Electrosynthesis of substituted 1H-indoles from o-nitrostyrenes

Article abstract of DOI:10.1021/ol2006049

A novel procedure has been devised for the synthesis of derivatives of 1H-indole that is based on the direct, room-temperature electrochemical reduction of substituted o-nitrostyrenes at carbon cathodes in N,N-dimethylformamide containing tetramethylammonium tetrafluoroborate as supporting electrolyte and in the presence of a 10-fold molar excess of a proton donor (phenol or methyl 3-oxobutanoate).

Full text of DOI:10.1021/ol2006049

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4072–4075
Electrosynthesis of Substituted 1H-Indoles
from o-Nitrostyrenes
Peng Du, Jonathan L. Brosmer, and Dennis G. Peters*
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States
peters@indiana.edu
Received June 14, 2011
ABSTRACT
A novel procedure has been devised for the synthesis of derivatives of 1H-indole that is based on the direct, room-temperature electrochemical
reduction of substituted o-nitrostyrenes at carbon cathodes in N,N-dimethylformamide containing tetramethylammonium tetrafluoroborate as
supporting electrolyte and in the presence of a 10-fold molar excess of a proton donor (phenol or methyl 3-oxobutanoate).
Derivatives of 1H-indole continue to capture the atten-
tion of synthetic chemists because of the diverse uses of these
substances as pharmaceutical agents. Although protocols
for the synthesis of 1H-indoles abound in the literature,
comparatively few publications have appeared that involve
o-substituted nitro aromatic compounds as starting
materials.1 In classic work by Sundberg,2 β-substituted
o-nitrostyrenes were heated in boiling triethyl phosphite at
163 °C for 18 h to afford 1H-indoles. Metal carbonyl
compounds [Fe(CO)5, Ru3(CO)12, and Rh6(CO)16] under
CO at 80 atm and 220 °C have been used to promote the
reductive cyclization of o-nitrostyrenes to 1H-indoles.3 Bar-
toli and co-workers4,5 developed a method for the prepara-
tion of 7-substituted 1H-indoles that is based on the low-
temperature treatment of a nitroarene with vinylmagnesium
bromide. Palladium(II)-catalyzed reduction of several
o-nitrostyrenes in the presence of carbon monoxide to afford
found as products of the palladium(II) trimethylbenzoate-
catalyzed reductive deoxygenation of o-nitrostyrenes in tetra-
hydrofuran under CO at 30 atm.8 Dobbs9 demonstrated that
4-bromo-3-nitrotoluene can be employed as a starting mate-
rial for the preparation of substituted 2-methyl-1H-indoles,
and Davies and collaborators10 converted a number of
derivatives of o-nitrostyrene to 1H-indoles by means of a
procedure involving the use of 0.1 mol % of palladium(II)
trifluoroacetate and 0.7 mol % of 3,4,7,8-tetramethyl-1,10-
phenanthroline in dimethylformamide (DMF) at 15 psig
CO and 80 °C for a period of 16 h. Each of the preceding
references1ꢀ10 cites additional work dealing with o-nitro-
styrenes as starting materials for the synthesis of 1H-indoles.
In the arena of electrochemistry, a paper by Mishra and
Mishra11 indicates that some 1H-indole is produced during
the constant-current electrolytic reduction of (Z)-1-nitro-
2-(2-nitrovinyl)benzene in an aqueous mixture of acetic acid
and sulfuric acid.
6
7
€
1H-indoles has been described, and a review by Soderberg
includes a discussion of several strategies for the reductive
deoxygenation of o-substituted nitroarenes that can be uti-
lized to obtain 1H-indoles. Substituted 1H-indoles have been
In a recent publication12 from our laboratory, we reported
on the room-temperature electrochemical reduction of
1-(2-haloethyl)-2-nitrobenzenes at carbon cathodes in DMF
containing 0.10 M tetramethylammonium tetrafluorobo-
rate (TMABF4) as supporting electrolyte. In the absence of
(1) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996.
(2) Sundberg, R. J. J. Org. Chem. 1965, 30, 3604–3610.
(3) Crotti, C.; Cenini, S.; Rindone, B.; Tollari, S.; Demartin, F. J.
Chem. Soc., Chem. Commun. 1986, 784–786.
(4) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129–2132.
(8) Tollari, S.; Penoni, A.; Cenini, S. J. Mol. Catal. A: Chem. 2000,
152, 47–54.
(9) Dobbs, A. J. Org. Chem. 2001, 66, 638–641.
(10) Davies, I. W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham, V.;
Bazaral, C. Tetrahedron 2005, 61, 6425–6437.
(11) Mishra, S. C.; Mishra, R. A. J. Electrochem. Soc. India 1990, 39,
51–53.
(5) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni,
E. J. Chem. Soc., Perkin Trans. 1 1991, 2757–2761.
€
(6) Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62,
5838–5845.
€
(7) Soderberg, B. C. G. Curr. Org. Chem. 2000, 4, 727–764.
(12) Du, P.; Peters, D. G. J. Electrochem. Soc. 2010, 157, F167–F172.
r
10.1021/ol2006049
Published on Web 07/08/2011
2011 American Chemical Society

Figure 2. Cyclic voltammograms recorded at 100 mV sꢀ1 for
reduction of 2.0 mM solutions of 2a at a glassy carbon electrode
(area = 0.077 cm2) in oxygen-free DMF containing 0.050 M
TMABF4: (A) with no phenol; (B) with 20 mM phenol. Poten-
tial scan goes from ca. ꢀ0.8 to ꢀ2.0 to ꢀ0.8 V vs SCE for curve A
and from ca. ꢀ0.8 to ꢀ1.8 to ꢀ0.8 V vs SCE for curve B.
Figure 1. Structures of commercially available starting materials
(1aꢀe), chemically synthesized o-nitrostyrenes (2aꢀe), and elec-
trochemically produced 1H-indoles (3aꢀe).
a deliberately added proton donor (phenol or 2,4-pentane-
dione), the principal electrolysis product (after a conven-
tional workup procedure) is 1-nitro-2-vinylbenzene, obtained
in 70ꢀ80% yield, along with small amounts (10ꢀ15%) of
1H-indole and even smaller quantities (3ꢀ7%) of a dimeric
species believed to be 1,10-biindole. A far more interesting
finding, however, was that direct electrolysis of 1-nitro-2-
vinylbenzene in the presence of a 5-fold excess of phenol
affords 1H-indole in high yield (>80%), together with traces
of 1-amino-2-vinylbenzene and the aforementioned dimer.
Accordingly, we became intrigued by the possibility that
the direct electroreduction of substituted o-nitrostyrenes in
the presence of a proton donor might offer a general and
straightforward approach to the synthesis of 1H-indole
derivatives. In this communication, we present early, yet
highly promising, results of an electrochemical investigation
of five compounds (2aꢀe) shown in Figure 1 to evaluate
an electrosynthetic procedure for the preparation of 3aꢀe,
respectively.
Substituted o-nitrostyrenes (2aꢀe) were prepared accord-
ing to a procedure published by Davies and co-workers;10 in
particular, commercially available 1aꢀe were each treated
separately with diethyl benzylphosphonate in DMF contain-
ing sodium methoxide for a period of 14 h, followed by
workup, purification, and crystallization. We confirmed the
identities of 2aꢀewith the aid of 1Hand13C NMR spectrom-
etry, along with mass spectrometry, and our experimentally
acquired spectral data were in excellent agreement with those
reported previously; more details about these syntheses as
well as spectroscopic data for each compound are available as
Supporting Information. Each o-nitrostyrene was investi-
gated by means of cyclic voltammetry and controlled-poten-
tial (bulk) electrolysis; information pertaining to electrodes
and electrochemical cells as well as the chromatographic and
spectrometric procedures for separation, identification, and
quantitation of products appears elsewhere.12
freshly polished glassy carbon electrode in oxygen-free
DMF containing 0.050 M TMABF4 and in the absence
or presence of an excess of phenol (introduced as a proton
donor). In Figure 2 are cyclic voltammograms for a 2.0
mM solution of 2a without and with 20.0 mM phenol.
Curve A of Figure 2, which depicts a cyclic voltammogram
in the absence of phenol, shows three cathodic peaks with
peak potentials (Epc) of ꢀ1.27, ꢀ1.59, and ꢀ1.79 V vs SCE
and two anodic peaks having peak potentials (Epa) of
ꢀ1.51 and ꢀ0.99 V vs SCE. We attribute the cathodic
peak at ꢀ1.27 V and the anodic peak at ꢀ0.99 V, respec-
tively, to the quasi-reversible one-electron reduction of the
nitro group of 2a to its radicalꢀanion and to the subse-
quent oxidation of this radicalꢀanion back to the starting
material. At more negative potentials, the second redox
couple (Epc = ꢀ1.59 V, Epa = ꢀ1.51 V) is probably
associated with reversible one-electron reduction of the
nitro radicalꢀanion to the nitro dianion and then one-
electron oxidation of the latter species to the radicalꢀ
anion; in the presence of residual water in the sol-
ventꢀsupporting electrolyte, the nitro dianion can be
protonated to initiate further reduction to afford a nitroso
compound and eventually a hydroxylamine. All of these
processes have been discussed in previous work.12ꢀ16
Finally, we believe that the third cathodic peak at ꢀ1.79 V
arises from the irreversible reduction of a substituted
diphenylethene moiety.17,18 However, future research, not
(13) Smith, W. H.; Bard, A. J. J. Am. Chem. Soc. 1975, 97, 5203–5210.
(14) Kemula, W.; Sioda, R. J. Electroanal. Chem. 1964, 7, 233–241.
(15) Jensen, B. S.; Parker, V. D. J. Chem. Soc., Chem. Commun. 1974,
367–368.
(16) Zuman, P.; Fijalek, Z. J. Electroanal. Chem. 1990, 296, 583–588.
(17) Grodzka, P. G.; Elving, P. J. J. Electrochem. Soc. 1963, 110,
231–236.
Cyclic voltammograms were recorded at a scan rate of
100 mV sꢀ1 for each o-nitrostyrene derivative (2aꢀe) at a
Org. Lett., Vol. 13, No. 15, 2011
(18) Fritsch, J. M.; Layloff, T. P.; Adams, R. N. J. Am. Chem. Soc.
1965, 87, 1724–1726.
4073

strictly related to the direct electrosynthesis of substituted
1H-indoles, would be desirable to clarify these reactions.
When a proton donor (phenol or methyl 3-oxobutanoate)
is added to the solution, the cyclic voltammogram changes
dramatically, as shown by curve B of Figure 2. Only one
very broad cathodic peak is seen at ꢀ1.25 V vs SCE, which is
in accord with observations made in our earlier study.12 It is
our belief, as revealed below, that this single, large cathodic
peak arises principally from the overall four-electron con-
version of the o-nitrostyrene (2a) to the desired 2-phenyl-
1H-indole (3a).
Compiled in Table 1 are cathodic and anodic peak
potentials for all five o-nitrostyrenes (2aꢀe) in the absence
of a proton donor as well as cathodic peak potentials for
these compounds in the presence of a 10-fold molar excess of
phenol. Although there are some differences in the various
peak potentials for the five species, the essential interpreta-
tion of their electrochemical behavior is quite comparable. It
is not unexpected that structural modifications for 2bꢀe can
lead to the appearance of a new voltammetric peak or to the
coalescence of two voltammetric peaks.
Table 2. Coulometric Data and Product Yields for the Direct
Reduction of 5.0 mM Solutions of o-Nitrostyrenes at a Retic-
ulated Vitreous Carbon Cathode in DMF Containing 0.050 M
TMABF4 and 50 mM Phenol
electrolysis
potential, Va
yield of
1H-indole
o-nitrostyrene
nb
2a
2b
2c
2d
2e
2ec
ꢀ1.31
ꢀ1.46
ꢀ1.26
ꢀ1.41
ꢀ1.41
ꢀ1.41
3.92
4.13
4.10
4.20
4.20
4.20
3a (82%)
3b (67%)
3c (57%)
3d (38%)
3e (35%)
3e (65%)
a All potentials are with respect to the saturated calomel electrode
(SCE); see Supporting Information for details about the actual reference
electrode used. b Average number of electrons required to reduce one
molecule of each parent o-nitrostyrene derivative. c Methyl 3-oxobu-
tanoate (50 mM) was used as the proton donor instead of phenol.
hydrogen gas and competing with direct electrolysis of the
chosen o-nitrostyrene.
Table 2 summarizes the coulometric data along with
yields of the 1H-indole derivatives (3aꢀe) for at least
duplicate electrolyses of each o-nitrostyrene; the n values
indicatethe average numberof electronsrequiredtoreduce
each molecule of o-nitrostyrene, and the product yield is
the percentage of the o-nitrostyrene derivative incorpo-
rated into each of the 1H-indoles (as determined by means
of gas chromatography, with a known quantity of an
electroinactive internal standard, n-dodecane, being added
to each solution prior to an electrolysis).19 At the end of
each experiment, none of the starting material remained
unreduced. As revealed in Table 2, an interesting observation
is that the use of methyl 3-oxobutanoate, which is more
acidic than phenol, raised the yield of 3e from 35% to 65%;
in a DMF medium, the pKa values for phenol and methyl
3-oxobutanoate are close to 18.9 and 15.2, respectively.20,21
In preliminary experiments a near doubling of the yield of 3d
has been obtained when phenol is replaced by methyl
3-oxobutanoate. Thus, the use of even more potent proton
donors should be a fruitful avenue for future exploration. We
have begun to explore a larger set of more potent proton
donors, including acetic acid (pKaDMF = 13.4) and benzoic
acid (pKaDMF = 12.1). Changing the proton donor has little
effect on the value of Epc for the single cathodic peak that is
governed essentially by reduction of the nitro group, but we
have not yet assessed whether these better proton donors
affect the yields of 1H-indoles.
Table 1. Cyclic Voltammetric Peak Potentials at 100 mV sꢀ1 for
2.0 mM Solutions of o-Nitrostyrenes at a Glassy Carbon
Electrode in DMF Containing 0.050 M TMABF4
o-nitrostyrene
Epc, Va
Epa, Va
Epcb,Va
2a
2b
2c
2d
2e
ꢀ1.27, ꢀ1.59, ꢀ1.79 ꢀ1.51, ꢀ0.99
ꢀ1.25
ꢀ1.45
ꢀ1.18
ꢀ1.33
ꢀ1.30
ꢀ1.54, ꢀ1.78
ꢀ1.42, ꢀ1.25, ꢀ0.87
ꢀ1.14, ꢀ1.54, ꢀ1.70 ꢀ1.37, ꢀ0.91
ꢀ1.25, ꢀ1.64, ꢀ1.74 ꢀ1.38, ꢀ1.04, ꢀ0.84
ꢀ1.29, ꢀ1.41, ꢀ1.68 ꢀ1.38, ꢀ1.08, ꢀ0.82
a Epc values are cathodic peak potentials, and Epa values are anodic
peak potentials with respect to the saturated calomel electrode (SCE);
see Supporting Information for details about the actual reference
electrode used. b 20 mM phenol was added to the solution.
On the basis of previous work done with 1-nitro-2-
vinylbenzene,12 separateroom-temperaturecontrolled-po-
tential (bulk) electrolyses of 5.0 mM solutions of 2aꢀe in
DMF containing 0.050 M TMABF4 and 50.0 mM phenol
were carried out at reticulated vitreous carbon cathodes.
We determined the potential needed for each bulk electrol-
ysis by inspecting a cyclic voltammogram for a 2.0 mM
solution of each compound in DMFꢀ0.050 M TMABF4
containing 20.0 mM phenol. For example, to carry out the
electrolysis of 2a, the potential chosen from curve B of
Figure 2 was ꢀ1.31 V vs SCE (Table 2), which is just
slightly more negative than the value for Epc (ꢀ1.25 V vs
SCE) listed in Table 1. Potentials for the electrochemical
reductions of 2bꢀe weresimilarlyselected, asacomparison
of data in Tables 1 and 2 reveals. Choosing a potential
more positive than Epc will prolong the electrolysis (and
may lead to extraneous products), whereas a potential
that is significantly more negative than Epc will induce
the formation of products (e.g., amines) that are more
extensively reduced than the desired 1H-indoles. More-
over, at more negative potentials, it is possible that the
proton donor itself will undergo some reduction, forming
It should be noted that the coulometric n values reported
in Table 2 are essentially 4, an observation in accord with
7
the postulate, as articulated by Soderberg, that a nitrene
€
intermediate might be involved in the reductive conversion
of o-nitrostyrenes to 1H-indoles. Finally, 3b is difficult to
isolate in pure form, as discussed in the Supporting
Information.
(19) Pritts, W. A.; Vieira, K. L.; Peters, D. G. Anal. Chem. 1993, 65,
2145–2149.
(20) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(21) Maran, F.; Celadon, D.; Severin, M. G.; Vianello, E. J. Am.
Chem. Soc. 1991, 113, 9320–9329.
4074
Org. Lett., Vol. 13, No. 15, 2011

In conclusion, we are strongly encouraged by the dis-
covery that 1H-indoles can be electrosynthesized from
o-nitrostyrenes in moderate to good yields at room tem-
perature in a relatively short time (40 min) and without the
use of harsh reagents or conditions. In future work, we
plan to explore how different proton donors and other
solvents affect the electrosynthesis of 1H-indoles via the
reduction of o-nitrostyrenes; we are already aware of the facts
that the identity of the proton donor and the choice of
electrolysis potential influence the yields of 1H-indoles.
Efforts will be directed to expand the molecular complexity
of o-nitrostyrenes that can be subjected to electrochemical
reduction, and there is the possibility that electrogenerated
catalysts can be used to carry out the indirect reduction
of o-nitrostyrenes to 1H-indoles. In addition, a single-pass,
flow-through electrochemical reactor has been constructed
that features a large reticulated vitreous carbon rod with a
surface area of approximately 2 m2 (100 times greater than
the areas of cathodes employed in the present investigation);
using this reactor, we hope to electrosynthesize 1H-indoles in
gram quantities.
Supporting Information Available. Experimental pro-
cedures as well as 1H and 13C NMR, GCꢀMS, and HRMS
data for key compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
4075