Communications
DOI: 10.1002/anie.200903035
À
C H Activation
3
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Palladium-Catalyzed Amidation of Unactivated C(sp ) H Bonds: from
Anilines to Indolines**
Julia J. Neumann, Souvik Rakshit, Thomas Drꢀge, and Frank Glorius*
À
Amines, amides, and nitrogen-containing heterocycles are
ubiquitous motifs[1] of biologically active compounds, such as
alkaloids. Consequently, the formation of carbon–nitrogen
bonds is of utmost importance, and many classical methods
exist, such as reductive amination. Furthermore, powerful
metal-catalyzed cross-coupling reactions, for example the
palladium-catalyzed amination of aryl halides (Buchwald–
Hartwig reaction)[2] or the copper-catalyzed amidation of aryl
halides,[3] have recently been added to the armory of the
synthetic chemist. However, these methods rely on the
presence and elaboration of functional groups in each of the
two reaction partners, which is a common feature in organic
synthesis.
activation/C N bond formation cascade without the involve-
ment of nitrenes. Herein we report on the first realization of
this strategy in a palladium-catalyzed synthesis of valuable
indoline[12] products from many differently substituted ani-
lides.
Our study commenced with the oxidative cyclization of
readily available N-(2-tert-butylphenyl)acetamide (1a) to the
corresponding indoline 2a using AgOAc as oxidant and
K2CO3 as base. No product was obtained using polar solvents,
such as DMSO (Table 1, entry 1), DMF, or MeCN.[13] In
Table 1: Optimization of the reaction parameters.[a]
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The activation and transformation of C H bonds is a
powerful exception to this requirement, and provides a more
direct route to complex products from simpler starting
materials. Many ground-breaking contributions have been
made to this field in the last few years,[4] with the activation of
Entry Oxidant (equiv) Base
Solvent
Yield[b] of 2a [%]
2
3
À
À
C(sp ) H bonds and activated C(sp ) H bonds being far
1
2
3
4
5
6
7
8
9
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
AgOAc (3.0)
Cu(OAc)2 (3.0) K2CO3 mesitylene
PhI(OAc)2 (3.0) Na2CO3 mesitylene
AgOAc (3.0)
K2CO3 DMSO
K2CO3 toluene
K2CO3 chlorobenzene
K2CO3 mesitylene
K2CO3 mesitylene+H2O[c]
1
32
41
53
8
11
<1
(48)
89 (80)
(77)
76 (73)
88 (79)
more facile and common than the activation of unactivated[5]
3
[6]
2
À
À
C(sp ) H bonds. Whereas the activation of C(sp ) H bonds
is most often triggered by an interaction between the
p electrons and the catalyst, the activation mode for unac-
3
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tivated C(sp ) H bonds is less understood. The combination
À
À
of these C H activation steps with C N bond formation is a
promising entry to nitrogen-containing compounds, and
–
mesitylene
AgOAc (3.0)
Na2CO3 mesitylene
Na2CO3 mesitylene
Na2CO3 mesitylene
Na2CO3 mesitylene
10[d] AgOAc (3.0)
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consequently, numerous C N bond formations based on
2
[7,8]
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C(sp ) H bond activations have been developed.
How-
11
AgOAc (2.1)
12[e] AgOAc (3.0)
ever, to our knowledge, the activation of an unactivated
3
[5]
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C(sp ) H bond followed by carbon–nitrogen bond forma-
[a] Reaction conditions: 1a (0.25 mmol), Pd(OAc)2 (10 mol%), oxidant
(0.75 mmol), base (0.75 mmol), solvent (3 mL), 1408C, 12 h. [b] Deter-
mined by GC-MS, with 1,3,5-tri-tert-butylbenzene as an internal standard.
Yield of isolated 2a (1 mmol scale reaction) in parentheses. [c] 6 mL of
water added. [d] 10 mmol scale. [e] Reaction performed at 1108C.
tion has only been reported using nitrenes.[9] As part of our
ongoing research into cross-coupling reactions,[10,11] we have
3
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been attempting the development of a C(sp ) H bond
[*] J. J. Neumann, S. Rakshit, T. Drꢀge, Prof. Dr. F. Glorius
Westfꢁlische Wilhelms-Universitꢁt Mꢂnster
Organisch-Chemisches Institut
contrast, the reaction proceeded to some extent in less polar
aromatic solvents (Table 1, entries 2–4), and was found to be
water-sensitive (entry 5). Variation of the oxidant showed that
AgOAc is superior to other silver(I) and copper(II) salts and
Corrensstrasse 40, 48149 Mꢂnster (Germany)
Fax: (+49)251-833-3202
E-mail: glorius@uni-muenster.de
over hypervalent iodine reagents (Table 1, entries 6,7).[13]
A
[**] Generous financial support by the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie (fellowship to J.J.N.),
and the International NRW Graduate School of Chemistry (fellow-
ship for S.R.) is gratefully acknowledged. The research of F.G. is
generously supported by the Alfried Krupp Prize for Young
University Lecturers of the Alfried Krupp von Bohlen und Halbach
Foundation. We thank N. Kuhl and M. Pawelczyk for help in the
preparation of some starting materials.
major improvement was achieved by changing the base to
Na2CO3. Under these optimized conditions, practically full
conversion (> 98%) was reached after 4 h, and the desired
product was obtained in 80% yield of isolated product
3
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(Table 1, entry 9). This activation of the C(sp ) H bond is
2
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especially remarkable, because the competing C(sp ) H bond
activation of acetanilides at the 6-position of the aromatic ring
has previously been reported.[14] A scale-up of this reaction
led to a virtually unchanged result (Table 1, entry 10).
Supporting information for this article is available on the WWW
6892
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 6892 –6895