Transition-metal catalyst free C=N coupling with phenol/phenoxide: A green synthesis of a benzoxazole scaffold by an anodic oxidation reaction

Article abstract of DOI:10.1039/c3ra00128h

By utilizing an anodic oxidative reaction and consuming 2.2 F mol ^-1 of electricity, C=N coupling with phenol/phenoxide to obtain the five-membered N,O-heteroatom ring of a benzoxazole has been achieved at room temperature. Transition-metal catalysts, chemical oxidants, strong acids, reactive chemical reagents and refluxing are not required. Studies of the electrode, solvent, electrolyte and additive effects to promote the anodic cyclization are included. From the CV studies, the reaction mechanisms of the anodic cyclization are proposed. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra00128h

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Transition-metal catalyst free CLN coupling with
phenol/phenoxide: a green synthesis of a benzoxazole
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7330
scaffold by an anodic oxidation reaction3
Yachen Shih, Chengyi Ke, Chinghao Pan and Yungtzung Huang*
By utilizing an anodic oxidative reaction and consuming 2.2 F mol21 of electricity, CLN coupling with
phenol/phenoxide to obtain the five-membered N,O-heteroatom ring of a benzoxazole has been
achieved at room temperature. Transition-metal catalysts, chemical oxidants, strong acids, reactive
chemical reagents and refluxing are not required. Studies of the electrode, solvent, electrolyte and additive
effects to promote the anodic cyclization are included. From the CV studies, the reaction mechanisms of
the anodic cyclization are proposed.
Received 9th January 2013,
Accepted 20th February 2013
DOI: 10.1039/c3ra00128h
www.rsc.org/advances
hazardous substances’’.14 Here we report an efficient synthesis
of the benzoxazole skeleton by an organo–electrochemical
Introduction
The 5-membered N,O-heterocyclic benzoxazole scaffold moiety
is a key structure in various biologically active natural
products1 and targets of synthetic pharmaceutical com-
pathway which produces little pollution.
It is hard to form a new bond between two nucleophiles
using traditional methods and usually transition-metal cata-
lysts are required. However, the umpolung character of anodic
pounds2
like
Nakijinol
B,1a
Pseudopteroxazoles,1d
Routiennocin,1e UK-1,2a etc. (Scheme 1).
Also, the strong luminescent properties of the benzoxazole
ring mean it is utilized in various photochromic materials,3
mesogenic polymers4 and liquid crystals.5
Due to the wide applications of its derivatives, new
methodologies to construct the benzoxazole ring have been
continuously developed and reported. The oxidative coupling
of imine from aldehydes,6 the cross coupling of amides,7 and
the condensation of 2-aminophenol with carboxylic acids or
derivatives8 are the most common approaches used to
synthesize such heterocyclic rings (Scheme 2).
Although those methodologies are efficient, they usually
require transition-metal catalysts,9 reflux conditions,10 the
consumption of hazardous chemical oxidants,11 the use of
reactive chemical reagents,12 or the addition of strong acids.13
The synthetic processes produce toxic chemical waste and
consume unnecessary energy in the form of heat. To reduce
the environmental impact, developing other economical and
green pathways should be taken into consideration when
designing artificial syntheses of the benzoxazole ring.
Green synthesis has received much attention due to the
concerns about environmental pollution and global warming,
and is defined as the ‘‘design of chemical products and
processes that reduce or eliminate the use and generation of
No. 700, Kaohsiung University Rd., Kaohsiung 81148, Taiwan R.O.C.
E-mail: ythuang@nuk.edu.tw; Fax: 886-7-591-9348; Tel: 886-7-591-9418
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
Scheme 1 Examples of benzoxazole derivatives.
c3ra00128h
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Scheme 4 The retrosynthesis of a benzoxazole ring in a green pathway utilizing
an anodic coupling reaction.
Scheme 5 The synthesis of a phenolic Schiff base, 2.
Scheme 2 Reported synthetic pathways for the benzoxazole ring.
ring is obtained in this electrochemical pathway without
consuming additional chemical reagents.
coupling means that this method can be used to create a new
bond between two nucleophiles without involving other
functional groups.15 First, a nucleophile with a low oxidation
potential is oxidized to a radical cation at the anode. At this
point, it becomes an electrophile and is trapped by the other
nucleophile to form a new bond. After the reduction of a
proton to hydrogen gas, the second oxidation and reduction, a
new bond between the two nucleophiles is formed without the
assistance of a transition-metal catalyst (Scheme 3).15c
To date, anodic olefin coupling offers a powerful tool in
organic synthesis and has been successfully applied in the
synthesis of various carbon–carbon and carbon–heteroatom
rings.16 Our approach was designed to utilize two nucleo-
philes, a Schiff base and a phenol, and an intramolecular
anodic cyclization to construct the 5-membered N,O-heteroa-
tom ring of the benzoxazole (Scheme 4).
Although various addition reactions to imines have been
reported,17 few efficient CLN coupling reactions have been
revealed and those reported usually involve transition-metal
catalysts.18 This is the first report of a CLN coupling using an
anodic oxidation reaction. In this pathway, electricity, a clean
energy, is consumed, not stoichiometric equivalents of
chemical oxidants. Therefore, the use of transition-metal
catalysts or harsh reaction conditions such as refluxing,
chemical oxidants, reactive chemical reagents and strong
acids are not required, and their corresponding harmful by-
product wastes are avoided. A green synthesis of a benzoxazole
Results and discussion
The synthesis of
a phenolic Schiff base (2) from the
dehydration of 2-aminophenol and aldehyde was obtained
using MgSO4, Na2SO4 or a Dean Stark trap (Scheme 5).19 These
two dehydrants are recoverable, and the solvents in a Dean
Stark trap can also be recycled. Therefore, apart from the
starting materials, 2-amino phenol and aldehyde, no addi-
tional chemicals are consumed.
After dehydration, we investigated the reactivity of the CLN
coupling with the phenol group by an anodic oxidation
reaction (Table 1). From previous results,20 we used Et4NOTs
as the electrolyte and reticulated vitreous carbon (RVC) as the
electrodes. Under pure methanol, the yield of cyclization was
low (8%) and most starting materials (64%) were recovered
Table 1 Electrode and solvent effects on anodic coupling using a Schiff base
and a phenol
Entry
Solvent
Anode
Cathode
Yield (%)
1
2
3
4
5
100% CH3OH
100% CH3OH
100% CH3OH
100% CH3OH
75% CH3OH
25% CH2Cl2
50% CH3OH
50% CH2Cl2
25% CH3OH
75% CH2Cl2
100% CH2Cl2
RVCa
RVC
Pt
Pt
Pt
RVC
Pt
RVC
Pt
8 (1) + 64 (2)
17 (1) + 36 (2)
52 (1)
72 (1)
72 (1)
Pt
6
7
Pt
Pt
Pt
Pt
Pt
Pt
78 (1)
83 (1)
8
6 (1) + 50 (2)
a
RVC: reticulated vitreous carbon.
Scheme 3 The reaction mechanism of an anodic coupling reaction.
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(entry 1). A small increase in the yield (17%) was observed
when using a Pt electrode as the cathode (entry 2), but more
product (52%) was obtained when using a Pt electrode as the
anode (entry 3). The yield increased considerably to 72% when
using a Pt electrode as the anode and cathode (entry 4). Since
using a Pt electrode showed better results than when using a
carbon electrode in this anodic cyclization reaction, we
decided to use a Pt electrode as the anode and cathode for
all other reaction conditions.
After investigating the effect of the electrodes, we investi-
gated the solvent effects. An increase in yield can be seen with
more CH2Cl2 in the solution (entries 5 and 6) and 83% product
was observed when using 75% CH2Cl2 in CH3OH (entry 7).
However, only 6% cyclized product was observed and 50%
starting material (2) was recovered when using 100% CH2Cl2
(entry 8). Also, insoluble polymer-like solids were formed on
the surface of the Pt anode.
It may not be surprising to see such poor reactivity in the
anodic coupling when using pure CH2Cl2 as the solvent in the
reaction because reduction at the cathode should accompany
oxidation at the anode. For anodic coupling reactions, usually
a proton is reduced to hydrogen gas at the cathode. When
using pure aprotic solvents such as CH2Cl2, a lack of protons
from the solvent to promote the reduction reaction at the
cathode may slow down the process. Also, the solubilities of
the substrates and intermediates in CH2Cl2 were not as high as
those in CH3OH. Therefore, for the radical cation intermediate
formed at the anode, the polymerization reaction was faster
than the cyclization reaction. The resulting polymers on the
surface of the anode further affected the electrical conductivity
of the electrode during the electrolysis process, which caused
low yields of the benzoxazole product (1) and a large amount
of starting material (2) recovery.
To prove this assumption, a catalytic amount of LiOCH3
was added to the reaction, which deprotonated phenol to
phenoxide. The resulting methanol product might serve as the
trace amount of protic solvent. When 0.1–0.5 eq. LiOCH3 were
added (Table 2, entries 9, 10 and 11), some product (15–28%)
was obtained. The yield dramatically increased to 75% when 1
eq. catalytic LiOCH3 was added (entry 12), compared to a yield
of 6% without LiOCH3 (entry 8).
Table 2 The addition of catalytic LiOCH3 in the anodic cyclization reaction
Entry
Solvent
LiOCH3
Yield (%)
9
100% CH2Cl2
100% CH2Cl2
100% CH2Cl2
100% CH2Cl2
100% CH3OH
100% CH3OH
100% CH3OH
100% CH3OH
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
19 (1) + 42 (2)
15 (1) + 5 (2)
28 (1) + 52 (2)
74 (1)
65 (1)
75 (1)
51 (1)
53 (1)
67 (1)
75 (1)
72 (1)
53 (1) + 5 (2)
70 (1)
77 (1)
88 (1)
66 (1)
83 (1)
82 (1)
75 (1)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
60 (1)
a
Reaction conditions: 0.1 M Et4NOTs, 10 eq. 2,6-lutidine, 10 mA, 2.2
F mole21, a Pt electrode as the anode and cathode.
using CH2Cl2 in CH3OH. Therefore we continued to use the
solution of CH2Cl2 in CH3OH in the reaction and investigated
the effects of the electrolyte.
LiClO4 has been widely utilized in electrochemical reac-
tions16a,c and could improve the efficiency of our anodic
cyclization reaction. In pure CH3OH (Table 3, entries 29–33),
there were a variety of yields, the highest being 78% (0.1 eq.
LiOCH3, entry 30). When using 25% CH2Cl2 in CH3OH (entries
34–38), the yields (78–84%) were higher than those obtained
when using ET4NOTs (53–72%), and an 84% yield was
observed without the LiOCH3 additive (entry 34).
Furthermore, yields of over 80% were obtained under
conditions of 50% CH2Cl2 in CH3OH (entries 39–43).
Conditions using less LiOCH3 additive gave a yield of 88%
(0.1 eq., entry 40), compared to the condition involving 0.5 eq.
LiOCH3 in Et4NOTs (entry 23). Under conditions of 75%
CH2Cl2 in CH3OH (entries 44–48), when using LiClO4, more
efficient cyclization reactions were obtained compared to the
reactions involving Et4NOTs (entries 7, 25–28). 86–88% yields
were achieved with 0–0.2 eq. LiOCH3 additive (entries 44–46).
In pure CH2Cl2, the yields were low and more starting
materials were recovered (entries 49–52) than under previous
conditions using Et4NOTs as the electrolyte (entries 8–11). This
might be because LiClO4 did not totally dissolve in CH2Cl2
during the electrolysis process. Conditions involving lower
concentrations of the electrolyte made designing the anodic
cyclization reaction harder, and more starting materials were
recovered. However, when adding 1.0 eq. LiOCH3 to the
solution (entry 53), LiClO4 was totally dissolved in 100%
CH2Cl2 during the electrolysis process and a 66% yield was
With the improvement in the reaction due to the addition
of catalytic LiOCH3, we applied this additive to previous
reaction conditions with different solvent ratios. Under
conditions of 100% CH3OH (entries 13–16) and 25% CH2Cl2
in CH3OH (entries 17–20), the LiOCH3 additive had little effect
on the anodic cyclization. However, under conditions of 50%
CH2Cl2 in CH3OH (entries 21–24), the yield increased to 88%
when 0.5 eq. LiOCH3 were added (entry 23). Also, 83% product
was obtained when a smaller amount of LiOCH3 (0.1 eq., entry
25) was used under conditions of 75% CH2Cl2 in CH3OH
(entries 25–28).
To search for other reaction conditions that give highly
efficient anodic cyclization reactions, other solvents such as
CH3CN or THF in CH3OH were utilized in the reaction.
However, the yields were not as high as those obtained when
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Table 3 Using LiClO4 as the electrolyte in the anodic cyclization reaction
Table 4 A summary of the CV studies
Entry
1
Substrate in CH3CNa
Ep/2 (V)
1.64 ¡ 0.020
Entry
Solvent
LiOCH3
Yield (%)
2
3
1.73 ¡ 0.015
1.27 ¡ 0.009
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49b
50b
51b
52b
53c
100% CH3OH
100% CH3OH
100% CH3OH
100% CH3OH
0 eq.
75 (1)
78 (1)
68 (1)
40 (1) + 5 (2)
42 (1) + 3 (2)
84 (1)
78 (1)
70 (1)
82 (1)
80 (1)
82 (1)
88 (1)
82 (1)
82 (1)
82 (1)
87 (1)
86 (1)
88 (1)
82 (1)
62 (1)
6 (1) + 65 (2)
15 (1) + 65 (2)
15 (1) + 55 (2)
15 (1) + 60 (2)
66 (1) + 11 (2)
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0 eq.
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
0 eq.
100% CH3OH
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
75% CH3OH/25% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
50% CH3OH/50% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
25% CH3OH/75% CH2Cl2
100% CH2Cl2
4
5
0.48 ¡ 0.003
0.59 ¡0.032
a
Substrate (0.025 M) and LiClO4 (0.1 M) were dissolved in CH3CN.
100% CH2Cl2
100% CH2Cl2
100% CH2Cl2
100% CH2Cl2
0.1 eq.
0.2 eq.
0.5 eq.
1.0 eq.
In reported anodic cyclization reactions, the neutral
substrate is oxidized to form a radical cation intermediate at
the anode.15 When the imine group of the phenolic Schiff base
(2) was oxidized at the anode, the radical cation intermediate
involves either a radical on the nitrogen and a cation on the
carbon (3), or a radical on the carbon and a cation on the
nitrogen (4a). The carbocation in 3 was trapped by the phenol
group to construct the benzoxazole five-membered ring of the
radical cation 5, which was further reduced at the cathode to
form a radical intermediate 7. The carbon radical in 4a could
not be trapped by the phenol group to form the ring due to the
octet rule. However, through resonance to form 4b, it might be
possible to reduce it to radical 6 which could then cyclize to
a
Reaction conditions: 0.1 M LiClO4, 10 eq. 2,6-lutidine, 10mA, 2.2 F
mole21, a Pt electrode as the anode and cathode. LiClO4 was not
b
c
totally dissolved in CH2Cl2 during electrolysis. LiClO4 was totally
dissolved in CH2Cl2 during electrolysis when 1.0 eq. of LiOCH3 was
added.
obtained, which is a 60% increase in yield compared to that
obtained with zero eq. additive (entry 49).
Highly efficient intramolecular anodic oxidation reactions
were observed when using the electrolytes of Et4NOTs or
LiClO4 in the solutions of CH3OH and/or CH2Cl2 at room
temperature, with or without addition of a catalytic amount of
LiOCH3. Yields of almost 90% were achieved. Compared to
Et4NOTs, the reaction is more efficient when utilizing LiClO4
as the electrolyte because the average yield was higher and less
catalytic LiOCH3 needed to be added to reach high yields. With
the success of the CLN coupling with phenol/phenoxide in the
anodic oxidation reaction, cyclic voltammetry (CV) was used to
search for suitable reaction mechanisms. As in previous CV
studies,21 the oxidation potentials (Ep/2) versus Ag/AgCl (3 M
NaCl) of related functional groups and substrates were
measured (Table 4).
In CH3CN, the observed Ep/2 value of Schiff base 11 (1.64 V,
entry 1) is 90 mV lower than that of phenol (1.73 V, entry 2).
The oxidation potential of the CLN group in the phenolic
Schiff base (2) further drops to 1.27 V possibly due to the
electron-donating effect of phenol (entry 3). Therefore in the
intramolecular anodic cyclization reaction of the phenolic
Schiff base (2), it is the imine group that is oxidized first at the
anode. The reaction mechanism is proposed in Scheme 6.
Scheme 6 A proposed reaction mechanism without the LiOCH3 additive.
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Table 5 CV studies using other solvents
Entry
6
Substrate in CH3OHa
Ep/2 (V)
1.54 ¡ 0.021
7
8
1.17 ¡ 0.008
0.98 ¡ 0.009
a
Substrate (0.025 M) and LiClO4 were dissolved in CH3OH.
Scheme 7 A proposed reaction mechanism with the LiOCH3 additive.
proton at the cathode was hard to obtain and low yields of
cyclization were observed (Table 1, entry 8 and Table 3, entry
49). However, when LiOCH3 was added, there was a larger
proton resource to promote the reduction process and higher
yields of product 1 were obtained (Table 2, entry 12 and
Table 3, entry 53).
obtain radical 7. After further oxidation of radical 7 to form
cation 8 and its reduction of a proton at the cathode, the
benzoxazole 1 was obtained.
However, when LiOCH3 was added, the reaction mechan-
ism changed. For phenolate, the measured Ep/2 value was 0.48
V (Table 4, entry 4) and this increases to 0.59 V in the
phenolate Schiff base 9 (entry 5) possibly due to the electron-
withdrawing effect of the imine group. The Ep/2 value of
phenolate is much lower than that of Schiff base 11 (1.64 V,
entry 2). For this reason, the phenolate group was oxidized
first at the anode when using the phenolate Schiff base (9) in
the anodic oxidation reaction. The reaction mechanism is
proposed in Scheme 7.
Deprotonation of the phenolic Schiff base (2) by LiOCH3
may form either the phenolate 9a or the N,O-acetal anion 9b.
After oxidization at the anode, the ‘‘radical’’ intermediate 10 or
7 was obtained, not the ‘‘radical cation’’ intermediate 3 or 4 in
Scheme 6. The phenoxide radical 10 can be trapped by the
imine groups to form the acetal radical 7. Before proceeding to
the second oxidation, there must be a one electron reduction
at the cathode due to the charge balance in the electro-
chemical process. It is hard to reduce the proton in radical 7 to
form the active radical anion intermediate at this step.
Instead, the proton in the complex [CH3O(H)–Li]+ can be
reduced and LiOCH3 is regenerated at the cathode. After
oxidation of radical 7 to cation 8 and the second reduction of a
proton at the cathode, the benzoxazole product 1 was
obtained.
In CH3CN, the difference in the measured Ep/2 values
between the Schiff base 11 and the phenol (Table 4, entries 1
and 2) is less than 0.15 V. This evidence may not be enough to
differentiate between the oxidation order of these two
functional groups at the anode. Also, the oxidation potential
of each functional group may change under different solvents.
To further prove that the imine group in the phenolic Schiff
base 2 is oxidized first in anodic coupling reactions, more CV
studies for the substrates in CH3OH or CH2Cl2 were
performed. As LiClO4 was not totally dissolved in CH2Cl2,
even after stirring overnight, the oxidation potentials of the
substrates dissolved in CH3OH were measured (Table 5).
For phenol, the Ep/2 value in CH3OH (1.54 V, Table 5, entry
6) is 190 mV lower than in CH3CN (1.73 V, Table 4, entry 2).
However, there is a difference of 470 mV in the Ep/2 values for
Schiff base 11 in CH3CN (1.64 V, Table 4, entry 1) and CH3OH
(1.17 V, Table 5, entry 7). Since that oxidation potential of
Schiff base 11 is 370 mV lower than that of phenol in CH3OH,
we can confirm that the imine group is oxidized first in the
anodic coupling of the phenolic Schiff base 2. The observed
Ep/2 value of 0.98 V for the phenolic Schiff base (2) in CH3OH
(Table 5, entry 8) is for the imine group, not the phenol group.
From this trend, our previous assumption that the Ep/2 value of
1.27 is for the imine group (Table 4, entry 3) is reasonable.
The lower oxidation potential of the phenolate enhances
the anodic cyclization to proceed more easily and efficiently.
LiOCH3 was not consumed and served as a catalyst. This may
explain why the yields of cyclization were increased to 88%
when a catalytic amount of LiOCH3 was added (entries 23, 40
and 46). Also, it matches the results obtained from the
reaction under conditions of 100% CH2Cl2 (entries 8–12 and
49–53). Without the protic solvent CH3OH, the reduction of a
Conclusions
Through investigating the effects of the electrode, solvent,
electrolyte and additive, a highly efficient CLN coupling with
phenol/phenoxide
N,O-heteroatom ring was achieved by an anodic oxidation
to
synthesize
a
5-membered
reaction at room temperature. Neither transition-metal cata-
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lysts nor refluxing conditions were needed. Also, toxic
chemical oxidants, strong acids and reactive chemical reagents
were avoided as was the production of hazardous chemical
waste. The synthesis was completed by consuming the clean
energy of electricity and a useful by-product, hydrogen gas, was
produced. All solvents and reagents used in this pathway were
not consumed except the starting materials of 2-aminophenol
and aldehyde.
From the oxidation potentials of the related functional
groups observed in the CV studies, the reaction mechanisms
of the anodic cyclization were proposed. After the addition of
catalytic LiOCH3 to deprotonate phenol to phenoxide, the
initial oxidation potential in the anodic oxidation reaction
decreased and the efficiency of the cyclization reaction
increased. This is the first time CLN coupling using an anodic
oxidative reaction without the use of a transition-metal catalyst
has been obtained. Also, this is the first report involving the
use of an anodic coupling reaction to synthesize the
benzoxazole skeleton. The newly developed electrochemical
pathway provides a clean, economical and reliable pathway for
the synthesis of benzoxazole derivatives. It offers a new way of
conducting CLN coupling reactions. Extensive studies of
substituent effects in the CLN coupling with phenol/phen-
oxide using anodic cyclization and sequential anodic cou-
plings for benzoxazole derivatives are underway.
The general procedure for electrolysis reactions
The model of the electrolysis machine is Potentiostat–
Gavlvanstat, made by Jiehan Technology Corporation in
Taiwan. The Pt electrode is a Pt plate (5 mm 6 40 mm 6
0.1 mm) welded with a Cu wire, purchased from Jiehan
Technology Corporation in Taiwan. The RVC (reticulated
vitreous carbon) electrode contains a piece of RVC inserted
on the sharpened tip of a carbon rod. The piece (15 mm 6 15
mm 6 20 mm) was cut from the RVC plate (280 mm 6 210
mm 6 20 mm) and further trimmed to fit through the neck of
a 25 mL three-neck round-bottomed flask (14/20). The RVC
plate was purchased from ERG Material and Aerospace
Corporation in Oakland, CA, USA, and the carbon rod was
purchased from Central Carbon Corporation, LTD in Taiwan.
After cleaning, the Pt electrode was recycled but the RVC
electrode was not.
Under argon in a 25 mL three-necked round-bottomed flask,
Schiff base 2 (y0.1 g) and electrolyte (Et4NOTs or LiClO4, 0.1
M) were dissolved in 20 mL anhydrous solvent before 2,6-
lutidine (10 eq.) and 1 M LiOCH3 in CH3OH were added. The
resulting mixture was electrolyzed at a constant current (10
mA) until 2.2 F mol21 electricity was consumed. The reaction
was concentrated and the residue was purified via chromato-
graphy (SiO2, hexane : EtOAc = 150 : 1 with 10% NEt3) to
afford product 1 as a white solid. 1H-NMR (300 MHz, CDCl3) d
8.32–8.24 (m, 2 H), 7.84–7.76 (m, 1 H), 7.64–7.58 (m, 1 H),
7.58–7.49 (m, 3 H), 7.41–7.34 (m, 2 H); 13C-NMR (75 MHz,
CDCl3) d 163.2, 151.0, 142.3, 131.7, 129.1, 127.8, 127.4, 125.3,
124.8, 120.2, 110.8.7c
Experimental section
Synthesis of phenolic Schiff base (2)
Under argon, 2-aminophenol (2.0004 g, 18.1471 mmol) and
MgSO4 (7.2854 g, 59.9198 mmol) were dissolved in anhydrous
THF (20 mL) before benzaldehyde (2.1 mL, 20.7190 mmol) was
added to the solution. The resulting mixture was stirred
overnight at room temperature. The reaction was filtered and
concentrated. The product was purified through a pad of silica
gel twice using 10% NEt3 in hexane : EtOAc = 10 : 1 as eluent
to afford 2 as an orange solid (3.5546 g, 18.0224 mmol, 99%).
1H-NMR (300 MHz, CDCl3) d 8.72 (s, 1 H), 7.97–7.90 (m, 2 H),
7.54–7.47 (m, 3 H), 7.35–7.30 (m, 1 H), 7.26–7.18 (m, 1 H),
7.06–7.01 (m, 1 H), 6.96–6.89 (m, 1 H), 1.60 (bs, 1 H); 13C-NMR
(75 MHz, CDCl3) d 157.3, 152.6, 136.1, 135.7, 131.9, 129.2,
129.1, 129.0, 120.3, 116.1, 115.2, 115.2.9d
Acknowledgements
We would like to thank the National Science Council for
financial support (NSC 101-2113-M-390-001-) of our research.
This article is dedicated to the memory of Professor Yung-Son
Hon.
References
1 (a) S. P. B. Ovenden, J. L. Nielson, C. H. Liptrot, R.
H. Willis, D. M. Tapiolas, A. D. Wright and C. A. Motti, J.
Nat. Prod., 2011, 74, 65; (b) A. D. Rodriguez, C. Ramirez, I.
I. Rodriguez and E. Gonazlez, Org. Lett., 1999, 1, 527; (c)
E. Dumez, J. S. Snaith, R. F. W. Jackson, A. B. McElroy,
J. Overington, M. J. Wythes, J. M. Withka and T.
J. McLellan, J. Org. Chem., 2002, 67, 4882; (d) M. W.
B. McCulloch, F. Berrue, B. Haltli and R. G. Kerr, J. Nat.
Prod., 2011, 74, 2250; (e) W. P. Cullen, W. D. Celmer, L.
R. Chappel, L. H. Huang, M. T. Jefferson, M. Ishiguro,
H. Maeda, S. Nishiyama, J. R. Oscarson, R. Shibakawa and
J. Tone, J. Ind. Microbiol., 1988, 2, 349; (f) C. Hohmann,
K. Schneider, C. Bruntner, E. Irran, G. Nicholson, A. T. Bull,
A. L. Jones, R. Brown, J. EM Stach, M. Goodfellow, W. Beil,
M. Kramer, J. F. Imhoff, R. D. Sussmuth and H.-P. Fiedler,
J. Antibiot., 2009, 1.
The general procedure for the CV studies
The working electrode is Pt, the reference electrode is 3 M
NaCl(aq) and the auxiliary electrode is Pt wire. The CV machine
is Model 600D series by CH Instrument.
Under argon, substrate (0.025 M) and LiClO4 (0.1 M) were
dissolved in 48 mL anhydrous solvent (CH3CN, CH3OH or
CH2Cl2), and the resulting solution was divided into four vials.
Each vial was separately measured five times at a scan rate of
0.025 V s21. The observed oxidation potential of each substrate
is the average of twenty measurements.
2 (a) M. L. McKee and S. M. Kerwin, Bioorg. Med. Chem.,
2008, 16, 1775; (b) L. Xing, J. H. McDonald, S. A. Kolodziej,
This journal is ß The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 7330–7336 | 7335

View Article Online
Paper
r. G. Kurumbail, J. M. Williams, C. J. Warren, J. M. O’neal,
RSC Advances
J. Canivet, J. Yamaguchi, I. Ban and K. Itami, Org. Lett.,
2009, 11, 1733; (c) W. Chen, B. D. Wright and Y. Pang,
Chem. Commun., 2012, 48, 3824; (d) S. Y. Chang, Y.
H. Cheng, B.-J. Uang and C. P. Cheng, J. Chem. Soc.,
Dalton Trans., 1999, 2769.
J. E. Skepner and S. L. Roberds, J. Med. Chem., 2011, 54,
1211; (c) M. A. Siracusa, L. Salerno, M. N. Modica, V. Pittala,
G. Romeo, M. E. Amato, M. Nowak, A. J. Bojarski,
I. Mereghetti, A. Cagnotto and T. Mennini, J. Med. Chem.,
2008, 51, 4529; (d) J. Easmon, G. Purstinger, K.-S. Thies,
G. Heinisch and J. Hofmann, J. Med. Chem., 2006, 49, 6343;
(e) T. W. von Geldern, C. Lai, R. J. Gum, M. Daly, C. Sun, E.
H. Fry and C. Abad-Zapatero, Bioorg. Med. Chem. Lett.,
2006, 16, 1811; (f) S. Aliello, G. Wells, E. L. Stone, H. Kadri,
R. Bazzi, D. R. Bell, M. F. G. Stevens, C. S. Matthews, T.
D. Bradshaw and A. D. Westwell, J. Med. Chem., 2008, 51,
5135; (g) M. Wysocka, A. Lesner, K. Guzow, J. Kulczycka,
A. Legowska, W. Wiczk and K. Rolka, Anal. Chem., 2010, 82,
3883.
3 (a) K. Tanaka, T. Kumagai, H. Aoki, M. Deguchi and S. Iwata,
J. Org. Chem., 2001, 66, 7328; (b) A. Rzeska, J. Malicka,
K. Guzow, M. Szabelski and W. Wiczk, J. Photochem.
Photobiol., A, 2001, 146, 9; (c) A. Ghodbane, S. D’Alterio,
N. Saffon, N. D. McClenaghan, L. Scarpantonio, P. Jolinat
and S. Fery-Forgues, Langmuir, 2012, 28, 855; (d) C.-W. Ko,
Y.-T. Tao, A. Danel, L. Krzeminska and P. Tomasik, Chem.
Mater., 2001, 13, 2441; (e) M. Taki, J. L. Wolford and T.
V. O’Halloran, J. Am. Chem. Soc., 2004, 126, 712; (f) C.-J. Chen,
Y.-C. Wu, H.-S. Sheu, G.-H. Lee and C. K. Lai, Tetrahedron,
2011, 67, 114.
4 (a) A. Ohshima, A. Momotake, R. Nagahata and T. Arai, J.
Phys. Chem. A, 2005, 109, 9731; (b) J.-B. Baek, S. R. Simko
and L.-S. Tan, Macromolecules, 2006, 39, 7959.
5 (a) K. C. Majumdar, T. Chosh, D. S. S. Rao and S. K. Prasad,
Liq. Cryst., 2011, 38, 625; (b) N. B. Kolhe, S. K. Asha, S.
P. Senanayak and K. S. Narayan, J. Phys. Chem. B, 2010, 114,
16694.
6 Aldehyde: (a) Y.-X. Chen, L.-F. Qian, W. Zhang and B. Han,
Angew. Chem., Int. Ed., 2008, 47, 9330; (b) A. J. Blacker, M.
W. Farah, M. I. Hall, S. P. Marsden, O. Saidi and J. M.
J. Williams, Org. Lett., 2009, 11, 2039; (c) A. Hari, C. Karan,
W. C. Rodrigues and B. L. Miller, J. Org. Chem., 2001, 66,
991.
10 Reflux: (a) R. D. Viirre, G. Evindar and R. A. Batey, J. Org.
Chem., 2008, 73, 3452; (b) M. Kidwai, W. Bansal, A. Saxena,
S. Aerry and S. Mozumdar, Tetrahedron Lett., 2006, 47,
8049.
11 Oxidative reagent: (a) K. Osowska and O. S. Miljanic, J. Am.
Chem. Soc., 2011, 133, 724; (b) J. Chang, K. Zhao and S. Pan,
Tetrahedron Lett., 2002, 43, 951.
12 Reactive reagent: (a) D. C. Tully, H. Liu, P. B. Alper, A.
K. Chatterjee, R. Epple, M. J. Roberts, J. A. Williams, K.
T. Nguyen, D. H. Woodmansee, C. Tumanut, J. Li,
G. Spraggon, J. Chang, T. Tuntland, J. L. Harris and D.
S. Karanewsky, Bioorg. Med. Chem. Lett., 2006, 16, 1975; (b)
C.-y. Chen, T. Andreani and H. Li, Org. Lett., 2011, 13, 6300;
(c) Y. Yoshida, Y. Hamada, K. Umezu and F. Tabuchi, Org.
Process Res. Dev., 2004, 8, 958.
13 S. acid, L.-Q. Sun, J. C. Katherine, G. Johnson, L. Iben, C.
D. Mahle, E. Ryan and C. Xu, Bioorg. Med. Chem. Lett., 2004,
14, 1197.
14 P. Anastas and N. Eghbali, Chem. Soc. Rev., 2010, 39, 301.
15 For reviews, see: (a) J.-i. Yoshida, K. Kataoka, R. Horcajada
and A. Nagaki, Chem. Rev., 2008, 108, 2265; (b) J. Utley,
Chem. Soc. Rev., 1997, 26, 157; (c) K. D. Moeller,
Tetrahedron, 2000, 56, 9527.
16 (a) J. B. Sperry and D. L. Wright, J. Am. Chem. Soc., 2005,
127, 8034; (b) J.-i. Yoshida, Y. Ishichi and S. Isoe, J. Am.
Chem. Soc., 1992, 114, 7594; (c) A. Redden and K.
D. Moeller, Org. Lett., 2011, 13, 1678.
17 (a) J. D. Sunderhaus, C. Dockendorff and S. F. Martin,
Tetrahedron, 2009, 65, 6454; (b) P. Wipf and J. G. Pierce,
Org. Lett., 2005, 7, 3537; (c) J. Nie, M.-Q. Hua, H.-Y. Xiong,
Y. Zheng and J.-A. Ma, J. Org. Chem., 2012, 77, 4209; (d) A.
K. Ghosh, C. D. Martyr and C.-X. Xu, Org. Lett., 2012, 14,
2002; (e) E. J. Roskamp and S. F. Pedersen, J. Am. Chem.
Soc., 1987, 109, 3152.
7 Amide: (a) H. Ohmori, C. Ueda, Y. Nobusue, N. Saitou,
T. Yokota and M. Masui, J. Chem. Soc., Perkin Trans. 2,
1981, 1599; (b) S. Ueda and H. Nagasawa, Angew. Chem., Int.
Ed., 2008, 47, 6411; (c) J. Bonnamour and C. Bolm, Org.
Lett., 2008, 10, 2665.
8 Carboxylic Acid: (a) R. V. Kumar, Asian. J. Chem., 2004, 16,
1241; (b) Y. Wang, K. Sarris, D. R. Sauer and S. W. Djuric,
Tetrahedron Lett., 2006, 47, 4823; (c) R. S. Pottorf, N.
K. Chadha, M. Katkevics, V. Ozola, E. Suna, H. Ghane,
T. Regberg and M. R. Player, Tetrahedron Lett., 2003, 44,
175.
18 (a) M. Takahashi and G. C. Micalizio, J. Am. Chem. Soc.,
2007, 129, 7514; (b) E. B. Hulley, P. T. Wolczanski and E.
B. Lobkovsky, J. Am. Chem. Soc., 2011, 133, 18058.
19 (a) C. L. Allaway, M. Daly, M. Nieuwenhuyzen and G.
C. Saunders, J. Fluorine Chem., 2002, 115, 91; (b) A.
K. Awasthi, M. L. Boys, K. J. Cain-Janicki, P.-J. Colson, W.
W. Doubleday, J. E. Duran and P. N. Farid, J. Org. Chem.,
2005, 70, 5387; (c) C. De Michelis, L. Rocheblave, G. Priem,
J. C. Chermann and J. L. Kraus, Bioorg. Med. Chem., 2000, 8,
1253; (d) E. Tauer and K. H. Grellmann, J. Org. Chem., 1981,
46, 4252.
9 Metal catalyst: (a) K. Ghosh, S. Kumar, R. Kumar, U.
P. Singh and N. Goel, Inorg. Chem., 2010, 49, 7235; (b)
20 Y.-T. Huang and K. D. Moeller, Org. Lett., 2004, 6, 4199.
21 Y.-T. Huang and K. D. Moeller, Tetrahedron, 2006, 62, 6536.
7336 | RSC Adv., 2013, 3, 7330–7336
This journal is ß The Royal Society of Chemistry 2013