Combinatorial synthesis of libraries of indole derivatives

Article abstract of DOI:10.1016/S0960-894X(01)00393-6

The synthesis of two indole derivative libraries is described. 2-Acyl-3-amino-indoles 4 can easily be accessed by treatment of the intermediates 3 with bases in a one-pot reaction sequence whereas the reaction of the isolated intermediates 5 (R₃ = aromatic-, heteroaromatic, or cycloalkyl) with acid chlorides yielded the novel indole derivatives 6. The products were purified by reversed phase column chromatography and obtained in multi-milligram quantities in acceptable yields.

Full text of DOI:10.1016/S0960-894X(01)00393-6

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2169–2171
Combinatorial Synthesis of Libraries of Indole Derivatives
Matthias Nettekoven*
F. Hoffmann-La Roche Ltd, Pharmaceutical Research, Discovery Chemistry—Lead Generation, CH-4070 Basel, Switzerland
Received 30 March 2001; revised 16 May 2001; accepted 29 May 2001
Abstract—The synthesis of two indole derivative libraries is described.2-Acyl-3-amino-indoles 4 can easily be accessed by treatment
of the intermediates 3 with bases in a one-pot reaction sequence whereas the reaction of the isolated intermediates 5 (R3=aromatic-,
heteroaromatic, or cycloalkyl) with acid chlorides yielded the novel indole derivatives 6.The products were purified by reversed
phase column chromatography and obtained in multi-milligram quantities in acceptable yields. # 2001 Elsevier Science Ltd.All
rights reserved.
Combinatorial organic synthesis1 is still of great interest
because it promises to accelerate the drug discovery
process as well as speed up the development of new
catalysts2 or determine reaction protocols faster via
automated techniques.3 In the pharmaceutical industry
the focus mainly lies on the synthesis of compound
libraries either for general screening or for project rela-
ted tasks.The synthesis of unbiased compound libraries
offers the advantage of rapidly producing a considerable
number of potentially active compounds resulting in
diverse structures.The synthesis of smaller compound
libraries supports the more rapid evaluation of hit
structures, thus enabling medicinal chemistry projects to
more rapidly identify potentially interesting drug candi-
dates to be further pursued.
that N-unsubstituted aminobenzonitriles themselves did
not react with a-bromoketones directly under various
conditions to yield the desired free indoles 4.5c
However, the free indole derivatives can be liberated
upon treatment of the crude DMF solutions of 3 with
6 N NaOH at room temperature in a one-pot reaction
sequence.6 Following this protocol the cleavage of the
benzoyl group was easily achieved (Scheme 1).
Indoles are known to play an important role in biology
and are a frequently found motif in natural products.4
The pharmacophoric potential is enormous and there-
fore the search for novel indole derivatives is a challen-
ging and ongoing process.The work presented shows
the interest in development and synthesis of novel sub-
stituted indole derivatives.5a
Amino-benzonitriles 1 can easily be converted to ben-
zoylamino-benzonitriles5b 2 which react cleanly with
various a-bromoketones in DMF with Cs2CO3 as base
to afford the corresponding indole derivatives 3.The
benzoyl-substituent in 2 can be regarded as an activat-
ing group for the nitrogen since it was previously found
*Tel.: +41-61-688-6227; fax: +41-61-688-6459; e-mail: matthias.
nettekoven@roche.com
Scheme 1.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd.All rights reserved.
PII: S0960-894X(01)00393-6

2170
M. Nettekoven / Bioorg. Med. Chem. Lett. 11 (2001) 2169–2171
6 Alkyl- and halogen substituted 1-benzoylamino-ben-
zonitriles 25d were reacted with 28 alkyl-, cycloalkyl-,
aryl- and heteroaryl a-bromoketones, in a combinator-
ial fashion, to yield the indole derivatives 3 which were
not isolated.Subsequently, the reaction mixtures were
treated with 6 N NaOH in a one-pot process at room
temperature for 12 h.This protocol allowed for an easy
and straightforward access to indole derivatives 4.The
combination of this widely amenable reaction sequence
with the power of parallel workup and purification of
the crude DMF solutions with reversed phase HPLC
yielded 89 indoles 4 with acceptable yields (2–77%;
average: 25%).7 For this reaction sequence, a wide vari-
ety of electron withdrawing and also electron donating
substituents on either the a-bromoketone or the benzoyl-
amidobenzonitriles 2 were tolerated.Representative
isolated indoles are displayed in Scheme 2.
Out of the numerous possible combinations, 200 reac-
tions of 159 different indoles 5 with 20 acid chlorides
were performed in a combinatorial fashion.The parallel
workup combined with the preparative reversed-phase
HPLC purification yielded 138 previously non-described
indole derivatives in multi-milligram quantities with
purities generally in excess of 90%.It was found that
the reaction worked unsatisfactorily in cases where the
indoles 5 were substituted in the 4-position and the acid
chlorides used were ortho-substituted benzoyl-chlorides.
The structures of the purified indoles 6 were corrobo-
rated by MS and the purity checked by HPLC at
230 nm.Representative examples are displayed in
Scheme 4.
Scheme 2. Representative examples of isolated indoles 3.
Alternatively, the intermediates 55b can, after isolation,
be further derivatised to add a fourth vector of diver-
sity.The reaction of the indoles 5 (R3=phenyl, sub-
stituted-phenyl, cycloalkyl) with various acid chlorides
in DCM and pyridine as base yielded in acceptable
yields the substituted indole derivatives 6 (Scheme 3).8
Scheme 4. Representative examples of isolated indoles 6.
With the members of the presented indole derivative
libraries 4 and 6, biological examination will be under-
taken to identify novel lead structures to be further
evaluated in depth in medicinal chemistry projects.
Scheme 3.

M. Nettekoven / Bioorg. Med. Chem. Lett. 11 (2001) 2169–2171
2171
In conclusion, the synthesis of two previously non-
described indole derivative libraries in a combinatorial
fashion was demonstrated.The synthesis of the inter-
mediates 3 and 5, respectively, was performed as earlier
described in DMF with Cs2CO3 as base.5b
A.H. Comb. Chem. 2000, 433. (c) Gennari, F.; Seneci, P.;
Miertus, S. Catal. Rev.-Sci. Eng. 2000, 42, 385.
3.(a) Hird, N.W. Drug Discovery Today 1999, 4, 265.(b)
Thiericke, R.; Grabley, S.; Geschwill, K. Drug Discovery Nat.
1999, 56.(c) Antonenko, V.V. Comb. Chem. Technol. 1999, 205.
4.Sundberg, R. Indoles (Best Synthetic Methods); Academic:
San Diego, 1996.
The resulting benzoyl-substituted indole derivatives 3
were subjected in a one-pot procedure to strongly basic
conditions that effected the cleavage of the benzoyl
group to liberate 89 indole derivatives 4 which were not
accessible from the reaction of amino-benzonitriles with
a-bromoketones directly.The purities of the final com-
pounds were generally higher then 90% after reversed-
phase HPLC purification.
5. (a) Viti, G.; Gianotto, D.; Nannicini, R.; Ricci, R.; Pes-
tellini, V. J. Heterocycl. Chem. 1991, 28, 379.(b) The synthesis
of 3-amino-2-acyl-indole derivatives as found earlier serves as
a basis for the investigations described.Nettekoven, M. Tet-
rahedron Lett. 2000, 41, 8251. (c) Radl, S.; Hezky, P.; Urban-
kova, J.; Vachal, P.; Krejci, I. Collect. Czech. Chem. Commun.
2000, 65, 280.(d) General procedure for the synthesis of
benzoyl-amidobenzonitriles 2: A mixture of 10 mmol amino-
benzonitrile 1 in 15 mL DCM and 15 mmol pyridine was trea-
ted with 11 mmol benzoyl chloride and reacted at room
temperature overnight (12 h).In the cases where the product is
soluble in DCM, 15 mL water was added and the layers were
separated by filtration through hydrophobic filter devices
(Macherey & Nagel) and the volatiles removed in vacuo.In
the cases where the product was not soluble in DCM, 15 mL
hexane was added and the precipitate collected, washed with
hexane and dried in vacuo.MS and HPLC at 230 nm corro-
borated the structures and purities.
6.General procedure for the synthesis of 4: To a solution of
0.3 mmol benzoyl-amidobenzonitrile 2 in 0.5 mL DMF was
added 0.45 mmol a-bromoketones in 0.5 mL DMF, approxi-
mately 150 mg (0.5 mmol) Cs2CO3 and stirred at rt overnight
(12 h).05. mL (3 mmol) 6 N NaOH was added and the mixture
was stirred at rt overnight (12 h).Filtration yielded a DMF
solution, which was directly applied to reversed-phase column
chromatography (Dynamax pumps and detector in combina-
tion with a Gilson 215 liquid handler on a YMC ODS-A col-
umn (50Â20 mm)) eluting with a gradient of acetonitrile and
water (20–95%).Evaporation of the elution solvents yielded
the desired indoles 4.
The isolated intermediates 55b served as the starting
point for a second previously non-described indole
derivative library.Two hundred reactions of indole
derivatives 5 with acid chlorides yielded 159 new indoles
6 which, after reversed-phase HPLC, were isolated with
purities in excess of 90%.
Based on these results, chemistry efforts towards novel
substituted indole derivatives are currently under
investigation.
Acknowledgements
Thanks to B.Mathys and C.Mu ller for technical assis-
tance and Drs.A.Alanine, A.Chucholowski and A.
Thomas for helpful discussions.
7.The structures of the purified indoles 4 were corroborated
by MS and the purity checked by HPLC at 230 nm.
8.General procedure for the synthesis of 6: To a solution of 1
equiv indole 5 (amount varies between 0.05 and 0.2 mmol) in
DCM was added 1 equiv pyridine and 1.2 equiv acid chloride,
and the mixture was stirred at rt overnight (12 h).The residues
were taken up in DMF and the raw DMF solutions were
subjected to reversed-phase column chromatography [Dyna-
max pumps and detector in combination with a Gilson 215
liquid handler on a YMC ODS-A column (50Â20 mm)] elut-
ing with a gradient of acetonitrile and water (20–95%).Eva-
poration of the elution solvents yielded the desired indoles 6.
References and Notes
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