Electrochemical oxidation of catechols in the presence of ketene N,O-acetals: Indole formation versus α-arylation

Article abstract of DOI:10.1016/j.tet.2011.09.126

Anodic oxidation of catechols has been investigated in the presence of ketene N,O-acetals using cyclic voltammetry and constant current electrolysis methods. The results show that in the presence of ketene N,O-acetals, the anodic oxidation of 4-methylcate

Full text of DOI:10.1016/j.tet.2011.09.126

Tetrahedron 67 (2011) 9334e9341
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Electrochemical oxidation of catechols in the presence of ketene N,O-acetals:
indole formation versus a-arylation
,
Yue-Xia Bai a, Da-Wei Ping a, R. Daniel Little b, Hong-Yu Tian c, Li-Ming Hu a, Cheng-Chu Zeng a
*
a College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China
b Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA 93106, USA
c School of Food Chemistry, Beijing Technology and Business University, Beijing 100048, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2011
Received in revised form 5 September 2011
Accepted 27 September 2011
Available online 10 October 2011
Anodic oxidation of catechols has been investigated in the presence of ketene N,O-acetals using cyclic
voltammetry and constant current electrolysis methods. The results show that in the presence of ketene
N,O-acetals, the anodic oxidation of 4-methylcatechol affords
Meanwhile, indoles can be synthesized from simple 3-substituted catechols or catechol itself following
an ECEC mechanism. In addition, either -arylation or indole formation could be the dominant pathway
by simply modifying the composition of the electrolyte solution.
Ó 2011 Elsevier Ltd. All rights reserved.
a-arylated products in satisfactory yields.
a
Keywords:
Anodic oxidation
Ketene N,O-acetals
Catechols
a
-Arylation
1. Introduction
As part of our ongoing studies on the electrochemical synthesis
of polyhydroxylated aromatics,4a,7 our attention has recently fo-
cused on polyhydroxylated indoles due to their potential HIV-1
integrase inhibitory activity.8 It has been suggested that an ECEC
mechanism (E¼electrochemical and C¼chemical step) is involved
with the electrochemical synthesis of disubstituted catechols and
benzofurans via the reaction of electro-generated o-benzoquinone
and nucleophiles. In principle, the indole ring could be constructed
in a similar manner from a catechol and an enamine by employing
a sequential intermolecular CeC coupling followed by an intra-
molecular CeN coupling sequence (Scheme 1).
The anodic oxidation of a catechol generates a reactive
o-benzoquinone that can be used to trigger a number of in-
teresting reactions. Typically, the in situ electro-generated
o-benzoquinone serves as a dienophile and is trapped with
a diene1 to generate an enone derivative. More often, this type of
intermediate serves as a Michael receptor to react with a C-,2 an
N-,3 or a S-based4 mono-nucleophile or a C,O-,5 an N,N-based6
doubly nucleophilic species to generate a variety of substituted
catechols or fused catechols. Generally the nucleophile is in-
R2
R1
R2
R2
NH
R1
R1
OH
N
OH
OH
OH
NH
R3
+
R3
anodic oxidation
OH
R3
anodic oxidation
intermolecular
C,C-coupling
H
intramolecular
OH
R4
R4
R4
C,N-coupling
Scheme 1. Retrosynthetic analysis of polyhydroxylated indoles.
troduced para to the initial hydroxyl groups of the catechol ring
via a Michael addition.
Recently, we reported the electrochemical oxidation of cate-
chols 1 in the presence of ketene N,N-acetals and found that the
reaction stopped at the intermolecular CeC coupling step and
generated exclusively a
-arylated products of ketene N,N-acetals.9
When the enamine substrates are replaced by N,O-acetals con-
taining a five-membered oxazolidine ring, indole derivatives did
* Corresponding author. Fax: þ86 10 67392001; e-mail address: zengcc@
bjut.edu.cn (C.-C. Zeng).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.126

Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
9335
form.10 Obviously, the nature of the starting ketene acetals (N,N-
acetal or N,O-acetal) plays a key role in the formation of indole or
arylated products. Herein we report the full details of the anodic
oxidation of catechols in the presence of heterocyclic ketene N,O-
acetals or noncyclic ketene N,O-acetal (Fig. 1).
which was reduced in the cathodic sweep at ꢀ0.03 V (C1), back to
1a (curve I). The ratio of the current amplitudes between the
oxidation and reduction processes is equal to unity (Iopx/Ipred), in-
dicating that the o-benzoquinone produced at the surface of the
electrode is stable in the pH 7 acetate buffer solution. To obtain
further information concerning the transformation of the in situ
generated o-benzoquinone, the anodic oxidation of 1a in the
presence of 2a was studied by cyclic voltammetry. As shown in
curve II of Fig. 2, when an equivalent amount of 2a was added, the
anodic potential shifts slightly to 0.27 V and a new anodic wave
centered at 0.68 V appears. Simultaneously, the current amplitude
of the initial cathodic peak (C1) decreased. Curve III is that of the
ketene N,O-acetal 2a itself; it shows a well-defined anodic peak
centered at 1.05 V (Fig. 2).
a
-
O
R1
NH
O
R3
R2
OH
OH
n
2a-f
n = 1, a: R3 = CH3; b: R3 = H; c: R3 = Cl
n = 0, d: R3 = CH3; e: R3 = H; f: R3 = OCH3
1
O
a: R1 = H, R2 = CH3
b: R1 = OCH3, R2 = H
c: R1 = H, R2 = H
PrHN
The voltammetric behavior indicates that a chemical reaction
occurs between the electrochemically generated intermediate (at
EtO
2g
A1) and the
that Michael addition products may be produced if anodic oxi-
dation of the mixture of a catechol and an -oxoheterocyclic
a-oxoheterocyclic ketene N,O-acetal 2a and suggest
Fig. 1. The structure of starting catechols and ketene N,O-acetals.
a
ketene N,O-acetal is carried out at the potential of catechol
(0.27 V vs Ag/AgCl (0.1 M) AgCl for 1a), or under constant current
conditions where the undesired oxidation of ketene N,O-acetal
will not take place due to the differing oxidation potentials be-
tween catechol and N,O-acetals (for example, 0.22 V for 1a vs
1.05 V for 2a).
2. Results and discussion
2.1. Cyclic voltammetric studies
Before the preparative scale electrolysis was performed, the
electrochemical behavior of catechols in the absence and presence
of enamine 2 was first examined by cyclic voltammetry (CV), at
room temperature, in 0.2 M acetate buffer (pH 7). The CV curve of
1a is typical of each of the catechols; it is shown in Fig. 2. Upon
2.2. Electrochemical oxidation of substituted catechols in the
presence of ketene N,O-acetals
Based upon the CV analysis of the catechols in the absence and
presence of heterocyclic ketene N,O-acetals acetals 2, we first car-
ried out the anodic oxidation of 4-methylcatechol (1a) in the
presence of 2aec containing a six-membered oxazinane ring and
also ketene N,O-acetals 2def containing a five-membered oxazo-
lidine ring (Scheme 2). The initial nucleophilic substrate was (E)-2-
(1,3-oxazinan-2-ylidene)-1-p-tolylethanone (2a). The conditions
employed for the synthesis were the optimized ones developed
earlier for the reaction of catechols in the presence of ketene N,N-
acetals.9 They consisted of an anode made from an assembly of
seven graphite rods held together with copper wire, a Pt cathode,
0.2 M sodium acetate in acetonitrile/acetate buffer (volume ratio of
acetonitrile to acetate buffer was 1:4) electrolyte solution, and in an
H-type divided cell. The reaction was conducted at a constant
current of w3 mA/cm2. In the course of electrolysis, a brown
powder precipitated. After the consumption of starting material 1a
80
A1
II
60
A0
40
I
III
20
0
C1
-20
C0
-40
-400
0
400
800
1200
1600
E
/ mV Ag/AgCl
Fig. 2. Cyclic voltammograms of (I) 2 mM of 4-methylcatechol (1a), (II) a mixture of
2 mM of 1a and 2 mM of ketene N,O-acetal 2a, and (III) 2 mM of ketene N,O-acetal 2a,
at a glassy carbon working electrode, platinum wire counter electrode, and Ag/AgCl
(0.1 M) reference electrodes, in 1:1 (v/v) acetate buffer/acetonitrile (0.2 M, pH 7) so-
lution; scan rate: 50 mV/s.
(2.24 F/mol charge), the a-arylated product 3a, stemming from the
Michael addition of 1a to the electro-generated o-benzoquinone
was obtained in 75% yield after simple filtration (Scheme 2 and
entry 1, Table 1).
H3C
OH
OH
O
H3C
OH
OH
NH
O
R
anodic oxidation
NaOAc buffer
O
n
n
NH
2a-f
O
R
1a
n = 1, a: R = CH3; b: R = H; c: R = Cl
n = 0, d: R = CH3; e: R = H; f: R = OCH3
3a-f
Scheme 2. Anodic oxidation of 4-methylcatechol (1a) in the presence of ketene N,O-acetals 2aef.
scanning anodically, catechol 1a exhibits one well-defined oxida-
tion wave (A1) at 0.22 V, corresponding to a cation radical that ul-
timately leads to the formation of an o-benzoquinone derivative,
A similar outcome was observed when 2b or 2c were used as
Michael donors. As shown in Table 1, additives 3b or 3c were ob-
tained in 46% and 78% yields, respectively (entries 2 and 3). In

9336
Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
Table 1
Anodic oxidation of catechols 1 in the presence of heterocyclic ketene N,O-acetals 2
Entry
1c
Catechol
Ketene acetal
Product
H3C
Ratioa
Yieldb (%)
75
OH
OH
3a
CH3
OH
O
1a
2a
d
NH
O
H3C
O
2c
3c
4c
1a
1a
1a
2b
2c
2d
d
d
d
46
78
68
OH
3b
NH
O
H3C
OH
OH
O
3c
NH
O
Cl
H3C
OH
OH
O
3d
N
H
O
CH3
H3C
OH
OH
O
5c
1a
2e
d
56
3e
N
H
O
H3C
OH
O
6c
1a
1b
2f
d
d
81
56
OH
3f
N
H
O
OCH3
OCH3
OH
O
7c
2a
OH
3g
NH
O
CH3
OCH3
OH
O
8c
1b
1b
2b
2c
d
43
75
OH
h
3
NH
O
OCH3
OH
O
9c
d
OH
3i
NH
O
Cl
CH3
OCH3
OH
OCH3
OH
N
O
+
10d
1b
2a
2: 1
45
O
OH
O
OH
O
N
4a
CH3
5a
OCH3
OCH3
OH
OH
N
O
11d
1b
2b
2: 1
25
O
OH
+
O
OH
O
N
4b
5b

Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
9337
Table 1 (continued )
Entry
Catechol
Ketene acetal
Product
Ratioa
Yieldb (%)
Pr
OH
N
12d
1c
2g
23
EtO
OH
O
4
d
a
Ratio of regioisomers determined by 1H NMR.
Isolated yield.
Experimental conditions: room temperature, 1 mmol of catechol 1 and 1 mmol of 2 in 50 mL of 0.2 M acetate buffer and acetonitrile (4:1¼v/v), an assembly of seven
b
c
graphite rods anode, Pt plate (2 cm2) cathode, divided cell; Constant current: 15 mL (w3 mA/cm); Charge passed: 2.24 F/mol.
d
Experimental conditions: 1.5 mmol of catechol 1b and 1 mmol of 2 in 100 mL of 0.2 M acetate buffer and acetonitrile (2:1¼v/v), charge passed: 4.0 F/mol, other conditions
were identical to the above.
addition, heterocyclic ketene acetals 2def containing an oxazoli-
dine ring afforded adducts 3d, 3e, and 3f in yields of 68%, 56%, and
81%, respectively, under similar reaction conditions (Scheme 2 and
entries 4e6).
Attention was next turned toward exploring the possible utility
of 3-substituted catechols. To this end, 3-methoxycatechol was ex-
amined (Scheme 3).11As shown in Table 1, under identical condi-
tions, products 3gei were obtained after simple filtration in 56%,
43%, and 75% yield, respectively (Scheme 3 and entries 7e9, Table 1).
remained unchanged. After 2.24 F/mol of current was passed, 3g
was detected by TLC, along with the formation of another com-
pound. Also, no precipitate formed. When a total of 4.39 F/mol of
charge was passed, a yellow powder precipitated, which was fil-
tered and identified. Spectroscopic methods demonstrated that the
precipitate was a 2:1 mixture of regioisomers 4a and 5a, formed in
a 45% yield (entry 10). Efforts to separate the polyhydroxylated
indoles 4a and 5a failed using conventional methods, due to
‘identical’ polarity of 4a and 5a (Scheme 3).
OCH3
OH
NH
R3
VNaOAc buffer:VCH3CN = 4:1
O
OH
Constant current
OCH3
3g: R3 = CH3; 3h: R3 = H;
3i: R3 = Cl
O
OH
R3
+
O
R3
OH
OCH3
OH
OCH3
OH
HN
O
1b
N
O
Constant current
+
2a-c
OH
OH
VNaOAc buffer:VCH3CN = 2:1
N
O
O
O
R3
5a-b
4a-b
4a and 5a: R3 = CH3; 4b and 5b: R3 = H
Scheme 3. Anodic oxidation of 3-methoxycatechol (1b) in the presence of ketene N,O-acetals 2aec.
Since we have reported the formation of the indole ring from 3-
methoxycatechol 1b and heterocyclic ketene N,O-acetals 2def us-
ing anodic oxidation, we expected that indole formation would also
take place when N,O-acetals 2aec were examined. However, in the
To further explore our hypothesis, the electrochemical oxidation
of 3-methoxycatechol (1b) in the presence of 2b was also carried out
under the modified conditions. After conventional workup and
column chromatography, a 2:1 mixture of regioisomers 4b and 5b
present instances, only the
a
-arylated products 3gei were pro-
was obtained in 25% yield, along with the isolation of 14% yield of a-
duced. Perhaps the presence of a six-membered oxazinane ring of
ketene N,O-acetals prevented intramolecular Michael addition
from generating the indole ring. Another rationale suggests that the
initially formed products 3gei do not dissolve and further oxida-
tion and intramolecular Michael addition is thus terminated. If the
second reason is true, then indole derivatives should be attainable
by modifying the electrolytic solution to ensure solubility of the
initially formed materials 3gei.
To test this hypothesis, we examined the reaction of 1b and 2a.
We changed the composition of the electrolytic solution from 1:4 to
a 1:2 ratio of acetonitrile to acetate buffer solution and repeated the
electrochemical oxidation. Other reaction conditions, such as ap-
plied current, the nature of the electrode material and cell type
arylation product 3h (Scheme 3 and entry 11). It is worth noting that
the corresponding indoles 4c and 5c did not form from the reaction
of 1b and 2c under the modified conditions. Once again, it is because
of the low solubility of 3i. For example, 3i precipitated when 2 F/mol
charge was passed and did not disappear after the consumption of
4 F/mol of charge. After conventional workup, a-arylation product 3i
was obtained in a 73% yield (Scheme 3 and entry 11).
Finally, noncyclic ketene N,O-acetal 2g was designed and syn-
thesized to examine whether the ring structure of the ketene N,O-
acetal would influence the selective formation of indole or a-ary-
lation product. As shown in Table 1, the anodic oxidation of a mix-
ture of 1c and 2g under identical conditions afforded corresponding
4d in 23% yield (Scheme 4 and entry 12, Table 1).

9338
Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
Pr
O
NHPr
OEt
OH
OH
OH
OH
anodic oxidation
NaOAc buffer
N
O
+
EtO
1c
2g
4d
Scheme 4. Anodic oxidation of catechol in the presence of ketene N,O-acetals 2g.
It is noteworthy that these polyhydroxylated
a-arylation prod-
If the initially formed a-arylated products 3 do not dissolve in
uct and indoles were quite difficult to separate by silica gel column
chromatography because they adhered so strongly to the chro-
matographic support.12 Therefore, somewhat lower yields of 4d
were obtained when it was isolated using column chromatography,
compared with that of 4a, which was isolated via simple filtration,
although almost quantitative of conversion was observed via TLC in
both cases.
On the basis of the above results and our previous examination
of the anodic oxidation of catechols in the presence of ketene N,N-
acetals,9 we conclude that the structure of the starting benzoyl-
substituted ketene N,O-acetals ketene plays a key role in de-
the electrolytic solution when the volume ratio of acetonitrile to
acetate buffer is 1:4, then 3 precipitates, over-oxidation is avoided,
and a-arylated products are produced exclusively. However, when
the ratio of acetate buffer to acetonitrile is increased to 2:1, then the
initially formed 3g and 3h can partially dissolve and further oxi-
dation proceeds to generate the corresponding o-benzoquinone
derivatives 8. To achieve the geometry needed for the subsequent
nucleophilic attack (see Scheme 5), an enamine-to-imine and an
imine-to-enamine tautomerization is required to convert 8 to 800.
From there, a Michael addition followed by aromatization to gen-
erate indole derivatives 4 or a 1,6-addtion leading to regioisomers 5
can occur.
termining the formation of
a-arylation products or indoles, al-
though the exact reason behind such results is not clear.
It should be pointed out that, due to steric and electronic effects,
the 1,4-addition pathway is preferable to 1,6-addition. This pre-
sumably accounts for the higher yield of 4 relative to 5 (the ratio of
4 to 5 is about 2:1 according to the 1H NMR data).
2.3. Reaction mechanism
Nematollahi et al. have demonstrated the formation of benzo-
furans from the anodic oxidation of catechols in the presence of 1,3-
dicarbonyl compounds and have suggested an ECEC mechanism.
Obviously, we can assume that a similar sequence may take place to
generate indole derivatives from catechols and ketene N,O-acetals.
As shown in Scheme 5, we suggest that the anodic oxidation of
catechol 1 transforms it to the corresponding highly reactive
o-benzoquinones 7, which then undergo Michael reaction with
3. Conclusion
The anodic oxidation of catechols has been investigated in the
presence of heterocyclic and noncyclic ketene N,O-acetals. The re-
sults showed that
4-substituted catechols and N,O-acetals, whereas, either
products or indoles could be generated from 3-substituted cate-
chols. Also, the composition of the electrolyte solution plays a key
a
-arylated products can obtained from
a
-arylated
ketene N,O-acetals 2 to generate
a
-arylated products 3aei.
EWG
NHR4
R1
R2
R1
O
R1
OR3
NHR4
OR3
2a-g
HO
HO
R2
O
O
R2
-2e, -2H+
HO
H
EWG
1a-c
7
R1
R1
R1
-2e, -2H+
enamine-imine
tautomerization
O
O
R3O
R2
HO
O
O
OR3
R3O
aromatization
NR
4
NHR4
EWG
HO
NHR4
EWG
EWG
3a-i
8
R1
R4
OH
OH
N
1,4-Michael
addition
aromatization
R3O
GWE
R1
4a,b,d
imine-enamine
tautomerization
R4HN
O
R1
OR3
OH
OH
1,6-Michael
addition
O
aromatization
EWG
8"
EWG
N
R4
5a,b
R3O
Scheme 5. Proposed mechanism for the conversion of catechols 1aec to indoles 4a,b,d and 5a,b.

Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
9339
role in ensuring that the reaction stops at the
a
-arylated products
AreH), 6.97 (d, 2H, J¼8.0 Hz, AreH), 8.27 (s, 1H, OH), 8.41 (s, 1H,
OH),13.16 (s, br,1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6):
19.8,
21.0, 21.2, 37.3, 66.0, 94.1, 117.1, 121.4, 127.8, 127.9, 128.0, 129.3, 137.5,
or proceeds leading to indole formation. In addition, we conclude
that the nature of the ketene acetal is one of the predominant
factors in determining whether or not the indole ring can be gen-
erated. Further investigation of the generality of this method for the
formation of indoles is in progress.
d
140.5, 142.6, 143.9, 166.0, 185.4 ppm. IR (KBr):
n 3427, 2919, 1606,
1520 cmꢀ1. ESI-MS: m/z 339.7 [Mþ1]þ, 361.7 [MþNa]þ, 337.8
[Mꢀ1]ꢀ, 676.9 [2Mꢀ1]ꢀ.
4. Experimental
4.3.2. (E)-2-(4,5-Dihydroxy-2-methylphenyl)-2-(1,3-oxazinan-2-
ylidene)-1-phenylethanone (3b). Yield 46%; mp 232e234 ꢂC. 1H
4.1. Instruments and reagents
NMR (400 MHz, DMSO-d6):
d
1.87 (s, 3H, CH3), 1.98 (t, 2H, J¼4.4 Hz,
CH2), 3.48 (s, 2H, CH2), 4.20 (t, 2H, J¼4.8 Hz, OeCH2), 6.27 (s, 1H,
AreH), 6.41 (s, 1H, AreH), 7.09 (m, 5H, AreH), 8.26 (s, 1H, OH), 8.40
(s,1H, OH),13.14 (s, br,1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6):
Melting points were measured with a XT4A Electrothermal
melting point apparatus and are uncorrected. IR spectra were
recorded as KBr pellets. 1H and 13C NMR spectra were recorded with
an AV 400 M Bruker spectrometer (400 MHz 1H frequency,100 MHz
d
19.8, 21.0, 37.3, 66.1, 94.2, 117.1, 121.4, 127.4, 127.6, 127.9, 128.2,
129.3, 142.6, 143.3, 143.9, 166.1, 185.5 ppm. IR (KBr):
n 3482, 1619,
13C frequency). Chemical shifts are given as
d
values (internal
1507, 1438 cmꢀ1. ESI-MS: m/z326.0 [Mþ1]þ, 347.9 [MþNa]þ, 673.0
standard: TMS). The MS spectra (ESI) were recorded on a Bruker
Esquire 6000 mass spectrometer.
[2MþNa]þ, 323.6 [Mꢀ1]ꢀ, 648.7 [2Mꢀ1]ꢀ.
Catechols 1a and 1b were reagent-grade and obtained from Alfa
Aesar China (Tianjin) Co. Ltd. Compounds 2aef and 2g were syn-
thesized by following known procedures.13 Other chemicals and
solvents were obtained from Beijing Chemicals Co. and used
without further purification. All electrodes for CV experiments
were from CH Instruments, Inc. USA. Doubly distilled de-ionized
water was used for the preparation of the aqueous acetate buffer.
All experiments were performed at room temperature and ambient
pressure.
4.3.3. (E)-1-(4-Chlorophenyl)-2-(4,5-dihydroxy-2-methylphenyl)-2-
(1,3-oxazinan-2-ylidene)ethanone (3c). Yield 78%; mp 248e249 ꢂC.
1H NMR (400 MHz, DMSO-d6):
d 1.86 (s, 3H, CH3), 1.98 (t, 2H,
J¼4.0 Hz, CH2), 3.49 (t, 2H, J¼4.0 Hz, NeCH2), 4.21 (t, 2H, J¼4.8 Hz,
OeCH2), 6.26 (s, 1H, AreH), 6.43 (s, 1H, AreH), 7.05 (d, 2H, J¼8.4 Hz,
AreH), 7.13 (d, 2H, J¼8.0 Hz, AreH), 8.30 (s, 1H, OH), 8.46 (s, 1H,
OH), 13.03 (s, br, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6):
d
19.7, 20.9, 37.3, 66.2, 94.2, 117.2, 121.4, 127.2, 127.4, 129.2, 129.7,
132.8, 142.1, 142.7, 144.1, 166.2, 183.9 ppm. IR (KBr):
n 3414, 2919,
2875, 2700, 2586, 1606, 1572, 1520, 1506 cmꢀ1. ESI-MS: m/z 359.8
[Mþ1]þ, 381.7 [MþNa]þ, 357.8 [Mꢀ1]ꢀ, 716.8 [2Mꢀ1]ꢀ.
4.2. Cyclic voltammetry
Cyclic voltammograms were measured by using a 273A Poten-
tiostat/Galvanostat equipped with an electrochemical analysis
software, using a conventional three-electrode cell. The working
electrode was a glassy carbon disk electrode (ca. ɸ¼3 mm). The
auxiliary and reference electrodes in these studies were Pt wire and
saturated Ag/AgCl (in 3 M KCl), respectively. Glassy carbon was
polished with polishing cloth before each measurement. Acetate
buffer solutions were prepared from NaOAc and HOAc and were
monitored by a digital pH meter. The scan rate was 50 mV/s. The
concentration of 1 and 2 were 2 mmol Lꢀ1, while that of the sup-
4.3.4. (E)-2-(4,5-Dihydroxy-2-methylphenyl)-2-(oxazolidin-2-
ylidene)-1-p-tolylethanone (3d). Yield: 68%; mp: 225e226 ꢂC; 1H
NMR (400 MHz, DMSO-d6):
d 1.84 (s, 3H, CH3), 2.20 (s, 3H, CH3),
3.78 (t, 2H, NeCH2), 4.38 (t, 2H, OeCH2), 6.33 (s, 1H, AreH), 6.44 (s,
1H, AreH), 6.91 (d, 2H, J¼8.0 Hz, AreH), 7.04 (d, 2H, J¼8.0 Hz,
AreH), 8.34 (s, 1H, OH), 8.47 (s, 1H, OH), 10.55 (s, br, 1H, NH); 13C
NMR (100 MHz, DMSO-d6):
d 19.7, 21.2, 43.9, 67.8, 90.8, 117.2, 120.9,
127.5, 128.1, 128.2, 128.9, 138.3, 139.9, 142.8, 144.1, 168.9, 187.3; IR
(KBr):
n 3414, 2921, 1603, 1567, 1518, 1463; ESI-MS: m/z 325.9
[Mþ1]þ, 323.7 [Mꢀ1]ꢀ, 648.8 [2Mꢀ1]ꢀ.
porting electrolyte was 0.2 mol Lꢀ1
.
4.3.5. (E)-2-(4,5-Dihydroxy-2-methylphenyl)-2-(oxazolidin-2-
4.3. General procedure for the synthesis of compounds 3aef
ylidene)-1-phenylethanone (3e). Yield: 56%; mp: 229e230 ꢂC; 1H
NMR (400 MHz, DMSO-d6): d 1.84 (s, 3H, CH3), 3.80 (t, 2H, NeCH2),
An H-type cell equipped with a medium porosity of glass frit as
a membrane was maintained in water bath at room temperature.
The anode compartment contained an anode assembly consisting
of seven graphite rods whose upper rims were wrapped by a copper
wire; a platinum plate (2 cm2) served as the counter electrode and
was immersed in the cathode compartment. The applied current
throughout electrolysis was 15 mA (w3 mA/cm) and was controlled
by a direct current power source. During the course of electrolysis,
a magnetic stirrer stirred the mixture.
4.39 (t, 2H, OeCH2), 6.33 (s, 1H, AreH), 6.43 (s, 1H, AreH), 7.08e7.18
(m, 5H, AreH), 8.32 (s, 1H, OH), 8.46 (s, 1H, OH), 10.55 (s, br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6):
d 19.7, 43.9, 67.9, 90.8, 117.2,
120.9, 127.3, 127.4, 128.0, 128.8, 128.9, 142.7, 142.8, 144.1, 168.9,
187.5; IR (KBr):
n
3424,1599,1520,1488; ESI-MS: m/z 309.6 [Mꢀ1]ꢀ.
4.3.6. (E)-2-(4,5-Dihydroxy-2-methylphenyl)-1-(4-methoxyphenyl)-
2-(oxazolidin-2-ylidene)ethanone (3f). Yield: 81%; mp: 151e152 ꢂC;
1H NMR (400 MHz, DMSO-d6):
d 1.84 (s, 3H, CH3), 3.68 (s, 3H,
In a typical procedure, to the anode compartment was added
a mixture of 50 mL 0.2 M acetate buffer/acetonitrile (the volume
ratio is 4:1). Subsequently, 1 mmol catechols 1 and 1 mmol 2 were
added to the anodic compartment and the solution was electro-
lyzed. The electrolysis was terminated after 2.24 F/mol of charge
was passed. The formed precipitate was filtered, washed with
water (3ꢁ10 mL), and dried to obtain the corresponding product, 3.
OCH3), 3.79 (m, 2H, NeCH2), 4.38 (m, 2H, OeCH2), 6.35 (s, 1H,
AreH), 6.46 (s, 1H, AreH), 6.66 (d, 2H, J¼8.8 Hz, AreH), 7.13 (d, 2H,
J¼8.8 Hz, AreH), 8.37 (s, 1H, OH), 8.50 (s, 1H, OH), 10.54 (s, br, 1H,
NH); 13C NMR (100 MHz, DMSO-d6):
d 19.7, 43.9, 55.4, 67.8, 90.6,
112.8, 117.3, 120.8, 127.7, 128.8, 130.1, 134.9, 142.8, 144.1, 159.9, 168.8,
186.4; IR (KBr):
n
3436,1602,1576,1469; ESI-MS: m/z 341.9 [Mþ1]þ,
363.8 [MþNa]þ, 339.7 [Mꢀ1]ꢀ.
4.3.1. (E)-2-(4,5-Dihydroxy-2-methylphenyl)-2-(1,3-oxazinan-2-
4.3.7. (E)-2-(3,4-Dihydroxy-5-methoxyphenyl)-2-(1,3-oxazinan-2-
ylidene)-1-p-tolylethanone (3a). Yield 75%; mp 227e228 ꢂC. 1H
ylidene)-1-p-tolylethanone (3g). Yield 56%; mp 210e211 ꢂC. 1H NMR
NMR (400 MHz, DMSO-d6):
d
1.86 (s, 3H, CH3), 1.97 (t, 2H, CH2), 2.18
(400 MHz, DMSO-d6):
3.48 (s, 2H, NeCH2), 3.48 (s, 3H, OCH3), 4.23 (t, 2H, J¼4.8 Hz,
OeCH2), 5.97 (d, 1H, J¼1.6 Hz, AreH), 6.08 (d, 1H, J¼1.6 Hz, AreH),
d
1.99 (t, 2H, J¼5.2 Hz, CH2), 2.19 (s, 3H, CH3),
(s, 3H, CH3), 3.47 (t, 2H, J¼4.0 Hz, NeCH2), 4.19 (t, 2H, J¼5.2 Hz,
OeCH2), 6.26 (s, 1H, AreH), 6.41 (s, 1H, AreH), 6.87 (d, 2H, J¼8.0 Hz,

9340
Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
6.89 (d, 2H, J¼8.0 Hz, AreH), 7.00 (d, 2H, J¼8.0 Hz, AreH), 7.89 (s,
electrolysis was terminated after 4.0 F/mol of charge was passed.
The solution was acidified to pH¼1 with 1 mol/L aqueous HCl and
then extracted using ethyl acetate (3ꢁ20 mL) and washed with
water (20 mL). The separated organic layer was dried over MgSO4,
filtered and evaporated. The crude product was purified by column
chromatography on silica gel, eluted with a mixture of petroleum
ether and acetone (v/v¼2:1) to afford 4b and 5b.
1H, OH), 8.45 (s, 1H, OH), 13.06 (s, br, 1H, NH) ppm. 13C NMR
(100 MHz, DMSO-d6):
d 20.9, 21.2, 37.3, 56.2, 66.0, 96.1, 109.7, 114.4,
127.8,127.9,128.3,129.0,129.6,132.5,137.3,140.8,145.2,147.8,166.1,
186.2 ppm. IR (KBr):
n 3372, 2969, 22,939, 2700, 2869, 1607, 1573,
1528, 1501, 1447 cmꢀ1. ESI-MS: m/z 355.9 [Mþ1]þ, 393.8 [MþK]þ.
4.3.8. (E)-2-(3,4-Dihydroxy-5-methoxyphenyl)-2-(1,3-oxazinan-2-
ylidene)-1-phenylethanone (3h). Yield 43%; mp 211e212 ꢂC. 1H
4.5.1. (7,8-Dihydroxy-6-methoxy-3,4-dihydro-2H-[1,3]oxazino[3,2-
a]indol-10-yl)(phenyl)methanone and (6,7-dihydroxy-8-methoxy-
3,4-dihydro-2H-[1,3]oxazino[3,2-a]indol-10-yl)(phenyl)meth-
anone. Yield 25%; mp 101e103 ꢂC; 1H NMR of 4b (400 MHz, DMSO-
NMR (400 MHz, DMSO-d6):
d
2.00 (t, 2H, J¼5.2 Hz, CH2), 3.45 (s, 3H,
OCH3), 3.48(s, 2H, CH2), 4.24 (t, 2H, J¼4.8 Hz, OeCH2), 5.93 (s, 1H,
AreH), 6.10 (s, 1H, AreH), 7.09 (m, 5H, AreH), 7.88 (s, 1H, OH), 8.45
(s, 1H, OH), 13.02 (s, br, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-
d6):
d
1.81 (m, 2H, CH2), 3.43 (t, 2H, J¼5.6 Hz, NCH2), 3.77 (s, 3H,
d6):
d
20.87, 37.3, 56.11, 66.1, 96.2, 109.7, 114.3, 127.4, 127.6, 127.9,
OCH3), 4.26 (t, 2H, J¼5.6 Hz, OCH2), 6.05 (s, 1H, AreH), 7.53e7.86
128.1, 132.4, 143.6, 145.1, 147.8, 166.1, 186.4 ppm. IR (KBr):
n 3468,
(m, 5H, AreH), 10.05 (br, s, H, OH); 1H NMR of 5b (400 MHz, DMSO-
1615, 1532, 1504 cmꢀ1. ESI-MS: m/z 341.8 [Mþ1]þ, 361.8 [MþNa]þ,
d6):
d
¼1.78 (m, 2H, CH2), 3.41 (t, 2H, J¼7.0 Hz, NCH2), 3.45 (s, 3H,
704.9 [2MþNa]þ, 339.8 [Mꢀ1]ꢀ.
OCH3), 4.22 (t, 2H, J¼7.0 Hz, OCH2), 7.57 (s,1H, AreH), 7.53e7.86 (m,
5H, AreH), 10.05 (br, s, H, OH) ppm. 13C NMR of 4b and 5b
4.3.9. (E)-1-(4-Chlorophenyl)-2-(3,4-dihydroxy-5-methoxyphenyl)-
(100 MHz, DMSO-d6): d 21.6, 31.1, 43.3, 55.6, 55.8, 65.9, 107.0, 107.0,
2-(1,3-oxazinan-2-ylidene)ethanone
(3i). Yield
75%;
mp:
109.1, 129.3, 129.4, 129.5, 133.0, 133.5, 134.2, 134.4, 137.3, 137.6,
138.5, 138.7 150.8, 151.4, 152.4, 153.0, 154.8, 176.3, 176.4, 194.5,
237e239 ꢂC. 1H NMR (400 MHz, DMSO-d6):
d
2.01 (m, 2H, CH2),
3.48 (s, 2H, NeCH2), 3.48 (s, 3H, OCH3), 4.25 (t, 2H, J¼5.2 Hz,
OeCH2), 5.95 (d, 1H, J¼1.6 Hz, AreH), 6.09 (d, 1H, J¼1.6 Hz, AreH),
7.09 (d, 2H, J¼8.4 Hz, AreH), 7.16 (d, 2H, J¼8.4 Hz, AreH), 7.97 (s,1H,
OH), 8.52 (s, 1H, OH), 12.93 (s, br, 1H, NH) ppm. 13C NMR (100 MHz,
194.7 ppm. IR (KBr): n
3434, 2931, 2856, 1640, 1534, 1448 cmꢀ1. ESI-
MS: m/z 340.0 [Mþ1]þ, 362.0 [MþNa]þ, 337.7 [Mꢀ1]ꢀ.
4.5.2. (2-Ethoxy-5,6-dihydroxy-1-propyl-1H-indol-3-yl)(phenyl)
DMSO-d6):
d
20.8, 37.4, 56.1, 66.2, 96.3, 109.5, 114.3, 127.3, 127.5,
methanone (4d). Yield: 23%; mp: 215e216 ꢂC; 1H NMR (400 MHz,
130.2, 132.5, 132.6, 142.4, 145.3, 147.9, 166.2, 186.7 ppm. IR (KBr):
n
DMSO-d6): d 0.84e0.91 (m, 6H, 2CH3), 1.68e1.73 (m, 2H, CH2), 3.68
3435, 1612,1530, 1508, 1484 cmꢀ1. ESI-MS: m/z 375.8 [Mþ1]þ, 397.8
(q, 2H, J¼6.8 Hz, NCH2), 3.91 (q, 2H, J¼6.8 Hz, OCH2), 6.81 (s, 1H,
[MþNa]þ, 373.8 [Mꢀ1]ꢀ, 748.7 [2Mꢀ1]ꢀ.
AreH), 7.28 (s, 1H, AreH), 7.55 (m, 5H, AreH), 8.64 (s, 1H, OH), 8.77
(s, 1H, OH); 13C NMR (100 MHz, DMSO-d6):
d
11.7, 15.1, 22.7, 43.4,
4.4. Procedure for the synthesis of compounds 4a and 5a
73.5, 97.5, 99.5, 106.9, 118.0, 125.4, 128.4, 128.7, 131.3, 141.4, 142.8,
143.4, 154.8, 189.5; IR (KBr):
n 3434, 2963, 2923, 2853, 2373, 2344,
The setups were identical to that for the synthesis of 3ae3f. To
the anode compartment was added a mixture of 100 mL of 0.2 M
acetate buffer and acetonitrile (the volume ratio is 2:1). Sub-
sequently, 1.5 mmol of catechols 1b and 1.5 mmol of 2a were added
to the anodic compartment and the solution was electrolyzed. The
electrolysis was terminated after 4.0 F/mol of charge was passed.
The precipitate was filtered, washed with water (3ꢁ10 mL) and
dried to obtain the desired products 4a and 5a.
1603, 1584, 1553, 1517, 1473, 1433 cmꢀ1; ESI-MS: m/z 339.9 (Mþþ1),
361.8 (MþþNaþ), 337.9 (Mꢀꢀ1), 677.0 (2Mꢀꢀ1).
Acknowledgements
This work was supported by Grants from the National Natural
Science Foundation of China (No. 20772010), the National Basic
Research Program of China (No. 2009CB930200, 2011CB933101),
The National Key Technology R&D Program (2011BAD23B01), Bei-
jing Natural Science Foundation (No. 7112008) and Beijing City
Education Committee (KM201010005009).
4.4.1. (7,8-Dihydroxy-6-methoxy-3,4-dihydro-2H-[1,3]oxazino[3,2-
a]indol-10-yl)-p-tolylmethanone and (6,7-dihydroxy-8-methoxy-3,4-
dihydro-2H-[1,3]-oxazino-[3,2-a]indol-10-yl)-p-tolylmethanone.-
Yield 45%; mp 151e152 ꢂC; 1H NMR of 4a (400 MHz, DMSO-d6):
References and notes
d
1.81 (s, 2H, CH2), 2.38 (s, 3H, CH3), 3.32 (s, NCH2), 3.77 (s, 3H,
1. (a) Nematollahi, D.; Workentin, M.; Tammari, E. Chem. Commun. 2006,
1631e1633; (b) Chiba, K.; Jinno, M.; Nozaki, A.; Tada, M. Chem. Commun. 1997,
1403e1404; (c) Chiba, K.; Tada, M. J. Chem. Soc., Chem. Commun. 1994,
2485e2486.
OCH3), 4.24 (s, 2H, OCH2), 6.03 (s, 1H, AreH), 7.36 (d, 2H, J¼6.4 Hz,
AreH), 7.53 (br, s, H, OH), 7.74 (d, 2H, J¼7.2 Hz, AreH),10.02 (br, s, H,
OH); 1H NMR of 5a (400 MHz, DMSO-d6):
d 1.80 (s, 2H, CH2), 2.38 (s,
3H, CH3), 3.32 (s, NCH2), 3.77 (s, 3H, OCH3), 4.24 (s, 2H, OCH2), 5.99
(s, 1H, AreH), 7.36 (d, 2H, J¼6.4 Hz, AreH), 7.44 (br, s, H, OH), 7.74
(d, 2H, J¼7.2 Hz, AreH), 10.06 (br, s, H, OH) ppm. 13C NMR of 4a and
2. (a) Nematollahi, D.; Dehdashtian, S. Tetrahedron Lett. 2008, 49, 645e649; (b)
Nematollahi, D.; Alimoradi, M.; Waqif Husain, S. Electrochim. Acta 2006, 51,
2620e2624.
3. (a) Davarani, S. S. H.; Fumani, N. S.; Vahidi, S.; Tabatabaei, M.; Arvin-Nezhad, H.
J. Heterocycl. Chem. 2010, 47, 40e45; (b) Nematollahi, D.; Afkhami, A.; Tammari,
E.; Shariatmanesh, T.; Hesari, M.; Shojaeifard, M. Chem. Commun. 2007,
162e164.
4. (a) Zeng, C. C.; Liu, F. J.; Ping, D. W.; Hu, L. M.; Cai, Y. L.; Zhong, R. G. Tetrahedron
2009, 65, 4505e4512; (b) Fotouhi, L.; Mosavi, M.; Heravi, M. M.; Nematollahi, D.
Tetrahedron Lett. 2006, 47, 8553e8557.
5. (a) Grujie, Z.; Tabakovic, I.; Trkovnik, M. Tetrahedron Lett. 1976, 52, 4823e4824;
(b) Fakhari, A. R.; Nematollahi, D.; Shamsipur, M.; Makarem, S.; Davarani, S. S.
H.; Alizadeh, A.; Khavasi, H. R. Tetrahedron 2007, 63, 3894e3898; (c) Nem-
atollahi, D.; Rafice, M. Green Chem. 2005, 7, 638e644.
5a (100 MHz, DMSO-d6):
d 21.6, 21.7, 43.2, 43.3, 55.6, 55.8, 65.9,
107.0, 109.2, 129.4, 129.6, 130.0, 130.0, 132.7, 133.2, 134.9, 135.1,
138.8, 139.1, 144.8,145.0, 150.7,151.3,152.4, 152.9, 154.7,176.3, 176.4,
194.0, 194.2 ppm. IR (KBr):
n 3419, 3366, 3124, 2972, 2941, 2855,
1664, 1622, 1606, 1580, 1528, 1472, 1449, 1427 cmꢀ1. ESI-MS: m/z
354.0 [Mþ1]þ, 729.0 [2MþNa]þ, 351.7 [Mꢀ1]ꢀ.
4.5. Procedure for the synthesis of compounds 4b, 5b and 4d
6. Habibi, D.; Nematollahi, D.; Al-Hoseini, Z. S.; Dehdashtian, S. Electrochim. Acta
2006, 52, 1234e1239.
The setups were identical to that for the synthesis of 3ae3f. To
the anode compartment was added a mixture of 100 mL of 0.2 M
acetate buffer and acetonitrile (the volume ratio is 2:1). Sub-
sequently, 1.5 mmol of catechols 1b and 1.5 mmol of 2b were added
to the anodic compartment and the solution was electrolyzed. The
7. (a) Zeng, C. C.; Liu, F. J.; Ping, D. W.; Cai, Y. L.; Zhong, R. G.; Becker, J. Y. J.
Electroanal. Chem. 2009, 625, 131e137; (b) Zeng, C. C.; Ping, D. W.; Zhang, S. C.;
Zhong, R. G.; Becker, J. Y. J. Electroanal. Chem. 2008, 622, 90e96; (c) Liu, F. J.;
Zeng, C. C.; Ping, D. W.; Cai, Y. L.; Zhong, R. G. Chin. J. Chem. 2008, 26,
1651e1655; (d) Zeng, C. C.; Liu, C. F.; Zeng, J.; Zhong, R. G. J. Electroanal. Chem.
2007, 608, 85e90.

Y.-X. Bai et al. / Tetrahedron 67 (2011) 9334e9341
9341
8. Xu, H.; Liu, W. Q.; Fan, L. L.; Chen, Y.; Yang, L. M.; Lv, L.; Zheng, Y. T. Chem. Pharm.
Bull. 2008, 56, 720e722.
9. (a) Zeng, C. C.; Ping, D. W.; Xu, Y. S.; Hu, L. M.; Zhong, R. G. Eur. J. Org. Chem.
2009, 33, 5832e5840; (b) Zeng, C. C.; Ping, D. W.; Hu, L. M.; Song, X. Q.; Zhong,
R. G. Org. Biomol. Chem. 2010, 8, 2465e2472.
11. The anodic oxidation of 3-methylcatechol in the presence of 2a was also in-
vestigated. However, high quality of sample for NMR identification was difficult
to obtain, although its ESI-MS demonstrated the formation of the corre-
sponding indole derivative.
12. Jung, M. E.; Perez, F. Org. Lett. 2009, 11, 2165e2167.
10. Zeng, C. C.; Liu, F. J.; Ping, D. W.; Cai, Y. L.; Hu, L. M.; Zhong, R. G. J. Org. Chem.
2009, 74, 6386e6389.
13. (a) Huang, Z. T.; Zhang, P. C. Chem. Ber. 1989, 122, 2011e2016; (b) Furukawa, I.;
Fujisawa, H.; Abe, T.; Ohta, T. Synth. Commun. 1999, 599e606.