One-pot electrochemical synthesis of fused indole derivatives containing active hydroxyl groups in aqueous medium

Article abstract of DOI:10.1021/jo901091s

(Chemical Equation Presented) An novel and convenient electrochemical approach was developed for the synthesis of indole derivatives from catechols and α-oxoheterocyclic ketene N,O-acetals. This method provides an environmentally benign access to fused in

Full text of DOI:10.1021/jo901091s

pubs.acs.org/joc
have been the object of research for over 100 years, and a
One-Pot Electrochemical Synthesis of Fused Indole
Derivatives Containing Active Hydroxyl Groups in
Aqueous Medium
variety of well-established classical methods are now avail-
able.8 Recently, due to the great advance in palladium-
catalyzed Sonogashira coupling reactions of alkynes and
aromatic iodide, 2-ethynylaniline derivatives can be easily
produced in large scale and, therefore, the synthesis of
indoles from 2-ethynylaniline derivatives by using transition
metal catalysts has become the main context of indole
synthetic chemistry.9,10
Cheng-Chu Zeng,*,† Fu-Jian Liu,†,‡ Da-Wei Ping,†
Li-Ming Hu,† Yuan-Li Cai,‡ and Ru-Gang Zhong†
†College of Life Science & Bioengineering,
Beijing University of Technology, Beijing 100124, China, and
‡College of Chemistry, Xiangtan University, Xiangtan,
Hunan 411105, China
As part of our ongoing studies on the electrochemical
synthesis of polyhydroxylated aromatics as potential HIV-1
integrase inhibitors, we have observed that the electro-
chemical oxidation of catechols in the presence of some
types of mononucleophiles involves an ECEC mechanism
(E = electrochemical and C = chemical step) to generate
disubstituted catechols.11,12 Following the same mechanism,
benzofuran derivatives are also produced from electroche-
mically generated o-benzoquinones and 1,3-dicarbonyl com-
pounds.13,14 With this in mind, we hypothesized that the
anodic oxidation of catechols in the presence of enamines
as dinucleophile may also follow an ECEC process and
undergo a C-C coupling and a C-N coupling sequence to
generate indole derivatives. In the present work, we report on
the electrochemical oxidation of catechols 1 in the presence
of R-oxoheterocyclic ketene N,O-acetals 215 to synthesize
fused indole derivatives containing active hydroxyl groups.
To the best of our knowledge, this is the first example of
the formation of highly functionalized fused indole deriva-
tives by a one-pot and transition metal-free electrochemical
approach, where protection-deprotection of the two active
hydroxyl groups is not required.
zengcc@bjut.edu.cn
Received June 4, 2009
An novel and convenient electrochemical approach was
developed for the synthesis of indole derivatives from
catechols and R-oxoheterocyclic ketene N,O-acetals. This
method provides an environmentally benign access to
fused indole derivatives containing active hydroxyls and
carbonyl under mild reaction conditions.
The electrochemical behaviors of catechols in the absence
and presence of 2a-c were first investigated by cyclic vol-
tammetry (CV), at room temperature, in 0.2 M acetate buffer
(pH 7). Taking 1b as an example, its typical CVs are shown in
Figure 1. Upon scanning anodically, catechol 1b exhibits one
well-defined oxidation wave (A1) at 0.34 V versus Ag/AgCl,
As one of the environmentally benign processes, organic
electrochemical synthesis in aqueous medium1 is attracting
considerable attention from organic chemists and pharma-
cologists and is being applied to the synthesis of organic
compounds with various biological properties or as key steps
for the synthesis of complex natural products.2,3
Nitrogen-containing heterocycles, especially indole deri-
vatives, constitute an important class of biologically active
natural and unnatural compounds.4 Some of them are used
as anticancer,5 antioxidant,6 and HIV integrase inhibitors.7
Consequently, the synthesis and functionalization of indoles
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(a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
(b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920. (c) Gribble,
G. W. J. Chem. Soc., Perkin Trans. I 2000, 1045–1075.
(9) Trost, B. M.; McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074–
2077.
(10) (a) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2007, 46, 2284–2287. (b) Nakamura, I.; Ilies, L.;
Otsubo, S.; Nakamura, E. Angew. Chem., Int. Ed. 2006, 45, 944–947.
(c) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8,
2803–2805. (d) Sakai, H.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K. Adv.
Synth. Catal. 2008, 350, 2498–2502. (e) Yin, Y.; Ma, W.-Y.; Chai, Z.; Zhao,
G. J. Org. Chem. 2007, 72, 5731–5736.
(1) (a) Asami, R.; Atobe, M.; Fuchigami, T. J. Am. Chem. Soc. 2005, 127,
13160–13161. (b) Steckhan, E.; Arns, T.; Heineman, W. R.; Hilt, G.;
(11) Zeng, C. C.; Liu, F. J.; Ping, D. W.; Cai, Y. L.; Zhong, R. G.; Becker,
J. Y. J. Electroanal. Chem. 2009, 625, 131–137.
(12) Zeng, C. C.; Liu, F. J.; Ping, D. W.; Hu, L. M.; Cai, Y. L.; Zhong, R.
G. Tetrahedron 2009, 65, 4505–4512.
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Hoormann, D.; Jorissen, J.; Kroner, L.; Lewall, B.; Putter, H. Chemosphere
2001, 43, 63–73. (c) Zha, Z. G.; Hui, A. L.; Zhou, Y. Q.; Miao, Q.; Wang, Z.
Y.; Zhang, H. C. Org. Lett. 2005, 7, 1903–1905.
(2) Xu, H.; Moeller, K. D. J. Am. Chem. Soc. 2008, 130, 13542–13543.
(3) Sperry, J. B.; Wright, D. L. J. Am. Chem. Soc. 2005, 127, 8034–8035.
(4) Dewick, P. M. Medicinal Natural Products; John Wiley & Sons, Ltd:
New York, 2002.
(5) Ismail, N. S. M.; El Dine, R. S.; Hattori, M.; Takahashi, K.; Ihara, M.
Bioorg. Med. Chem. 2008, 16, 7877–7887.
(6) Liou, J. P.; Wu, C. Y.; Hsieh, H. P.; Chang, C. Y.; Chen, C. M.; Kuo,
C. C.; Chang, J. Y. J. Med. Chem. 2007, 50, 4548–4552.
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Published on Web 07/06/2009
DOI: 10.1021/jo901091s
r
2009 American Chemical Society

Zeng et al.
JOCNote
SCHEME 1. One-Pot Synthesis of Fused Indole Derivatives 3, 4,
and 5 with Anodic Oxidation
FIGURE 1. Cyclic voltammogram of (a) 2 mM 3-methoxycatechol
1b, (b) a mixture of 2 mM 3-methoxycatechol and 2 mM hetero-
cyclic ketene N,O-acetal 2a, and (c) 2 mM heterocyclic ketene N,O-
acetal 2a, at a glassy carbon electrode, platinum wire counter and
Ag/AgCl reference, in 4:1 (v/v) acetate buffer solution/acetronitrile
(0.2 M, pH 7); scan rate 50 mV/s.
subunit and two hydroxyl groups, respectively. In addition,
there are two singlets residing at 6.98 and 7.42 ppm, assigned
to the signals of two protons of the catechol unit, apart
from two doublets (AA0BB0 system of the benzene ring of
p-methylbenzoyl subunit) in the aromatic region. All this
information along with other spectral and analytical data
(see the Experimental Section) demonstrate that what we
obtained was a fused indole derivative 3a.
Prompted by the successful synthesis of indole derivative
3a, we then examined the scope of different catechols and
ketene N,O-acetals 2 and the results are summarized in
Table 1. As shown in Scheme 1 and Table 1, we first extended
this reaction to 2b and 2c with a view to investigate the scope
of heterocyclic ketene N,O-acetals. Therefore, electroche-
mical oxidation of 4-tert-butylcatechol in the presence of 2b
and 2c was performed and produced the expected products
3b and 3c in 56% and 48% yields, respectively.
To further extend the scope of this reaction, we then
investigated the flexibility of catechols. Thus, 3-methoxyca-
techol (1b) and 3-methylcatechol (1c) were subjected to
anodic oxidation under identical conditions. After simple
filtration, indole derivatives 4a and 5a as a mixture of
regioisomers in the ratio of 2:1 were obtained in 71% yield
from the anodic oxidation of 1b in the presence of 2a
(Scheme 1). In the case of 3-methylcatechol (1c), the regioi-
somers of 4b and 5b in a ratio of 1:1 were also isolated in 62%
yield.
A similar trend was observed when 3-methoxycatechol
(1b) was oxidized anodically in the presence of 2b or 2c.
Under identical conditions, the corresponding mixtures of
regioisomers (4c and 5c, 4d and 5d) were accomplished in
51% and 40% yields, respectively. This result indicates that
indole derivatives could indeed be synthesized by reaction
between catechols and enamine derivatives (such as com-
pound 2a) on the electrochemical oxidation conditions.
Mechanistically, Nematollahi et al.13,14 have proposed the
formation of benzofurans from anodic oxidation of cate-
chols in the presence of 1,3-dicarbonyl compounds employ-
ing the ECEC mechanism. Obviously, we can assume that a
similar process may take place to generate the final indole
derivatives from catechols and ketene N,O-acetals. There-
fore, as shown in Scheme 2, the anodic oxidation of 4-tert-
butyl catechol 1a transforms to the corresponding o-benzo-
quinones 6a, which are highly reactive and undergo Michael
reaction with ketene N,O-acetals, to generate intermediates
7 due to the greater nucleophilicity of the R-C of ketene
N,O-acetals. The initially formed intermediate 7, by itself
presumably corresponding to the formation of o-benzoqui-
none derivative involving a simultaneous 2e process,13,14
which was reduced in the cathodic sweep at 0.10 V (C1),
back to 1a (curve a). The ratio of the current amplitudes
between the oxidation and reduction processes is equal to
unity (Ipox/Ipred), indicating that the o-benzoquinone pro-
duced at the surface of the electrode is stable under pH 7
acetate buffer. To get further information on the transfor-
mation of the in situ generated o-benzoquinone in the
presence of 2 as dinucleophile, the anodic oxidation of 1b
in the presence of 2a has also been studied by the cyclic
voltammetry method. As shown in curve b, when an equiva-
lent amount of 2a was added, the anodic potential slightly
shifts positively to 0.36 V and a new cathodic peak (C2) at
0.00 V appears. Simultaneously, the current amplitude of the
initial cathodic peak (C1) obviously decreased. Curve c is the
CV of R-oxoheterocyclic ketene N,O-acetal 2a with a not
well-defined anodic peak centered at 0.89 V. This behavior
indicates that a chemical reaction occurs between the elec-
trochemically generated o-benzoquinone (at A1) and the
R-oxoheterocyclic ketene N,O-acetal 2a, and therefore
Michael addition products may be synthesized upon anodic
oxidation of the mixture of catechol and R-oxoheterocyclic
ketene N,O-acetals when the electrolyzed potential was
controlled at the anodic potential of catechol (0.34 V versus
Ag/AgCl for 1b), where, undesired oxidation of ketene
N,O-acetals will not take place due to their significantly
higher anodic potentials.
On the basis of the above CV analysis of catechols in the
absence and presence of heterocyclic ketene N,O-acetals 2, we
first carried out the controlled-potential electrolysis (CPE) of
a mixture of 4-tert-butylcatechol and 2a. Thus, according to
our reported conditions,11,12 an equivalent amount of 2a and
1a in a divided cell was electrolyzed at 0.20.V vs. Ag wire
in acetate buffer. After the consumption of starting 4-tert-
butylcatechol, a brown powder was finally isolated by column
chromatography and its structure was characterized by
1H NMR, 13C NMR, IR, and HRMS. Surprisingly, no tert-
1
butyl signal was observed in its H NMR spectrum, which
exhibits two triplets (at δ 3.98 and 4.32 ppm) and two singlets
(at δ 9.08 and 9.22 ppm) attributed to the NCH2CH2O
J. Org. Chem. Vol. 74, No. 16, 2009 6387

Zeng et al.
JOCNote
TABLE 1. Anodic Oxidation of Catechols 1 in the Presence of Reaction of Heterocyclic Ketene N,O-Acetals 2
aRatio of region-isomers by 1H NMR. bIsolated yield.
a catechol derivative, is further oxidized to the corresponding
o-benzoquinone derivatives 8. To take a preferable configura-
tion for further nucleophilic attack, an enamine-imine and an
imine-enamine tautomerization process are required, which
led to the formation of 800. After the Michael addition reaction
and subsequent loss of a tert-butyl carbonium followed by
aromatization, indoles 3a-c were finally generated.
The electrochemical oxidation of 3-substituted catechol 1b
and 1c in the presence of 2a-c proceeded in a similar manner.
However, the asymmetry of 3-substituted catechol led to two
indole isomers 4 and 5 because the initial nucleophilic
addition of the carbine C of ketene N,O-acetals to the
3-substituted o-benzoquinone (formed from the oxidation
of corresponding 3-substituted catechols) can occur in the
C-4 and C-5 of the benzene ring, leading to the formation of
intermediates 9 and 10. Upon anodic oxidation, enamine-
imine tautomerization, imine-enamine tautomerization, the
Michael feature of addition, and the aromazation process,
indole derivatives 4 and 5 were finally generated. It should be
pointed out that, due to the steric hindrance as well as the less
electropositive C-4, the initial Michael addition on the C-5
position is preferable to that on the C-4 position, which
results in the yield of 4 being higher than that of 5 (the ratio of
4 to 5 is about 2:1 according to the 1H NMR data). Both of
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Zeng et al.
JOCNote
SCHEME 2. A Plausible Mechanism for the Synthesis of Indoles
3
the use of metal catalyst and ligand is avoided. Moreover, the
electrochemical formation of indole derivatives extends the
application of electrochemical synthesis of o-benzoquinone
and its in situ transformation. Further investigation for other
indoles and the generality of this method are in progress.
Experimental Section
General Procedure for the Synthesis of Compounds 3a-c. In a
typical procedure, 50 mL of sodium acetate solution (0.2 M,
pH 7) was pre-electrolyzed at the chosen potential (0.20 V vs. Ag
wire) in an H-type cell, which was kept in water at room
temperature for 10 min to remove impurities present in the
electrolytic system. Subsequently, 4-tert-butyl catechol (2 mmol)
and R-oxoheterocyclic ketene N,O-acetal 2 (2 mmol) were added
to the anodic compartment and electrolyzed. The typical working
currents were in the range of 40-90 mA and the electrolysis was
terminated when the starting 1 was consumed by TLC following
the reaction process. After electrolysis, the anolyte was adjusted
to pH 7 by a few drop of acetic acid. The reaction mixture
was extracted by ethyl acetate (3 ꢀ 30 mL) and washed with water
(2 ꢀ 30 mL). The separated organic layer was dried over MgSO4,
then filtered and evaporated. The crude product was purified by
column chromatography on silica gel, eluted with a mixture of
acetone-petroleum ether (v:v 1:3) to give indole derivatives 3.
(6,7-Dihydroxy-2,3-dihydrooxazolo[3,2-a]indol-9-yl)(4-methyl-
SCHEME 3. A Plausible Mechanism for the Synthesis of Indoles
4 and 5
1
phenyl)methanone (3a): mp 220-222 °C; H NMR (400 MHz,
DMSO-d6, ppm) δ 2.36 (s, 3H, CH3), 3.98 (t, 2H, J=9.2 Hz,
NCH2), 4.32 (t, 2H, J=9.2 Hz, OCH2), 6.99 (s, 1H, Ar-H), 7.28
(d, 2H, J=8.0 Hz, Ar-H), 7.41 (s, 1H, ArH), 7.79 (d, 2H, J=
8.0 Hz, Ar-H), 9.08 (s, 1H, OH), 9.22 (s, 1H, OH); 13C NMR
(100 MHz, DMSO-d6, ppm) δ 21.4, 54.8, 67.0, 98.1, 105.2, 106.9,
119.2, 127.6, 128.8, 129.2, 139.3, 143.9, 145.7, 148.0, 155.1,
159.6; IR (KBr) (cm-1) ν max 3414, 2923, 1628, 1328; ESI-MS
m/z 307.6 (Mþ - 1); HRMS (EI) m/z calcd for C18H14NO4
308.0923, found 308.0925.
(6,7-Dihydroxy-2,3-dihydrooxazolo[3,2-a]indol-9-yl)(phenyl)-
methanone (3b): mp 191-193 °C; 1H NMR (400 MHz, acetone-
d6, ppm) δ 4.04 (t, 2H, J=9.6 Hz, NCH2), 4.37 (t, 2H, J=9.6 Hz,
OCH2), 7.05 (s, 1H, Ar-H), 7.43-7.49 (m, 3H, Ar-H), 7.59
(s, 1H, ArH), 7.99-8.01 (m, 2H, Ar-H); 13C NMR (100 MHz,
acetone-d6, ppm) δ 55.4, 67.3, 98.0, 106.6, 107.7, 120.7, 128.7,
129.5, 129.8, 131.4, 143.7, 145.8, 149.3, 156.0, 160.5; IR (KBr)
(cm-1) ν max 3468, 2928, 2871, 1624, 1566, 1482, 1315; ESI-MS
m/z 295.8 (Mþþ1), 293.5 (Mþ - 1); HRMS (EI) m/z calcd for
C17H12NO4 294.0722, found 294.0711.
Acknowledgment. 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), and the Beijing Novel Project
(No. 2005B10).
them have very similar polarity and could not be separated
(Scheme 3).
In conclusion, we have developed a novel and convenient
electrochemical approach for the synthesis of indole deriva-
tives from heterocyclic ketene N,O-acetals and catechols.
This method provides an environmentally benign access to
fused indole derivatives with multiactive functional groups
for further derivatization under mild reaction conditions.
The commonly known process of protection-deprotection
of the two active hydroxyl groups is not required here and
Supporting Information Available: Electrochemical appa-
ratus description and general procedure for the synthesis of
4a-d and 5a-d and spectral data for compounds 3c, 4a-d, and
5a-d. This material is available free of charge via the Internet at
http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6389