A flexible, palladium-catalyzed indole and azaindole synthesis by direct annulation of chloroanilines and chloroaminopyridines with ketones

Article abstract of DOI:10.1002/anie.200460122

The "ringmaster" [Pd(tBu₃P)₂] serves as the catalyst in the direct synthesis of indoles by annulation of ortho-chloroanilines with ketones (see picture). This versatile method can be used to synthesize a variety of functionalized indoles and azaindoles. DMA = dimethylacetarnide.

Full text of DOI:10.1002/anie.200460122

Communications
Indole Synthesis
A Flexible, Palladium-Catalyzed Indole and
Azaindole Synthesis by Direct Annulation of
Chloroanilines and Chloroaminopyridines with
Ketones
Marc NazarØ,* Claudia Schneider, Andreas
Lindenschmidt, and David William Will
The prominent role played by indoles as privileged structures
[
1]
in biological systems has been well documented through a
multitude of natural products and bioactive compounds which
are indole derivatives and which interact with diverse bio-
[
2]
logical targets. For this reason, the development of simple,
general, and especially regioselective synthetic methods for
this structural moiety continues to be of tremendous inter-
[
3]
est. In this context, palladium-catalyzed methods for the
construction of the indole scaffold, using ortho-alkynylani-
[
4]
[5]
lines or N-acylated ortho-alkynylanilines, as well as the
[
6]
reaction of ortho-haloanilines and internal alkynes, have
been intensively studied. Recently, direct palladium-catalyzed
annulation of ortho-iodoanilines with ketones by means of
enamine formation in situ followed by a Heck reaction has
[
7]
been reported. Not only do 2-iodoanilines have limited
commercial availability, but they are also often difficult and
expensive to synthesize. The corresponding annulation of 2-
chloroanilines does not work under the reported conditions,
and to the best of our knowledge has never been investigated.
The same applies for heterocyclic derivatives, such as ortho-
chloroaminopyridines. A procedure for the reaction of 2-
chloroanilines, and presumably also 2-bromoanilines, with
ketones to give indoles would overcome these limitations.
Here we report a very general, mild, one-step palladium-
catalyzed annulation procedure for the synthesis of substi-
tuted, polyfunctionalized indoles and azaindoles, by reaction
of 2-chloroanilines and ortho-chloroaminopyridines, respec-
tively, with a variety of ketones.
An extensive screening of palladium catalysts and ligands
[
8]
revealed that commercially available [Pd(tBu P) ] in com-
3
2
bination with a base, such as K PO or KOAc, and 0.5 equiv-
3
4
alents of MgSO as a water-binder, was able to catalyze this
4
reaction in dimethylacetamide (DMA) at 1408C to form
indole 3 within 3 h (Table 1). However, variable amounts of
side products were formed during the reaction. Investigation
of milder, less basic reaction conditions led to the surprising
discovery that the addition of 1.5 equivalents of acetic acid to
the moderately active base K PO was extremely effective
3
4
and led to a highly selective and almost quantitative
[*] Dr. M. NazarØ, C. Schneider, Dr. A. Lindenschmidt, Dr. D. W. Will
Aventis Pharma Deutschland GmbH
Medicinal Chemistry, DI&A Chemistry
Building G878, 65926 Frankfurt am Main (Germany)
Fax : (+49)69-331-399
E-mail: marc.nazare@aventis.com
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4
526
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200460122
Angew. Chem. Int. Ed. 2004, 43, 4526 –4528

Angewandte
Chemie
[
a]
Table 1: Role of the base and additive in the conversion of 2-chloroaniline
Table 2: Annulation reaction with cyclic ketones.
with cyclohexanone to indole
[b]
Entry Aryl amine
Indole
t [h]/ Yield [%]
T [8C]
1
1
4/
25
1
2
62
[
a]
Entry
Base
Additive
Conv. [%]
1
2
3
4
5
6
Cs CO3
–
–
–
63
78
56
83
70
2
2/140 80
KOAc
K3PO4
Cs CO3
1.5 equiv HOAc
1.5 equiv HOAc
1.5 equiv HOAc
2
2
9
/
0
KOAc
K3PO4
3
4
5
98
96
80
[b]
88
[a] Conversion by HPLC-MS analysis. [b] Yield of isolated product: 82%
1
with >95% purity by H NMR and HPLC.
2
9
/
0
conversion to the desired product 3. This effect could also be
observed, although to a lesser extent, with Cs CO as base, but
not with KOAc.
The optimized reaction conditions, using K PO /acetic
1
140
4/
2
3
[
9]
3
4
acid and [Pd(tBu P) ], are very broadly applicable and
tolerate a wide variety of substitution patterns and function-
alities (Scheme 1, Tables 2 and 3). Cyclic ketones with various
14/
3
2
6
7
8
67
73
57
140
1
1
4/
40
[
c]
1
1
4/
40
1
140
4/
9
46
Scheme 1. Annulation of ortho-chloroanilines by reaction with ketones.
The method can be used with cyclic and acyclic ketones and with bro-
moanilines as well as chloroaminopyridines (see Tables 2 and 3 ).
10
14/90 70
ring sizes and functionalization react with comparable
efficiency (Table 2, entries 1–3), and even acid-labile moiet-
ies, such as dioxolane, are stable under the reaction conditions
[a] Reaction conditions: 1.0 equiv aniline, 3.0 equiv ketone, 1.3 equiv
K PO , 0.1 equiv [Pd(tBu P) ], 1.5 equiv acetic acid, 0.5 equiv MgSO in
3
4
3
2
4
1
DMA. [b] Yields of isolated products with >95% purity by H NMR and
HPLC. [c] Isolated as a mixture with the oxidation product 2,3,9-
trimethoxy-11H-benzo[a]carbazole-8-carboxylic acid. PMB=para-methoxy-
benzyl.
(
entry 4). The breadth of the 2-chloroaniline substrate
spectrum is considerable: both electron-rich and electron-
poor 2-chloroanilines are effective substrates. Furthermore,
diverse functional groups, such as free acids, amides, methyl
and methoxy groups, as well as N-alkylated anilines are
tolerated (entries 5–7, 10). It should be emphasized that
ortho-chloroaminopyridines can be cyclized smoothly to give
analogues (entry 4). The synthetically useful intermediate 2-
[
12,13]
(trimethylsilyl)indole
can be synthesized in high yield
[
10]
the pharmacologically important azaindoles (entries 8, 9).
The reaction is remarkably selective for the ortho-chloroani-
line moiety. Additional, potentially reactive chloro substitu-
ents do not react under these conditions (entries 8, 9). This
observation supports the postulated enamine–Heck mecha-
using acetyltrimethylsilane (entry 5). 2-Carboxyindole deriv-
atives, which are valuable scaffolds for the synthesis of
biologically active compounds, can be obtained directly using
pyruvic acid, or its amides (entries 6–11). Other palladium-
catalyzed annulation methods allow only indirect access to
these derivatives. Under the mild reaction conditions no
decarboxylation of the 2-carboxyindole derivatives is
observed.
[
7]
[14]
nism, as opposed to a direct a-arylation process of a keto-
[
11]
enolate followed by cyclization. As expected, the corre-
sponding 2-bromoanilines react with similar efficiency
(
entry 10).
Acetophenones also react under the conditions described,
In conclusion, we have developed a new, mild, and
efficient method for the synthesis of polyfunctionalized
indoles by direct reaction of substituted 2-chloroanilines
with cyclic or acyclic ketones. This procedure is simple to
carry out and broadly applicable. It considerably extends the
giving the corresponding indoles in good yield (Table 3,
entries 1–4). It is remarkable that also in this case N-alkylated
ortho-chloroanilines react as efficiently as their unsubstituted
Angew. Chem. Int. Ed. 2004, 43, 4526 –4528
www.angewandte.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4527

Communications
[
a]
Table 3: Annulation reaction with acyclic ketones.
under reduced pressure the residue was purified either by flash
chromatography on silica or by recrystallization.
[b]
Entry Aryl amine
Indole
t [h]/T [8C] Yield [%]
Received: March 25, 2004
Revised: May 26, 2004 [Z460122]
1
21/140
14/140
60
65
Keywords: annulation · cyclization · indoles ·
2
3
.
nitrogen heterocycles · palladium
2/90
81
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3
4
3
2
4
1
spectrum of products that can be obtained regiospecifically by
palladium-catalyzed indole formation starting from easily
synthesized or commercially available starting materials. The
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3
2
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General procedure: The appropriate 2-chloroaniline (4 mmol),
ketone (12 mmol), acetic acid (0.3 mL, 6 mmol) and MgSO4
(240 mg, 2 mmol) were suspended in dimethylacetamide (12 mL) in
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3
[
Pd(tBu P) ] (202 mg, 0.4 mmol) were added to the solution, and
3 2
argon was bubbled through the mixture for an additional 5 min. The
reaction mixture was heated to the temperature reported for the time
reported in a preheated parallel synthesis block (HPLC-MS reaction
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were dried over MgSO and filtered. After removal of the solvents
4
4
528
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 4526 –4528