First synthetic entry to the trimer stage of 5,6-dihydroxyindole polymerization: Ortho-alkynylaniline-based access to the missing 2,7′:2′,7′′-triindole

Article abstract of DOI:10.1039/c0ob00037j

5,6-Dihydroxyindole oligomers are valuable synthetic targets for the structural characterization of eumelanin biopolymers as well as for the realization of bioinspired functional materials. An ortho-alkynylaniline-based strategy allowed the first access to a trimer, the missing 5,5′, 5′′,6,6′,6′′-hexaacetoxy-2,7′:2′, 7′′-triindole, and its detection as a minor intermediate en route from 5,6-dihydroxyindole to eumelanin-like polymers.

Full text of DOI:10.1039/c0ob00037j

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First synthetic entry to the trimer stage of 5,6-dihydroxyindole
polymerization: ortho-alkynylaniline-based access to the missing
2,7¢:2¢,7¢¢-triindole†
Luigia Capelli, Paola Manini,* Alessandro Pezzella and Marco d’Ischia
Received 22nd April 2010, Accepted 19th July 2010
DOI: 10.1039/c0ob00037j
5,6-Dihydroxyindole oligomers are valuable synthetic targets
for the structural characterization of eumelanin biopolymers
as well as for the realization of bioinspired functional mate-
rials. An ortho-alkynylaniline-based strategy allowed the first
access to a trimer, the missing 5,5¢,5¢¢,6,6¢,6¢¢-hexaacetoxy-
2,7¢:2¢,7¢¢-triindole, and its detection as a minor intermediate
en route from 5,6-dihydroxyindole to eumelanin-like poly-
mers.
The development of efficient and versatile synthetic approaches
toward oligomer derivatives of 5,6-dihydroxyindole (1) provides a
useful strategy to model the complex oxidative process leading
to the biosynthesis of eumelanins, the black photoprotective
biopolymers of human skin, hair and eyes.1–3 The oxidative
polymerization of 1 to eumelanin proceeds through a range of
oligomer intermediates which appear to arise mainly via 2,4¢- and
2,7¢-coupling steps, as indicated by the isolation of biindoles 2 and
3 and triindoles 4 and 5.4,5
Further insights into the structure of the oligomeric species
generated during the oxidative polymerization of 1 have been
hindered by the marked complexity of the reaction mixtures and
the poor isolated yields. The availability of a collection of 5,6-
dihydroxyindole oligomers of variable molecular size is therefore
pivotal for future advances in the structural characterization
of eumelanin biopolymers6 as well as for the realization of
bioinspired functional materials for technological applications,
e.g. as light-harvesting systems.7,8 Interest in these synthetic targets
is also spurred by the potential of indole-based scaffolds for the
The versatile methodology developed in that study was en-
preparation of anion sensing architectures.9–12
visaged to provide a convenient general strategy toward higher
5,6-dihydroxyindole oligomers. In extending that procedure we
report herein the first synthetic approach to a trimer of 1,
namely the 2,7¢:2¢,7¢¢-triindole 6. Trimer 6 was an interesting target
for the following reasons. Although this structure embodies the
characteristic 2,7¢-coupling mode of 5,6-dihydroxyindoles,4 it has
never been identified in the oxidation mixtures of 1, and availability
of an authentic standard may guide its detection during the
polymerization process. Moreover, preparation of the missing
triindole would integrate current knowledge of the structural
properties of 5,6-dihydroxyindole oligomers,20 and would provide
a useful starting material for assembling high molecular polymers
via the oligomer-oligomer coupling approach.21,22 The triindole
skeleton of 6, featuring three nitrogen groups in a suitable disposi-
tion for ion coordination, also offers interesting opportunities for
anion sensing.
Whereas numerous procedures are available in the literature
for the synthesis of biindoles, triindoles and higher indole
oligomers,13–16 the extension to the 5,6-dihydroxyindole series may
not be straightforward. Considerable constraints are posed, for
example, by the highly oxidizable ortho-dihydroxy functionality,
which requires careful selection of protecting groups, reagents
and reaction conditions. Recently, we reported the first successful
approach to a series of dimers of 1, namely the 2,7¢-, 2,2¢-
and 2,3¢-biindoles,17 which was based on a judicious sequence
of Sonogashira coupling and cyclization steps involving suitably
protected ortho-ethynylaniline intermediates.18,19
Department of Organic Chemistry and Biochemistry, University of Naples
Federico II, Complesso Universitario Monte S. Angelo, via Cintia 4, I-80126,
Naples, Italy. E-mail: pmanini@unina.it; Fax: +39-081-674393; Tel: +39-
081-674128
† Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data; copies of mono- and bidimensional
NMR spectra; LC-MS analysis. See DOI: 10.1039/c0ob00037j
The synthetic approach to 6 capitalizes on 3,4-diacetoxy-6-
ethynyl-2-iodoaniline (10a) as the starting material. This key in-
termediate was readily obtained from commercial 4-nitrocatechol
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(7) by the sequence of reactions reported in the previous study and
summarized in Scheme 1.17
16
Scheme 1
Protection of the labile ortho-diphenol functionality by acety-
lation combines the advantage of a decreased aromatic reactivity
during the critical iodination steps and the ease of deprotection.17
Conversion of 10a to 6 was achieved by the sequence of steps
outlined in Scheme 2.
The initial cyclization to 5,6-diacetoxy-7-iodoindole (11) was
efficiently carried out by an improved procedure which was
based on Cu(OAc)2 (0.6 molar eqs.) as catalyst in dry CH2Cl2.23
Under these improved conditions, the reaction proceeded in
18 h and in good yield (80%) without the need for extensive
purification steps. Sonogashira coupling on 11 then led to 5,6-
diacetoxy-7-ethynylindole (12b) which was reacted with the o,o-
diiodoaniline 8, an intermediate in the synthesis of 10a, to give
the indolylethynylaniline 13. Surprisingly, cyclization of 13 to
7-iodo-2,7¢-biindole 14 proved less efficient than in the case of
10a, possibly because of steric effects. However, a brief screening
of some potential catalysts24 for ortho-alkynylaniline cyclization
showed that AuCl3 or NaAuCl4·2H2O, this latter with longer
reaction time, could efficiently promote the reaction to give 14
in good yield. A similar sequence of Sonogashira coupling-
cyclization steps from 14 eventually led to the desired 6-Ac.
Structural assignment was secured by extensive 2D NMR25 and
MS analysis also in comparison with trimers 4 and 5.26
To the best of our knowledge, this paper describes the first
synthesis of a 2,7¢:2¢,7¢¢-triindole and provides a simple and
versatile procedure for the preparation of indole-based scaffolds
with variable substitution patterns. The synthetic approach in
Scheme 2 stems largely from the previously reported strategy to
isomeric biindoles, however it features some aspects of general
interest. In particular, all cyclization steps have been significantly
improved with respect to the preceding study,17 as a result of a
27
Scheme 2
systematic screening of different catalysts under various reaction
conditions (see ESI†).
Replacement of CuI with Cu(OAc)2 increased the yield of
23
28
conversion of 10a to 11 from 50% to 80% whereas AuCl3
and NaAuCl4·2H2O29 proved to be superior catalysts for the
subsequent cyclization steps leading to the biindole 14 and 6-Ac.
We have no clear-cut explanation of why Cu(OAc)2 works only
well on the monomer precursor 10a and less efficiently on the
bulkier substrates 13 and 15, and why AuCl3 and NaAuCl4·2H2O
work better in the latter case. Although gold catalysts have been
successfully utilized in the preparation of various indole systems
from ortho-alkynylanilines,24,29–32 the use of AuCl3 to promote
the cyclization of ortho-alkynylanilines has remained so far
confined to few examples leading to 2-arylindoles.28 Key changes
introduced in the present methodology with respect to the previous
AuCl3 protocol include higher ortho-ethynylaniline and cata◦lyst
◦
concentration and a lower temperature (45 C instead of 70 C)
with ultrasound activation, which resulted in shorter reaction
times (30–90 min) without the need for extensive chromatographic
purification. Comparable results in terms of yields, but with longer
reaction time, have been obtained by using NaAuCl4·2H2O as
reported.29
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The development of a convenient access protocol to 6, besides
the intrinsic synthetic interest, allowed the probing of the genera-
tion of this trimer during 5,6-dihydroxyindole polymerization. LC-
MS analyses of various oxidation mixtures of 1 under previously
reported biomimetic conditions4,21,22 disclosed the presence of 6 as
a minor component of the oligomer intermediates that populate
the trimer level, confirming the generation of 4 and 5 as the
prevailing isomers (see ESI†). It is concluded that 2,4¢- and 2,7¢-
bonds are of comparable importance in the oxidative dimerization
of 1, but the 2,4¢-coupling mode prevails beyond the dimer stage,
a finding which may have interesting mechanistic implications for
eumelanin build-up.
In conclusion, we have developed an improved ortho-
alkynylaniline-based procedure for the first synthesis of a 5,6-
dihydroxyindole trimer which combines mild, expedient and
potentially scaleable protocols with easy-to-perform work-up and
satisfactory yields. Assessment of the actual scope of the optimized
ortho-alkynylaniline cyclization methodology for the preparation
of higher indole oligomers is a main goal of ongoing work in our
laboratory.
7 M. d’Ischia, A. Napolitano, A Pezzella, P. Meredith and T. Sarna,
Angew. Chem., Int. Ed., 2009, 48, 3914–3921.
8 A. Pezzella, A. Iadonisi, S. Valerio, L. Panzella, A. Napolitano, M.
Adinolfi and M. d’Ischia, J. Am. Chem. Soc., 2009, 131, 15270–
15275.
9 K.-J. Chang, D. Moon, M. S. Lah and K.-S Jeong, Angew. Chem., Int.
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10 P. A. Gale, Chem. Commun., 2008, 4525–4540.
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This work was supported in part by grants from Italian Ministry
of University (MIUR), PRIN 2008 (2008LMY5WX). We would
like to thank Prof. G. Fabrizi (Rome University) for a generous
gift of NaAuCl4·2H2O.
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25 Structural assignment was secured by comparing 1D and 2D NMR
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a 10% solution of NH4Cl in H2O (see ESI†).
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