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
1.(a) Balkenhohl, F;.von den Bussche-Hu nefeld, C.; Lansky,
A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288.(b)
Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees,
D.C. Tetrahedron 1998, 54, 15385.(c) Thompson, L.A;. Ell-
mann, J.A. Chem. Rev. 1996, 96, 555.
2. (a) Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. Curr.
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