A new facile synthesis of 3-amidoindole derivatives and their evaluation as potential GSK-3β inhibitors

Article abstract of DOI:10.1039/b920861e

3-Amidoindoles were synthesized from commercially available arylhydrazines and propargylamines over Zn-salt mediated one pot procedure in excellent regioselectivity and up to 94% yield. The Royal Society of Chemistry.

Full text of DOI:10.1039/b920861e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new facile synthesis of 3-amidoindole derivatives and their evaluation as
potential GSK-3b inhibitors†
Anahit Pews-Davtyan,a Annegret Tillack,a Anne-Caroline Schmo¨le,b Stefanie Ortinau,b Moritz J. Frech,b
Arndt Rolfs*b and Matthias Beller*a
Received 6th October 2009, Accepted 27th November 2009
First published as an Advance Article on the web 14th January 2010
DOI: 10.1039/b920861e
3-Amidoindoles were synthesized from commercially available arylhydrazines and propargylamines
over Zn-salt mediated one pot procedure in excellent regioselectivity and up to 94% yield.
The indole ring is a privileged structural motif present in a wide
variety of natural and synthetic therapeutic products.1,2 Among the
numerous known derivatives, 3-amido and 3-amino-substituted
indoles have been scarcely investigated. Few exceptions constitute
d-carbolines, quindolines, and cryptolepines, which have been
isolated from different plants (Fig. 1).3
to 3-aminoindoles is nitrosylation15 or nitration5,7,10,11,15,16 of a
respective indole followed by reduction to the amino function
and subsequent derivatizations. Few 3-aminoindoles were also
prepared via amination of indoles with azodicarboxylates17 or
hydrolysis of isonitrosoindole.18 Clearly, the known syntheses of
this class of compounds possess several drawbacks and a more
general and concise synthesis of 3-aminoindole derivatives will be
a valuable tool for the further exploration of their chemistry and
biology.
For some years we are interested in novel syntheses of biologi-
cally active indoles.19 Here, we investigated especially intermolec-
ular hydroamination reactions of alkynes with phenylhydrazines
(hydrohydrazination) towards 2,3-disubstituted indoles. The con-
cept of this domino alkyne-amination-Fischer-indole-sequence
was first developed by Bergman et al. on a stoichiometric basis20
and further improved by Odom and co-workers using titanium-
based catalysts.21,22 More recently, we showed that simple zinc
salts are able to promote the intermolecular hydroamination of
the arylhydrazines with alkynes, too. Subsequent [3.3]-sigmatropic
cyclization led to the corresponding indoles.19a,b,23,24 Advanta-
geously, this protocol is conveniently performed on air and offers
broad functional group tolerance. Based on this work, here we
describe a new general and direct synthesis of 3-amidoindoles
by zinc-promoted hydrohydrazination of N-acyl propargylamines.
Furthermore, it is shown that some of the resulting products show
Fig. 1 d-Carbolines and indoloquinoline alkaloids.
Notably, these compounds represent attractive pharmacological
targets and show antimalarial, anti-muscarinic, anti-bacterial,
anti-viral, anti-plasmoidal, and anti-hyperglycemic activities.4
Furthermore, synthetic derivatives of 3-aminoindoles are known
to be antagonists of different receptors such as CRTH2,5
V1a,6 mPGES-1,7 NMDA8 or valuable kinase inhibitors, e.g.
COX-29 and are useful for treating hyper-proliferative disorders,
diseases associated with angiogenesis,10 inflammatory diseases,
e.g. psoriasis, eczema, arthritis, neurodegenerative diseases,8 e.g.
Huntington’s and Alzheimer’s diseases, depressive disorders, and
anxiety. Besides this pharmacological potential, 3-aminoindole
derivatives have also been proposed as fungicides.11
So far, 3-aminoindoles have been prepared by multistep pro-
cesses often including protection and deprotection steps of the
indole nitrogen. In general, the heterocycle is constructed by re-
acting 2-aminobenzonitrile8,9,12 or substituted phenylhydrazines6,13
as N-nucleophiles with appropriate carbonyl-compounds (Fischer
indole synthesis). More recently, 3-aminoindoles have been also
synthesized via acid catalyzed multicomponent reaction between
imines and isocyanides.14 However, the most common approach
Table 1 Selected Zn-salts and solvents for indole synthesisa
Yield
Entry
Zn-salt
Solvent
[%]b
1
2
3
4
5
6
7
8
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
Toluene
Dioxane
DME
Heptane
Toluene
Dioxane
DME
71
53
73
61
73
55
78
56
aLeibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, D-18059, Rostock, Germany. E-mail: matthias.
beller@catalysis.de; Fax: +49 381 1281 51113; Tel: +49 381 1281 113
bAlbrecht-Kossel-Institute for Neuroregeneration, Center for Mental Health
Disease, University of Rostock, Gehlsheimerstr. 20, D-18147, Rostock,
Germany. E-mail: arndt.rolfs@med.uni-rostock.de; Fax: +49 381 494 4699;
Tel: +49 381 494 9540
Heptane
a Reaction conditions: Alkyne (1 mmol), arylhydrazine (1.5 mmol), Zn-salt
(3 mmol), solvent (3 mL), 110 ◦C, 20–22 h. b Isolated yield.
† Electronic supplementary information (ESI) available: Procedures and
characterisation data for all new compounds, scans of NMR spectra. See
DOI: 10.1039/b920861e
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Table 2 Hydrohydrazination of acylated propargylamines with different phenylhydrazines to 3-amidoindolesa
Entry
1
Arylhydrazine
Alkyne
Zn-salt
Solvent
Product
Yield [%]b
1a
1b
2a
2a
ZnBr2
ZnCl2
DME
Toluene
3
4
78
71
2
ZnCl2
ZnCl2
DME
Toluene
72
71
3
4
5
1c
1d
1e
2a
2a
2a
ZnBr2
ZnCl2
DME
DME
5
6
7
89
77
ZnCl2
ZnBr2
Toluene
DME
70
46
ZnBr2
ZnCl2
DME
DME
89
86
6
7
8
1f
2a
2a
2a
ZnCl2
ZnBr2
DME
DME
8
80
69
1g
1h
ZnBr2
ZnCl2
DME
DME
9
94
71
ZnCl2
ZnBr2
DME
DME
10
66
65
9
1i
2a
ZnCl2
ZnBr2
Toluene
DME
11
77
71
1027
1j
2a
2a
ZnBr2
ZnCl2
DME
DME
12
13
91
69
11
1k
ZnCl2
ZnBr2
DME
DME
55
53
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Table 2 (Contd.)
Entry
12
Arylhydrazine
Alkyne
Zn-salt
Solvent
Product
Yield [%]b
1a
1a
2b
2c
ZnBr2
ZnCl2
DME
DME
14
15
74
60
13c
ZnBr2
ZnCl2
DME
Toluene
67
54
14c
1k
2c
ZnBr2
ZnCl2
DME
DME
16a 52 (19d)
48 (10d)
15e
1a
2d
ZnCl2
ZnBr2
Toluene
DME
17
51
<10
a Reaction conditions: alkyne (1 mmol), arylhydrazine (1.5 mmol), Zn-salt (3 mmol), solvent (5 mL), 110 ◦C, 20–22 h. b Yield of isolated product. c Zn-salt
(5 mmol). d Yield of anti-Markovnikov product 16b. e 80 ◦C, 24 h.
promising accumulation of b-Catenin in cell assays, which makes
them potential candidates as novel GSK-3b inhibitors.
As shown in Table 2 a variety of 4-substituted phenylhydrazines
and acylated propargylamines gave the desired products in good to
excellent yield. To our delight unprotected phenylhydrazines react
well making protection/deprotection steps unnecessary (Table 2,
entries 1–10, 12, 13 and 15).
In addition to N-acetylated and N-benzoylated propargyl-
amines, N-propargylphthalimide (2c) gave the corresponding
indole also in high yield. However, in this case for full conversion
a larger excess of Lewis acid was necessary (Table 2, entries 13 and
14). Notably, reacting alkyne 2c with 1-methyl-1-phenylhydrazine
(1k) formation of anti-Markovnikov product was also observed
(Table 2, entry 14). To demonstrate the possibility to attach
pharmacologically important heterocycles onto the indol, the
sulfonylated propargylamine 2d was synthesized. Applying this
substrate domino alkyne hydroamination andin situ Fischer indole
cyclization proceeded at lower temperature and at temperatures
>100 ◦C only decomposition of the starting materials occurred.
Our previous synthetic investigations have shown that the suc-
cess of a domino sequence is strongly dependent on the selection
of the Zn-source, temperature, and solvent. Hence, we performed
some test reactions to indentify optimal reaction conditions
using N-acetylpropargylamine25 and N-phenylhydrazines. The
initial hydroamination reaction of the alkyne proceeds with high
Markovnikov selectivity (>99%) to give 2,3-disubstituted indoles
in good yield.26 Testing different Zn salts like ZnCl2, ZnBr2, ZnI2,
Zn(OTf)2, Zn(OAc)2 in several solvents (THF, DMF, DME, NMP,
toluene, heptane, acetonitrile, 1,4-dioxane) at temperature 80 to
◦
120 C proved that ZnCl2 and ZnBr2 are the best Zn-sources in
aprotic solvents at 110 ◦C. In Table 1 selected results of the reaction
of (4-bromophenyl)hydrazine (1a) and N-acetylpropargylamine
(2a) are shown. Next, the optimized reaction conditions were
used to demonstrate the scope and limitations of our protocol.
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It is important to note that all new compounds are crystalline,
stable materials which make their storage, handling, and further
transformations easy. In solution the N-acetylated 3-aminoindoles
exist as rotamers. In polar aprotic solvents, like DMSO or acetone
rotation is very fast and only minor signals of the second rotamer
in NMR were detectable.
3-aminosubstituted indoles. Some of the synthesized compounds
show significant inhibition of GSK-3b. Further studies will inves-
tigate the biological impact of the new designed 3-amidoindoles on
the canonical Wnt signalling in detail, especially their mechanism
of action towards GSK-3b inhibition.
To prove their biological activity, the newly synthesized com-
pounds were tested in a cellular assay towards the inhibition
of GSK-3b. GSK-3b is the key enzyme in the canonical Wnt
signalling. Deregulation of GSK-3b is linked to several diseases
such as bipolar disorders, Alzheimer’s disease, and diabetes,28
as well as to the differentiation of progenitor cell into cells
with neuronal phenotype. Therefore, GSK-3b is an important
current pharmacological target. Inhibition of GSK-3b, either
by activating canonical Wnt signalling or by specific GSK-3b-
inhibitors results in a disrupture of the b-catenin degradation
complex. b-Catenin is stabilized in the cytosol and translocated to
the nucleus where it binds to the TCF/LEF complex and regulates
the transcription of Wnt specific target genes.29 Several inhibitors
have been described yet, together with different mechanisms of
action. Most of them act either ATP- or Mg-competitive. The most
prominent ones are Paullones (Kenpaullone and Alsterpaullones),
Indirubines (6-bromoindirubin-3¢-oxime, aka BIO) or lithium
salts. The disadvantage of these substances is that they inhibit
other kinases as well (Indirubines and Paullones) or have high Ki-
concentrations (lithium salts). In contrast, anilinomaleimides (SB-
216763, SB-415286) show high specificity combined with low IC50-
concentrations.30 Here, the prepared 3-amidoindoles were tested
on their impact on total b-catenin accumulation using an ELISA
test specific for total b-catenin. As model system we used the
human neural progenitor cell line ReNcell VM.31 Briefly, cells
were treated for 2 h with the new synthesized compounds under
differentiation. Then, the cells were lysed and the protein was
extracted. To our delight several of the newly developed substances
showed a significant increase of b-catenin. This clearly indicates
that they are able to inhibit GSK-3b (Fig. 2). Notably, the iodo-
substituted compound 6 was even able to reach the inhibition level
of Kenpaullone, a prominent GSK-3b inhibitor.
Acknowledgements
This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF (Bundesministerium fu¨r Bildung
und Forschung), the Deutsche Forschungsgemeinschaft (Leibniz-
price; GRK 1113), and the Fonds der Chemischen Industrie
(FCI). We also thank Dr W. Baumann, Dr C. Fischer, K. Mevius,
S. Buchholz, S. Schareina, A. Lehmann, and K. Reincke for their
excellent technical and analytical support.
Notes and references
1 Selected recent examples: (a) H. Ishikawa, D. A. Colby, S. Seto, P. Va,
A. Tam, H. Kakei, T. J. Rayl, I. Hwang and D. L. Boger, J. Am. Chem.
Soc., 2009, 131, 4904; (b) H. Yu and Z. Yu, Angew. Chem., 2009, 121,
2973, (Angew. Chem., Int. Ed., 2009, 48, 2929); (c) S. Petit, Y. Duroc,
V. Larue, C. Giglione, C. Le´on, C. Soulama, A. Denis, F. Dardel, T.
Meinnel and I. Artaud, ChemMedChem, 2009, 4, 261; (d) D. E. Nichols
and C. D. Nichols, Chem. Rev., 2008, 108, 1614; (e) K. Cariou, B.
Ronan, S. Mignani, L. Fensterbank and M. Malacria, Angew. Chem.,
2007, 119, 1913, (Angew. Chem., Int. Ed., 2007, 46, 1881); (f) Y. Yin,
W. Ma, Z. Chai and G. Zhao, J. Org. Chem., 2007, 72, 5731; (g) K. G.
Liu, A. J. Robicahud, J. R. Lo, J. F. Mattes and Y. Cai, Org. Lett.,
2006, 8, 5769; (h) L. T. Kaspar and L. Ackermann, Tetrahedron, 2005,
61, 11311; (i) K. R. Campos, J. C. S. Woo, S. Lee and R. D. Tillyer,
Org. Lett., 2004, 6, 79; (j) K. B. Hong, C. W. Lee and E. K. Yum,
Tetrahedron Lett., 2004, 45, 693; (k) S. Cacchi, G. Fabrizi and L. M.
Parisi, Org. Lett., 2003, 5, 3843; (l) H. Siebeneicher, I. Bytschkov and S.
Doye, Angew. Chem., 2003, 115, 3151, (Angew. Chem., Int. Ed., 2003,
42, 3042); (m) K. Onitsuka, S. Suzuki and S. Takahashi, Tetrahedron
Lett., 2002, 43, 6197; (n) J. F. Rutherford, M. P. Rainka and S. L.
Buchwald, J. Am. Chem. Soc., 2002, 124, 15168; (o) M. Tokunaga, M.
Ota, M. Haga and Y. Wakatsuki, Tetrahedron Lett., 2001, 42, 3865;
(p) G. Verspui, G. Elbertse, F. A. Sheldon, M. A. P. J. Hacking and
R. A. Sheldon, Chem. Commun., 2000, 1363; (q) M. Beller, C. Breindl,
T. H. Riermeier, M. Eichberger and H. Trauthwein, Angew. Chem.,
1998, 110, 3571, (Angew. Chem., Int. Ed., 1998, 37, 3389).
2 For recent reviews on the synthesis of indoles, see: (a) L. Joucla and L.
Djakovitch, Adv. Synth. Catal., 2009, 351, 673; (b) K. Kru¨ger, A. Tillack
and M. Beller, Adv. Synth. Catal., 2008, 350, 2153; (c) L. Ackermann,
Synlett, 2007, 507; (d) G. R. Humphrey and J. T. Kuethe, Chem. Rev.,
2006, 106, 2875; (e) T. L. Gilchrist, J. Chem. Soc., Perkin Trans. 1, 2001,
2491; (f) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.
3 (a) O. A. Olajide, A. M. Ajayi and C. W. Wright, Phytother. Res.,
2009, 23, 1421; (b) H. Ishiyama, K. Ohshita, T. Abe, H. Nakata and J.
Kobayashi, Bioorg. Med. Chem., 2008, 16, 3825; (c) M.-J. R. P. Queiroz,
E. M. S. Castanheira, A. M. R. Pinto, I. C. F. R. Ferreira, A. Begouin
and G. Kirsch, J. Photochem. Photobiol., A, 2006, 181, 290; (d) C. W.
Wright, J. Addae-Kyereme, A. G. Breen, J. E. Brown, M. F. Cox,
S. L. Croft, Y. Go¨kc¸ek, H. Kendrick, R. M. Phillips and P. L. Pollet,
J. Med. Chem., 2001, 44, 3187; (e) S. Yu. Ryabova, L. M. Alekseeva,
E. A. Lisitza, A. S. Shashkov, V. V. Chernyshev, G. B. Tichomirova,
M. S. Goyzman and V. G. Granik, Russ. Chem. Bull., 2001, 50, 1449;
(f) K. Cimanga, T. De Bruyne, L. Pieters, M. Claeys and A. Vlietinck,
Tetrahedron Lett., 1996, 37, 1703.
Fig. 2 Total b-catenin in ReNcell VM cells after treatment with new
synthesized substances.32
4 (a) K. Go¨rlitzer, C. Kramer, H. Meyer, R. D. Walter, H. Jomaa and J.
Wiesner, Pharmazie, 2004, 59, 243; (b) E. Arzel, P. Rocca, P. Grellier,
M. Labaed, F. Frappier, F. Guritte, C. Gaspard, F. Marsais, A. Godard
and G. Quguiner, J. Med. Chem., 2001, 44, 949.
5 N. C. Ray, G. Hynd, R. Arienzo, H. Finch, (Argenta Discovery Ltd.),
WO 2007045867, 2007.
6 C. Bissantz, C. Grundschober, R. Masciadri, H. Ratni, M. Rogers-
Evans, P. Schnider, (F. Hoffmann, – La Roche AG), WO 2008068184,
2008.
In conclusion, we have developed an effective, general, and one-
step approach for the Zn-mediated synthesis of 3-amidoindoles
from commercially available hydrazines and terminal alkynes.
These are the first examples of a one-pot synthesis of 3-amido-
substituted indoles without the necessity for indole protection.
Advantageously, broad functional group tolerance is observed and
the resulting products are highly stable compared to other known
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7 K. Olofsson, E. Suna, B. Pelcman, V. Ozola, M. Katkevics, I. Kalvins,
(Biolipox AB), WO 2005005415, 2005.
8 F. G. Salituro, B. M. Baron, (Merrell Dow Pharmaceuticals Inc.), EP
0483881, 1992.
9 (a) A. Kumar, S. Sharma, A. K. Bajaj, S. Sharma, H. Panwar, T. Singh
and V. K. Srivastava, Bioorg. Med. Chem., 2003, 11, 5293; (b) R. W.
Stevens, K. Nakao, K. Kawamura, (Pfitzr Pharmaceuticals Inc.), WO
9905104, 1999.
10 G. H. Ladouceur, B. Bear, C. Bi, D. R. Brittelli, M. J. Burke, G. Chen,
J. Cook, J. Dumas, R. Sibley, M. R. Turner, (Bayer Pharmaceuticals
Corporation), WO 2004043950, 2004.
11 E. Yasuhiro, M. Kan, E. Yoshinori, K. Tomozo, S. Kazumi, Y. Kunio,
(Otsuka Kagaku Kabushiki Kaisha), WO 9706141, 1997.
12 (a) C. M. Seong, C. M. Park, J. Choi and N. S. Park, Tetrahedron
Lett., 2009, 50, 1029; (b) R. Romagnoli, P. G. Baraldi, T. Sarkar,
M. D. Carrion, C. L. Cara, O. Cruz-Lopez, D. Preti, M. A. Tabrizi,
M. Tolomeo, S. Grimaudo, A. Di Cristina, N. Zonta, J. Balzarini, A.
Brancale, H.-P. Hsieh and R. Hamel, J. Med. Chem., 2008, 51, 1464;
(c) P. C. Unangst, J. Heterocycl. Chem., 1983, 20, 495.
Doye, Synthesis, 2005, 7, 1200; (i) A. Heutling, F. Pohlki, I. Bytschkov
and S. Doye, Angew. Chem., 2005, 117, 3011, (Angew. Chem., Int. Ed.,
2005, 44, 2951); (j) N. Hazari and P. Mountford, Acc. Chem. Res., 2005,
38, 839; (k) H. Wang, H.-S. Chan and Z. Xie, Organometallics, 2005, 24,
3772; (l) Review: A. L. Odom, Dalton Trans., 2005, 225; (m) Review: S.
Doye, Synlett, 2004, 1653; (n) C. Lorber, R. Choukroun and L. Vendier,
Organometallics, 2004, 23, 1845; (o) L. Ackermann, Organometallics,
2003, 22, 4367; (p) L. Ackermann, R. G. Bergman and R. N. Loy,
J. Am. Chem. Soc., 2003, 125, 11956.
23 For intramolecular Zn- and Cu-catalyzed hydroaminations of alkynes
see: (a) S. R. Chemler, Org. Biomol. Chem., 2009, 7, 3009; (b) K.
Okuma, J.-I. Seto, K.-I. Sakaguchi, S. Ozaki, N. Nagahora and K.
Shioji, Tetrahedron Lett., 2009, 50, 2943; (c) L. Ackermann, S. Barfu¨ßer
and H. K. Potukuchi, Adv. Synth. Catal., 2009, 351, 1064; (d) N.
Meyer, K. Lo¨hnwitz, A. Zulys, P. W. Roesky, M. Dochnahl and S.
Blechert, Organometallics, 2006, 25, 3730; (e) A. Zulys, M. Dochnahl,
D. Hollmann, K. Lo¨hnwitz, J.-S. Herrmann, P. W. Roesky and S.
Blechert, Angew. Chem., 2005, 117, 7972, (Angew. Chem., Int. Ed.,
2005, 44, 7794).
13 N. M. Przheval’skii, N. S. Skvortsova and I. V. Magadov, Khim.
Geterotsikl. Soed., 2004, 11, 1662.
14 J. S. Schneekloth, Jr., J. Kim and E. J. Sorensen, Tetrahedron, 2009, 65,
3096.
15 R. H. Bahekar, M. R. Jain, A. Goel, D. N. Patel, V. M. Prajapati, A. A.
Gupta, P. A. Jadav and P. R. Patel, Bioorg. Med. Chem., 2007, 15, 3248.
16 (a) S. Roy, S. Roy and G. W. Gribble, Tetrahedron Lett., 2008, 49, 1531;
(b) S. Roy and G. W. Gribble, Heterocycles, 2006, 70, 51.
17 H. Mitchell and Y. Leblanc, J. Org. Chem., 1994, 59, 682.
18 (a) A. V. Yarosh, V. S. Velezheva, T. A. Kozik and N. N. Suvorov, Khim.
Geterotsikl. Soed., 1977, 4, 481; (b) N. N. Suvorov, V. S. Velezheva, A. V.
Yarosh, Yu. V. Erofeev and T. A. Kozik, Khim. Geterotsikl. Soed., 1975,
8, 1099.
19 (a) K. Alex, A. Tillack, N. Schwarz and M. Beller, Angew. Chem., 2008,
120, 2337, (Angew. Chem., Int. Ed., 2008, 47, 2304); (b) N. Schwarz,
A. Pews-Davtyan, D. Michalik, A. Tillack, K. Kru¨ger, A. Torrens,
J. L. Diaz and M. Beller, Eur. J. Org. Chem., 2008, 5425; (c) K. Alex,
N. Schwarz, V. Khedkar, I. A. Sayyed, A. Tillack, D. Michalik, J.
Holenz, J. L. Diaz and M. Beller, Org. Biomol. Chem., 2008, 6, 1802;
(d) N. Schwarz, K. Alex, I. A. Sayyed, V. Khedkar, A. Tillack and M.
Beller, Synlett, 2007, 7, 1091; (e) I. A. Sayyed, K. Alex, A. Tillack, N.
Schwarz, D. Michalik and M. Beller, Eur. J. Org. Chem., 2007, 4525;
(f) V. Khedkar, A. Tillack, M. Michalik and M. Beller, Tetrahedron,
2005, 61, 7622; (g) V. Khedkar, A. Tillack, M. Michalik and M. Beller,
Tetrahedron Lett., 2004, 45, 3123; (h) A. Tillack, H. Jiao, I. G. Castro,
C. G. Hartung and M. Beller, Chem.–Eur. J., 2004, 10, 2409.
20 P. T. Walsh, M. J. Carney and R. G. Bergman, J. Am. Chem. Soc., 1991,
113, 6343.
21 C. Cao, Y. Shi and A. L. Odom, Org. Lett., 2002, 4, 2853.
22 Selected recent titanium-catalyzed hydroaminations of alkynes: (a) Re-
view: T. E. Mu¨ller, K. C. Hultzsch, M. Yus, F. Foubelo and M.
Tada, Chem. Rev., 2008, 108, 3795; (b) Review: R. Severin and S.
Doye, Chem. Soc. Rev., 2007, 36, 1407; (c) Microreview: A. V. Lee
and L. L. Schafer, Eur. J. Inorg. Chem., 2007, 2245; (d) K. Takaki, S.
Koizumi, Y. Yamamoto and K. Komeyama, Tetrahedron Lett., 2006,
47, 7335; (e) A. V. Lee and L. L. Schafer, Organometallics, 2006, 25,
5249; (f) M. L. Buil, A. Esteruelas, A. M. Lopez and A. C. Mateo,
Organometallics, 2006, 25, 4079; (g) K. Marcsekova, B. Wegener and S.
Doye, Eur. J. Org. Chem., 2005, 4843; (h) A. Heutling, R. Severin and S.
24 For intermolecular heterogeneous Zn-catalyzed hydroaminations of
alkynes see: (a) G. V. Shanbhag, S. M. Kumbar, T. Joseph and S. B.
Halligudi, Tetrahedron Lett., 2006, 47, 141; (b) G. V. Shanbhag and S. B.
Halligudi, J. Mol. Catal. A: Chem., 2004, 222, 223; (c) S. Breitenlechner,
M. Fleck, T. E. Mu¨ller and A. Suppan, J. Mol. Catal. A: Chem., 2004,
214, 175; (d) J. Bodis, T. E. Mu¨ller and J. A. Lercher, Green Chem.,
2003, 5, 227.
25 (a) X. Xu, M. Weitzberg, R. F. Keyes, Q. Li, R. Wang, X. Wang, X.
Zhang, E. U. Frevert, H. S. Camp, B. A. Beutel, H. L. Sham and Y. G.
Gu, Bioorg. Med. Chem. Lett., 2007, 17, 1803; (b) A. S. K. Hashmi,
J. P. Weyrauch, W. Frey and J. W. Bats, Org. Lett., 2004, 6, 4391; (c) R.
Nomura, J. Tabei and T. Masuda, Macromolecules, 2002, 35, 2955.
26 For a recent review on Markovnikov and anti-Markovnikov function-
alization of olefins and alkynes, see: J. Seayad, A. Tillack, H. Jiao and
M. Beller, Angew. Chem., 2004, 116, 3448, (Angew. Chem., Int. Ed.,
2004, 43, 3368).
27 Compound 12 was synthesized in two step procedure in 68% total yield
starting from 2-methylindole, ref. 17.
28 (a) T. D. Gould, Expert Opin. Ther. Targets, 2006, 10, 377; (b) J. Ryder,
Y. S u a n d B. N i , Cell. Signalling, 2004, 16, 187; (c) P. Cohen and M.
Goedert, Nat. Rev. Drug Discov., 2004, 3, 479.
29 C. Y. Logan and R. Nusse, Annu. Rev. Cell Dev. Biol., 2004, 20, 781.
30 (a) J. E. Forde and T. C. Dale, Cell. Mol. Life Sci., 2007, 64, 1930; (b) L.
Meijer, M. Flajolet and P. Greengard, Trends Pharmacol. Sci., 2004,
25, 471.
31 (a) P. J. Morgan, S. Ortinau, J. Frahm, N. Kru¨ger, A. Rolfs and M. J.
Frech, NeuroReport, 2009, 20, 1225; (b) R. Donato, E. A. Miljan, S. J.
Hines, S. Aouabdi, K. Pollock, S. Patel, F. A. Edwards and J. D. Sinden,
BMC Neurosci., 2007, 8, 36; (c) R. Hoffrogge, S. Mikkat, C. Scharf, S.
Beyer, H. Christoph, J. Pahnke, E. Mix, M. Berth, A. Uhrmacher, I. Z.
Zubrzycki, E. A. Miljan, U. Volker and A. Rolfs, Proteomics, 2006, 6,
1833.
32 Cells were cultured for 2h under differentiation conditions in the
presence of known GSK-3b inhibitors and derivatives, based on SB-
216763. Concentrations were 1 mM for Kenpaullone (KP) and 3 mM
for SB-216763 (SB21) and derivatives. Data were normalized to DMSO
control and represent mean SEM (N=4-8, each done in triplicates).
Values were significantly different between drug treated and DMSO
treated control cells at *p < 0.05 or **p < 0.01).
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