Synthesis of 3-Indolyl-2,5-dihydroxybenzoquinones

Article abstract of DOI:10.1021/ol006852l

(Matrix Presented) 3-Indolylquinones can be efficiently prepared by the acid-catalyzed condensation of indoles with 2,5-dichlorobenzoquinone, followed by DDQ oxidation. The resulting dichloroquinones are hydrolyzed to the 3-indolyldihydroxybenzoquinones.

Full text of DOI:10.1021/ol006852l

ORGANIC
LETTERS
2001
Vol. 3, No. 3
365-367
Synthesis of
3-Indolyl-2,5-dihydroxybenzoquinones
Michael C. Pirrung,* Kaapjoo Park, and Zhitao Li
Department of Chemistry, LeVine Science Research Center, Duke UniVersity,
Box 90317, Durham, North Carolina 27708
pirrung@chem.duke.edu
Received November 10, 2000
ABSTRACT
3-Indolylquinones can be efficiently prepared by the acid-catalyzed condensation of indoles with 2,5-dichlorobenzoquinone, followed by DDQ
oxidation. The resulting dichloroquinones are hydrolyzed to the 3-indolyldihydroxybenzoquinones. The 3-indolylquinone substructure is of
interest because of its presence in natural products that modulate biological processes through protein−protein interactions, including the
asterriquinones.
The 3-indolylbenzoquinone substructure is present in a
number of biologically significant natural products. The
asterriquinones, a large group of compounds found in fungi,
have two such units.1 The asterriquinones exhibit a range of
biological activities, including antitumor properties and
inhibition of HIV reverse transcriptase. One member of the
class, asterriquinone A1, has been shown to arrest the cell
cycle in G1 and promote apoptotic cell death.2 Asterriquinone
analogues inhibit the interaction between the SH2 (Src
homology 2) domains of receptor tyrosine kinases and their
“adapter” protein Grb2.3 Known asterriquinone activities
have recently expanded to non-protein, orally active insulin
mimetics4 (Figure 1). All of these properties apparently stem
from the ability of asterriquinones to either promote or
prevent protein-protein interactions. The asterriquinones are
also notable for their modular structures, consisting of two
prenylated indoles appended to a dihydroxyquinone core.
Novel synthetic methods are needed for the preparation
of 3-indolylquinones. Such methods could be used in total
syntheses of asterriquinones or to prepare reagents designed
to probe the biological activity of the indolylquinones. The
3-indolylquinone structure may represent a “pharmacophore”
for protein-protein interactions, and compounds bearing it
should exhibit actions similar to or antagonistic of the bis-
(1) Arai, K.; Yamamoto, Y. Chem. Pharm. Bull. 1990, 38, 2929-2932.
Kaji, A.; Saito, R.; Nomura, M.; Miyamoto, K.-i.; Kiriyama, N. Biol. Pharm.
Bull. 1998, 21, 945-949.
(2) Kaji, A.; Saito, R.; Nomura, M.; Miyamoto, K.-i.; Kiriyama, N.
Anticancer Res. 1997, 17, 3675-3679. Alvi, K. A.; Pu, H.; Luche, M.;
Rice, A.; App, H.; McMahon, G.; Dare, H.; Margolis, B. J. Antibiot. 1999,
52, 215-223.
(3) Harris, G. D.; Nguyen, A.; Strawn, L.; Fong, A.; App, H.; Le, T.;
Sutton, B.; Tang, P. C. Abstracts of Papers, 215th National Meeting of the
American Chemical Society; American Chemical Society: Washington, DC,
1998; MEDI 163.
(4) Zhang, B.; Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.; Royo, I.;
Vilella, D.; Diez, M. T.; Pelaez, F.; Ruby, C.; Kendall, R. L.; Mao, X.;
Griffin, P.; Calaycay, J.; Zierath, J. R.; Heck, J. V.; Smith, R. G.; Moller,
D. E. Science 1999, 284, 974-977.
Figure 1. L-783,281, demethylasterriquinone B1.
10.1021/ol006852l CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/18/2001

Scheme 1. Proposed Mechanism of the Acid-Catalyzed
Condensation of an Indole with 2,5-Dichlorobenzoquinone
indolylquinones. A simple approach to this unit is direct
reaction of an indole with a quinone. A method for the
synthesis of bis-indolylquinones involving condensation of
tetrabromobenzoquinone with 2 equiv of a 2-substituted
indole under basic conditions was recently used in a synthesis
of tetrahydroasterriquinone E.5 Historically, the reaction of
indole with benzoquinone goes back to 1911, though these
workers did not isolate their red product.6 This reaction was
reinvestigated by Bu’Lock in 1951, but the indolylquinone
product was only isolated in a low yield.7 The efficiency of
the condensation of excess benzoquinone with 2-methylin-
dole was recently improved by conducting it anaerobically.8
The second quinone molecule evidently serves to oxidize
an initial hydroquinone addition product to the 3-indolylquino-
ne (vide infra). No examples of this reaction beyond indole
and 2-methylindole were presented.
Figure 2. Indoles used in the two-step synthesis of 3-indolyl-2,5-
dihydroxyquinones (yield for the condensation step is given above,
and the yield for the hydrolysis step below). A superscript b
indicates the yield for two steps. The intermediate dichloroquinone
is unstable when concentrated and was not isolated. An asterisk
indicates that this indole required the modified protocol with 0.3
equiv of HCl.
As a starting point for the preparation of more highly
oxidized 3-indolylquinones, we examined anaerobic con-
densation reactions (promoted by stoichiometric HCl in THF)
of 2-methylindole with a variety of 2,5-dihalogenated or 2,5-
dioxygenated benzoquinones. Among the compounds inves-
tigated, 2,5-dichlorobenzoquinone was uniquely successful
in participating in this reaction. Despite the fact that, as in
the precedented reaction, 2 mol of quinone was used per
mole of 2-methylindole, the product was a mixture of the
3-indolylquinone and the corresponding hydroquinone. Evi-
dently, unlike the condensation with benzoquinone, the
starting quinone does not readily oxidize the hydroquinone
product. Consequently, the condensation was followed by
addition of dichlorodicyanoquinone (DDQ) to provide the
product in a single oxidation state. Even in these early
studies, the product was isolated in very high yield after
chromatography. The extended conjugated system engenders
strong visible absorption, and the characteristic blue color
of the product makes it easy to follow.
Mechanistically, we envision this reaction proceeding as
shown in Scheme 1. The nucleophilic carbon 3 of the indole
adds to the quinone. A priori, one could propose nucleophilic
attack at either the chlorinated or non-chlorinated carbon.
The former might be favored on the basis of the “vinylogous
acid chloride” character, while the latter might be favored
by sterics. Molecular orbital calculations (AM1) show the
Mulliken charge at the non-chlorinated carbon is -0.18 and
at the chlorinated carbon is -0.1, suggesting that the former
should be the favored site of nucleophilic attack. This is
desirable for the indole addition step and undesirable for the
following hydrolysis step. The initial addition product
tautomerizes to the hydroquinone, which is oxidized either
by 2,5-dichlorobenzoquinone or DDQ.
(5) Harris, G. D.; Nguyen, A.; App, H.; Hirth, P.; McMahon, G.; Tang,
C. Org. Lett. 1999, 1, 431.
(6) Mohlau, R.; Redlich, R. Ber. 1911, 44, 3605.
(7) Bu’Lock, J. D.; Harley-Mason, J. J. Chem. Soc. 1951, 703.
(8) Corradini, M. G.; Costantini, C.; Prota, G.; Schultz, T. M. Gazz. Chim.
Ital. 1989, 119, 153-6.
The scope of this new reaction sequence was investigated
with many 3-unsubstituted indoles. A standard reaction
366
Org. Lett., Vol. 3, No. 3, 2001

protocol was adopted using 0.5 mmol of indole and 1 mmol
of quinone with 1 equiv of concentrated HCl in 3 mL of
THF. After overnight stirring at room temperature, DDQ (1
mmol) is added and the reaction mixture is stirred for 2-4
h. Examples are collected in Figure 2.9 With a few indoles
(marked with a *), trichloro-3-indolylquinone byproducts
were formed. This observation is attributed to reaction of
the product 3-indolylquinone with HCl, leading to a trichloro-
hydroquinone that is further oxidized. This process can be
eliminated by reducing the HCl to 0.3 equiv.
The reactivity of indoles in the condensation reaction is a
consequence of both steric and electronic factors. Indoles
bearing electron-withdrawing groups do not participate. The
most electron-rich indoles with a carbon 2 substituent are
the best reactants. Indoles with no substitution on the
heterocycle give a slightly lower yield. The reaction is limited
by steric effects, and the limit is reached at 2-tert-butylindole.
Indoles with any higher tert-alkyl substitution fail completely
in the reaction.
The 3-indolyldichloroquinones are closely analogous to
bis-indolyldibromoquinones earlier used as intermediates in
asterriquinone analogue synthesis.5 Those materials were
directly hydrolyzed in alkali, but this deceptively simple
transformation proved to be problematic with the 3-indolyl-
dichloroquinones. The unsubstituted quinone carbon can be
readily attacked by hydroxide, a process similar to that
observed in the formation of the trichloroquinone byproduct
above, eventually leading to the hydroxylated 3-indolyldi-
chloroquinone. Diligent experimentation provided a modified
reaction protocol involving adding 10% aqueous NaOH (3
mL) to a warm solution of 3-indolyldichloroquinone (0.14
mmol) in MeOH (6 mL) and heating at reflux for 20-30
min. The concentration is crucial, as a 2-fold increase causes
a decrease in yield by half. Hydrolysis reactions using this
method proceed in 52-87% isolated yield (Figure 2).10 The
3-indolyldihydroxyquinone products are generally blue-green
crystalline compounds.
A challenging aspect of preparing 3-indolyldihydroxy
quinones is their instability to standard silica gel chroma-
tography. Reverse-phase HPLC has been used to purify
asterriquinone analogues,5 but a more practical alternative
was sought. Oxalic acid-coated silica gel has been used for
purification of the asterriquinones.11 This adsorbent was
prepared and used in the purification of all 3-indolyldihy-
droxyquinones in Figure 2.
In conclusion, the condensation of electron-rich indoles
with 2,5-dichlorobenzoquinone followed by hydrolysis with
alkali constitutes an efficient synthetic route to the 3-indolyl-
2,5-dihydroxyquinone substructures of the asterriquinones,
which are desirable for their abilities to modulate protein-
protein interactions.
Acknowledgment. Financial support was provided by the
American Diabetes Association and Diabetes Action Re-
search and Education Foundation.
Supporting Information Available: 1H and 13C NMR
spectra of new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL006852L
1
(10) All new compounds were characterized by H and 13C NMR and
MS.
(9) Those indoles failing include indole-2-carboxylic ester, 2-isopre-
(11) Yamamoto, Y.; Nishimura, K.; Kiriyama, N. Chem. Pharm. Bull.
1976, 24, 1853-1859.
nylindole, 5-nitroindole, and N-tosylindole.
Org. Lett., Vol. 3, No. 3, 2001
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