Bi(OTf)3-catalyzed conjugate addition of indoles to p-quinones: a facile synthesis of 3-indolyl quinones

Article abstract of DOI:10.1016/j.tetlet.2003.10.041

A wide range of indoles undergo conjugate addition to p-benzoquinones in the presence of 2 mol percent bismuth triflate under mild conditions to afford the corresponding 3-indolyl quinones in excellent yields with high selectivity.

Full text of DOI:10.1016/j.tetlet.2003.10.041

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9121–9124
Bi(OTf)3-catalyzed conjugate addition of indoles to p-quinones:
a facile synthesis of 3-indolyl quinones
J. S. Yadav,* B. V. S. Reddy and T. Swamy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 June 2003; revised 2 October 2003; accepted 10 October 2003
Abstract—A wide range of indoles undergo conjugate addition to p-benzoquinones in the presence of 2 mol% bismuth triflate
under mild conditions to afford the corresponding 3-indolyl quinones in excellent yields with high selectivity.
© 2003 Elsevier Ltd. All rights reserved.
The 3-indolylbenzoquinone fragment is a core structure
in a number of biologically active natural products such
as asterriquinones.1 The asterriquinones and demethyl-
asterriquinones exhibit a wide spectrum of biological
activities including antitumor properties and are
inhibitors of HIV reverse transcriptase.2 Asterriquinone
A1, has been shown to arrest the cell cycle in G1 and
promote apoptotic cell death.3 Recently, asterriquinone
has been reported as an orally active non-peptidyl
mimetic of insulin with antidiabetic activity.4 All these
properties apparently stem from the ability of aster-
riquinones to either promote or prevent protein–protein
interactions. Bisindolyl quinones (Fig. 1) have been
isolated from a wide range of fungi, including Asper-
gillus terreus, Chaetomium sp., and Pseudomassaria sp.5
In this report, we wish to describe a simple, convenient
and efficient protocol for the synthesis of indol-3-ylben-
zoquinones using a catalytic amount of Bi(OTf)3 under
mild conditions. For example, treatment of indole 1
with 2,5-dichloro-p-benzoquinone 2 in the presence of 2
mol% of Bi(OTf)3 led to the formation of 3-indolyl-2,5-
dichlorohydroquinone 3a in 85% yield (Scheme 1).
Similarly, treatment of 2,5-dichloro-p-benzoquinone or
p-benzoquinone with 5-methoxy-, 5-bromo-, 7-ethyl-,
2-methyl- and ethyl 2-carboxyindoles afforded the cor-
responding indol-3-yl hydroquinones (entries 3b–g,
The simplest and the most straightforward approach
for the synthesis of indol-3-ylbenzoquinones involves
the condensation of indoles with quinones under acidic
conditions.6,7
Recently, bismuth(III) triflate has attracted the atten-
tion of synthetic organic chemists because it is inexpen-
sive and it can be easily prepared even on multi-gram
scale in the laboratory from commercially available
bismuth(III) oxide and triflic acid.8 Owing to its unique
catalytic properties, bismuth(III) triflate has been exten-
sively used for a plethora of organic transformations.9
However, there have been no reports on the conjugate
addition of indoles to p-quinones employing bismuth
triflate as a catalyst.
Figure 1.
Keywords: p-quinones; indoles; bismuth triflate; indol-3-ylbenzo-
quinones.
* Corresponding author. Fax: +91-40-27160512; e-mail: yadav@
iict.ap.nic.in
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.041

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 9121–9124
Table 1). Interestingly, the reaction of indole with
p-benzoquinone gave 2,5-bis(3-indolyl)-1,4-hydroquin-
one 4h in 82% yield under similar reaction conditions
(Scheme 2).
smoothly with indole and 2-methylindole to give the
corresponding indol-3-ylbenzoquinones in high yields
(entries 5i–n, Table 1, Scheme 3).
In the case of mono-substituted quinones, the indole
regioselectively added to the quinones at the less hin-
However, substituted quinones such as 2-methyl-, 2-
methoxy-, and 2,6-dimethyl-p-benzoquinones reacted
1
dered position which was confirmed by H NMR spec-
Table 1. Bismuth(III) triflate catalyzed addition of indoles to p-quinones

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 9121–9124
9123
This method is clean and free from the chlorinated side
products which are normally observed under protic acid
(conc. HCl in THF) conditions. This method also
works well with the electron-deficient ethyl 2-car-
boxyindole to give the corresponding indol-3-ylhy-
droquinone 3e in fairly good yield. However, most
other methods fail to produce 3-indolylquinones with
electron-deficient indoles. Thus, this method is an
efficient and very useful synthetic procedure for the
synthesis of natural product core structures. Among the
various metal triflates such as Cu(OTf)2, Yb(OTf)3,
In(OTf)3 and Ce(OTf)3 studied for this transformation,
bismuth(III) triflate was found to be the most effective
in terms of conversion and reaction rates. However,
similar yields and selectivity were also obtained using 5
mol% of scandium(III) triflate under these reaction
conditions. The scope and generality of this process is
illustrated with respect to various indoles and a wide
range of quinones and the results are presented in Table
1.11
Scheme 2.
trum of the products (entries 5i, 5j, 5k, 5l, Table 1).
Like the substituted quinones (Scheme 3), 1,4-naphtho-
quinone and 2-methyl-1,4-naphthoquinone afforded 2-
(3-indolyl)-1,4-naphthoquinone
derivatives
under
identical conditions (entries 6o–r, Table 1, Scheme 4)10.
In all cases, the reactions proceeded rapidly at room
temperature with high regioselectivity. As solvent, ace-
tonitrile appeared to give the best results. The products
were characterized by 1H, 13C NMR, IR and mass
spectroscopic data and also by comparison with
authentic samples.7b The probable mechanism seems to
be the addition of the indole to the unsaturated posi-
tion of the quinone, which is activated by bismuth
triflate. The initial addition product tautomerizes to the
hydroquinone which subsequently undergoes rapid oxi-
dation with another equivalent of p-quinone resulting
in the formation of the indol-3-ylquinone (Scheme 5).
In summary, we describe a simple and highly efficient
protocol for the preparation of 3-indolylquinones
through the nucleophilic addition of indoles to
quinones using bismuth(III) triflate as a catalyst. This
method is applicable to both electron-rich as well as
electron-deficient indoles and can be applied to the
total synthesis of naturally occurring asterriquinones.
Scheme 3.
Scheme 4.
Scheme 5.

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 9121–9124
indole (1 mmol) in acetonitrile (10 mL) was stirred at
Acknowledgements
room temperature for the specified time (see Table 1).
After completion of the reaction as indicated by TLC, the
reaction mixture was quenched with water (15 mL) and
extracted with dichloromethane (2×10 mL). Evaporation
of the solvent followed by purification on silica gel
(Merck, 100–200 mesh, ethyl acetate-hexane, 0.5–9.5)
afforded pure indol-3ylbenzoquinone. Spectral data for
B.V. S. and T. S. thank CSIR, New Delhi for the award
of fellowships.
References
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products:
3g:
2-(2-methyl-3-indolyl)-1,4-
hydroquinone (see Table 1): solid, mp 106–108°C, 1H
NMR (CDCl3): l 2.40 (s, 3H), 4.40 (brs, 1H, OH), 4.60
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1
solid, mp 116–118°C, H NMR (CDCl3): l 4.80 (brs, 2H,
OH), 7.05 (d, 2H, J=1.7 Hz), 7.05–7.45 (m, 8H), 7.80 (d,
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133.8, 138.3, 142.3, 145.4, 146.3, 187.2, 187.8. IR (KBr):
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1
solid, mp 180°C, H NMR (CDCl3): l 2.50 (s, 3H), 7.10
(s, 1H), 7.15–7.20 (m, 2H), 7.25–7.30 (m, 1H), 7.50–7.60
(m, 1H), 7.70–7.80 (m, 2H), 8.10–8.20 (m, 2H), 8.25 (brs,
1H, NH). 13C NMR (50 MHz, CDCl3): l 14.2, 107.6,
111.1, 119.7, 121.2, 122.6, 126.3, 127.4, 128.0, 132.6,
133.2, 133.9, 134.1, 135.1, 135.9, 137.5, 144.8, 185.2,
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