the peak current ratio potential coulometry accompanied by the spectroscopic data
(IpC1/IpA1) is less than one and increases when the sweep rate of the final products (see ESI†) indicate that the reaction mech-
increases. A similar situation was observed when the 2b to 3,5- anism of electrochemical oxidation of 3,5-di- tert-butylcatechol
di-tert-butylcatechol (1) concentration ratio was decreased.
(1) in the presence of benzylamines 2a–2e is ECCE, “electron
Controlled-potential coulometry was performed in a water– transfer + chemical reaction (imine formation) + chemical
ethanol solution containing phosphate buffer (c = 0.1 M and reaction (cyclization) + electron transfer” (Scheme 1).25 Accord-
pH = 7.5) and 0.25 mmol of 3,5-di-tert-butylcatechol (1) and ing to this Scheme, the generation of o-benzoquinone 1ox is
0.25 mmol of 4-methylbenzylamine (2b) at 0.2 V versus followed by a condensation reaction with benzylamine 2 at the
Ag/AgCl. The electrolysis progress was monitored using linear most electrophilic carbonyl of 1ox and generates intermediate
sweep voltammetry (Fig. 3).
imine 3 (imine formation). Intermediate 3 then is converted to
As shown, the following changes are observed: (a) a the Schiff base 4. In the next step, the Schiff base 4 via a cycli-
decrease in the anodic peak current A1 and (b) the appearance zation reaction is converted to benzoxazoline 5. In the final
of the anodic peak current A2 at slightly more positive poten- step, electrochemical oxidative dehydrogenation of benz-
tials. The anodic peak A1 disappeared when the charge con- oxazoline 5 leads to the corresponding benzoxazole 6 as the final
sumption was 2.2 e− per molecule of 1. In addition, all the product.
anodic peaks (A1 and A2) disappeared when the charge con-
In the Schiff base 4, the imine function may be further
attacked by the excess amine to form the secondary amine
sumption was 4.3 e− per molecule of 1 (Fig. 4).
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Fig. 4 Variation of peak current during controlled potential coulometry for
peaks A1 and “A1 + A2” versus charge consumed.
N-methyl and N-benzylamine. In these cases, our attempts to
synthesise the benzoxazole were unsuccessful.
Fig. 2 Cyclic voltammograms of 0.1 mM 3,5-di-tert-butylcatechol (1) in the
presence of 30 mM 4-methylbenzylamine (2b) at various scan rates. Scan rates
from (a) to (d) are: 2.5, 5, 10 and 20 mV s−1, at a glassy carbon electrode, in
aqueous solution containing 0.2 M phosphate buffer pH 7.5; t = 25 1 °C.
Galvanostatic studies
The applicability of the electrochemical synthesis of the
product was improved by means of galvanostatic electrolysis.
Constant-current synthesis was performed under the same
conditions as described above. To take the high product yield,
some affecting electrosynthesis factors must be optimized.
Among the electrochemical parameters for the synthesis of
organic or inorganic compounds, the current density is one of
the most important factors influencing the yield and purity.
This factor can also play an important role in determining the
dominant reaction at the surface of the electrode. Therefore, in
this work, the current density varied from 0.1 to 1 mA cm−2
,
while the other parameters (temperature = 298 K, charge con-
sumed = 100 C, electrode surface: 50 cm2, 3,5-di-tert-butyl-
catechol: 0.25 mmol, and 4-methylbenzylamine (6b): 0.25 mmol)
are kept constant. Fig. 5 shows the effect of current density on
the yield of 6b. As can be seen the highest product yield was
obtained at lower current densities (0.2 mA cm−2). Higher
current densities result in an increase in side reactions such as
the oxidation of water and secondary reactions, resulting in a
decrease in product yield.
For more data on galvanostatic studies, constant-current
coulometry was performed in an aqueous ethanol (70 : 30 v : v)
solution containing 0.25 mmol of 1 and 0.25 mmol of 2b in a
divided cell, under a low constant current density (0.2 mA
cm−2). The monitoring of electrolysis progress was carried out
Fig. 3 Linear sweep voltammograms of 0.25 mmol 3,5-di-tert-butylcatechol (1)
in the presence of 0.25 mmol 4-methylbenzylamine (2b) during controlled
potential coulometry at 0.2 V versus Ag/AgCl. After consumption of: (a) 0, (b)
10, (c) 20, (d) 30, (e) 40 and (f) 50 C.
(PhCH2NHCH2Ph). Largeron and Fleury used this principle for by cyclic voltammetry. It is shown that, proportional to the
chemoselective synthesis of secondary amines.26 But under advancement of coulometry, the current of anodic peak A1
our experimental conditions the Schiff base 4 undergoes a
cyclization reaction to generate benzoxazoline 5 (Scheme 1).
Five primary benzylamine derivatives with ortho and para
substituents (2a–2e) were used in this work for the synthesis of
decreases. The variation of the anodic peak A1 versus charge
consumed is indicated in Fig. 6.
In addition, the current efficiency for various current den-
sities was examined (Fig. 7). In this study, the current density
substituted benzoxazoles (6a–6e) by the in situ formation varied from 0.25 to 5 mA cm−2, while the other parameters
of the Schiff base 4 in good yields. For more data, electro- (temperature = 298 K, charge consumed = 100 C, electrode
surface: 50 cm2, 3,5-di-tert-butylcatechol: 0.25 mmol, and
chemical oxidation of 3,5-di-tert-butylcatechol (1) has also
been studied in the presence of secondary benzylamines 4-methylbenzylamine, 6b: 0.25 mmol) are kept constant. The
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results show that, with increasing the current density the
current efficiency decreases. Increasing the current density
increases the side reactions such as oxidation of water or
other secondary reactions, resulting in a decrease in current
efficiency.
Conclusions
The present method for the synthesis of 2-arylbenzoxazoles
has several advantages over conventional methods. (a) This
process is practically convenient to carry out and can be per-
formed at atmospheric pressure. (b) Neither catalyst nor
organic/inorganic oxidizing agents are necessary and the reac-
tion can be performed under green and mild condition. (c)
The in situ formation of Schiff bases is achieved and there is
no need to prepare Schiff bases in advance.15 In summary, we
have reported an efficient method for the preparation of benz-
oxazole containing molecules using a one-pot electrochemical
process. The extension of this electrochemical system for the
preparation of other useful heterocycles is under way in our
laboratory. To the best of our knowledge, this is the first
example in which benzoxazoles have been obtained directly
and efficiently from the electrooxidation of 3,5-di-tert-butyl-
catechol in the presence of benzylamines using water as a reac-
tion medium in the absence of any catalyst and/or oxidant.
Finally, although the experiments were conducted on a rela-
tively small scale, there is little difficulty in producing larger
quantities either by using larger cells or by running several
cells in series.
Fig. 5 Effect of current density on the yield of 6b. Charge passed: 1 F mol−1
Charge consumed = 100 C. Electrode surface: 50 cm2.
.
Experimental section
General remarks
Fig. 6 Variation of IpA1 vs. charge consumed during constant current coulome-
try of 3,5-di-tert-butylcatechol (1) (0.25 mmol) in the presence of 0.25 mmol
4-methylbenzylamine (2b). Current density: 0.2 mA cm−2. Electrode surface:
50 cm2.
Reaction equipment is described in an earlier paper.27 3,5-di-
tert-butylcatechol and benzylamine derivatives were purchased
from Aldrich. These chemicals were used without further puri-
fication. The purity of products has been checked by TLC, and
characterization has been done using H NMR, 13C NMR, IR
1
spectroscopic techniques and mass spectrometry.
Electroorganic synthesis of 6a–6e
Controlled-potential method. A mixture (70 mL) of water
(phosphate buffer, c = 0.1 M, pH = 7.5)–ethanol (70/30 v/v) con-
taining 0.25 mmol of 3,5-di-tert-butylcatechol and 0.25 mmol
of benzylamine derivative was subjected to electrolysis at 0.20
V versus Ag/AgCl in a divided cell. The electrolysis was termi-
nated when the decay of current became more than 95%. The
precipitated solid was collected by filtration and was washed
several times with water. The crude product is then recrystal-
lized in methanol (or n-hexane). In the case of 6c, thin layer
chromatography (acetone–n-hexane 1 : 8) was used for separ-
ation of the product. After drying, the products were charac-
Fig. 7 Effect of current density on the current efficiency of synthesis of 6b.
Charge passed: 1 F mol−1. Charge consumed = 100 C. Electrode surface: 50 cm2. terized by IR, 1H NMR, 13C NMR and MS. In this work, ethanol
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was used as a co-solvent for the solubility of 3,5-di-tert-butyl-
catechol in the electrolysis medium.
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Galvanostatic method. A mixture (70 mL) of water (phos-
phate buffer, c = 0.1 M, pH = 7.5)–ethanol (70/30 v/v) contain-
ing 0.25 mmol of 3,5-di-tert-butylcatechol and 0.25 mmol of
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50 cm2) and a large platinum gauze cathode at 25 °C under a
constant-current density of 0.2 mA cm−2. The quantity of the
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The IR, 1H and 13C NMR, and mass spectra of compounds 6a–
6d are identical to those reported by Vinsova et al24 (for the
data, see ESI†). The yields and melting points of compounds
6a–6e are shown in Scheme 1.
5,7-Di-tert-butyl-2-(2-chlorophenyl)benzo[d]oxazole (6e). IR
(KBr, cm−1): 2957, 2907, 2867, 1598, 1572, 1554, 1481, 1463,
1438, 1400, 1366, 1331, 1306, 1265, 1085, 1043, 1008, 934, 838,
818, 735, 768, 735. 1H NMR (90 MHz, CDCl3): 1H NMR
(400 MHz, CDCl3): δ 1.41 (s, 9H, CH3), 1.56 (s, 9H, CH3), 7.36
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8.18 (m, 1H, Ar). 13C NMR (CDCl3, 100 MHz): δ 30.3, 32.1, 34.7,
35.4, 114.8, 120.2, 127.0, 127.2, 131.7, 131.9, 132.1, 133.6,
142.1, 147.3, 148.2, 160.9. MS (EI) m/z (relative intensity): 341.1
(35), 326.1 (100), 270 (10).
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