Pd(II)-catalyzed intramolecular amidoarylation of alkenes with molecular oxygen as sole oxidant

Article abstract of DOI:10.1021/ol2006083

Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described. New C-N and C-C bonds form across an alkene in an intramolecular manner. The C-N bond-forming step proceeds via a syn-amidopalladation pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.

Full text of DOI:10.1021/ol2006083

ORGANIC
LETTERS
2011
Vol. 13, No. 8
2134–2137
Pd(II)-Catalyzed Intramolecular
Amidoarylation of Alkenes with Molecular
Oxygen as Sole Oxidant
Kai-Tai Yip and Dan Yang*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong,
P.R. China
yangdan@hku.hk
Received March 7, 2011
ABSTRACT
Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described.
New CÀN and CÀC bonds form across an alkene in an intramolecular manner. The CÀN bond-forming step proceeds via a syn-amidopalladation
pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.
Oxidative functionalization of alkenes has emerged as a
rapid, selective, and versatile bond-formingstrategy, there-
by offering opportunities to advance chemical synthesis
and address the increasing demands for economical and
sustainable synthetic methods. Over the past few decades,
significant progress has been made on the selective con-
struction of carbonÀheteroatom bonds across an alkene
by utilizing transition-metal catalysis.1 Selective difunctio-
nalization methods of forming both CÀC and CÀX bonds
across an alkene are of great potential to the rapid con-
struction of molecular complexity in the context of bio-
logically relevant heterocyclic architectures. With the
poineering works established by Hegedus2 and Sem-
melhack,3 nucleopalladation of alkenes became a versatile
entry tonew CÀC bondformation inthepresenceofCOor
an alkene/alkyne. However, the analogous bond-forming
events that involve an arene as the coupling partner are
relatively uncommon, partly because of the general inert-
ness of the aromatic system and the need of arene-activa-
tion mechanisms.4
Scheme 1. Alternative Strategy of Multibond-forming Cycliza-
tion
(1) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
~
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r
10.1021/ol2006083
Published on Web 03/21/2011
2011 American Chemical Society

Recently, Wolfe developed carboamination reactions
between aryl bromides and aminoalkenes.5 Chemler estab-
lished the copper-catalyzed double cyclization of ami-
noalkenes through intramolecular arylation with an alkyl
radical generated in situ from a CuÀC bond.6 Michael
reported the intermolecular carboamination of alkenes
with unactivated arenes through a PdII/PdIV catalytic
manifold.7 Zhang and Toste independently demonstrated
intramolecular carboamination between arylboronic acid
and aminoalkenes via AuI/AuIII catalytic cycles.8 How-
ever, these strategies inevitably require either stoichio-
metric external oxidants, which are transition-metal or
organic reagents, or preactivated reactants for completing
the catalytic cycle. Molecular oxygen is regarded as an
ideal oxidizing agent because it is abundant in the atmo-
sphere and benign to the envirnoment, and redox reac-
tions coupled with it would not lead to waste treatment
issues.9,10 In this regard, our group has pursued the
development of palladium-catalyzed functionalization
of alkenes, under simple aerobic conditions, as an effi-
cient multibond-forming cyclization strategy for rapid
access to a wide array of ring scaffolds (Scheme 1),11
which represent core structures of biologically impor-
tant pyrrolizidine and mitomycin alkaloids.12 Herein
we report the palladium-catalyzed intramolecular ami-
doarylation of alkenes using 1 atm of molecular oxygen
as the sole oxidant.
As shown in Table 1, the cyclization reaction of 1a to
yield 2a is dependent on the nature of the ligand. For
instance, triphenylphosphine was not suitable since it was
susceptible to oxidation (entry 1). Ligand screening was
then focused on N-heteroaromatics, owing to its easy
availability, structural diversity, and tolerance to oxidants.11c
Pyridine and various benzo-fused pyridine analogs only
led to modest yields (entries 2À5). Substantial improve-
ments were made when the 3-position, rather than the 4-
and 2-positions, of the pyridine core was substituted with
an electron-withdrawing group (entries 6À8). 3-Acetylpyr-
idine resulted in moderate yield (entry 9). Gratifyingly,
ethyl nicotinate13 was identified as the superior ligand
(entry 10). Lowering the ligand loading was deleterious
to the cyclization (entries 11À13). The use of a slight excess
of sodium carbonate as the base was beneficial to improve
the yields (entries 14À16).
This intramolecular amidoarylation reaction is applic-
able to a variety of aromatic systems (Scheme 2). On
para-substituted arene systems, electron-deficient anilides
Scheme 2. Oxidative Double Cyclizationa
Table 1. Optimization of Reaction Conditionsa
entry
ligand
PPh3
% yieldb entry
ligand
% yieldb
1
2
3
4
5
6
7
8
5
58
44
55
20
6
9
3-acetylpyridine
51
83
79
28
15
82
80
66
pyridine
10 ethyl nicotinate
11c ethyl nicotinate
12d ethyl nicotinate
quinoline
isoquinoline
acridine
13
À
2-cyanopyridine
3-cyanopyridine
4-cyanopyridine
14e ethyl nicotinate
15f ethyl nicotinate
16g ethyl nicotinate
44
22
a Reaction conditions: 0.2 mmol of substrate 1a, 40 mol % of ligand,
10 mol % of Pd(OAc)2, 1.5 equiv of Na2CO3, 1 atm of O2, 2 mL of
dioxane, 70 °C, 24 h. b Determined by 1H NMR using nitrobenzene as
the internal standard. c 20 mol % of ethyl nicotinate. d 10 mol % of ethyl
nicotinate. e 1.0 equiv of Na2CO3. f 0.5 equiv of Na2CO3. g In the absence
of Na2CO3.
ꢀ
ꢀ
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Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
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2010, 132, 1474. (b) Brenzovich, W. E., Jr.; Benitez, D.; Lackner, A. D.;
a Unless otherwise indicated, all reactions were performed at 70 °C
with substrate (0.3 mmol), ethyl nicotinate (40 mol %), Na2CO3
(1.5 equiv), and Pd(OAc)2 (10 mol %) in dioxane (3 mL) under 1 atm
of O2. bDetermined by 1H NMR analysis of the crude reaction mixtures.
cDetermined by LCMS analysis. dMinor regioisomer was obtained in
2% yield. eDiastereomeric ratios were determined by 1H NMR analysis
of the crude reaction mixtures. f Indoline-type cyclization product was
obtained in 23% yield.
Org. Lett., Vol. 13, No. 8, 2011
2135

(1bÀd) cyclize faster than did their electron-rich counter-
parts (1eÀf). The regioselectivity issue of amidoarylation
arises from anilides having two sterically distinct aryl CÀH
bonds for cyclization: on the meta-substituted anilide
system, 2ba was formed as a mixture of regioisomers
(1.3:1) in 57% yield. Notably, the regioselectivities im-
proved significantly inothermeta-substituents (13:1for Cl;
11:1 for Me; 49:1 for OMe). Despite steric crowding with
the amide carbonyl, ortho-substituted arenes such as 2eb
could also be obtained in good yields. Interestingly, the
cyclization of meta,meta-dimethoxy-substituted anilide,
leading to 2fb, was even faster than that which formed
2fa. On the other hand, the highly regioselective amidoar-
ylation took place on the naphthyl ring system, guided by
the ease of forming corresponding palladacycles, leading
to the formation of 2g and 2h, respectively.
amidoarylation, a nitrogen-tethered olefin furnished cyclic
urea 2j. Tricyclic fused frameworks 2k and 2l could be
established from exocyclic olefins of various ring sizes.
Notably, pyrrolidine-related ring scaffold 2m was formed
in 63% yield upon selective arylation with a β-phenyl ring,
instead of an N-substituted arene. However, the exclusive
formation of 2n and 2o and the inertness of the δ-arenes
implied that the electronic property of the arene is not the
controlling factor in the cyclization.
Sincethe oxidative cascade cyclization representsa rapid
and economical strategy to construct polycyclic systems,
weextendedthe scope ofamidoarylationtooxidative triple
cyclization (Scheme 3). Cyclization of o-allyl anilide 1p
proceeded through sequential amidopalladation/olefin in-
sertion/arylation events to give 2p in 70% yield (equivalent
to 89% yield per bond formation). Importantly, cascade
cyclizations are highly diastereoselective for establishing
spiro-ring frameworks 2qÀs upon the formation of three
bonds and two chiral centers (one of which being a
quaternary center) in a single step in good yields.
Indoline 2i was produced in 94% yield and the delicate
R,β-unsaturation unit was tolerated, reflecting the mild-
ness of the reaction conditions. In comparison with pre-
vious methods developed by Hegedus2a and us,11a the
Scheme 3. Oxidative Triple Cyclizationa
In contrast to common nitrogen nucleophiles such as
arylsulfonyl amides, anilides in possession of a less acidic
NÀH bond are less prone to undergo transition-metal-
assisted NÀH deprotonation, a prerequisite step of syn-
nucleopalladation. As a result, studying the stereochemical
outcomes of the amidoarylation reactionmay shedlight on
the mechanistic details. The Pd-catalyzed amidoarylation
of E-alkene 1t furnished 2t selectively in 66% yield (eq 1).
On the other hand, cyclization of Z-alkene 1u led to the
exclusive formation of 2u, thereby supporting a syn-ami-
dopalladation as the cyclization pathway.11d,14
a The reaction conditions are identical to those mentioned in
Scheme 2. bDiastereomeric ratios were determined by 1H NMR analysis
of the crude reaction mixtures.
present strategy of accessing related indoline skeletons
is superior in both product yield and reaction rate. Upon
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Figure 1. Deuterium kinetic isotope effects.
The low value of the intermolecular kinetic isotope effect
(kH/kD) indicates that the CÀH bond-breaking step occurs
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J. D.; Perch, N. S.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 6276. (b)
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2136
Org. Lett., Vol. 13, No. 8, 2011

after the turnover-limiting step (Figure 1). The observed
intramolecular KIE of 3.56 (average of 4 runs) is in the
normal range of electrophilic palladation of arenes.15 The
fact that electron-deficient anilides (e.g., p-NO2 and p-Cl
bearing) also cyclized efficiently and even reacted faster
than electron-rich anilides (p-OMe and p-Me bearing), in
contrast to most arylation processes proceeding via an
SEAr mechanism,16 can be rationalized such that electro-
philic palladation is not a kinetically prominent process in
the course of cascade cyclization.
Scheme 4. Plausible Mechanism
Based on the above results, a proposed mechanism is
outlined in Scheme 4.17 Anilide 1a gives amidopallada-
tion intermediate A in the presence of ligated PdII
species. Upon syn-amidopalladation, σ-alkylpalladium
species B is generated and the resulting PdII center
activates the arene via resonance-stabilized B-2 instead
of following the counterion-assisted deprotonation
process (B-1). The intermediacy of PdII species, instead
of PdIV, is likely associated with the areneÀactivation
step because of two reasons: (1) high reaction conver-
sion from 1a to 2a was achieved with a stoichiomet-
ric amount of Pd(OAc)2 under an argon atmosphere
(oxygen-free); (2) cyclization of a monosubstituted
alkene (1v) led to the enamide (3v) via a midway
β-hydride elimination (eq 2), thereby ruling out the
possibility of a PdII/PdIV catalytic manifold.18 Subse-
quently, the second ring is closed through CÀC bond-
forming reductive elimination of palladacycle C. The
catalytic cycle is completed by the regeneration of
PdII from Pd0 with molecular oxygen as the terminal
oxidant.
shows the bifunctionality (both nucleophilic and arylation
site) of anilide as a simple building block to the construction of
a range of common ring scaffolds. Elucidations of the cycliza-
tion mechanism provide the basis for further development of
the enantioselective variant and a practical synthetic strategy
toward the synthesis of alkaloids of biological interest.
Acknowledgment. This work was supported by the
University of Hong Kong and the Hong Kong Research
Grants Council (HKU 705807P and HKU 706109P).
Supporting Information Available. Experimental de-
tails; syntheses and characterization of 1aÀu and 2aÀu;
determination of kinetic isotope effects. This material is
available free of charge via the Internet at http://pubs.acs.
org.
In summary, we have demonstrated the broad scope of
the Pd(II)-catalyzed intramolecular amidoarylation of
alkenes that utilizes oxygen as a green oxidant. This work
(17) An alternative mechanism involving sequential CÀH bond
activation/carbopalladation of alkene/CÀN bond formation is unlikely
in our system because the bimolecular palladation of arenes is often
assisted by protic acids. For example, see: ref 13d and Houlden, C. E.;
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M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.;
de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124,
1586. (c) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
12084. (d) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.;
Gevorgyan, V. Org. Lett. 2004, 6, 1159. (e) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.
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Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-Jones, G. C.; Booker-
Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. In additon,
successful oxidative triple cyclization (Scheme 3) also rules out this
mechanism. We thank the reviewer for pointing out this possibility.
(18) Termination with β-hydride elimination is characteristic of an
oxidative amination of alkene under a Pd0/PdII catalytic cycle. For
recent reviews, see: (a) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg.
(16) For overviews, see: Smitch, M. B.; March, J. Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure, 6th ed.; Wiley-Inter-
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