Palladium-catalyzed tandem alkenyl and aryl C-N bond formation: A cascade N-annulation route to 1-functionalized indoles

Article abstract of DOI:10.1002/anie.200461598

(Chemical Equation Presented) A single tandem operation allows rapid access to a variety of substituted N-functionalized indoles. The nitrogen atom of the indole nucleus is incorporated through Pd-catalyzed aryl and alkenyl C-N bond-forming reactions (see scheme; dba = dibenzylideneacetone). Amine, aniline, amide, carbamate, and sulfonamide functional groups can be introduced efficiently.

Full text of DOI:10.1002/anie.200461598

Angewandte
Chemie
Nitrogen Heterocycles
Palladium-Catalyzed Tandem Alkenyl and Aryl
À
C N Bond Formation: A Cascade N-Annulation
Route to 1-Functionalized Indoles**
Michael C. Willis,* Gareth N. Brace, and Ian P. Holmes
Indoles are preeminent amongst the heterocyclic motifs
found in both designed medicinal agents and in natural
products, and accordingly there exists a large and varied
selection of methods for their preparation.[1] The majority of
syntheses incorporate the key nitrogen atom of the indole
nucleus early in the synthetic route. This can be problematic if
systematic variation of the N-substituent is required without
recourse to functionalization of the relatively non-nucleo-
À
philic indole N H group. Herein we describe a tandem
palladium-catalyzed process that allows installation of a
diverse range of functionalized N units in a cascade indole-
forming event that combines the introduction of the nitrogen
atom with cyclization.
Palladium catalysis has had a major impact on indole
synthesis;[2] arguably, the most important of the many
reported methods are those based on Pd-catalyzed coupling
of o-haloanilines with unsaturated carbon units.[3] Syntheses
À À
based on intra- and intermolecular Pd-catalyzed aryl C N
bond formation,[4] the preparation of intermediates used in
Fischer indole syntheses,[5] together with the use of Pd
catalysis to functionalize intact indole rings[6] have all been
the subjects of recent interest. To effect the desired cascade
process, we focused on the introduction of functionalized
nitrogen derivatives to an acyclic carbon framework 1 under
À
À
the action of Pd catalysis; tandem alkenyl C N and aryl C N
formation would then provide the indole structure
À
(Scheme 1). Palladium-catalyzed aryl C N bond formation
Scheme 1. A cascade N-annulation route to indoles.
[*] Dr. M. C. Willis, G. N. Brace
Department of Chemistry, University of Bath
Bath, BA27AY (UK)
Fax: (+44)1225-386231
E-mail: m.c.willis@bath.ac.uk
I. P. Holmes
Discovery Research, GlaxoSmithKline
Medicines Research Centre, Gunnels Wood Road
Stevenage, Hertfordshire, SG12NY (UK)
[**] This work was supported by the EPSRC and GlaxoSmithKline. We
thank Miss Dawn Taylor for helpful discussions. The EPSRC Mass
Spectrometry Service at the University of Wales, Swansea, is also
thanked for their assistance.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 403 –406
DOI: 10.1002/anie.200461598
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
403

Communications
Table 1: Synthesis of N-substituted indoles.[a]
is now a well-established synthetic
tool[7] and alkenyl C N systems are
À
also beginning to appear.[8] How-
ever, to the best of our knowledge,
no examples of such a tandem
process have been reported.[9]
Entry
H2N-R
Ligand
Base
Solvent
T [8C]
t [h]
Yield [%]
The biological relevance of N-
arylated indoles,[10] together with
the steric and electronic challenges
associated with aniline nucleo-
philes, prompted us to select the
union of triflate 1a[11] with aniline
as a platform to evaluate our
proposed synthesis. Literature
precedents suggested that for Pd-
1
2
3
4
5
6
7
H2N-Ph
4
4
4
4
4
4
4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOtBu
Cs2CO3
NaOtBu
toluene
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
20
20
20
40
16
24
24
83
86
51
75
62
70
46
H2N-4-MeOC6H4
H2N-4-ClC6H4
H2N-2-ClC6H4
H2N-Bu
H2N-Bn
H2N-Cy
8
5
Cs2CO3
toluene
115
21
82
À
catalyzed C N bond-forming proc-
9
5
5
Cs2CO3
Cs2CO3
dioxane
dioxane
115
115
24
25
61
70
esses, ligand choice is highly
dependent on the electronic and
steric properties of both the nucle-
ophilic and electrophilic reaction
components,[7] suggesting that
identification of a catalyst capable
of mediating both aryl and alkenyl
10
11
H2N-Ts
5
5
5
Cs2CO3
Cs2CO3
Cs2CO3
toluene
dioxane
dioxane
120
115
115
23
24
24
63
12
79
13[c]
80[c]
14
5
Cs2CO3
dioxane
115
26
66
À
C N bond formation would pres-
ent a challenge; in the event,
phenanthrene ligand 3[12] and dpe-
phos (4)[13] were the most success-
ful.[14] Dpephos has the advantage
that it is commercially available
[a] Conditions: triflate (1.0 equiv), amine (1.2 equiv), [Pd2(dba)3] (2.5 mol%); dpephos (6 mol%) or
xantphos (7.5 mol%), base (2.5 equiv). [b] Yields of isolated products. [c] Free indole isolated following
addition of KOH, H2O, EtOH for 2 h. Ts=p-toluenesulfonyl, Tf=trifluoromethanesulfonyl, Cy=cyclo-
hexyl, dba=dibenzylideneacetone.
were all incorporated in good yields (Table 1, entries 9–14).
The use of propionamide has the benefit of also allowing
efficient access to the free indole NH function; addition of
ethanolic KOH prior to workup delivers the deprotected
indole in 80% yield (Table 1, entry 13).
The required bis-activated carbon frameworks 1 could be
conveniently prepared by triflate formation on the corre-
sponding arylated ketones,[14] which in turn were readily
available by Pd-catalyzed arylation of the parent ketone with
and was selected for further application. Under optimized
conditions ([Pd2(dba)3], dpephos, Cs2CO3, PhMe, 1008C,
20 h) the coupling of triflate 1a with aniline delivered the
required indole in 83% yield (Table 1, entry 1).
The scope of the process with respect to the
a 1,2-dihaloarene.[16,17] For example, triflate 1a was prepared
from the arylation of cyclohexanone with 2-bromo-iodoben-
zene in the presence of a [Pd2(dba)3]/xantphos catalyst system
followed by triflate formation with PhNTf2 (Scheme 2).
N fragment was found to be broad and allowed
good yields of indoles for a varied range of
coupling partners (Table 1). Substituted aryl,
alkyl, and benzyl amines all performed well,
although the steric hindrance associated with
the cyclohexyl group resulted in a lower
reactivity (Table 1, entries 1–7). The use of 4-
and 2-chloroanilines is notable as it allows the
Scheme 2. Preparation of triflate 1a.
potential for product functionalization by sub-
sequent palladium catalysis.[15] Hydrazine func-
tionality could be readily incorporated, with the resultant
protected 1-aminoindole being produced in high yield
(Table 1, entry 8). For electron-poor nucleophiles, the use of
xantphos (5)[13] as ligand was optimal. Under these modified
conditions carbamate, sulfonamide, and amide functionalities
Variations in the ketone and aryl halide components were
explored with aniline as the nitrogen unit (Table 2). Indole
formation was effective for a variety of architectures; five-,
six-, and seven-membered cyclic ketones, simple acyclic, and
aryl- and ketal-functionalized[18] ketones were all incorpo-
404
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Angew. Chem. Int. Ed. 2005, 44, 403 –406

Angewandte
Chemie
Table 2: Scope of the ketone and arene components.[a]
1,2-dihaloarene; variations in both components is well
tolerated and allows the efficient synthesis of structurally
varied indole systems. Studies to apply similar tandem
processes to alternative heterocyclic motifs are underway.
Entry Substrate
1
Ligand Product
Yield (%)[b]
71
Experimental Section
General procedure (Table 1, entry 1): Cesium carbonate (420 mg,
1.30 mmol) was added to an oven-dried flask charged with [Pd2(dba)3]
(12 mg, 0.01298 mmol) and dpephos (17 mg, 0.0312 mmol) under
nitrogen. The flask was evacuated and back-filled with nitrogen three
times. The reagents were suspended in anhydrous toluene (1.10 mL)
and 2-(2-bromophenyl)cyclohexen-1-yl triflate (200 mg, 0.519 mmol)
and aniline (58 mg, 0.057 mL, 0.623 mmol) were added under nitro-
gen. The reaction was heated at 1008C for 20 h. After cooling, the
reaction mixture was diluted with diethyl ether (ꢀ 5 mL) and water
(25 mL). The product was extracted with diethyl ether (3 ꢀ 25 mL).
The combined organic extracts were washed with HCl (1m; 2 ꢀ
25 mL) and brine (20 mL) and then dried over MgSO4, filtered, and
concentrated in vacuo. The product was purified by flash chromatog-
raphy (1% diethyl ether/petroleum ether) to yield the title compound
(106 mg, 83%) as an off-white solid.
4
2
4
82
3[c]
4[c]
5[c]
4
4
4
90
74
65
Received: August 10, 2004
Keywords: amination · cascade reactions · indoles ·
.
nitrogen heterocycles · palladium
6[c]
4
80
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88
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(2.5 mol%), dpephos (6 mol%) or xantphos (7.5 mol%), base
(2.5 equiv), PhMe, 1008C. [b] Yields of isolated products. [c] NaOtBu
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rated efficiently. Medicinally attractive fluorine-substituted
arenes together with simple heterocycles could also be readily
introduced.
In summary, we have developed a new palladium-
catalyzed route to N-functionalized indoles in which the
N fragments are introduced in a single-step cascade sequence
onto an acyclic carbon framework. A wide range of electroni-
cally and structurally varied N fragments can be introduced
À
À
[7] For recent reviews on Pd-catalyzed C O and C N bond
formation, see: a) J. F. Hartwig in Modern Amination Methods
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À
through a tandem C N bond-forming process that employs
commercially available catalyst components. This new syn-
thesis allows the nitrogen atom of the indole core to be
introduced as the final synthetic operation. The cyclization
precursors are assembled from the union of a ketone and a
[9] For a carbazole synthesis that involves tandem palladium-
À
catalyzed aryl C N bond formation, see: K. Nozaki, K.
Takahashi, K. Nakano, T. Hiyama, H.-Z. Tang, M. Fujiki, S.
Angew. Chem. Int. Ed. 2005, 44, 403 –406
www.angewandte.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
405

Communications
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[11] Triflate 1 was prepared in 64% yield by the arylation of
cyclohexanone with 1-bromo-2-iodobenzene, in the presence of
a catalyst generated from [Pd2(dba)3] and xantphos, followed by
triflate formation (NaH, Tf2NPh, Scheme 2). See Supporting
Information for details.
[12] J. Yin, M. P. Rainka, X.-X. Zhang, S. L. Buchwald, J. Am. Chem.
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[13] M. Kranenburg, Y. E. M. van der Burgt, P. C. J. Kamer,
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[14] See Supporting Information for details.
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[18] The ketal-functionalized indole could be deprotected to provide
the corresponding ketone in 78% yield (PPTS, acetone, H2O).
406
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Angew. Chem. Int. Ed. 2005, 44, 403 –406