Traceless Fischer indole synthesis on the solid phase

Article abstract of DOI:10.1039/b305497g

The Fischer indole synthesis using polymer-bound hydrazines is employed as the key step for the development of a traceless indole synthesis on a solid support.

Full text of DOI:10.1039/b305497g

Traceless Fischer indole synthesis on the solid phase†
Claudia Rosenbaum,a Catherine Katzka,a Andreas Marzinzikb and Herbert Waldmann*a
a Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Str. 11, 44227
Dortmund, Germany and Universität Dortmund, Fachbereich 3, Organische Chemie, 44227 Dortmund,
Germany. E-mail: herbert.waldmann@mpi-dortmund.mpg.de; Fax: +49/231/133-2499;
Tel: +49/231/133-2400
b Novartis Pharma AG, CCU/CT Combinatorial Chemistry, WSJ-507.509, 4002 Basel, Switzerland.
E-mail: andreas.marzinzik@pharma.novartis.com; Fax: +41 61 324 6589; Tel: +41 61 324 6891
Received (in Cambridge, UK) 15th May 2003, Accepted 17th June 2003
First published as an Advance Article on the web 1st July 2003
The Fischer indole synthesis using polymer-bound hydra-
zines is employed as the key step for the development of a
traceless indole synthesis on a solid support.
The combinatorial synthesis of small-molecule collections on
polymeric supports is a powerful method for the discovery and
development of new molecules with a predetermined profile of
properties, in particular for subsequent application in chemical
biology investigations and pharmaceutical research. Vital to
success in this area is the development of synthetic methods that
make the desired compounds available in an efficient and
reliable manner. In this respect, methods which allow the
detachment of the synthesized compounds from the resin
without leaving behind traces of the solid-phase synthesis are of
particular interest. They avoid the functional groups required
for resin attachment remaining in the target molecules which
may have an undesired effect on their biological activity. In
Scheme 1 Plan for the development and proposed mechanism of the
traceless Fischer indole synthesis on a solid support.
addition, synthesis sequences are of particular interest where the
desired products are formed and simultaneously released into
solution in the last step of the synthesis, i.e. in the sense of a
libraries. The plan for the synthesis was executed as shown in
safety catch mechanism. Such a strategy ensures that only the
Scheme 2.
desired compounds are released, unwanted side products not
fulfilling the demand for safety catch release remain bound to a
solid support. Equally if not more vital to success is the choice
of the underlying molecular framework of the compound
Initially p-hydroxyphenylpropionic acid 8 was converted into
the methyl ester which was deprotonated to give phenolate 9.8
Nucleophilic attack on Merrifield resin 10 (resin loading 1.1
mmol g21) in the sense of a Williamson ether synthesis and
library. The hit rates in biological assays and the quality of the
saponification of the methyl ester yielded polymer-bound
compounds are expected to be particularly high if the compound
carboxylic acid 11 (resin loading 0.78 mmol g21, determined by
class in question can be regarded as biologically pre-validated,1
in particular if they incorporate a so-called priviledged
coupling with H-lysine(Fmoc)-OH and UV-spectrometric
quantification of the Fmoc group attached to the resin). This
polymer–linker conjugate was then converted into substituted
immobilized hydrazide 13 employing diisopropylcarbodiimide
(DIC) and N-hydroxybenzotriazole (HOBt) as condensing
reagents. Reduction of hydrazide 13 to hydrazine 14 was best
accomplished by treatment with 10 equiv. of the BH3·THF
complex at 60 °C overnight. Formation of the hydrazines was
structure, i.e. a structure that mediates binding to multiple
proteins.2 In this regard, indoles represent one of the most
important structural classes. A plethora of indole-based bio-
logically active natural products and indole-derived drugs span
an enormous range of biological activity.3 Consequently, the
combinatorial synthesis of indole libraries has received intense
attention.3–6
We now report on the development of a traceless5 solid phase
indole synthesis employing the Fischer indole synthesis6 as the
key step. In planning the synthesis we envisioned generating
hydrazines 2 on a solid support and treating them with
appropriate ketones under typical conditions of the Fischer
indole synthesis (Scheme 1). In the ensuing process an enamine
3 would be formed which upon protonation and [3,3]-sigma-
tropic rearrangement would give rise to an iminium inter-
mediate 5. Intramolecular attack of the formed aniline nitrogen
would lead to traceless release of indole derivatives 7 from the
polymeric carrier 6. It was planned to generate the immobilized
hydrazines 2 from polymer-bound hydrazides 1 by reduction of
the hydrazide carbonyl group. Appropriately substituted hydra-
zides 1 are compatible with a variety of organic-chemical
transformations like Pd(0)-catalyzed sp2–sp2-coupling proc-
esses, Grignard reactions and Wittig olefinations.7 Surely they
open up the opportunity to establish highly diverse compound
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b3/b305497g/
Scheme 2 Traceless Fischer indole synthesis in the solid phase.
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This journal is © The Royal Society of Chemistry 2003

ascertained by means of high resolution magic angle spinning
(MAS) NMR-spectroscopic investigation9 of resin 14 (R1
=
Br). An HMQC experiment allowed for unambiguous establish-
ment of a C/H correlation characteristic for a polymer-bound
hydrazine (Fig. 1). Alternative reduction to an immobilized
hydrazone which might react with a ketone in the presence of
traces of water to a new hydrazone released into solution before
undergoing a subsequent Fischer rearrangement (Scheme 3)
was not detected.
Fig. 3 Results of the traceless Fischer indole synthesis.
Immediately after the traceless synthesis, the indole deriva-
tives are isolated in approx. 80% purity. After chromatographic
separation they were obtained with a purity of 99%. The results
show that the solid phase sequence tolerates several different
functional groups and that it delivers the desired products in a
very straightforward and practical manner. Mono- and di-
substituted aryl hydrazines as well as mono- and di-keto
compounds were successfully used.
In conclusion we have developed a traceless indole synthesis
on a solid support. It employs the Fischer indole rearrangement
as a key step, is operationally very practical, tolerant to a variety
of functional groups in both types of building blocks and makes
the desired compounds available in preparatively useful overall
yields and with high purity.
Fig. 1 HMQC-NMR spectrum of the polymer-bound hydrazine 14.
This research was supported by the Max Planck Gesellschaft
and the Fonds der Chemischen Industrie. C. R. is grateful to the
Landesgraduiertenstiftung Baden-Württemberg for financial
support.
Notes and references
1 R. Breinbauer, I. R. Vetter and H. Waldmann, Angew. Chem., 2002, 114,
3002–3015 (Angew. Chem., Int. Ed., 2002, 41, 2878–2890).
2 B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger,
W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson, R. S. L. Chang,
V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P.
Springer and J. Hirshfield, J. Med. Chem., 1988, 31, 2235–2246.
Scheme 3 Possible pathways for formation and traceless release of the
indoles.
3 For reviews on the indole ring as
a priviledged structure and
combinatorial synthesis of indole-based compound libraries see: (a) D. A.
Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103,
893–930; (b) S. Bräse, C. Gil and K. Knepper, Bioorg. Med. Chem., 2002,
10, 2415–2437.
4 S.-H. Lee, B. Clapham, G. Koch, J. Zimmermann and K. D. Janda, J.
Comb. Chem., 2003, 5, 188–196. This paper contains a compilation of
various indole syntheses on the solid phase.
Polymer-bound hydrazines 14 were suspended in a mixture
of dichloroethane/trifluoroacetic acid (1 : 3), and after addition
of a ketone 15 the mixture was shaken at 80 °C for 1–3 days
(Scheme 2). The building blocks employed in the traceless
indole synthesis are shown in Fig. 2, i.e. differently substituted
hydrazines and ketones were chosen.
5 For a traceless indole synthesis on a solid support see: K. C. Nicolau, A.
J. Roecker, R. Hughes, R. van Summeren, J. A. Pfefferkorn and N.
Winssinger, Bioorg. Med. Chem., 2003, 11, 465–476.
Notably, in both cases functional groups are present which
allow for further structural modification of the obtained indoles,
i.e. an aromatic bromide or keto groups. The results of the
synthesis are shown in Fig. 3. In total eleven compounds were
synthesized enabling use of all building blocks chosen. The
overall yield from attachment of the hydrazine on a solid
support to release of the desired indole into solution vary from
6 to 41% after chromatographic separation.
6 For non-traceless Fischer indole syntheses on a solid support see: (a) S.
M. Hutchins and K. T. Chapman, Tetrahedron Lett., 1996, 37,
4869–4872; (b) L. Yang, Tetrahedron Lett., 2000, 41, 6981–6984; (c) L.
C. Cooper, G. G. Chicchi, K. Dinnell, J. M. Elliott, G. J. Hollingworth, M.
M. Kurtz, K. L. Locker, D. Morrison, D. E. Shaw, K.-L. Tsao, A. P. Watt,
A. R. Williams and C. J. Swain, Bioorg. Med. Chem. Lett., 2001, 11,
1233–1236; (d) J. Tois, R. Franzèn, O. Aitio, K. Huikko and J. Taskinen,
Tetrahedron Lett., 2000, 41, 2443–2446.
7 (a) F. Stieber, U. Grether and H. Waldmann, Angew. Chem., 1999, 111,
1142–1145 (Angew. Chem., Int. Ed., 1999, 38, 1073–1077); (b) F.
Stieber, U. Grether and H. Waldmann, Chem. Eur. J., 2003, 9, in press;
(c) F. Stieber, R. Mazitschek, N. Soric, A. Giannis and H. Waldmann,
Chem. Eur. J., 2003, 9, in press.
8 B. Das, B. Venkataiah and P. Madhusudhan, Synlett, 2000, 59–60.
9 MAS-NMR measurements: Varian Mercury 400, gHX Nano Probe
Probehead, 400 MHz, spin rate of 2.5 kHz.
Fig. 2 Building blocks employed in the solid phase synthesis.
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