Synthesis of 3,3-disubstituted oxindoles by palladium-catalyzed asymmetric intramolecular α-arylation of amides: Reaction development and mechanistic studies

Article abstract of DOI:10.1002/chem.201301572

Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency. Copyright

Full text of DOI:10.1002/chem.201301572

DOI: 10.1002/chem.201301572
Synthesis of 3,3-Disubstituted Oxindoles by Palladium-Catalyzed
Asymmetric Intramolecular a-Arylation of Amides: Reaction Development
and Mechanistic Studies
Dmitry Katayev,[a] Yi-Xia Jia,[a, c] Akhilesh K. Sharma,[b] Dipshikha Banerjee,[a]
Cꢀline Besnard,[a] Raghavan B. Sunoj,*[b] and E. Peter Kꢁndig*[a]
Abstract: Palladium complexes incor-
porating chiral N-heterocyclic carbene
(NHC) ligands catalyze the asymmetric
intramolecular a-arylation of amides
producing 3,3-disubstituted oxindoles.
Comprehensive DFT studies have been
performed to gain insight into the
mechanism of this transformation. Oxi-
dative addition is shown to be rate-de-
termining and reductive elimination to
be enantioselectivity-determining. The
synthesis of seven new NHC ligands is
detailed and their performance is com-
pared. One of them, L8, containing a
tBu and a 1-naphthyl group at the ster-
eogenic centre, proved superior and
was very efficient in the asymmetric
synthesis of fifteen new spiro-oxindoles
and three azaspiro-oxindoles often in
high yields (up to 99%) and enantiose-
lectivities (up to 97% ee; ee=enantio-
meric excess). Three palladacycle inter-
mediates resulting from the oxidative
addition of [PdACTHNUTRGNE(UNG NHC)] into the aryl
halide bond were isolated and structur-
ally characterized (X-ray). Using these
intermediates as catalysts showed
alkene additives to play an important
role in increasing turnover number and
frequency.
Keywords: arylation · asymmetric
catalysis · N-heterocyclic carbenes ·
oxindoles · palladium
Introduction
functionalization of 3-substituted oxindoles by alkylation or
arylation,[4] fluorination,[5] hydroxylation,[6] aldol reaction,[7]
Mannich reaction,[8] Michael addition,[9] amination,[10] and
arylation[11] reactions.
Alternatively, the stereogenic center can be formed
during cyclization of an acyclic precursor. Pioneering ele-
gant work here stems from the Overman group[12] who have
developed an enantioselective intramolecular Mizoroki–
Heck reaction for this transformation. An example detailing
the formation of a spiro-oxindole is shown in Scheme 1. Zhu
extended these studies by an asymmetric tandem Heck-
cyanation reaction.[13]
The oxindole motif is found in a large number of natural
products and synthetic analogues with a wide array of bio-
logical activities.[1] The intense interest in these heterocycles
is also manifest by the frequent reviews dedicated to aspects
of oxindole synthesis.[1d,e 2] Many of these compounds incor-
porate a stereogenic center at C(3). Consequently much ac-
tivity has focused on the synthesis of enantiomerically en-
riched compounds of this family. One route of access is by
modification of a pre-existing ring system—typically either a
simpler oxindole or an isatin. Recent examples include
enantioselective nucleophilic addition to isatins,[3] direct
[a] Dr. D. Katayev, Prof. Y.-X. Jia, Dr. D. Banerjee, Dr. C. Besnard,
Prof. E. P. Kꢀndig
Department of Organic Chemistry, University of Geneva
30 Quai Ernest Ansermet, 1211 Geneva 4 (Switzerland)
Fax : (+41)22-379-3215
E-mail: peter.kundig@unige.ch
[b] A. K. Sharma, Prof. R. B. Sunoj
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400076 (India)
Scheme 1. Spiro-oxindole synthesis by asymmetric Heck cyclization.[12]
BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
Fax : (+22)2576-7151
E-mail: sunoj@chem.iitb.ac.in
In 2001, Hartwig and co-workers reported the results of
an extensive study of the Pd0-catalyzed intramolecular a-ar-
ylation of anilides to give 3,3-disubstituted oxindoles
(Scheme 2).[14] This included a large number of chiral li-
gands. Chiral bidentate phosphine ligands generally afforded
products with poor asymmetric induction. The most promis-
ing ligands were bulky chiral N-heterocyclic carbenes
[c] Prof. Y.-X. Jia
Present address:
Zhejiang University of Technology
State Key Laboratory Breeding Base of
Green Chemistry-Synthesis Technology
Chaowang Road 18, Hangzhou, 310014 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301572.
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FULL PAPER
these chiral monodentate ligands as the chiral backbone in
bidentate chiral ligands. The entropic advantage of the bi-
dentate phosphorous ligands is compensated by the robust
metal–NH–carbene bond. This hypothesis was strengthened
by X-ray crystal structures of a PdII–NHC complex[15e] and
of a number of NHC–borane and NHC–gold complexes.[16]
More recently these ligands also have found application in
the Pd-catalyzed intramolecular coupling reactions between
aryl bromides and unactivated methylene groups leading to
the 2-substituted and 2,3-disubstituted indolines with high
asymmetric induction.[17] A monodentate ligand proved es-
sential in that reaction.
In our previous studies of the transformation of 1a!2a,
we used an in situ procedure to generate the catalysts. Thus,
generation of [Pd0(L1)] involved treating a mixture of [Pd2-
AHCTUNGRTEG(NNNU dba)2] (dba=dibenzylideneacetone, 1,5-diphenyl-1,4-penta-
dion-3-one) and the imidazolium iodide [(S,S)-L1H][I] in di-
methoxyethane with tBuONa. Hartwig and co-workers pro-
posed a catalytic cycle analogous to that shown in Scheme 3
Scheme 2. Progress in the Pd-catalyzed asymmetric intramolecular aryla-
tion of amides by using chiral NHC ligands.
(NHC) though the results left much room for improvement.
This study was followed by those of the groups of Glorius[15a]
and Aoyama[15b,c] but only moderate enantioselectivities
were obtained. The breakthrough in this area came in 2007
with the development of new chiral NHC ligands[15d,e] and
both high yields and asymmetric induction were achieved in
this approach to oxindoles. The main features of these li-
gands are bulky tBu groups at the stereogenic centers a to
nitrogen and ortho-substituents on the aromatic groups.
Modification of the ligand aryl groups also gave access to
highly enantioenriched oxindoles bearing heteroatoms at
the oxindole stereogenic center (O and N).[15f] Since then,
this chemistry has been expanded further[15g] and a number
of other chiral carbene ligands have been reported to give
excellent results (Scheme 2). Dorta developed new NHC li-
gands with a chiral N-heterocycle and naphthyl side chains
and successfully applied palladium complexes incorporating
these ligands in 3-alkyl-3-aryl,[15h] 3-allyl-3-aryl,[15i] and re-
cently 3-flouro-3-aryl[15j] oxindole synthesis. Importantly, the
initial drawback of having to separate stereoisomers of the
Pd catalyst has now been overcome.[15k] Conformationally
restricted chiral ligands developed by Glorius[15l] and Mura-
kami[15m] also showed high asymmetric induction in this reac-
tion, whereas a catalyst with a six-membered NHC ligand
did not reach the same level of asymmetric induction.[15l]
We argued that in the ligand family reported from this
laboratory, minimization of allylic strain places the catalysts
stereodirecting aryl planes into the appropriate space.
Hence, minimization of allylic strain plays a similar role in
Scheme 3. Energetically most preferred mechanistic pathway for Pd–
NHC*-catalyzed synthesis of oxindole (S)-2a.
and they isolated and analytically and spectroscopically
characterized palladacycle 5. These authors also established
the oxidative addition step to be rate-determining. Structur-
al and energetic information of the key intermediates was
not available, however, and the step in which asymmetric in-
duction occurs remained unknown.
In the present article we probe the mechanism of the in-
tramolecular arylation of amides by a detailed DFT investi-
gation and report the synthesis of new chiral NHC ligands,
one of them showing strongly improved performance in cat-
alysis leading to spiro-oxindoles. We also describe the isola-
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R. B. Sunoj, E. P. Kꢀndig et al.
tion and structural characterization of palladacycle inter-
mediates and their use as catalysts in this reaction.
Enantioselectivity could be controlled by any of the three
steps: 1) the substrate benzylic deprotonation leading to E
or Z enolates, 2) the conversion of O-enolate to C-enolate,
or 3) reductive elimination from the palladacycle leading to
Results and Discussion
the oxindole product. DFTACTHNGUTRENNU(G B3LYP) computation was em-
ployed to identify the transition states (TSs) in an effort to
delineate the factors contributing to enantioselectivity as
well as to recognize the most likely step(s) responsible for
asymmetric induction. The effect of solvent continuum is
taken into account by computing energies by using 1,4-diox-
ane as the solvent. The discussion in the manuscript is based
on the SMD1,4-dioxane/B3LYP/6-311+G**(C,H,N,O,Na,Br),
LANL2TZ(f)(Pd)/B3LYP/6-31G*(C,H,N,O,Na,Br);
LANL2DZ(Pd) energies. The mechanisms emanating from
both R and S enantiomers of the racemic substrate were
considered. The energy difference between the diastereo-
meric transition states for the oxidative addition of [Pd(L1)]
to (R)-1a and (S)-1a is only 1.0 kcalmolꢀ1, in favor of the S
enantiomer. This leads to the two diastereomeric intermedi-
ates (S,S,S)-5 and (S,S,R)-5. The optimized geometry of the
oxidative addition transition state A° (for the R configura-
tion) is shown in Figure 1.[20] As will be shown later, the two
diastereomeric intermediates corresponding to 5 were isolat-
ed (as iodo-palladacycles) and structurally characterized.
DFT investigations: A number of different mechanistic sce-
narios were examined for the [Pd0(L1)]-catalyzed oxindole
formation. Here, we focus only on the energetically most
preferred pathway (Scheme 3). Alternative possibilities that
differ in terms of the geometries of the palladacycle or in
the mode and timing of bromide loss from various inter-
mediates are detailed in the Supporting Information. Very
recently, Curran and co-workers analyzed the implications
of atropisomers of N-methyl-N-bromoarylacetamides and
their Pd insertion products in this reaction sequence. Their
study revealed isomerization to be rapid relative to the for-
ward reaction. Cyclization to oxindoles is thus preceded by
a dynamic kinetic resolution at an early stage of the reac-
tion.[18]
The reaction is envisaged to begin with the formation of
[Pd0(dba)(L1)] (3) complex from [Pd0
ACHTUNGTRENNUNG HCATUGNTERN(NUGN dba)2] (Figure 4). The
energy of 3 is taken as the reference for comparisons. The
Figure 1. Optimized geometry of transition-state A°.
Figure 2. Preferred torsional transition states involved in the conversion
of O-enolate to C-enolate. C° and C’° represent the conversion of Z-
and E-O-enolates to C-enolates, respectively.
catalytic cycle starts with the loss of dba from 3 and forma-
tion of a catalyst–substrate complex involving a Pd-h2 arene
bond (4). Oxidative addition follows next to provide palla-
dacycle 5. In the absence of additional base, 5 can be isolat-
ed. Hartwig and co-workers reported NMR spectroscopic
data with tricyclohexylphosphine (PCy3) as the ligand and,
as will be shown later, we have isolated and structurally
characterized palladacycles 5 incorporating chiral NHC li-
gands.
In the next step of the catalytic cycle, tBuONa abstracts
the benzylic proton leading to the Pd-O-enolate 6.[19] This is
followed by isomerization to Pd-C-enolate 7. Reductive
elimination furnishes the final product and regenerates the
[Pd0(L1)] catalyst. In the next level of detail, features of the
catalytic cycle, such as the formation of two diastereomeric
palladacycles 5 from the racemic substrate, the role of base,
the formation of the E or the Z-enolate, and the asymmetric
induction provided by the ligand is addressed.
The next step is the deprotonation of 5 leading to palladi-
um O-enolates 6. For convenience to the reader we will
leave out the descriptors for the ligand chirality as this will
remain unchanged. The key features of the computed ener-
getics can be gathered from the Gibbs free energy profile as
given in Figure 4. The barrier for deprotonation of diaster-
eomer (S)-5 is 5.4 kcalmolꢀ1, whereas that for (R)-5 it is
4.6 kcalmolꢀ1.[21] The computed energetics further indicate
that (R)-5 preferably leads to the Z-enolate, whereas (S)-5
can result in both E and Z-enolate. The step leading to the
generation of the enolate intermediate is not expected to be
significant in the eventual enantioselectivity of this reaction.
A key point to note is a likely accumulation of the ener-
getically more favored Z-O-enolate due to the equilibrium
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Synthesis of 3,3-Disubstituted Oxindoles
FULL PAPER
between intermediates 5 and 6 connected by transition state
B. Further, the barrier for E/Z conversion (within O-eno-
late) by rotation around the C=C bond is lower than those
of the forward reactions. The next major event in the cata-
lytic cycle is the transition from O-enolate 6 to C-enolate 7.
The barrier for rotation of the Z-O-enolate to (R)-7 is
found to be 0.9 kcalmolꢀ1 lower than that for the Z-O-eno-
late to (S)-7. This step can influence the stereochemical out-
come of the reaction. The E-enolate will give rise to pallada-
cycle (S)-7, which will eventually lead to R-oxindole. The Z-
O-enolate on the other hand, will convert to (R)-7 and then
to (S)-oxindole. Hence, different geometric isomers of 6 will
lead to different enantiomers if the interconversion between
E and Z-enolates is prevented. The optimized geometries of
these transition states are provided in Figure 2 (TS C).[22]
bond formation. Transition states D° and D’°, in which the
phenyl group of the substrate is positioned towards the cata-
lyst, are found to be of lower energy (Figure 3). A favorable
interaction between the substrate phenyl ring and palladium
is noticed in both D° and D’°. The chiral NHC side chain
bearing tert-butyl and 2-methylphenyl groups is identified to
provide differential steric environments to the substrate in
the ring-closing step. Upon analysis of these transition states
with the help of an activation strain model, it became evi-
dent that transition state D’° suffers from higher steric-
induced strain. The origin of increased strain has been
traced to the closer proximity between the 2-methylphenyl
arm of the catalyst and the phenyl and methyl substituents
on the developing oxindole ring. Detailed geometric analysis
of the transition state is provided in the Supporting Informa-
tion.[24] When the oxindole ring is closer to the tert-butyl
group of NHC, as in transition state D°, the distortion and
proportionately the energy is found to be lower.[25]
In summary, the analysis of the Gibbs free energy profile
(Figure 4) reveals that oxidative addition is the rate-limiting
step leading to the formation of a stable intermediate 5. The
transition state for the reductive elimination presents the
next-highest activation barrier (23.5 kcalmolꢀ1) to give the
oxindole product (2a). The intermediates 6 and 7, represent-
ing the ꢂblackꢃ pathway and ultimately leading to (S)-2a are
lower in energy than those leading to (R)-2a and intermedi-
ates likely accumulate here. The energy barrier to (S)-2a
from the lowest energy intermediate 7 thus favors the for-
mation of (S)-2a.
Figure 3. Optimized geometries of transition states for the reductive elim-
ination leading to oxindole formation. D° and D’° are diastereomeric
transition states leading to (S)-2a and (R)-2a products, respectively.
New chiral NHC ligands: As previously stated, we presume
that the ligandꢃs aryl ortho-substituent fixes the orientation
of the aryl ring in space through minimization of allylic
strain. If correct, the substitution of the ortho-Me group by
a fused aromatic ring could improve the ligandꢃs performan-
ce.[15d–f] We have, therefore, extended this family of chiral
NHC ligands to the naphthyl ligands L8–L11 (Scheme 4). In
preliminary communications we have shown that L8 is the
best performer in an intramolecular asymmetric Ar-Br/C-
The structural features indicate the involvement of an early
transition state wherein the incipient bond length between
Pd and the new chiral center is much longer. It is further
evident from the transition-state geometries that the new
benzylic stereogenic centers in the two transition states are
stereochemically distinct.
Finally, a reductive elimination leads to the product oxin-
dole. The configuration at the benzylic carbon atom gets car-
ried forward to the product as the reductive elimination is
identified to be a concerted process with no additional inter-
mediates. The stereochemistry of product oxindole, there-
fore, depends on the configuration as rendered in the previ-
ous step. The intermediate (R)-7, therefore, corresponds to
the formation of oxindole (S)-2a, whereas (S)-7 yields (R)-
2a. The energy barrier for the reductive elimination in (R)-7
to (S)-2a is 4.2 kcalmolꢀ1 lower in energy than the corre-
sponding conversion of (S)-7 to (R)-2a. Hence, the transi-
tion state for formation of the (S)-oxindole is more favora-
ble.[23] This prediction is in concert with the experimental
observations.
(sp3)-H coupling reaction leading to indolines.[17] The excel-
ACHTUNGTRENNUNG
lent performance was linked to the high thermal stability of
the Pd–L8 bond. The X-ray structure of (S,S)-L8-BH3 was
also reported very recently.[16] We now detail the synthesis
of the naphthyl imidazolium and dihydroimidazolium salts
[L8H][I]–[L11H][I] and of the C1-symmetric ligand precur-
sors [L12H]ACHTNUGTRENN[UG BF4]–[L14H]ACHUTGNTREN[NUGN BF4].
The syntheses of enantiopure amines 8 and 9 are shown
in Scheme 5. Alkylation of the corresponding napthonitriles
with tBuMgCl in the presence of a catalytic amount of CuBr
followed by in situ reduction with NaBH4 afforded (rac)-8
and (rac)-9 in good yields.
Amine (rac)-8 was resolved by forming the diastereoiso-
meric salt with (l)-malic acid in a mixture of isopropanol
and ethyl acetate. Other chiral acids (N-acetyl leucine, man-
delic acid, and tartaric acid) showed poor performance as
resolving agents. The (S,S)-salt of malic acid/8 crystallized
preferentially (6:94 diastereomeric ratio, d.r.) and a second
The different transition states for the stereoselective re-
ductive elimination leading to oxindole formation is exam-
ined. These transition states differ in the orientation and in
terms of the prochiral faces of the substrate involved in the
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R. B. Sunoj, E. P. Kꢀndig et al.
Figure 4. Gibbs free energy diagram (in kcalmolꢀ1) of key steps in the asymmetric synthesis of oxindole (S)-2a in solution at the SMD1,4-dioxane/B3LYP/6-
311+G** (C,H,N,O,Na,Br); LANL2TZ(f)(Pd)//B3LYP/6-31G*(C,H,N,O,Na,Br); LANL2DZ(Pd) level of theory. Transition-states A°–D° and inter-
mediates shown are those derived from the (R)-enantiomer of the starting material.
the best results. After two re-
crystallizations of the (R,R)-
salt of tartaric acid/9 in etha-
nol and amine recovery, (R)-9
was obtained in 36% overall
yield with 99% ee.
With the chiral amines in
hand, the imidazolium salts
[L8H][I]and [L10H][I] were
synthesized by following litera-
ture methods.[15a,d–f] The chiral
amines were condensed with
glyoxal and the resulting dii-
mines were reacted with chlor-
omethylpivalate in the pres-
ence of silver triflate to obtain
the
imidazolium
triflates.
Anion exchange to the corre-
sponding iodides gave solid
products instead of oily triflate
salts. Overall, this procedure is
Scheme 4. Ligand library of chiral NHCs.
quite simple and no further
recrystallization furnished, after hydrolysis, the amine (S)-8
in 38% overall yield (max.=50%) with >99% ee. For the
resolution of amine 9 (l)-tartaric acid was found to give
purification of intermediates is needed. The product yields
were modest.
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Synthesis of 3,3-Disubstituted Oxindoles
FULL PAPER
Scheme 5. Chiral amines (S)-8 and (R)-9 for the synthesis of imidazolium
and dihydroimidazolium salts: a) tBuMgCl, CuBr (cat.), Et2O, reflux
24 h; b) NaBH4, MeOH, ꢀ78 to 258C, 16 h; c) (l)-maleic acid, iPrOH/
EtOAc; d) (l)-(+)-tartaric acid, EtOH; e) 1m NaOH, Et2O.
For the synthesis of dihidroimidazolium salts [(S,S)-L9H]
[I] and [(R,R)-L11H][I], the diimines were reduced with
LiAlH4 to the corresponding diamines. Ring-closure was
carried out according to the standard procedure with trie-
thylorthoformate and NH4BF4. This afforded the tetrafluor-
Scheme 7. Synthesis of C1-symmetric imidazolium salts.
ꢀ
oborate dihydroimidazolium salts. Anion exchange BF4 /Iꢀ
afforded dihydroimidazolium iodide salts in high yields
(Scheme 6).
imidazolium salt 13 thus formed was treated with HBF4 at
808C. The imidazolium salts [L12H][BF4]–[L14H][BF4] were
N
ACHTUNGTRENNUNG
isolated by flash column chromatography in moderate yield
(40–52%; over the last three steps).
Palladium-catalyzed synthesis of oxindoles: Catalysis with
the new ligand (S,S)-[L8H][I] and, in less detail, with
[L12H]
ly reported methodology.[15d–f] As is immediately apparent
from the data in Table 1, the ligands [L12H][BF4]–[L14H]-
[BF4], while leading to fast reactions, fell far short in asym-
ACHTUGNRTEN[UNNG BF4]–ACHTUNREGTG[NNUN L14H]ACHTNUGTREN[NUGN BF4] was probed by applying previous-
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
metric induction (Table 1, entries 2–4). Conversely, (S,S)-
[L8H][I] gave identical or slightly better yields than reac-
tions with (S,S)-[L1H][I] or (S,S)-[L2H][I] and it outper-
formed these ligands in asymmetric induction by 2–3% ee, a
significant improvement in the 90–95% ee range.
The optimized reaction conditions were applied to sub-
strates leading to the spirocyclic products 15a–d (Table 2)
and 17a–n (Table 3). A very important increase in asymmet-
ric induction is observed for 15b (Table 2, entry 3). This spi-
roxindole had been obtained previously in only 59% ee
(using L1).[15e] Yields were good to excellent throughout.
Products were generally obtained with high asymmetric in-
duction. Exceptions are 15a incorporating a four-membered
spirocyclic system and 17 f bearing an o-CF3 group.
Table 3, entries 9–12, demonstrate that the reaction toler-
ates different N-protecting groups albeit that Bn, methoxy-
methyl ether (MOM), and benzyloxymethyl acetal (BOM)
derivatives formed products with somewhat lower enantio-
meric purity relative to N-Me due to the required heating to
508C with MOM and BOM protection (entries 11–12).[27]
3,3-Disubstituted aza-oxindoles form an important family
of biologically active products.[28] A literature search re-
vealed only a very limited number of reports for the synthe-
sis of compounds containing the aza-oxindole motif.[29]
Scheme 6. Synthesis of imidazolium and dihydroimidazolium ligand pre-
cursors.
In extension of the modification of C2-symmetric NHC li-
gands, the three C1-symmetric imidazolium salts [L12H]-
ACHTUNGTRENNUNG[BF4]–[L14H]ACHTUNGTRENNUNG[BF4] were prepared by the route reported by
the Fꢀrstner group.[25] Nucleophilic addition of 2,6-diisopro-
pylaniline to bromoacetaldehyde diethyl acetal in the pres-
ence of nBuLi led to the b-amino acetal 10 in excellent
yield. The formamide derivative 11 was synthesized by treat-
ing 10 with HCO2H in acetic anhydride and was obtained in
near quantitative yield (Scheme 7).[26]
The acetoxyoxazolinium tetrafluoroborate derivative 12
was obtained as a white solid by treating 11 with HBF4·Et2O
in acetic anhydride. It was engaged in the next step by reac-
tion with the requisite enantiopure amine. The hydroxylated
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R. B. Sunoj, E. P. Kꢀndig et al.
Table 1. Palladium-catalyzed a-arylation of 1a–d by using (S,S)-L8, L12–
L14.[a]
Table 3. Palladium-catalyzed a-arylation of 16.[a]
Entry
1[d]
Product
t
Yield
[%][b]
ee
Entry
Product
Ligand precursor
Yield
[%][b]
ee
N
[%][c]
[%][c]
1
A
99
95
99
98
96
ꢀ25
ꢀ18
0
2[d]
3[d]
4[d]
A
ACHTUNGTRENNUNG
98
95
89
77
ꢀ87
ꢀ89
ꢀ74
ꢀ51
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
5
6
(S,S)-[L8H][I]
99
97
97
96
2[d]
3[d]
4
48
10
10
AHCTUNGTREG(NNUN S,S)-[L8H][I]
7
(S,S)-[L8H][I]
85
93
[a] 0.2 mmol substrate, 0.05m in DME, absolute configurations of 2b–d
were assigned by comparison of the CD spectrum with that of (S)-
2a.[15d,e] [b] Isolated yield. [c] The enantiomeric ratio was determined by
HPLC analysis on a chiral stationary phase. [d] Reaction time is 3 h.
5[d]
48
10
48
91
95
92
ꢀ77
4
Table 2. Ring-size effect in asymmetric synthesis of spirooxindoles.[a]
6
7
88
Entry
Product
Ligand precursor
Yield
[%][b]
ee
[%][c]
1[d]
2[d]
N
89
82
23
52
8
48
98
88
3[e]
(S,S)-[L8H][I]
99
81
9
PG=Me, (R)-17i
PG=Bn, (R)-17j
PG=MOM, (R)-17k
PG=BOM, (R)-17l
48
48
24
24
98
94
97
94
90
84
86
86
10
11[e]
12[e]
4[f]
G
96
97
86
83
13
48
75
56
5[f]
[a] 0.2 mmol substrate with 0.05m in DME, absolute configurations were
assigned by analogy and were tentative. [b] Isolated yield. [c] Enantio-
meric ratio was determined by HPLC analysis on a chiral stationary
phase. [d] (R,R)-[L8H][I] was used. [e] 508C.
[a] 0.2 mmol substrate with 0.05m in DME, absolute configurations were
assigned by analogy and were tentative. [b] Isolated yield. [c] The enan-
tiomeric ratio was determined by HPLC analysis on a chiral stationary
phase. [d] 36 h. [e] 20 min. [f] 48 h.
11922
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Chem. Eur. J. 2013, 19, 11916 – 11927

Synthesis of 3,3-Disubstituted Oxindoles
FULL PAPER
Table 4. Enantioselective synthesis of aza-spirooxindoles by palladium-
catalyzed a-arylation.[a]
Entry
Product
t [h]/T [8C]
Yield
[%][b]
ee
[%][c]
1[d]
2[d]
0.2/25
24/ꢀ10
99
99
84
86
3[d]
4[d]
5[e]
0.3/25
24/ꢀ10
24/25
99
99
86
88
91
88
6[d]
7[d]
0.3/25
24/ꢀ10
99
99
86
90
Scheme 8. Synthesis of chiral Pd–NHC complexes.
complex 5 as a 1:1 mixture of diastereoisomers (5a/5b) in
60% yield (Scheme 8).
Table 5 summarizes the results of the reaction depicted in
Scheme 2. The catalytic activity of 5, 20, and 21 was com-
[a] 0.2 mmol substrate with 0.05m in DME, absolute configurations were
assigned by analogy and were tentative. [b] Isolated yield. [c] Enantio-
meric ratio was determined by chiral HPLC analyis. [d] X=Br. [e] X=
Cl.
Table 5. Intramolecular arylation of anilide 1a (see Scheme 2) by using
either in situ generated or preformed Pd0–(S,S)-L1 catalysts.[a]
Enantioenriched aza-spiro-oxindoles are accessible using the
arylation procedure as shown in Table 4. The short reaction
times of ortho-pyridyl-based substrates is attributed to the
faster oxidative addition of electron-poor aryl bromides to
palladium.[30] Carrying out the reaction at ꢀ108C allowed
us to improve the enantioselectivty of aza-spirooxindoles
19a–c (Table 4, entries 2, 4, and 7). Finally, we were pleased
to see that the pyridyl chloride substrate 18a undergoes the
cyclization reaction even at room temperature, producing,
after 24 h, the desired product in 86% yield with 88% ee
(entry 5).
Entry
Cat.
A
Base
(1.5 equiv)
t
Yield
[%][b]
ee
[h]
[%][c]
1[d]
2
in situ
(S,S)-20
(S,S)-21
(S,S)-21
(S,S)-20
(S,S)-21
(S,S)-5
(S,S)-5
tBuONa
tBuONa
tBuONa
tBuONa
tBuOK
tBuOK
tBuONa
tBuONa
4
24
24
48
24
24
24
99
<10
<10
99
98
98
94
94
94
90
94
94
94
94
AHCTUNGTRENNUNG
3
ACHTUNGTRENNUNG
4[e]
5
ACHTUNGTRENNUNG
T
6
7
N
R
65
99
8[f]
A
1.5
[a] 0.2 mmol substrate, 0.05m in DME, 258C. [b] Isolated yield. [c] The
enantiomeric ratio was determined by HPLC analysis on a chiral station-
ary phase. (Chiracel OD-H column). [d] 5 mol% (S,S)-[L1H][I], 5 mol%
[PdACHTNUTRGNENG(U dba)2], 1.5 equiv tBuONa. [e] At 508C [f] Reaction performed with
10 mol% of dba.
Isolation of metallacycle intermediates and their application
as catalysts: In all of our previous studies of oxindole and
azaoxindole products, we used an in situ procedure to gener-
ate the chiral Pd0–NHC* (NHC*=L1–L11) catalysts. Gen-
eration of [Pd0(L1)] involved treating a mixture of [Pd2-
A
pared to the original in situ procedure. The reaction using in
situ generation of the catalyst was monitored by GC analy-
sis. This showed complete conversion of starting material to
oxindole 2a in 4 h (Table 5, entry 1). Reactions carried out
with (S,S)-20 in the presence of tBuONa showed very poor
conversion at RT (entry 2). Although subject to a nucleo-
philic addition/ligand exchange under milder conditions, the
cinnamyl complex 21 behaved analogously (entry 3). Raising
the temperature to 508C in this case led to the formation of
oxindole 2a in quantitative yield in 48 h with 90% enantio-
selectivity (entry 4). The use of tBuOK was superior as
shown in entries 5 and 6, but the reaction was still not as ef-
ficient as the in situ procedure.
thoxyethane with tBuONa. An excess of base was used that
then generated the amide enolate from the initially formed
palladacycle 5 (Scheme 3).[14]
Complexes 20 and 21 were obtained readily by reaction of
[Pd{(R)-allyl}Cl]2 and [Pd{(R)-cinnamyl}Cl]2, respectively,
with imidazolium salt (S,S)-[L1H][I] and tBuONa. The reac-
tion was carried out in DME at RT and produced the air
and moisture-stable (S,S)-20 and (S,S)-21 in high yields
(Scheme 8).
The reaction of exactly one equivalent of base together
with aryl bromide 1a, chiral imidazolium salt (S,S)-[L1H][I],
and a stoichiometric amount of [PdACTHNUTRGNENUG(dba)2] in DME afforded
Chem. Eur. J. 2013, 19, 11916 – 11927
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11923

R. B. Sunoj, E. P. Kꢀndig et al.
Surprisingly, the palladacyle (S,S)-5 was a poor performer
as a catalyst. After 24 h, only 65% conversion of starting
material was achieved (Table 5, entry 7). A clue here was
the observation of some catalyst decomposition as indicated
by the formation of palladium black. Adding dba restored
catalyst lifetime and under these conditions the original in
situ procedure could be improved (entry 8). The effect of
other additives was probed (Figure 5). Not unexpectedly, PIII
Scheme 9. Metallacycles incorporating ligands (S,S)-L2 and (S,S)-L8. Syn-
thesized according to the same procedure as shown in Scheme 4 ((S,S)-
22, 64% yield; (S,S)-23, 58% yield).
5b, and (S,S)-22 are slightly distorted square-planar [PdII-
AHCTUNGTREG(NNUN NHC)] complexes with the iodide trans to the substrate
aryl and the amide trans to the NHC ligand. The O-Pd-CNHC
angle in (S,S)-5a is 169.18, and in (S,S)-5b it is 173.48. Palla-
dacycle (S,S)-22 includes a p–p stacking arrangement be-
tween one of the naphthyl groups of the NHC ligand and
the aryl group of the substrate (3.462 ꢄ). This may be of
some importance in the transition state leading to the prod-
uct with high asymmetric induction. A comparison of the
structures of the palladacycles show all stereoelements of
the chiral ligand to be located similarly. The minimization of
allylic strain (A1,3), both in the Pd-C-N-C-H and also in H-
Figure 5. Effect of additives on the Pd-catalyzed a-arylation of amide 1a
to give 2a by using a diasteromeric mixture of 5 as the catalyst. Reaction
conditions: [1a]=0.05m, (S,S)-5 5 mol%, additive (10 mol%), tBuONa
(1.5 equiv), DME, RT. Reaction monitored by GC analysis using decane
as the internal standard. In all reactions, the oxindole 2a formed in
94% ee. a) 65% conversion of starting material 1a after 24 h. b) 7% con-
version of starting material 1a after 24 h.
C
benzylic-CAr-Corttho-CH3 parts of the ligand fix the aryl stereo-
control elements of the NHC ligand in the complex
(Figure 6).
Overall, the ligand, when coordinated to PdII adopts an
approximate C2 chiral structure. In contrast, in the immida-
zolium salt both tBu groups are in one hemisphere and the
aryl groups are in the other with respect to the heterocycle
plane.[15e,16]
Catalysis with palladacycles (S,S)-22 and (S,S)-23
(Scheme 9) in the presence of maleic anhydride proved
slightly less efficient than with (S,S)-5 (Figure 7).
ligands (PPh3, PCy3) interrupted the catalytic cycle, whereas
alkenes rendered the process more efficient in the order of
styrene<dba<maleic anhydride. In the presence of the al-
kenes (10 mol%), the half-life (t1/2) of the first-order reac-
tion was 39 (styrene), 30 (dba), and 19 min (maleic anhy-
dride). This sequence likely reflects the ability of the al-
kenes to stabilize the Pd0–NHC catalyst after a catalytic
cycle. Electron-deficient olefins also decrease the activation
energy barrier of the reductive elimination step.[31] Catalyst
loading was reduced to 0.5 mol% with [1a]=0.8m, 1 mol%
maleic anhydride (reaction time=48 h). This produced 78%
conversion of [1a] and a TON of 156. Asymmetric induction
remained at 94% ee in all reactions.
Conclusion
The DFT computational analysis of the reaction mechanism
reveals that the oxidative insertion of palladium–NHC* to
ꢀ
Caryl Br bond initially generates a palladacycle, which upon
Structure of metallacycles (S,S)-5a, (S,S)-5b, and (S,S)-
22:[32] The diastereoisomers 5a and 5b were separated by
column chromatography and were fully characterized. In
(S,S)-5b, one of the o-methyl groups of the NHC ligand in-
teracts with the aromatic
deprotonation gives an O-enolate. The subsequent conver-
sion of O-enolate to C-enolate followed by reductive elimi-
nation accounts for the asymmetric induction to give highly
enantioenriched oxindoles. The metallacycles formed in the
system of the substrate. The
1H NMR spectrum of (S,S)-5b
shows a shift of close to d=
1 ppm for these hydrogen
atoms ((S,S)-5a, d=2.03 ppm,
(S,S)-5b, d=2.98 ppm).
The palladacycles (S,S)-22
and (S,S)-23 were prepared
analogously to 5 (Scheme 9)
and the X-ray structure of
(S,S)-22 is included in Figure 5.
Metallacycles (S,S)-5a, (S,S)-
Figure 6. ORTEP diagrams of palladacycles left: (S,S)-5a, middle: (S,S)-5b, and right: (S,S)-22 (50% probabili-
ty level for the thermal ellipsoids). All H atoms except those on the stereogenic centers have been omitted for
clarity.[31]
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Chem. Eur. J. 2013, 19, 11916 – 11927

Synthesis of 3,3-Disubstituted Oxindoles
FULL PAPER
123.8, 125.0, 125.10, 125.19, 125.4, 127.2, 128.9, 132.4, 133.5, 140.5 ppm;
IR (neat, cmꢀ1): n˜ =3366, 3296, 2962, 1948, 1594, 1509, 1473, 1389, 1358,
1328, 1069, 1026, 909, 872, 802, 780, 749, 633 cmꢀ1
.
Resolution of amine rac-8: An equimolar mixture of rac-8 (34.0 g,
159.62 mmol) and (l)-malic acid (21.4 g, 159.62 mmol) was placed in a
2 L round-bottomed flask equipped with a reflux condenser. iPrOH
(900 mL) and EtOAc (120 mL) were added and the magnetically stirred
mixture was heated to reflux until all the solid had dissolved. The flask
was then placed in a cold room (58C) overnight. The crystalline precipi-
tate was filtered from the mother liquid and washed with iPrOH
(100 mL). After drying under vacuum, the enantiomerically enriched salt
of amine 8 (23.2 g, 67.04 mmol, 42% yield) was obtained with 88% ee
(checked by HPLC analysis after treating a sample with NaOH (1n) and
extracted with Et2O: Chiracel OD-H column, n-hexane/iPrOH=99:1,
Figure 7. Variation of precatalysts in Pd-catalyzed a-arylation of amide
1a. Reaction conditions: [1a]=0.05m, catalyst 5 mol%, maleic anhydride
(10 mol%), tBuONa (1.5 equiv), DME, RT. Reaction was monitored by
GC analysis using decane as the internal standard.
1.0 mLminꢀ1
, 254 nm; tR =26.09 (major) and 21.47 min (minor)). A
second recrystallization was carried out by refluxing the salt of amine 8
(23.2 g, 67.04 mmol, 88% ee) in iPrOH (500 mL) and EtOAc (100 mL)
until the solid had dissolved. The hot solution was cooled to RT over-
night, crystals separated by filtration, washed with iPrOH (80 mL), and
dried under vacuum. Addition of NaOH (1n) and extraction with ether
afforded amine (S)-8 (12.90 g, 38%, >99% ee) as a colorless crystalline
solid. M.p. 82–838C; [a]2D5 =ꢀ59.1 (c=1.0 in CH2Cl2).
Representative procedure for the synthesis of imidazolium iodide salt
(S,S)-[L8H][I]: Aq. glyoxal (40%; 690 mL, 6 mmol, 0.5 equiv) was intro-
duced into dichloromethane (25 mL) and vigorously stirred with freshly
dehydrated sodium sulfate (6.0 g). Formic acid (98%; 34 mL, 0.9 mmol,
7 mol%) and (S)-8 (2.55 g, 12 mmol, 1.0 equiv) were added. The mixture
was stirred for 5 min and then additional sodium sulfate (6.0 g) was
added. During 5 h of stirring at RT the solution turned slightly yellow.
The mixture was then filtered and the solvent was removed in vacuo to
yield the diimine intermediate, which was purified by crystallization from
MeOH.
initial step were isolated and spectroscopically and structur-
ally characterized. They are efficient catalysts for the reac-
tion provided that an alkene is added to stabilize the Pd0–
NHC catalyst at the end of the catalytic cycle. New bulky
NHC ligands were synthesized and one of them (L8) proved
to vastly outperform previous catalysts in the reactions
yielding spirooxindoles and aza-spirooxindoles.
Experimental Section
Chloromethyl pivalate (0.47 mL, 3.26 mmol) was added to AgOTf
(830 mg, 3.26 mmol) in CH2Cl2 (16 mL) and the resulting mixture was
stirred for 45 min under N2 in the absence of light. The resulting suspen-
sion was transferred via a cannula, equipped with a filter, into a second
Schlenk tube containing the diimine (890 mg, 2.17 mmol). The solution
was stirred in the absence of light at 408C for 24 h. The reaction was
cooled to ambient temperature and the solvent was evaporated and sub-
sequently taken up in dry acetone (10.0 mL). NaI (109 mg) was added
and the reaction was stirred overnight. All volatiles were removed by
evaporation. The residue was taken up in a small amount of CHCl3 and
filtered through cotton. The entire procedure for the ion exchange was
repeated with NaI (99 mg, 1.0 equiv). Column chromatography (CH2Cl2/
Et2O 1:1) afforded the product (S,S)-[L8H][I] (574 mg, 45% yield over
two steps). Yellow solid; m.p. 156–1588C; [a]2D5 = +35.1 (c=1.0 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=1.18 (s, 18H), 6.75 (s, 2H),
7.42 (d, J=7.3 Hz, 2H), 7.49 (d, J=1.5 Hz, 2H), 7.52 (t, J=7.8 Hz, 2H),
7.61 (dd, J=6.9, 1.3 Hz, 1H), 7.63 (dd, J=6.9, 1.3 Hz, 1H), 7.80 (dd, J=
8.2, 0.6 Hz, 2H), 7.83 (d, J=8.2 Hz, 2H), 8.04 (d, J=6.7 Hz, 2H), 8.79 (d,
J=8.7 Hz, 2H), 11.48 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=
28.1, 37.3, 67.0, 122.0, 123.9, 124.9, 126.5, 126.6, 128.1, 129.2, 130.2, 131.0,
132.1, 134.2, 138.3 ppm; IR (neat, cmꢀ1): n˜ =2962, 1599, 1536, 1476, 1369,
1140, 1030, 786, 756, 667 cmꢀ1; HRMS (EI): m/z: calcd for C33H37N2:
461.2956 [MꢀI]+; found: 461.2970.
General: Solvents were purified by filtration on drying columns using a
Solvtek system or by distillation over Na/benzophenone. Reactions and
manipulations involving organometallic or moisture sensitive compounds
were carried out under purified nitrogen in glassware dried by heating
under high vacuum. M.p.: Bꢀchi 510 (uncorrected). GC: Hewlett Packard
6890 gas chromatograph with FID detection using a Permabond OV-
1701–0.25 column (25 mꢅ0.32 mm ID). HPLC: Agilent 1100 series chro-
matograph. NMR: Bruker AMX-500, AMX-400, or AMX-300 FT; inter-
nal d-lock. IR spectra: Perkin–Elmer Spectrum One. Neat liquids;
Golden Gate accessory. HRMS: +TOF mode, ESI-MS mode, Applied
Biosystems/Scix (Q-STA) spectrometer. [a]D: Perkin–Elmer 241 polarim-
eter, quartz cell (l=10 cm), Na high-pressure lamp (l=589 nm). CD
spectra: Jasco J-715, quartz cell (l=1 cm).
Synthesis of rac-amine 8: A 250 mL flask, equipped with condenser and
stirring bar was dried under vacuum by using a heat gun. After cooling
under
a current of N2, it was charged with 1-naphonitrile (10.0 g,
65.35 mmol, 1.0 equiv), followed by tBuMgCl (40.35 mL of 1.7m solution
in Et2O, 68.61 mmol, 1.05 equiv) and CuBr (262 mg, 2.8 mol%,
1.83 mmol). The reaction was refluxed for 24 h under N2. After cooling
to ꢀ788C, dry methanol (50 mL) was added cautiously followed by
NaBH4 (3.2 g, 85 mmol, 1.3 equiv) in two portions and the reaction was
allowed to warm to RT over 6 h and stirred overnight. H2O (50 mL) was
added slowly and the precipitate was removed by filtration and washed
with Et2O. The filtrate was evaporated and the product was distilled
under reduced pressure. The material obtained was dissolved in Et2O
and precipitated by adding 1m HCl in Et2O. The solid was suspended in
Et2O and then aq. NaOH (1m) solution was added until a clear two-
phase solution was obtained. The organic layer was separated and the aq.
phase was washed repeatedly with small quantities of Et2O. The com-
bined organic phases were dried over MgSO4. Filtration over Celite and
evaporation of volatiles under reduced pressure afforded amine 8 as a
colorless solid (9.30 g, 67%).
Catalytic asymmetric intramolecular a-arylation reaction
Spirocyclic oxindole (S)-15c: Under N2, a dried Schlenk tube was charg-
ed with [PdACHTNUTRGNENG(U dba)2] (5.7 mg, 0.01 mmol), (S,S)-[L8H][I] (5.88 mg,
0.01 mmol), and tBuONa (28.8 mg, 0.3 mmol). Dimethoxyethane (DME)
(1 mL) was added and the mixture was stirred for 10 min. Substrate 14c
(68.8 mg, 0.2 mmol) was then added as a solution in DME (3 mL). The
reaction was stirred at RT for 48 h and then quenched with aq. NH4Cl
and extracted with diethyl ether. The combined organic phases were
washed with water and brine and then dried over Na2SO4. Flash chroma-
tography over SiO2 afforded (S)-15c as a white solid (50.5 mg, 96%).
M.p. 146–1488C; [a]2D5 = +4.31 (c=1.0 in CH2Cl2); 86% ee (Chiracel AS-
2,2-Dimethyl-1-(naphthalen-1-yl)propan-1-amine
(rac-8):
1H NMR
(400 MHz, CDCl3): d=1.02 (s, 9H), 1.59 (brs, 2H), 4.84 (s, 1H), 7.47–
7.57 (m, 3H), 7.73–7.79 (m, 2H), 7.82 (d, J=21 Hz, 1H), 8.26 ppm (d,
J=7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=26.9, 36.3, 57.2, 99.9,
H
column, n-hexane/iPrOH=98:2, 1.0 mLminꢀ1
(major) and 15.46 min. (minor)); 1H NMR (400 MHz, CDCl3): d=1.98–
, 254 nm; tR =11.26
Chem. Eur. J. 2013, 19, 11916 – 11927
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11925

R. B. Sunoj, E. P. Kꢀndig et al.
2.13 (m, 2H), 2.21–2.28 (m, 1H), 2.37–2.46 (m, 1H), 2.98–3.12 (m, 1H),
3.35 (s, 3H), 6.53 (d, J=7.7 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.01 (t, J=
8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.18 (t, J=
8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.37 ppm (td, J=8.0, 1.3 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=18.7, 26.5, 29.7, 34.0, 52.2, 108.0, 122.8,
124.0, 126.3, 127.1, 127.8, 128.0, 129.7, 135.1, 137.3, 137.8, 143.1,
180.5 ppm; IR (neat, cmꢀ1): n˜ =2933, 1707, 1610, 1491, 1342, 1255, 1125,
1091, 965, 749, 692 cmꢀ1; HRMS (EI): m/z: calcd for C18H17NO: 264.1382
[M+H]+; found: 264.1388.
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Computational methods: All calculations were carried out using the
Gaussian 09 suite of quantum chemical programs.[33] The hybrid density-
functional B3LYP was used for the calculations.[34] The LANL2DZ basis
set consisting of effective core potential (ECP) for 28 electrons and Hay–
Wadtꢃs valance basis functions for all other electrons has been used for
palladium and iodine.[35] The remaining elements (C,H,N,O,Br,Na) were
represented by using the 6-31G* basis set.[36] In all computations, pure d
functions were employed. The effect of solvent for the most preferred
pathway was taken into account by computing the energy at the
SMD1,4-dioxane/B3LYP/6-311+G** (C,H,N,O,Br,Na); LANL2TZ(f)(Pd)//
B3LYP/6-31G* (C,H,N,O,Br,Na); LANL2DZ(Pd) level of theory. The
thermal and entropic corrections, as obtained at the B3LYP/6-
31G*(C,H,N,O,Br,Na); LANL2DZ(Pd) level of theory, were included to
the single-point energies obtained in the solvent continuum to estimate
the Gibbs free energies. The closely related 1,4-dioxane was used as the
solvent due to the lack of parameters for DME in the Gaussian 09 suite
of programs. The nature of the stationary points was verified by the
visual inspection of the imaginary frequencies pertaining to the desired
reaction coordinate. The transition states were characterized by one and
only one imaginary frequency representing the reaction coordinate. Fur-
ther, the intrinsic reaction coordinate (IRC) calculations were performed
to authenticate the transition states.[37] The final geometries obtained by
IRC calculation were further subjected to optimization with “OPT=
RCFC” option to obtain minima on either sides of the transition state.
The discussion in the main text is based on the solvent phase energies.
The gas phase energies are provided in the Supporting Information.
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Acknowledgements
We thank the Swiss National Science Foundation (grant no.
200020 134682/1 to E.P.K.), BRNS-Mumbai (RBS), and the University
of Geneva for financial support and the IITB computer center for com-
puting time. A.K.S. acknowledges CSIR (New Delhi) for a senior re-
search fellowship.
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Chem. Eur. J. 2013, 19, 11916 – 11927

Synthesis of 3,3-Disubstituted Oxindoles
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ꢀ
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are provided in Figure S1 in the Supporting Information.
[21] Optimized geometries for the deprotonation are provided in Fig-
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[22] The optimized geometries of two other transition states involved in
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Scheme S2 and Figure S7 in the Supporting Information). Rotation
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ꢀ
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ꢀ
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energy barrier for the C C bond formation TS in this mode is found
to be higher. The geometries for this possibility are provided in Fig-
Received: April 24, 2013
ure S10, TS-(7R-2S)Conf-PdBr, in the Supporting Information.
Published online: July 25, 2013
Chem. Eur. J. 2013, 19, 11916 – 11927
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11927