Electrochemically promoted synthesis of polysubstituted oxazoles from β-diketone derivatives and benzylamines under mild conditions

Article abstract of DOI:10.1039/c4ra03865g

An efficient electrochemical synthesis of poly-substituted oxazoles from readily available β-diketone derivatives and benzylamines is described. This electrochemical procedure does not need hazardous oxidants and transition metal catalysts as well as molecular I₂ additives. Compared with the traditional thermo-chemical method, the present electrochemical method is greener and more efficient. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4ra03865g

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Electrochemically promoted synthesis of
polysubstituted oxazoles from b-diketone
derivatives and benzylamines under mild
conditions†
Cite this: RSC Adv., 2014, 4, 24300
Received 28th April 2014
Accepted 27th May 2014
*
Gaoqing Yuan, Zechen Zhu, Xiaofang Gao and Huanfeng Jiang
DOI: 10.1039/c4ra03865g
www.rsc.org/advances
An efficient electrochemical synthesis of poly-substituted oxazoles decrease pollution and make the chemistry environmentally
from readily available b-diketone derivatives and benzylamines is friendly.7 The advantage of an electrochemical method lies in
described. This electrochemical procedure does not need hazardous the fact that electrons can act as green and safe “reagents” to
oxidants and transition metal catalysts as well as molecular I2 additives. replace hazardous redox chemicals to carry out oxidation or
Compared with the traditional thermo-chemical method, the present reduction reactions. On the other hand, the desired reactive
electrochemical method is greener and more efficient.
species could be conveniently electrogenerated in situ through
the transfer of electrons. Based on the green characteristic of an
electrochemical method, we have been interested in developing
new electrochemical process in organic synthesis.8 Herein, we
report for the rst time an efficient electrochemical synthesis of
polysubstituted oxazoles from readily available benzylamine
and b-diketone derivatives under mild conditions, without the
use of hazardous or toxic oxidants and transition metal
catalysts.
Many natural and synthetic compounds containing oxazole
moieties exhibit promising antitumor, antibacterial, antiviral or
antifungal activities.1 For example, Leucamide A and its
analogues composed of several oxazole moieties have been
conrmed as signicant antitumor agents.2 Owing to their
important applications, the synthesis of oxazole derivatives has
attracted extensive attention in both academic and industrial
elds. Some synthetic methods have been developed for the
preparation of oxazoles, mainly including cyclization of acyclic
precursors,3 the coupling of the prefunctionalized oxazoles with
organometallic reagents,4 and oxidation of oxazolines.5
However, these methods still face some challenges such as
starting materials not easily accessible, harsh reaction condi-
tions and tedious synthetic procedures. Recently, the Wang
group has reported a novel method for the synthesis of poly-
substituted oxazoles from readily available materials (benzyl-
amine with b-diketone derivatives) via a tandem oxidative
cyclization.6 Unfortunately, the oxidative procedures require the
use of a stoichiometric amount of hazardous oxidant TBHP
(t-BuOOH) and molecular I2 additive, and transition metal
catalysts. From the viewpoint of green chemistry and synthetic
methodology, it is still highly desirable to develop eco-friendly
and more efficient method for the synthesis of polysubstituted
oxazoles from benzylamine and b-diketone derivatives.
In our investigation, ethyl acetoacetate 1a and benzylamine
2a were chosen as model substrates. In order to obtain satis-
factory results, some important factors (including supporting
electrolytes, solvents and electrode materials) were carefully
examined, as shown in Table 1. With NaI as the supporting
electrolyte and DMF as the solvent, 1a with 2a could be
smoothly transformed into the target product ethyl 5-methyl-2-
phenyl-oxazole-4-carboxylate 3aa in a 60% yield (Table 1, entry
1). However, the electrolysis with KI or n-Bu4NI as the sup-
porting electrolyte gave unsatisfactory results (Table 1, entries 2
and 3). Very pleasingly, the yield of 3aa could be enhanced up to
91% when the supporting electrolyte was changed from NaI to
NH4I (Table 1, entry 4). With NH4Br as supporting electrolyte,
benzonitrile was the main product (64% yield), while the target
product 3aa was only obtained in a low yield (34%, Table 1,
entry 5). With NH4Cl as supporting electrolyte, 3aa was not
detected and some by-products such as benzonitrile and benz-
aldehyde were observed (Table 1, entry 6). These results indicate
that supporting electrolytes have a great impact on the forma-
tion of oxazoles. NH4I appears to be the most suitable sup-
porting electrolyte for this electrochemical process. In the
present electrochemical system with graphite as the inert
anode, the supporting electrolyte could not only act as con-
ducting salts but also take part in electrochemical reactions to
An electrochemical method is particularly attractive in
organic synthesis because electrochemical processes can
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou, China. E-mail: gqyuan@scut.edu.cn
† Electronic supplementary information (ESI) available: Experimental Protocols
and NMR Spectra for products 3aa–3ak. See DOI: 10.1039/c4ra03865g
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generate reactive species. According to the Wang group's work,6 benzylamine 2a could be perform smoothly to give the corre-
the molecular I2 additive was utilized to effectively improve the sponding products in 77–81% yields (Table 2, 3fa–3ga). With b-
reaction efficiency of ethyl acetoacetate 1a with benzylamine 2a. keto amides, good yields were obtained as well (Table 2, 3ha and
In the present case, we deduce that the I2 electrogenerated in 3ia). For the benzylamine derivatives, an electron-donating
situ at the graphite anode (2IÀ / I2 + 2eÀ) could play the same group on the aromatic ring gave somewhat lower yields of
important role in this transformation. Electrolytic medium oxazoles (Table 2, compare 3aa (85%) with 3ab–3ae (68–74%)),
(solvent) is another key factor. When DMF was replaced with while an electron-withdrawing substituent had little inuence
MeCN or H2O as the solvent, the yield of 3aa was less than 5% (Table 2, compare 3aa with 3ah (85%)). The position of the
(Table 1, entries 8 and 11), and the substrates were almost OCH3 group on the benzylamine (para, meta, and ortho posi-
quantitatively recovered. When THF or MeOH was employed as tions) has very little inuence on the reaction yield (Table 2,
the solvent, 3aa was obtained in a low yield of 36% and 16%, 3ac–3ae). In the heterocyclic amine case, the corresponding
respectively (Table 1, entries 7 and 9). In DMSO solvent, the products could be obtained in moderate to high yields (Table 2,
yield is much lower than in DMF (Table 1, entries 10 and 4). 3ai–3ak). However, the desired product was not formed with n-
Among the tested solvents, DMF seems to be the most appro- BuNH2 as the substrate (Table 2, 3al). This probably means that
priate solvent for this transformation. Subsequently, several it is necessary to have a weak C–H bond to be adjacent to the
cathode materials including Zn, Al and Cu were used to carry amino group for this transformation.6
out the transformation under the same conditions. These
In order to probe the reaction process, several control
electrode materials give quite satisfactory results (Table 1, experiments were carried out. In the absence of benzylamine
entries 12–14). According to the experimental result of entry 4 (2a), ethyl-2-iodo-3-oxobutanoate (A) was observed (Scheme 1,
(Table 1), the optimized electrolytic system should consist of eqn (1)). Although the yield of A was low (only 21%), this result
NH4I as supporting electrolyte, DMF as solvent, a graphite indicates that A could be formed under the electrochemical
anode and a Ni cathode.
conditions. Further investigation revealed that A with benzyl-
To test the scope of this electrochemical methodology, our amine (2a) could be electrochemically converted into the target
investigation was extended to different 1,3-dicarbonyl product 3aa in a 61% yield (Scheme 1, eqn (2)). However, 3aa
compounds and benzylamines. All the electrosyntheses were was not formed at all if no electric current was passed through
carried out under the optimized conditions (Table 1, entry 4) the electrolytic cell (Scheme 1, eqn (3)). This means that elec-
and the results are listed in Table 2. Pleasingly, the b-keto esters trochemical oxidation or activation is necessary for the forma-
with different alkyl substituents, regardless of their electronic tion of 3aa.
or steric properties, could provide the corresponding products
Based on our experimental results and the previous
with satisfactory yields (Table 2, 3aa–3ea). Moreover, when 1,3- reports,6,9,10 a possible reaction mechanism is outlined in
diketones were used as the substrate, the reactions with Scheme 2. I2 generated in situ at the anode (2IÀ / I2 + 2eÀ)
Table 1 Optimization of electrolytic conditionsa
Entry
Anode–cathode
Supporting electrolyte
Solvent
Yieldb (%)
hc (%)
1
2
3
4
5
6
7
8
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Ni
C–Zn
C–Al
C–Cu
NaI
KI
DMF
DMF
DMF
DMF
DMF
DMF
THF
MeCN
EtOH
DMSO
H2O
62
40
18
91
34
0
36
<5
16
60
<5
89
84
81
42
27
12
62
23
0
24
<3
11
40
<3
60
56
54
n-Bu4NI
NH4I
NH4Br
NH4Cl
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
9
10
11
12
13
14
DMF
DMF
DMF
a
Electrolytic conditions: 1a (2.0 mmol), 2a (2.0 mmol), solvent (10 mL), supporting electrolyte (0.4 mol LÀ1), undivided cell, current density 12 mA
cmÀ2, 8 h and rt. Determined by GC. c Current yield.
b
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Table 2 Electrosynthesis of polysubstituted oxazoles from 1,3-dicar-
bonyl compounds and benzylamine derivativesa
Scheme 2 Proposed reaction mechanism.
could react with 1a to form A. Then A with BnNH2 (2a) is con-
verted to B. Subsequently, the electrooxidation of B generates C,
which undergoes an intramolecular cyclization to give the
intermediate D in a tandem process. Finally, D is transformed
into the product (3aa) by deprotonation and electrochemical
oxidation. It is worthy to note that IÀ ions are regenerated
during the electrolysis. The formation of 3aa consumes elec-
trons only.
In conclusion, an efficient synthesis of polysubstituted oxa-
zoles derivatives via an electrochemical route from readily
available benzylamine and b-diketone derivatives was demon-
strated. The molecular I2 electrogenerated in situ at the anode
and electrochemical oxidation play a key role in the formation
of polysubstituted oxazoles. It is noteworthy that the present
electrochemical procedure gives the oxazoles in good to excel-
lent yields, under mild conditions, and does not involve
hazardous oxidants, transition metal catalysts, and molecular I2
additive. Furthermore, it is accessible to any synthetic organic
laboratory and it can be easily scaled up because no sophisti-
cated and expensive electrochemical instruments (such as a
potentiostat) are required. Therefore, compared with the
reported thermo-chemical method,6 the present electro-
chemical method appears to be more eco-friendly and more
attractive.
a
Isolated yield (electrolytic conditions as shown in Table 1, entry 4).
Acknowledgements
We thank the National Natural Science Foundation of China
(21172079), the Science and Technology Planning Project of
Guangdong Province (2011B090400031), the National Basic
Research Program of China (973 Program, 2011CB808600), and
Guangdong Natural Science Foundation (10351064101000000).
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