Angewandte
Chemie
DOI: 10.1002/anie.201402661
Indole Synthesis
Indole Synthesis Based On A Modified Koser Reagent**
Laura Fra, Alba Millꢀn, Josꢁ A. Souto, and Kilian MuÇiz*
Abstract: A new metal-free method for the rapid and
productive preparation of indoles has been developed. This
process is based on sterically congested hypervalent iodine
compounds of the family of Koser reagents, and iodosoben-
zene in combination with 2,4,5-tris-isopropylbenzene sulfonic
acid provides the highest yields and fastest reaction times. This
reagent alone promotes the chemoselective oxidative cycliza-
tion of 2-amino styrenes to indoles in high yields under mild
conditions.
Scheme 1. Intramolecular alkene amination with hypervalent iodine(III)
reagents.
I
ndoles constitute privileged structures in natural products,
reagent has been suggested to generate a cationic nitrogen
atom, which is subsequently attacked by the alkene to initiate
the intramolecular amination. While this concept has proven
extremely versatile for the intramolecular synthesis of a large
series of nitrogen heterocycles,[10,11] it is surprising to note that
the notable class of indoles has so far precluded this approach.
We herein present the successful realization of such an
approach of indole synthesis through a hypervalent iodine-
(III) mediated oxidation of 2-vinyl anilines.[12]
as well as in medicinal and biological chemistry.[1] Starting
with the seminal synthesis by Emil Fischer,[2] synthetic access
to this class of compounds has received huge attention for
more than 130 years, and numerous routes to their synthesis
have become available.[1,3] Important contributions from
recent years are based on innovative transition-metal-cata-
lyzed transformations.[4,5] A particularly useful reaction in the
area has been the oxidative cyclization of 2-vinyl anilines to
indoles. This reaction has been a hallmark in the area of
palladium catalysis.[6]
The reaction was developed exploring the potential of
different hypervalent iodine compounds to promote the
intramolecular cyclization of various 2-vinyl anilines. In
order to introduce a standard substituent at nitrogen, N-
Cbz-protected 2-vinyl aniline 1a was employed as standard
substrate (Table 1). This compound was found to deliver the
desired indole 2a upon exposure to several hypervalent
iodine reagents, although yields remained low. Examples of
this initial screening include iodosobenzene diacetate
(Table 1, entry 1), PIFA (entry 2), and combinations of the
former with Brønsted acids (entries 3 and 4). While these
reactions resulted only in low yields of the desired isolated
product 2a, the use of Koserꢁs reagent ([(hydroxy)-
(tosyloxy)iodo]benzene, Table 1, entry 5)[13] gave the product
in 55% yield together with some unidentified side products.
The yield could be further increased by using chloroform as
the solvent (Table 1, entry 6). An in situ formation[13a] of the
active reagent from iodosobenzene and 4-toluene sulfonic
acid gave the same result (Table 1, entry 7). Formation of
related Koser reagents with different steric arrangements at
the aryl group of the sulfonic acid, as in 2,4,6-tris-isopropyl-
benzene sulfonic acid (A) and 2,4,5-tris-isopropylbenzene
sulfonic acid (TIPBSA, B) led to the identification of the
latter as an efficient promoter (Table 1, entries 8 and 9,
respectively). For this optimum combination of PhIO and B,
the reaction time could be lowered to 1 h without loss of yield
(Table 1, entry 10).
The development of the corresponding metal-free oxida-
tion reaction would be an important addition to the field of
indole synthesis, given the particular purity requirements in
the areas of biological and medicinal chemistry. In view that
such a reaction is notably absent, we started to explore the
synthetic basis for the realization of such a process using
hypervalent iodine reagents as sole oxidants.[7] For example,
the corresponding intramolecular cyclization reactions are
available for carbazole synthesis from 2-amino biphenyls.[8]
Though conceptually related, the switch from aromatic
amination in these cases to the required amination of an
alkene represents a significantly more challenging process to
pursue.
Important intramolecular amination reactions of alkenes
were developed by Domꢀnguez. These reactions are charac-
terized by the use of iodosobenzene bis(trifluoroacetate)
(PhI(O2CCF3)2, PIFA) as an efficient oxidant (Scheme 1).[9]
An initial interaction between an amino group and this
[*] L. Fra, Dr. A. Millꢀn, Dr. J. A. Souto, Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
Av. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Prof. Dr. K. MuÇiz
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluꢂs Companys 23, 08010 Barcelona (Spain)
This reagent combination also promotes the indole
cyclization from related N-carbamoyl precursors such as the
methyl carbamate 1b and the Fmoc derivative 1c. To a certain
extent, a benzoyl group is also tolerated (Table 1, entries 11–
13). Because of the acidic conditions, the Boc group is beyond
the scope of the present transformation (Table 1, entry 14), as
[**] The authors thank the Fundaciꢃn ICIQ and the Spanish Ministerio
de Economꢂa (CTQ2011-25027) for financial support. L.F. and A.M.
thank the Ministerio de Economꢂa y Competitividad and Universi-
dad de Granada for respective fellowships.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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