A novel imidazol-2-ylidene as a ligand for palladium-catalyzed synthesis of oxyindoles from o-haloanilides

Article abstract of DOI:10.1016/S0040-4039(01)02138-4

Oxyindoles were formed in good yields from 2-bromo- or chloroanilide in the presence of a base and a novel palladium imidazol-2-ylidene complex, through a process of metal-catalyzed intramolecular arylation of amide enolates. A wide range of substrates, including electron rich aryl chlorides, were found active under the catalysis of this non-phosphinic, easily prepared ligand-metal system.

Full text of DOI:10.1016/S0040-4039(01)02138-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 193–195
A novel imidazol-2-ylidene as a ligand for palladium-catalyzed
synthesis of oxyindoles from o-haloanilides
Tony Y. Zhang* and Hongbin Zhang
Chemical Process Research and Development, Lilly Research Laboratories, A Division of Eli Lilly and Company,
Lilly Corporate Center, Indianapolis, IN 46285-4813, USA
Received 9 October 2001; accepted 5 November 2001
Abstract—Oxyindoles were formed in good yields from 2-bromo- or chloroanilide in the presence of a base and a novel palladium
imidazol-2-ylidene complex, through a process of metal-catalyzed intramolecular arylation of amide enolates. A wide range of
substrates, including electron rich aryl chlorides, were found active under the catalysis of this non-phosphinic, easily prepared
ligand–metal system. © 2002 Elsevier Science Ltd. All rights reserved.
Oxyindoles (2-indolinones, 1) are a ubiquitous class of
heterocyclic compounds found in many natural
products1 and a number of marketed drugs and drug
candidates.2 They have served as intriguing targets as
well as essential intermediates in the total synthesis
other indolic alkaloids. Methods of preparation for
these compounds3 include oxidation of the parent
indoles, reduction of isatins, cyclization of o-
aminophenylacetate, construction of the phenyl ring by
intramolecular cycloaddition of amides, and a number
of metal-catalyzed processes.4 A conceptually new syn-
thesis has recently been reported by Hartwig et al.,5
where a palladium-catalyzed intramolecular arylation
of o-bromoanilide (2) enolate has been realized to give
the heterocycle in good yields.
failed to give any appreciable level of conversion when
they were subjected to the Pd2(dba)3/BINAP system,
even at elevated temperature over a prolonged reaction
time. A quick screen of catalysts using several bulky
and electron rich phosphines was conducted, in light of
the findings that these ligands generally favor palladium
mediated reactions of inactivated aryl halides.5,6 How-
ever, most of these ligands were found ineffective for
this particular transformation. Additionally, the use of
phosphinic ligands presents certain concerns over cost
and air stability.
We then turned our attention to bis-aryl imidazol-2-yl-
idene ligand derived from (3) for its superior activity
toward aryl chlorides in Suzuki couplings.7–10 Interest-
ingly, this ligand also proved unsatisfactory for the
intended oxindole formation from the corresponding
anilides, when a ligand/palladium ratio of 2:1 or 1:1,
and a catalyst loading of 3 mol% was employed. Sus-
pecting that the steric bulk of 3 may have been detri-
mental to the intramolecular cyclization process, we
prepared ligand 4 by simply alkylating mesitylimidazole
This palladium-catalyzed indole synthesis appeared as
the method of choice when we encountered the need for
an efficient synthesis for a drug candidate containing an
oxindole moiety. Indeed, the Hartwig procedure proved
reproducible when BINAP was used in combination of
Pd2(dba)3. However, we were disappointed to find that
the o-chloroanilides, unlike their bromo derivatives,
Me
Me
R
R3
O
Br R3
R
Br-
+N
Br-
N
Me
N
Me
+N
R1
R1
R1
+N
Br-
N
R1
N
R2
N
O
Me
Br
Me
R2
R
R
1
2
3
4
5
Keywords: catalysis; catalyst; oxindole; indole; palladium; imidazolylidene.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02138-4

194
T. Y. Zhang, H. Zhang / Tetrahedron Letters 43 (2002) 193–195
Table 1. Synthesis of oxindoles from o-haloanilides
with benzyl bromide. Unfortunately, catalyst prepared
from ligand 4 with palladium also failed to promote
cyclization. These events, coupled with the observation
by Nolan8 et al., respectively, seem to suggest that a
palladium species with at least two tight coordinating
ligands is required for the CꢀC bond forming reaction
to proceed. However, having two imidazolylene ligands
around the palladium center may impose too much
steric hindrance for the cyclization to occur.
R3
O
Br R3
Pd2(dba)2, 5
R1
R1
N
R2
LiN(TMS)2
N
R2
O
2
1
Yielda
Product
Entry
Substrate
Me
Me
Br
O
Me
In light of these findings, we prepared 1-mesitylimida-
zolium salt, 5, from 1-mesitylimidazole and o-bromo-
benzyl bromide, with the intention of providing a
less bulky, intramolecular coordination site so as to
limit the possibility of forming a bis-(bis-imidazolidene)
complex. Indeed, when compound 5 was mixed with an
equal molar amount of palladium, the in situ generated
catalyst proved to be effective catalyst in the oxyindole
forming reactions for a variety of substrates (Table 1).
Catalyst derived from 5 is generally more active than
the Pd/BINAP combination, as indicated by both reac-
tion rates and product yields. Moreover, o-
chloroanilide was found to undergo cyclization, albeit
in moderate yield (entry 2).11
1
80%
Me
O
N
N
Me
Me
Me
Me
Me
Cl
O
Me
Me
2
3
43%
83%
Me
Me
O
O
N
Me
N
Me
Me
Br
O
N
Bn
N
Bn
Me
Br
O
4
5
90%
40%
Me
N
O
N
Bn
Bn
Me
F
Br
O
F
Me
O
O
N
N
Bn
Bn
The exact mechanism of this reaction is unclear. As a
working hypotheses, we offer that the initial episode of
the catalytic cycle may involve the formation of a
carbene complexed palladocycle 6 through oxidative
insertion of Pd(0) into the aryl bromide bond (Scheme
1). The nature of the putative palladocycle 6 should be
markedly different from that of the increasingly popu-
lar palladocycle prepared from Pd(OAc)2 and P(o-
MeC6H5),9 and may offer some distinctive
opportunities in other processes which are of current
interests to the general synthetic community. Isolation
and identification of the active catalytic species are in
progress.
Me
MeO
Me
Br
MeO
O
67%
47%
6
7
Me
N
Me
N
Me
Br
OBn
Me
OBn
O
O
O
N
Bn
N
Bn
Me
O
Me
Br
Me
8
9
62%
82%
N
Bn
Me
N
Bn
Br
N
O
OMe
OMe
O
N
Me
Me
In summary, we have discovered a novel metal–ligand
system and applied it to the synthesis of oxyindole from
o-haloanilides. A few features are noteworthy: first the
ligand is easily prepared from readily available starting
materials, and stable toward air and prolonged storage.
Secondly, it represents a new class of palladocycle with
its unique set of activities and selectivity with a good
chance of being applied to other transition metal-cata-
lyzed processes, a work currently in progress in these
laboratories.
a
Isolated yields. All compounds were characterized by 1H and 13C
NMR. Reactions were carried out using 1.5–3 mol% of Pd2(dba)3,
3–6 mol% of 5, and 1.5–2 equiv. of LiN(TMS)2 in THF at 68°C for
1–4 h.
Enolate
N
Mes
N
N
N Mes
..
PdBr
..
-HBr
+ Pd2(dba)3
5
Pd
O
N
Br
R3
R2
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O
N
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-
Br-
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Pd
Pd
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R2
R3
R3
O
R2
Base
8
Scheme 1.

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