Palladium-catalyzed synthesis of 2-aminoindoles by a heteroanulation reaction

Article abstract of DOI:10.1002/anie.200351977

Chelates are the key: A conceptually novel indole ring forming reaction through heteroanulation is available through the palladium-catalyzed reaction of N-alkenylanilides with primary or secondary amines. The key feature is the formation of an unprecedented σ,π-chelated palladium species (see scheme); nitrogen nucleophiles can add to the activated alkyne unit of this species to form the indole skeleton. (X = I, Br; HNR²R³= prim. or sec. amine; Ts =tosyl.).

Full text of DOI:10.1002/anie.200351977

Angewandte
Chemie
Pd-Catalyzed Heteroanulation
Palladium-Catalyzed Synthesis of 2-Aminoindoles
by a Heteroanulation Reaction**
Bernhard Witulski,* Carole Alayrac, and Lali Tevzadze-
Saeftel
The diversity of indole-based molecules found in naturally
occurring alkaloids as well as their biological and pharma-
ceutical relevance have stimulated research into the develop-
ment of new synthetic strategies for the synthesis of readily
functionalized indole ring systems.[1] Although numerous
procedures have been established for this purpose, palladium-
catalyzed heteroannulation reactions have proven to be most
powerful and many of them have found applications in target-
or diversity-oriented syntheses.[2]
Previous palladium-based strategies for the assembly of
the indole framework are summarized in Scheme 1: Palla-
dium-induced cycloadditions of 2-haloanilines with terminal
or internal alkynes (disconnection path a,e)[3] and intra- as
Scheme 1. Retro-synthetic representation of Palladium-catalyzed indole
syntheses.
well as intermolecular reactions with 2-alkynyl anilides path
b,e) give either 2-, or 2,3-disubtituted indoles.[4] Other
approaches are based on Heck-type cyclization reactions
(path a),[5] reactions of alkynes with imines (path c),[6] or on
heteroannulation sequences achieved through palladium-
catalyzed aryl amination reactions (disconnection f).[7]
Herein we report an entirely new and straightforward
route to 2,3-substituted indoles that is characterized by the
following features: 1) the indole-ring formation relies on the
unprecedented disconnection pattern a,d; 2) a unique s,p-
chelated palladium species is exploited as the key intermedi-
ate for a diversity-tolerant assembly of the indole nucleus.
[*] Priv.-Doz. Dr. B. Witulski, Dr. C. Alayrac, Dr. L. Tevzadze-Saeftel
Fachbereich Chemie
Universität Kaiserslautern
Erwin-Schrödinger-Strasse, 67663 Kaiserslautern (Germany)
Fax: (+49)631-205-3921
E-mail: witulski@rhrk.uni-kl.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft.
C.A. is grateful to the Alexander von Humboldt Foundation for a
Research Fellowship.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 4257 –4260
DOI: 10.1002/anie.200351977
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4257

Communications
Table 1: Influence of base, catalyst precursor, and solvent on the catalytic
reaction of 3a and 4b to give 2-aminoindole 5b.
Entry
Base
Solvent
Catalyst
Yield [%][a]
1
2
3
4
5
6
7
8
9
DABCO[b]
DMF
DMF
DMF
DMF
DMF
toluene
THF
THF
THF
THF
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[Pd(PPh3)4]
23
64
76
75
8
64
98
95
79
69
C
2CO3 s
K2CO3
KOH
tBuOK
Scheme 2. a) TsCl, pyridine, THF, room temperature, 85–90%;
b) KHMDS, toluene, 08C, then addition of 2 (1.3 equiv), room temper-
ature, 80–98%; c) see Table 2 and Table 3; d) TBAF, THF, 08C , 93%;
e) LiHMDS, n-pentyl bromide, THF, ꢀ50 to room temperature, 50%.
KHMDS=potassium hexamethyldisilazane; OTf=[CF3SO3]ꢀ, Ts=
p-tolylsulfonyl, MHMDS=metal hexamethyldisilylazide, TBAF=tetra-
butylammoniumfluoride.
C
C
2CO3 s
2CO3 s
K2CO3
C
2CO3 s
10
K2CO3
[Pd(PPh3)4]
[a] Yields refer to products obtained after column chromatography on
silica gel. [b] DABCO=diazabicyclo[2.2.2]octane
Our approach is based on the palladium-catalyzed reac-
tion of alkynyl-2-halogenanilides 3 with primary or secondary
amines 4 affording a wide range of 2-aminoindoles ((1H-
indol-2-yl)amines) 5 (Scheme 2). Although the 2-aminoindole
moiety can be found in naturally occurring alkaloids,[8] its
access by known methods is quite limited.[9]
results we assume that the active catalyst is a palladium(0)
species, that is generated in situ from [PdCl2(PPh3)2]—a
process also found in other palladium catalyzed cross-
couplings employing similar reaction conditions.[12] The
lower yield obtained with the catalyst precursor [Pd(PPh3)4]
is presumably an effect of its higher phosphane content, which
reduces the activity of the actual palladium(0) catalyst.
The scope of this 2-aminoindole synthesis is not limited to
simple amines (Table 2). Besides secondary amines (4a–c),
primary amines—such as allylamine (4d) and cyclopropyl-
Generation of the required starting material was accom-
plished by tosylation of readily available 2-iodo- or 2-
bromoanilines 1 followed by an N-ethynylation reaction
with the alkynyliodonium salts 2 (R1 = Ph or SiMe3) to give
the alkynylhalogenanilides 3 in 80–90% yield.[10] Additional
modifications of the ynamide functionality were then made by
first desilylation of 3b to 3c, and subsequent alkylation of the
thus obtained terminal alkyne moiety (3c!3d).
Table 2: Palladium-catalyzed reaction of 3a with the primary and
secondary amines 4c–f.[a]
In a preliminary study, we observed that 3a in the
presence of 5 mol% of [PdCl2(PPh3)2] and a large excess of
diethyl amine 4a was readily converted into the 2-amino-
indole 5a [Eq. (1)]. 2-Aminoindoles are quite sensitive
Entry
Amine (equiv.)
Indole
Yield [%][b]
1
94[c]
2
3
98
94
towards hydrolysis. However, product 5a bearing a tosyl
group at the indole nitrogen atom withstood an aqueous
workup and could be isolated by silica-gel column chroma-
tography (petroleum ether/diethyl ether) in 98% yield.
To reduce the amount of the amine component 4 and with
the aim to create a general catalytic method, the influences of
a series of additional bases, solvents, and PdII- or Pd0-based
precatalysts were studied (Table 1).
Amongst all additional bases tested, K2CO3 and Cs2CO3
proved to be the most efficient ones. In the presence of a
twofold excess of either K2CO3 or Cs2CO3 the amount of the
amine component 4b could be reduced to 1.3 equivalents for
the formation of the 2-aminoindole 5b.[11] THF was found to
be more suitable than DMF or toluene as the solvent. Higher
yields were obtained with the precatalyst [PdCl2(PPh3)2] than
with [Pd(PPh3)4] (Table 1, entries 7–10). Based on these
4
77
[a] Reaction conditions: 5 mol% [PdCl2(PPh3)2], THF, K2CO3 (2 equiv),
808C, 2–24 h. [b] Yields refer to products obtained after column
chromatography on silica gel (5c–e) or neutral Al2O3 (5 f). [c] No
K2CO3 was added because a large excess of amine was used.
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Angewandte
Chemie
Table 3: Palladium-catalyzed synthesis of the 2-aminoindoles 5 g–p.[a]
amine (4e)—were accepted by the catalytic
process without any loss in the overall
efficiency (Table 2, entries 2 and 3).[11] Fur-
thermore, the less basic aniline 4 f could be
introduced successfully to give 5 f in 77%
yield (entry 4).
Entry
3
Amine (equiv)
Indole
Yield [%][b]
1
3d
97[c]
The 2-aminoindole synthesis was
extended to the anilides 3b and 3d–f bearing
either an alkylalkynyl or (trimethylsilyl)-
alkynyl group leading to a wide range of
substituted 2-aminoindoles in good to excel-
lent yields (Table 3). The use of silylated
ynamides (3b, 3e, and 3 f) offered a synthetic
handle for additional modifications of the
indole nucleus. For example, a complete
desilylation of 5h and 5j was readily ach-
ieved with TBAF in wet THF at room
temperature to give the 2-aminoindoles 5i
and 5k in 84% and 91% yield, respectively
(Table 3, entries 2and 3). Furthermore, the
replacement of the silyl group by an iodine
atom was accomplished by treatment of 5j
with NIS/KF (NIS = N-iodosuccinimide) in
methanol resulting in iodoindole 5l (entry
3)—thus offering the opportunity for further
elaboration by transition-metal catalyzed
cross-coupling reactions. Finally, the viability
of the reaction was not limited to the use of
ortho-iodoanilides. The catalytic process was
preserved with anilide 3 f bearing an ortho-
bromine substituent and indole 5p was
obtained in 99% yield following desilylation
of the crude reaction product (entry 7).
A proposed mechanism is shown in
Scheme 3. Initially, the Pd0 center formed
in situ inserts into the aryl–halogen bond of 3
to give the s,p-chelated palladium inter-
2
3b
83
3
4
3b
3b
95
66[c,d]
5
6
7
3b
3e
3 f
75[d]
89[d]
99[d]
[a] Reaction conditions: 5 mol% [PdCl2(PPh3)2], THF, K2CO3 (2 equiv), 808C, 5–24 h. [b] Yields refer to
products obtained after column chromatography on silica gel or neutral Al2O3. [c] 10 mol% palladium
mediate A. Addition of amine 4 to the catalyst was used. [d] yield over both steps, after desilylation with TBAF in wet THFat room temperature.
activated ynamide triple bond in A leads to
the s-vinylpalladium intermediate B. Subsequently, the
positively charged nitrogen atom in B is deprotonated (B!
C) by the base (K2CO3 or excess amine 4) and thereby
preparing the final reductive elimination step (C!5) by
which the catalytic active Pd0 species is regenerated.
In conclusion, we have developed an efficient and
diversity-tolerant synthesis of otherwise difficult to obtain 2-
aminoindoles 5 based on a novel palladium-catalyzed cross-
coupling sequence between N-alkynyl-2-halogenanilides 3
and primary, as well as secondary amines 4. Further studies on
synthetic applications and mechanistic investigations are in
progress.
The key step in this proposed mechanism is the formation
of the s,p-chelated palladium species A, that induces an
alkyne activation and allows the addition of external amines
to the carbon–carbon triple bond. The complementary
version of such a heteroannulation—the formation of the
externally bound s,p-palladium complex D that gives 2,3-
substituted indoles by an endo-dig type cyclization—is
considered to play a key role in the well-explored palla-
dium-mediated indole synthesis along disconnection path b,e
in Scheme 1.[4] However, the s,p-chelation controlled alkyne
activation for the assembly of the indole scaffold, as effected
by the palladium intermediate A, is unprecedented and it
should offer further options for the introduction of other
nucleophiles, such as enolates, thiols, or alcohols into the 2-
position of the indole ring.
Experimental Section
Representative procedure: A dry Schlenk flask with screw cap was
charged under argon with amine 4b (26 mg, 0.14 mmol), alkynylani-
lide 3a (50 mg, 0.11 mmol), [PdCl2(PPh3)2] (4 mg, 5 mol%), K2CO3
(29 mg, 0.21 mmol), and THF (1.5 mL). The resulting mixture was
stirred at 808C until the starting material was consumed (20 h, thin
layer chromatography (TLC)). Workup was by addition of CH2Cl2
and brine, followed by extraction with CH2Cl2, extraction with brine,
drying (MgSO4), and filtration through celite. Purification by column
chromatography (silica gel, petroleum ether:diethyl ether= 75:25
(v/v)) afforded the pure indole 5b (54 mg, 95% yield).
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Communications
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Scheme 3. Proposed mechanism for the palladium-catalyzed formation of
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Further experimental details, as well as spectroscopic and analytic
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Received: May 26, 2003 [Z51977]
Keywords: homogeneous catalysis · indoles · nitrogen
.
heterocycles · palladium · ynamides
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