Pd-catalyzed dehydrogenative aryl-aryl bond formation via double C(sp2)-H bond activation: Efficient synthesis of [3,4]-fused oxindoles

Article abstract of DOI:10.1021/ol503442n

A Pd(0)-catalyzed double cyclization of easily available o-bromoanilides leading to strained [3,4]-fused oxindoles was developed. The reaction proceeded through a highly ordered sequence involving key carbopalladation, 1,4-Pd migration, and C(sp²)-H functionalization steps. (Chemical Equation Presented).

Full text of DOI:10.1021/ol503442n

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Dehydrogenative Aryl−Aryl Bond Formation via
Double C(sp2)−H Bond Activation: Efficient Synthesis of [3,4]-Fused
Oxindoles
Ala Bunescu, Tiffany Piou, Qian Wang, and Jieping Zhu*
́ ́
Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: A Pd(0)-catalyzed double cyclization of easily
available o-bromoanilides leading to strained [3,4]-fused oxindoles
was developed. The reaction proceeded through a highly ordered
sequence involving key carbopalladation, 1,4-Pd migration, and
C(sp2)−H functionalization steps.
iaryls are important structural units found in many
bioactive natural products, marketed drugs, and advanced
to the formation of one C(sp2)−C(sp3) and one C(sp2)−
C(sp2) bond with concurrent creation of a quaternary carbon
center. Although many efficient methods have been developed
allowing the rapid access to diversely functionalized oxindoles
as well as spirooxindoles,6 there are only few methods available
for the direct synthesis of [3,4]-fused oxindoles from simple
linear precursors.7,8 Structurally, compound 2 is a hybrid
between oxindole and fluorene motifs. The latter is also an
important motif in organic dyes,9 molecular superconducting
materials,10 and organic light-emitting diodes11 and is found in
the structure of antiviral12 and antimalarial drugs.13 Since both
oxindole and fluorene are important pharmacophores, a hybrid
structure could be of potential interest in medicinal
chemistry.14
B
materials.1 Among many different synthetic approaches,
transition-metal-catalyzed cross-couplings of organometallics
(Ar-M) with aryl(pseudo)halides Ar-X (e.g., Suzuki−Miyaura,
Stille, Neigishi, and Hiyama couplings) have met with great
success (eq 1, Scheme 1).2 To avoid the use of organometallics
Scheme 1. Transition-Metal-Catalyzed Synthesis of Biaryls
We began our investigation using the easily accessible (E)-N-
(2-bromophenyl)-N-methyl-2,3-diphenylacrylamide (1a) as a
model substrate.15 Applying the conditions we developed
previously in the related studies [[Pd(OAc)2, PCy3·HBF4,
CsOPiv/PhNEt2 (1/1), DMA, 140 °C],8 the expected [3,4]-
fused oxindole 2a was formed in 39% yield together with 1-
methyl-3,4-diphenylquinolin-2(1H)-one (3a) in a 1:1 ratio
(entry 1, Table 1). The formation of quinolinone 3a could be
accounted for by a sequence involving 6-endo-trig cyclization/β-
hydride elimination, although this cyclization mode is generally
considered to be less favorable relative to the alternative 5-exo-
trig cyclization.16,17 Using potassium pivalate as a base
improved the selectivity (2.5/1) in favor of the desired
tetracycle 2a (entry 3). When P(o-tolyl)3 was used as a ligand
instead of PCy3, 2a was isolated in 81% yield (entry 4, Table 1).
Using bulky PMes3 in combination with potassium pivalate
(KOPiv), the yield of 2a was further increased (84% at 90%
conversion, entry 5). Interestingly, by adding N,N-diethylani-
line (2.0 equiv) to the reaction mixture, the reaction reached
completion furnishing the desired [3,4]-fused oxindoles in 97%
(Ar-M), two alternatives have emerged, namely direct cross-
coupling between Ar-H and Ar-X (eq 2) and cross-dehydrogen-
ative coupling (CDC).3 Both routes involve a C(sp2)−H
functionalization step.4 Inherent to the CDC reaction
mechanism, an external oxidant is generally required to
regenerate the active catalytic species.
In continuation with our current research interest in the area
of palladium-catalyzed C−H functionalization reaction,5 we
report herein a palladium-catalyzed double cyclization of easily
available o-bromoanilides 1 for the synthesis of strained [3,4]-
fused oxindoles 2 (eq 4, Scheme 1). In this transformation, an
appropriately positioned internal aryl bromide served both as
an oxidant and a trigger to initiate the domino process leading
Received: November 27, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503442n | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Synthesis of [3,4]-Fused Oxindoles: A Survey of
Reaction Conditions
Scheme 2. Synthesis of [3,4]-Fused Oxindoles: Scope
a
b
c
entry
ligand
base(s)
ratio 2a/3a
yield (%)
1
2
3
4
PCy3·HBF4
PCy3·HBF4
PCy3·HBF4
P(o-tolyl)3
PMes3
CsOPiv/PhNEt2 (1/1)
CsOPiv
1.0
1.1
38
b
42
b
KOPiv
2.5
65
KOPiv
9
81
84
93
97
93
d
5
KOPiv
>20
6
PMes3
KOPiv/PhNEt2 (1/1)
KOPiv/PhNEt2 (1/1)
KOPiv/PhNEt2 (2/3)
e
7
PMes3
e,f
8
PMes3
a
All reactions were carried out under nitrogen atmosphere using 1a
(0.05 mmol), Pd(OAc)2 (0.1 equiv), ligand (0.2 equiv), and base (2.0
b
1
equiv) in DMA (c 0.1 M) at 140 °C. Determined by H NMR.
c
d
e
Isolated yield. Conversion = 90% (1H NMR). Reaction temperature
100 °C. Pd(OAc)2 (0.05 equiv), PMes3 (0.1 equiv), c 0.2 M.
f
isolated yield. Similar efficiency was observed when the loading
of Pd was reduced from 10 to 5 mol % (entry 8, Table 1).
Overall, the optimized conditions consisted of heating a DMA
solution of 1a (c 0.2 M) at 100 °C in the presence of Pd(OAc)2
(0.05 equiv), PMes3 (0.1 equiv), KOPiv (2.0 equiv) and
PhNEt2 (3.0 equiv). Under these conditions, tetracycle 2a was
isolated in 93% yield (entry 8). The structure of 2a was
confirmed by single-crystal X-ray structural analysis.
a
All reactions were carried out under nitrogen atmosphere using 1a
(0.1 mmol), Pd(OAc)2 (0.05 equiv), Mes3P (0.1 equiv), PhNEt2 (3.0
equiv), and KOPiv (2.0 equiv) in DMA (c 0.2 M) at 100 °C.
b
c
d
Pd(OAc)2 (0.1 equiv), Mes3P (0.2 equiv). Single isomer. Only the
1
major regioisomer is represented (the ratio was determined by H
NMR analysis). Pd(OAc)2 (0.2 equiv), Mes3P (0.4 equiv).
e
With the optimized conditions in hand, the scope of the
domino process was next studied. When N-(p-methoxybenzyl)-
and N-benzyl-substituted anilides were subjected to reaction
conditions, the desired compounds 2b and 2c were obtained in
yields of 90% and 81%, respectively (Scheme 2). Electron-
donating (Me, OMe) and electron-withdrawing (Cl) sub-
stituents on the ring A were well tolerated as evidenced by the
high yield obtained for compounds 2d−g. The influence of
substitution on the ring B of anilide was subsequently
examined. Substituents at the para-position regardless of its
electronic nature (methyl, phenyl, methoxy, and fluoro) have a
negligible effect on the outcome of the reaction providing
tetracyclic [3,4]-fused oxindoles (2h−k) in excellent yields. In
the case of meta-substituted substrates, two regioisomers could
be formed and the regioselectivity was found to be substituent
dependent. With a m-methyl substituent, the cyclization
occurred exclusively at the less hindered position to afford 2n
in excellent yield. Similarly, 2-naphthyl-substituted substrate
afforded 2l as a single compound. However, the regioselectivity
was diminished with a substrate having a dioxolanyl substituent
leading to a mixture of two regioisomers (2o/2o′ = 55/45).
Next the effect of substitution on the double bond was
evaluated (2p−w). Terminal unsubstituted double bond
furnished the desired compounds in excellent yields (2p−r).
With a trisubstituted double bond (R4 = Ar), the reaction was
insensitive to the electronic nature of the R4 group providing
the desired tetracycles (2s−w) in excellent yields.
A possible reaction pathway accounting for the conversion of
1 to 2 is depicted in Scheme 3. An oxidative addition of an Ar−
Br bond to a Pd(0) species followed by an intramolecular
carbopalladation gave intermediate A in which the σ-alkyl-
Pd(II) function was ideally positioned to activate the
neighboring aromatic C(sp2)−H bond to afford a five
membered palladacycle B.18 A formal proton transfer from B
resulted in a net 1,4-palladium shift from the alkyl to the aryl
position.19 The so-generated Pd(II) species would then activate
the neighboring C4 position of oxindole to furnish after
reductive elimination the desired tetracyclic oxindole 2 with the
concurrent regeneration of the active Pd(0) species. In the case
of R4 = aryl, it is worth noting that formation of spirooxindole 4
B
dx.doi.org/10.1021/ol503442n | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
lides. In this transformation, one C(sp2)−C(sp3) and one
C(sp2)−C(sp2) bond were formed with concurrent creation of
a quaternary carbon center. A transient σ-C(sp3)−Pd species
generated in situ by an intramolcular carbopalladation served as
a lynchpin to activate successively the two C(sp2)−H bond
leading to the formation of an aryl−aryl bond.
Scheme 3. Possible Reaction Pathway
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization data, 1H and
13C NMR spectra for new compounds, and X-ray crystallo-
graphic data (CIF) of compounds 2a and 2s. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jieping.zhu@epfl.ch.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank EPFL (Switzerland) and Swiss National Science
Foundation (SNSF) for financial support.
■
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