A novel palladium catalyst for the amination of electron-rich indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.02.082

The palladium-catalyzed amination of a 3-silyloxy-substituted bromo-indole with primary and secondary amines is described for the first time. In the presence of the novel catalyst system of Pd(OAc)₂/N-phenyl-2-(di-1-adamantylphosphino)pyrrole p

Full text of DOI:10.1016/j.tetlet.2007.02.082

Tetrahedron Letters 48 (2007) 2897–2900
A novel palladium catalyst for the amination of electron-rich
indole derivatives
Nicolle Schwarz, Annegret Tillack, Karolin Alex, Iliyas Ali Sayyed,
Ralf Jackstell and Matthias Beller*
Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 23 January 2007; revised 15 February 2007; accepted 16 February 2007
Available online 22 February 2007
Abstract—The palladium-catalyzed amination of a 3-silyloxy-substituted bromo-indole with primary and secondary amines is
described for the first time. In the presence of the novel catalyst system of Pd(OAc)2/N-phenyl-2-(di-1-adamantylphosphino)pyrrole
potentially bioactive amino-functionalized indole derivatives are obtained in a general manner in high yield.
Ó 2007 Elsevier Ltd. All rights reserved.
The indole ring system constitutes one of the most
important heterocycles in nature and substituted indoles
have been referred to as ‘privileged pharmaceutical
structures’ since they are capable of binding to many
biological receptors with high affinity.1 Due to their
importance as building blocks for pharmaceuticals and
natural products the preparation of new indole deriva-
tives is an actual topic in organic chemistry. Owing to
the great structural diversity of biologically active in-
doles, there is also a continuing interest in the develop-
ment of improved methods for the synthesis of indoles.2
O
Cl
N
N
NH2
NH
HO
Cl
Cl
N
N
N
H
2
H
N
N
N
HN
S
F
O2
N
H
1
3
4
Among the numerous known indoles, especially amino-
functionalized derivatives represent key structures for
various biologically active compounds (Scheme 1). In
particular tryptamine derivatives are involved in several
biological processes, for example, melatonin in the con-
trol of the circadian rhythm and serotonin 2 in neuro-
logical processes. Thus, amino-functionalized indoles
are used for the medical treatment of diverse diseases
like migraine (Sumatriptan 3), schizophrenia (Sertindole
1), and many others. Due to the pharmaceutical rele-
vance of amino-substituted tryptamine and its ana-
logues, numerous syntheses have been reported and
the development of new methods is still a subject of
intensive research.3
Scheme 1. Examples of amino-substituted indole derivatives.
Based on our long standing interest in indole syntheses4
as well as in palladium-catalyzed coupling reactions,5
we became interested in the preparation of new func-
tionalized indole derivatives via Buchwald–Hartwig
aminations.
Clearly, palladium-catalyzed C–N-bond formation
(Buchwald–Hartwig reaction) of aryl halides with
amines has been extensively studied in the past few
years.6 In general, these processes have excellent func-
tional group tolerance and wide substrate scope, which
make them ideally suited for applications in the pharma-
ceutical area. However, there is relatively little known
on the coupling reactions of electron-rich indoles.
Keywords: Amination; C–N coupling; Palladium; Indoles.
*
Corresponding author. Tel.: +49 0 381 1281113; fax: +49 0 381
12815000; e-mail addresses: matthias.beller@catalysis.de; matthias.
beller@ifok-rostock.de
Clearly, the palladium-catalyzed activation is more diffi-
cult here compared to electron-poor substrates.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.082

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N. Schwarz et al. / Tetrahedron Letters 48 (2007) 2897–2900
Table 1. Reaction of 3-tert-butyldimethylsilyloxy-5-bromo-indole
with benzylamine in the presence of different ligands and basesa
Table 1 (continued)
Entry Ligand
Base
Yieldb (%)
N
N
H2N
OTBDMS
CH3
OTBDMS
CH3
P
Br
HN
+
N
N
12
LiHMDS
40
CH3
CH3
5
5a
13
Yieldb (%)
Cy
P
Entry
Ligand
Base
Cy
1
2
3
4
5
LiHMDSc
K3PO4
Cs2CO3
NaOtBu
Without
85
5
70
40
0
P
13
LiHMDS
85
N
6
14
a Reaction conditions: 3-tert-butyldimethylsilyloxy-5-bromo-2-methyl-
indole (0.56 mmol), benzylamine (0.67 mmol), solvent: toluene
(3 mL), 1 mol % Pd(OAc)2, 2 mol % ligand, base (0.73 mmol), 24 h,
100 °C.
P
b Isolated yield based on 3-tert-butyldimethylsilyloxy-5-bromo-2-
methylindole.
6
LiHMDS
<10
c 1 M solution of lithium-bis(trimethylsilyl)amide in toluene.
7
In the present Letter we describe for the first time the
palladium-catalyzed amination of 3-silyloxy-5-bromo-
indole with primary and secondary amines in the pres-
ence of Pd(OAc)2 and N-phenyl-2-(di-1-adamant-
ylphosphino)-pyrrole as ligand to give new indole
derivatives.
P
7
LiHMDS
<10
8
In exploratory experiments, we studied the effect of base
and ligands on the reaction of 3-tert-butyldimethylsilyl-
oxy-5-bromo-2-methylindole 5 and benzylamine to the
corresponding indole 5a. As shown in Table 1 the best
yield of indole 5a (85%) is achieved with 1.3 equiv of
1 M solution of LiHMDS in toluene. Further variation
of the base revealed only lower yields (5–70%) of the
corresponding indole (Table 1, entries 2–5). As expected
the reaction without any base was not successful (Table
1, entry 5). Next, we were interested in the influence of
different sterically demanding ligands on our model
reaction. All reactions were performed at 100 °C for
24 h in toluene in the presence of 1 mol % Pd(OAc)2
and 1.3 equiv of LiHMDS (Table 1, entries 6–13). In
general, sterically hindered biaryl-type ligands gave the
best yields. Thus, using ligands 11, 12, and 14 gave
75–95% yield of the corresponding indole. Employing
di-1-adamantyl-n-butylphosphine 7 or tricyclohexyl-
phosphine 8 the isolated yield decreased to <10%. Here,
we observed mainly reductive dehalogenation via b-
hydride-elimination as competing reaction pathway.
PCy3
NMe2
8
LiHMDS
51
9
P
N
9
LiHMDS
25
10
P
N
10
LiHMDS
75
11
After testing different ligands and bases, we were inter-
ested in the scope and limitations of the catalyst system
for different amines. For this purpose we used the silyl-
protected 3-oxy-5-bromo-2-methylindole 5 and diverse
primary and secondary amines.
P
N
11
LiHMDS
95
Si
Although ligands 12 and 14 gave comparable or even
improved results in the model coupling reaction,
nevertheless, we used 6 for the further synthesis of
12

N. Schwarz et al. / Tetrahedron Letters 48 (2007) 2897–2900
2899
Table 2. Reaction of different amines with the silyl-protected 3-oxy-5-bromo-2-methylindolea
R1
OTBDMS
CH3
N
CH3
OTBDMS
Pd(OAc)2
N
Br
R2
R1
CH3
CH3
HN
R2
+
N
ligand 6
5
5a-j
Entry
1
Amine
Product
Yieldb (%)
5a
85
OTBDMS
CH3
CH3
NH2
HN
N
OTBDMS
CH3
N
CH3
HN
2
3
5b
5c
40
85
NH2
OTBDMS
CH3
HN
NH2
N
CH3
OTBDMS
CH3
N
CH3
H
N
4
5
5d
5e
60
91
NH2
OTBDMS
H
N
F
CH3
NH2
N
F
CH3
N
OTBDMS
CH3
N
6
7
5f
50
75
HN
HN
N
N
CH3
OTBDMS
CH3
CH3
N
5g8
N
O
OTBDMS
CH3
N
8
5h
55
HN
O
N
CH3
OTBDMS
CH3
N
CH3
N
9
5i
5j
73
91
NH
OTBDMS
CH3
H
N
10
NH2
N
CH3
a Reaction conditions: 3-tert-butyldimethylsilyloxy-5-bromo-2-methylindole (0.56 mmol), amine (0.67 mmol), solvent: toluene (3 mL), 1 mol %
Pd(OAc)2, 2 mol % ligand 6, 1 M solution of lithium-bis(trimethylsilyl)amide in toluene (0.73 mmol), 24 h, 100 °C.
b Isolated yield based on 3-tert-butyldimethylsilyloxy-5-bromo-2-methylindole.

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N. Schwarz et al. / Tetrahedron Letters 48 (2007) 2897–2900
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amino-functionalized indoles, because of the easier
availability of this in-house developed ligand.7 As shown
in Table 2 the corresponding indole products are
obtained in 40–91% yield. The novel catalyst system
works well with different primary and secondary amines
which are all commercially available. With respect to the
yield there is no clear trend on the electronic or steric
factors of the amine.
In conclusion, we presented the first palladium-cata-
lyzed amination of silyl-protected 3-oxyhaloindoles, a
novel class of electron-rich indoles. Different amines re-
acted smoothly in the presence of Pd(OAc)2, N-phenyl-
2-(diadamantyl-phosphino)pyrrole 6 to give potentially
bioactive amino-functionalized indoles.
Acknowledgments
This work has been funded by the State of Mecklen-
burg-Western Pomerania, the BMBF (Bundesministe-
rium fur Bildung und Forschung), the Deutsche
¨
6. (a) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R.
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mar, M. V.; Verkade, J. G. Angew. Chem. 2005, 117, 5040–
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7. (a) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.;
Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.;
Beller, M. Tetrahedron Lett. 2005, 46, 3237–3240; (b) Junge,
H.; Beller, M. Tetrahedron Lett. 2005, 46, 1031–1034; (c)
Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier,
T.; Monsees, A.; Dingerdissen, U.; Beller, M. Chem. Eur. J.
2004, 10, 2983–2990.
8. Preparative procedure for the Pd-catalyzed amination
reaction (5g): In an Ace-pressure tube under an argon
atmosphere 3-tert-butyldimethylsilyloxy-5-bromo-2-methyl-
indole (0.56 mmol), Pd(OAc)2 (1 mol %) and ligand 6
(2 mol %) were dissolved in toluene (3 mL). To this solution
LiHMDS (0.73 mmol) and piperidine (0.67 mmol) were
added. The pressure tube was fitted with a Teflon cap and
heated at 100 °C for 24 h. After removal of the solvent in
vacuo, the desired indole product was isolated by column
chromatography in hexane/ethyl acetate. Isolated
yield: 150 mg (75%), (mp: 85–88 °C). 1H NMR (300.13,
CDCl3) d = À0.17 (s, 6H, H-12a,b); 1.09 (s, 9H, H-13a,b,c);
1.5–1.9 (m, 7H, H-16a,b; H-17); 2.28 (s, 3H, H-11); 3.08 (t,
4H, 3J15,16 = 5.4 Hz, H-15a,b); 3.57 (s, 3H, H-10); 6.92 (dd,
Forschungsgemeinschaft (Leibniz-price, Graduierten-
kolleg 1213), and the Fonds der Chemischen Industrie
´
(FCI). We thank Dr. J. Holenz and Dr. J. L. Dıaz
´
Fernandez (Esteve, Spain) for general discussions.
We also thank Dr. W. Baumann, Dr. D. Michalik,
Dr. C. Fischer, S. Buchholz, and A. Lehmann for their
excellent technical and analytical support.
References and notes
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1H, 4J4,6 = 2.2 Hz, 3J6,7 = 8.8 Hz, H-6); 7.01 (d, 1H, 4J4,6
=
2.2 Hz, H-4); 7.11 (d, 1H, J6,7 = 8.8 Hz, H-7) ppm. 13C
NMR (CDCl3, 75.5 MHz,) d = À3.9 (C-12); 9.4 (C-11);
18.4 (C-14); 24.6 (C-17); 26.1 (C-13); 26.6 (C-16a,b); 29.7
(C-10); 53.8 (C-15a,b); 105.1 (C-4); 108.9 (C-6); 115.2 (C-7);
121.8, 122.9, 129.8, 130.4, 146.1 (C-9, C-8, C-5, C-3, C-2)
ppm. MS (EI, 70 eV) m/z (rel. intensity): 358 (100) [M+],
343 (3), 301 (6), 228 (12). HRMS calcd for C21H34N2OSi:
358.24349. Found: 358.242665.
3