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Notes and references
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2 For some active compounds, see: (a) A. Brancale and R. Silvestri, Med.
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Scheme 3 (a) Synthesis of 4k from 7; (b) plausible mechanism for 4a formation.
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¨
¨
C. Schachtele, F. Uberall, M. U. Kassack, S. Dove and F.-D. Bohmer,
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Scheme 4 Synthesis of the natural product quindolinone.
synthesis of 4k. Since ethyl carbamate (pKa = 24.6) has a
comparable pKa value to acetophenone,14 we surmised an alter-
native mechanism for the 2-acylindoline formation (Scheme 3b).
The process was initiated to form the a-iodo ketone D, and
consequently cyclisation could take place to produce 4a with
much less likelihood of elimination of the N-Boc group.
6 For other strategies of 2-acylindole synthesis, see: (a) K. O. Hessian
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7 (a) D. Sole, X. Urbaneja, A. C. Vargas and J. Bonjoch, Tetrahedron, 2007,
The success in the indole synthesis inspired us to explore the
synthetic utility of the present method. Quindolinone (12) was
isolated from the Cryptolepis sanguinolenta, a shrub indigenous
to West Africa.17a The roots’ aqueous extracts of this plant have
been used for centuries by African traditional healers mainly for
the treatment of various fevers.17b,c 12 could be accessed from
cyclic ketone 10 in 78% yield by a one-pot procedure (Scheme 4).
The isolation of intermediate 11 indicated that this transforma-
tion proceeded via intramolecular amination and dehydrogena-
tion,18 followed by the detosylation of 11 with 2 N NaOH. Among
the previous reports,19 the most efficient route for 12 started with
anthranilic acid in 44% overall yield via amidation, substitution
of aniline and polyphosphoric acid-promoted cyclisation, which
suffered from high temperature (>120 1C) and purification
issues. By comparison, the present method gave 12 in 58%
overall yield after two steps under milder conditions.
In summary, for the first time, a general method for 2-acylindole
and 2-acylindoline synthesis via I2-mediated C–N bond formation
has been developed. The switchable access is realized by tuning
N-protecting groups of b-20-aminophenyl ketones. From the mecha-
nism study, it is believed that the intramolecular a-iodination of
ketones via the N–I intermediate A was involved in 2-acylindole
synthesis, while the direct a-iodination of ketones with iodine was
involved in the 2-acylindoline synthesis. This facile method is
successfully applied to the concise synthesis of the natural product
quindolinone. The generality, high efficiency and operational
simplicity make the present method attractive for constructing
2-acylindoles and 2-acylindolines alternatively.
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12 Compared with the conventional synthesis (28% yield, 5 steps in
ref. 2b), this process (46% yield, 3 steps) was more efficient starting
from 2-tosylaminobenzaldehyde (9), which can be purchased from
Fluorochem Ltd.
13 For the N-Boc deprotection, see: (a) P. G. M. Wuts and T. W. Greene,
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J. Qu, Chem. Commun., 2009, 5144–5146.
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This work was financially supported by The National Natural
Science Foundation of China (21172110 and 21121002).
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c
4892 Chem. Commun., 2013, 49, 4890--4892
This journal is The Royal Society of Chemistry 2013