Tetrahedron Letters
Formation of tryptanthrin compounds upon Oxone-induced
dimerization of indole-3-carbaldehydes
⇑
Amber C. Nelson, Emily S. Kalinowski, Taylor L. Jacobson, Peter Grundt
Department of Chemistry & Biochemistry, University of Minnesota Duluth, 1039 University Drive, Duluth, MN 55812, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Tryptanthrin is a natural product with numerous important pharmacological properties. Tryptanthrin
and its analogs are commonly prepared by condensation of isatoic anhydride and isatin. In this Letter
we investigate the formation of tryptanthrin derivatives upon Oxone-induced oxidative dimerization
of indole-3-carbaldehydes.
Received 18 November 2012
Revised 27 September 2013
Accepted 28 September 2013
Available online 3 October 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Natural product synthesis
Tryptanthrin
Oxidation
Introduction
compounds can form in water without adding base at room
temperature.
5
Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione, 1, Scheme 1)
is a natural product, which shows significant biological activity. The
biological activity demonstrated by tryptanthrin and its derivatives
pertains to antibacterial, antiparasitic, and antineoplastic proper-
ties. Our interest in these compounds stems from their ability to in-
hibit the lifecycle of the parasite Toxoplasma gondii.
There are numerous alternative procedures and methods to
synthesize tryptanthrin compounds. Several groups have investi-
gated the dimerization of isatin (3) as an approach to obtain these
1
2
3
6
compounds. This procedure has been achieved electrochemically,
7
by radiation with laser light and in the presence of an oxidizing
8
agent; such as potassium permanganate. Alternatively, a very ele-
Tryptanthrin compounds are highly functionalized molecules.
Fortunately, the synthesis of this class of compounds can be easily
achieved from readily available starting materials. The most com-
gant method was developed by Moskovkina et al. These research-
ers induced the dimerization of isatin (3) by phosphoryl chloride.9
The synthesis of tryptanthrin and its derivatives has also been
achieved by dimerization of other heterocycles. During the prepa-
ration of this manuscript Wang et al. disclosed copper-catalyzed
aerobic oxidation of indole as the method to access this class of
4
mon approach for the synthesis of these compounds involves the
condensation of isatoic anhydride (2) and isatin (3) to give
tryptanthrin in moderate to high yields. The driving force for this
reaction is the development of carbon dioxide and water. If weak
bases are used, such as triethylamine or morpholine, then heat is
required to induce the formation of tryptanthrin. However, in the
presence of strong bases such as sodium hydride or water scaveng-
ers, tryptanthrin forms even at room temperature. Interestingly, in
the presence of b-cyclodextrin as the catalyst tryptanthrin
1
0
compounds.
In this Letter we consider the formation of tryptanthrin com-
pounds as a result of the Oxone-induced oxidation of indole-3-car-
baldehydes. Oxone, a potassium triple salt containing potassium
1
1
peroxymonosulfate, is a versatile oxidant. Compared to other
oxidation reagents, Oxone is particularly attractive in part due to
its stability, nontoxic nature, and non-polluting by-products.
Oxone induces numerous oxidation reactions. However, there are
only limited examples that show the effect of Oxone on indole
1
2,13
compounds.
Results and discussion
Scheme 1. Laboratory synthesis of the natural product tryptanthrin (1).
When we treated indole-3-carbaldehyde (4, Scheme 2) in a 2:1
mixture of acetonitrile/water at room temperature with an excess
of Oxone we were able to isolate the following products: tryp-
⇑
tanthrin (1), isatoic anhydride (2), and indirubin (5). From 1
H