Orthogonal Pd- and Cu-based catalyst systems for C- and N-arylation of oxindoles

Article abstract of DOI:10.1021/ja803179s

In the cross-coupling reactions of unprotected oxindoles with aryl halides, Pd- and Cu-based catalyst systems displayed orthogonal chemoselectivity. A Pd-dialkylbiarylphosphine-based catalyst system chemoselectively arylated oxindole at the 3 position, while arylation occurred exclusively at the nitrogen using a Cu-diamine-based catalyst system. Computational examination of the relevant L₁Pd(Ar)(oxindolate) and diamine-Cu(oxindolate) species was performed to gain mechanistic insight into the controlling features of the observed chemoselectivity.

Full text of DOI:10.1021/ja803179s

Published on Web 06/28/2008
Orthogonal Pd- and Cu-Based Catalyst Systems for C- and
N-Arylation of Oxindoles
Ryan A. Altman, Alan M. Hyde, Xiaohua Huang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
Received May 2, 2008; E-mail: sbuchwal@mit.edu
Abstract: In the cross-coupling reactions of unprotected oxindoles with aryl halides, Pd- and Cu-based
catalyst systems displayed orthogonal chemoselectivity. A Pd-dialkylbiarylphosphine-based catalyst system
chemoselectively arylated oxindole at the 3 position, while arylation occurred exclusively at the nitrogen
using a Cu-diamine-based catalyst system. Computational examination of the relevant L1Pd(Ar)(oxindolate)
and diamine-Cu(oxindolate) species was performed to gain mechanistic insight into the controlling features
of the observed chemoselectivity.
Introduction
of the identical acidities of the protons in positions C3 and N1
(pKa ) 18.5),8 the cross-coupling reactions of oxindole with
In recent years, Pd-catalyzed1 and Cu-catalyzed2 nucleophilic
substitution reactions of aryl halides have been areas of intensive
research. Our laboratory has been intimately involved in
designing and developing highly efficient and user-friendly Pd-
and Cu-based catalyst systems to cross-couple aryl halides with
a wide variety of nucleophiles, including amides3,4 and ketone
enolate derivatives.5,6
Generally, Cu- and Pd-catalyzed arylation reactions of both
linear and cyclic aliphatic amides react at the more acidic N-H
moiety as opposed to the less acidic C-HR position. For
instance, when reacting 2-pyrrolidinone with aryl halides, both
Cu-diamine- and Pd-biarylmonophosphine-based catalyst sys-
tems provide the N-aryl amide in excellent yield (Scheme 1).3,4
Ongoing work in our and other laboratories7 has identified
oxindole as a unique substrate for chemoselective metal-
catalyzed cross-coupling reactions with aryl halides. Because
aryl halides might provide either the C-aryl or the N-aryl
products.
Importantly, N1-aryl and C3-aryl oxindole products of the
type generated from the reactions described in this manuscript
display interesting biological activities with therapeutic applica-
tions (Figure 1).9 In addition, the amide of the N-aryl oxindole
can be cleaved to provide access to a variety of derivatives of
2-(2-phenylamino)phenyl)ethanoic acid nonsteroidal anti-inflam-
matory agents, such as Lumiracoxib10 and Diclofenac.11
Herein, we describe improved reaction conditions for the Cu-
catalyzed N1-arylation reaction with aryl iodides and bromides
and general reaction conditions for the Pd-catalyzed C3-arylation
reaction of unprotected oxindoles with aryl chlorides and
tosylates. Further, we report computational studies that suggest
reasonable explanations for the observed selectivity.
Results
(1) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (b)
Jiang, L.; Buchwald, S. L. Palladium-catalyzed aromatic carbon-
nitrogen bond formation. In Metal-Catalyzed Cross-Coupling Reac-
tions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 699-760.
Pd-Catalyzed C3-Arylation of Oxindoles. The use of 1%
Pd2(dba)3 and 5% XPhos (Figure 2) was found to facilitate the
(2) (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096.
(b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 2337.
(c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(3) For Cu-catalyzed N-arylation of amides using N,N′-dimethyl-1,2-
ethylenediamine-derived ligands, see:(a) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (b)
Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(7) (a) Phillips, D. P.; Hudson, A. R.; Nguyen, B.; Lau, T. L.; McNeill,
M. H.; Dalgard, J. E.; Chen, J. H.; Penuliar, R. J.; Miller, T. A.; Zhi,
L. Tetrahedron Lett. 2006, 47, 7137. (b) Huang, J.; Bunel, E.; Faul,
M. M. Org. Lett. 2007, 9, 4343. (c) Durbin, M. J.; Willis, M. C. Org.
Lett. 2008, 10, 1413. (d) van den Hoogenband, A.; Lange, J. H. M.;
Iwema-Bakker, W. I.;.; den Hartog, J. A. J.; van Schaik, J.; Feenstra,
R. W.; Terpstra, J. W. Tetrahedron Lett. 2006, 47, 4361.
(8) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
(9) (a) Luk, K. C.; So, S. S.; Zhang, J.; Zhang, Z. (F. Hoffman-LaRoche
AG) Oxindole Derivatives. WO 2006/136606 A3, December 28, 2006.
(b) Hewawasam, P.; Gribkoff, V. K.; Pendri, Y.; Dworetzky, S. I.;
Meanwell, N. A.; Martinez, E.; Boissard, C. G.; Post-Munson, D. J.;
Trojnacki, J. T.; Yeleswaram, K.; Pajor, L. M.; Knipe, J.; Gao, Q.;
Perrone, R.; Starrett, J. E., Jr. Bioorg. Med. Chem. Lett. 2002, 12,
1023. (c) Sarges, R.; Howard, H. R.; Koe, K.; Weissman, A. J. Med.
Chem. 1989, 32, 437.
(4) For Pd-catalyzed amidation of aryl halides using Xantphos and
dialkylbiarylmonophosphine ligands, see:(a) Yin, J.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 6043. (b) Huang, X.; Anderson, K. W.;
Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653. (c) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2007, 129, 13001.
(5) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (c) Hamada, T.; Chieffi, A.; Ahman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261. (d) Nguyen,
H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11818.
(10) Karnachi, A. A.; Bateman, S. D. (Novartis-AG) Pharmaceutical
Composition Comprising Lumiracoxib. WO 03/020261 A1, March 13,
2003.
(11) Acemoglu, M.; Allmendinger, T.; Calienni, J.; Cercus, J.; Loiseleur,
O.; Sedelmier, G. H.; Xu, D. Tetrahedron 2004, 60, 11571.
(6) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
9
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 9613–9620 9613

A R T I C L E S
Altman et al.
Scheme 1. Pd- and Cu-Catalyzed C- and N-Arylation of 2-Pyrrolidinone and Oxindole
cross-coupling of aryl chlorides with oxindoles unsubstituted
at C3 using K2CO3 as the base in THF or 1,4-dioxane at
temperatures ranging between 80 and 100 °C (Table 1). The
use of bidentate or other dialkylbiarylmonophosphine ligands
provided a low conversion of starting material and yield of
products. The Pd-catalyzed C3-arylation reaction of oxindoles
with aryl chlorides tolerated a variety of functional groups on
the meta and para positions of the electrophile (Table 1, entries
1-10); however, ortho-substituted aryl chlorides provided a low
conversion of reactants (>5%) even at slightly elevated tem-
peratures (up to 120 °C) with a variety of biarylmonophosphine
ligands. Under the standard reaction conditions, the use of
3-chlorobenzonitrile provided low yields of coupled product due
to partial hydrolysis of the nitrile functional group to an amide
(Table 1, entry 4). This side reaction could be partially impeded
by the addition of activated 4 Å molecular sieves to the reaction
vessel. Using t-BuOH as a solvent, an unactivated aryl benze-
nesulfonate could be successfully cross-coupled to provide the
C-aryl product in modest yield (Table 1, entry 5). Substrates
possessing substituents on the benzannulated backbone (Table
1, entries 6-8) as well as on the nitrogen atom (Table 1, entries
9-10) provided more highly substituted products. Using XPhos
as a ligand, the reaction of a 3-substituted oxindole was
unsuccessful;7b however, using reoptimized reaction conditions
(RuPhos/NaOt-Bu/toluene), the cross-coupling reactions of
3-methyl- and 3-benzyloxindole were successfully accomplished
to generate quaternary stereocenters at the C3 positions to
produce racemic products (Table 1, entries 11-12). In contrast
to the previously reported catalyst systems for the C3-vinylation
of unprotected oxindoles and C3-arylation of protected oxin-
doles, which required strong bases such as potassium bis(tri-
methylsilyl)amide (KHMDS) and Lithium bis(trimethylsilyl)-
amide (LHMDS), respectively, for the reactions to proceed,7b,c
K2CO3 and NaOt-Bu were found to be suitable bases with our
catalyst system.
Cu-Catalyzed N-Arylation of Oxindoles. The Cu-catalyzed
N-arylation reactions of meta- and para-substituted aryl iodides
generally proceeded smoothly at temperatures ranging from 80
to 100 °C using 1-5% catalyst loading, 4-10% trans-N,N′-
dimethylcyclohexane-1,2-diamine (CyDMEDA) (Figure 2) as
the ligand, K2CO3 as the base, and 1,4-dioxane as the solvent
(Table 2, entries 1-8). In these reactions, the C3-aryl product
was not detected by GC-MS analysis of the crude reaction
mixtures. Using this catalyst system, ortho-substituted aryl
iodides were unreactive, even at temperatures up to 150 °C in
high boiling-point solvents. This serves to reinforce the notion
that ortho-substituted aryl halides can be quite difficult to
activate in Cu-catalyzed C-heteroatom bond-forming reactions.
At 60-100 °C, the cross-coupling reaction of 1-bromo-4-
iodobenzene with oxindole provided a complex mixture of
products; however, by lowering the reaction temperature to 40
°C, the bromide-containing product could be isolated in accept-
able yield (Table 2, entry 3). The addition of activated 4 Å
molecular sieves to the reaction mixtures was necessary for
substrates containing hydroxide- or water-sensitive functional
groups (Table 2, entries 4 and 7). As anticipated, substituents
on the nucleophile also were tolerated (Table 2, entries 6-7).
Figure 1. Therapeutically relevant C-aryl and N-aryl oxindoles and related
compounds.
Figure 2. Ligands employed for metal-catalyzed C- and N-arylation of
oxindole.
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Cu- and Pd-Catalyzed N- and C-Arylation of Oxindole
A R T I C L E S
Table 1. Pd-Catalyzed C-Arylation of Oxindolesa
Table 2. Cu-Catalyzed N-Arylation of Oxindolesa
a Reactions conditions: 1.0-1.2 mmol of oxindole, 1.2-1.0 mmol of
ArI, 2.0 mmol of K2CO3, and 1.0 mL of 1,4-dioxane in a sealed tube
under Ar atmosphere. Yields reported are an average of at least two
runs determined to be >95% pure by elemental analysis or 1H NMR.
b 4 Å mol sieves.
Aryl bromides also proved to be reactive in the Cu-catalyzed
cross-coupling reactions with oxindoles (Table 2, entries 8-11),
although higher catalyst loadings were necessary to ensure full
conversion of the substrates within a 24 h time period. Although
the C3-aryl oxindole product was not observed, up to 5% of
the N1,C3-bis-arylated product (10% aryl halide consumption)
was isolated in the reaction of 5-bromo-m-xylene (Table 2, entry
9). A second common side product, when using aryl bromides,
was the reduced arene. Aryl chlorides were not suitable coupling
a Reactions conditions: 1.0-1.2 mmol of oxindole, 1.2-1.0 mmol of
ArCl, 2.0 mmol of K2CO3, 0.010 mmol of Pd2dba3, 0.050 mmol of
XPhos, and 1.0 mL of solvent in a sealed tube under Ar atmosphere.
Yields reported are an average of at least two runs determined to be
>95% pure by elemental analysis or 1H NMR. b 3.0 mmol of K2CO3.
c 4 Å mol sieves. d From ArOSO2Ph. e K3PO4 used as base. f From
ArBr. RuPhos and NaOt-Bu employed as ligand and base; 9 h reaction
time. g From ArBr. RuPhos and NaOt-Bu employed as ligand and base;
20 h reaction time.
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A R T I C L E S
Altman et al.
Scheme 2. Mechanisms of Pd- and Cu-Catalyzed Nucleophilic Substitution Reactions of Aryl Halides
partners for this reaction. These substrates are generally unre-
active in Cu-catalyzed C-heteroatom bond-forming reactions due
to the high energy required for activating the Caryl-Cl bond
relative to the -Br or -I bonds.2
Computational Studies of Ligand-Metal(Oxindole) Complexes.
The catalytic cycle of Pd-catalyzed nucleophilic substitution
reactions of aryl halides involves three steps: (1) oxidative-
addition, (2) transmetalation, and (3) reductive-elimination
(Scheme 2, Cycle A).1
Since oxindole does not participate in the oxidative-addition
step of the cycle, the selectivity-controlling feature for the Pd-
based catalyst system must involve either transmetalation or
reductive-elimination. To gain further insight into the observed
selectivity, the relative energies and structures of various
L1Pd(Ph)(oxindolate) complexes were calculated by DFT
methods (Figures 3 and 4; see Computational Methods for full
details).
arylated oxindole product, it was critical to model structures
that contained the entire ligand without any approximations.
The geometry of the XPhos ·Pd(Ph)(oxindolate) complex formed
following transmetalation was minimized with the Pd bound to
either the nitrogen or the R-carbon of the oxindole (Figure 3).
This minimization was performed with structures in which the
Pd points toward or away from the lower biaryl ring. Consistent
with previous computational studies from our group,12 three-
coordinate Pd(II)/dialkylbiarylmonophosphine intermediates
prefer the orientation shown in structures 1 and 2 with the Pd
sitting above the lower biaryl ring. In both cases, the C-bound
oxindolate was significantly higher in energy than the N-bound
complex. This energy difference was 4.8 kcal/mol between 1
and 2 and 7.0 kcal/mol between 3 and 4. We then determined
the energies of the κ2-amidate (5 and 9), O-bound amidate and
enolate (6, 7, 10, and 11), and η3-oxyallyl (8 and 12) structures,
as they may be intermediates in the N to C isomerization process
(Figure 4). As expected, the three-coordinate O-bound enolate
and amidate structures are lower in energy when the Pd is
pointing toward the lower ring. However, the four-coordinate
κ2-amidate- and η3-oxyallyl-bound structures are lower in energy
when the Pd is distal to the lower ring.
In light of the experimental findings that catalysts derived
from XPhos were the ones that produced high yields of the C3-
If the N- and C-bound structures exist in rapid equilibrium,
then the barriers for reductive-elimination should be product
determining. Thus, transition states for both C-C and C-N
reductive-elimination processes were calculated (Figure 5). The
mechanism for reductive-elimination from Pd-bound enolates
has not been well-studied and could occur by different mech-
anisms involving O-bound, C-bound, or η3-oxyallyl Pd inter-
mediates. Hartwig and Culkin13 put forth circumstantial evidence
in support of a simple reduction-elimination between an η1-
bound enolate and an arene. However, these studies were
primarily performed using bidentate ligands, which may prevent
η3-bound intermediates and relevant transition states. Several
reports have appeared that indicate that η3-oxyallyl Pd inter-
mediates may be involved in some Pd-enolate-based processes.14
Reasonable starting geometries for the transition states of
enolate C-C reductive-elimination were arrived at by examining
calculations reported by others for methyl-methyl reductive-
Figure 3. Calculated geometries and energies of C- and N-bound
XPhos·Pd(Ph)(oxindolate) complexes with B3LYP (calculated at 298 K
in THF).
(12) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
(13) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
(b) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
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Cu- and Pd-Catalyzed N- and C-Arylation of Oxindole
A R T I C L E S
Figure 5. Calculated reductive-elimination transition states for XPhos·
Pd(Ph)(oxindolate) with B3LYP (calculated at 298 K in THF). ∆Erel values
are relative to complex 1 in Figure 3.
Figure 6. Calculated geometries and energies of CyDMEDA ·Cu(oxindolate)
Figure 4. Calculated geometries and energies of the κ2-O- and η3-oxyallyl-
bound XPhos ·Pd(Ph)(oxindolate) complexes with B3LYP (calculated at
298 K in THF). ∆Erel values are relative to complex 1 in Figure 3.
complexes with B3LYP (calculated at 298 K).
starting geometries for amidate C-N reductive-elimination.12
We were then able to quickly find transition states for both C-C
and C-N reductive-elimination toward and away from the lower
biaryl ring. ∆E+ for 1 f 1-TS was calculated to be 21.7 kcal/
mol, while ∆E+ for 2 f 2-TS was significantly less at 14.5
kcal/mol. For structures with the Pd swung away, ∆E+ of 3 f
3-TS was calculated to be 20.9 kcal/mol, and ∆E+ of 4 f 4-TS
was 12.6 kcal/mol. Although these barriers are lower than when
the Pd is pointed toward the lower biaryl ring, their absolute
energies are much higher. Therefore, it is unlikely that 3-TS
and 4-TS contribute to the reaction course. We also attempted
to find a transition state for C-C reductive-elimination, which
proceeds through an η3 pathway, but one could not be
located.
elimination from Pd.15 A prior publication by our group on the
mechanism of aryl amination provided us with reasonable
(14) (a) Ito, Y.; Nakatsuka, M.; Kise, N.; Saegusa, T. Tetrahedron Lett.
1980, 21, 2873. (b) Sodeoka, M.; Ohrai, K.; Shibasaki, M. J. Org.
Chem. 1995, 60, 2648. (c) Albe´niz, A. C.; Catalina, N. M.; Espinet,
P.; Redo´n, R. Organometallics 1999, 18, 5571. (d) For a DFT study
that reports an η3-oxyallyl Pd transition state between O- and C-bound
enolates, see: Ca´mpora, J.; Maya, C. M.; Palma, P.; Carmona, E.;
Gutie´rrez, E.; Ruiz, C.; Graiff, C.; Tiripicchio, A. Chem.sEur. J. 2005,
11, 6889.
(15) (a) Low, J. J.; Goddard, W. A. J. Am. Chem. Soc. 1984, 106, 8321.
(b) Ananikov, V. P.; Musaev, D. G.; Morokuma, K. Organometallics
2005, 24, 715.
9
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A R T I C L E S
Altman et al.
Scheme 3. Transmetalation of Oxindole to XPhos ·Pd(Ph)(Cl)
Cu-catalyzed amidation reactions of aryl halides initiate by
addition of the nucleophile to a L2Cu(I)X complex to provide
an L2Cu(I)amidate, followed by aryl halide activation and
subsequent product formation.16,17 Although Guo et al. recently
published a computational study that calculates the transition
states and intermediates of the catalytic cycle for the Goldberg
reaction,18 this study only considered a mechanism based on
an insertion reaction between an L2Cu(I)(amidate) and an aryl
halide to generate an L2Cu(III)-(Ar)(X)(amidate) species and
neglected to evaluate evidence that an electron-transfer mech-
anism might be occurring, as suggested by Hida et al.19
Therefore, we assume that the mechanism of the rate-limiting
aryl halide activation step is yet to be fully elucidated (Scheme
2, Cycle B). According to this paradigm, reaction of a molecule
of oxindole with the CyDMEDA-CuI complex and base may
provide multiple regioisomeric products, which could react with
aryl halides to provide the N-aryl and C3-aryl products,
respectively. To gain insight into the features that control the
selectivity of the reaction, the energies of relevant CyDMEDA-
Cu(I)(oxindolate) complexes were examined (Figure 6).
As observed with the Pd-based catalyst system, the N-bound
(CyDMEDA)·Cu(oxindolate) 13 was found to be significantly
lower in energy than both C3-bound and O-bound structures.
In this structure, the geometry around Cu is a distorted T-shape,
consistent with known neutral tricoordinate Cu(I) structures.20
Interestingly, the calculation predicts a hydrogen bonding
interaction between the carbonyl and one hydrogen of the amine
(O-H distance of 1.9 Å). The C3-bound oxindolate 14 is
significantly higher in energy by 14.1 kcal/mol. It is noteworthy
that the geometry about Cu is no longer planar but trigonal
pyramidal and equidistant to both nitrogen atoms. There also
appears to be a hydrogen bond between the carbonyl oxygen
and the amine hydrogen (O-H distance of 2.0 Å). The O-bound
amidate 15 and enolate 16 are 9.3 and 19.2 kcal/mol higher in
energy, respectively, than the N-bound structure. We also
optimized κ2-amidate and η3-oxyallyl-bound structures, but no
reasonable stationary points were found.
nucleophile during the transmetalation step of the catalytic cycle
occur at the more acidic N-H position as opposed to the less
acidic C-HR position (Scheme 1). In the case of oxindole, both
the N-H and the C-HR protons are significantly acidified due
to the conjugation of the deprotonated anion with the aromatic
ring. Further, the predisposition for the anion to reside on the
more electronegative nitrogen atom is overcome by the aromatic
stabilization gained from isomerization of the anion to generate
an enolate.8 Thus, a 1:1 ratio of amidate/enolate exists in
solution. As such, the difference in reactivity between typical
aliphatic amides and oxindole demonstrated by Cu- and Pd-
based catalyst systems might not be entirely unexpected.
Since a weak base was employed (K2CO3), the large pKa
difference (∼5) between oxindole and base indicates that an
appreciable quantity of an anionic amidate species does not exist
in solution; thus, an intermolecular ligand exchange between
an oxindolate anion and XPhos ·Pd(Ar)(Cl) 17 is unlikely. As
such, it is likely that the oxindole is further acidified by
reversible coordination of the Pd(II) intermediate 17 to the
oxindole carbonyl to form 18 (Scheme 3). Deprotonation of the
acidified oxindole should occur at N as opposed to C3 since
deprotonation is kinetically faster from N-H than from C-H
bonds, in which rehybridization must occur at the carbon atom.21
Thus, deprotonation of 18 would initially lead to 6, followed
by an intramolecular migration of Pd from O to either N or C.
If intramolecular isomerization is the preferred pathway, then
a plausible reaction sequence to form a C-bound Pd enolate
that does not involve formation a Pd-N bond may be 17 f 18
f 6 f 7 f 8 f 2. If a Pd-N bond does transiently form,
then the reaction pathway might proceed as such, 17 f 18 f
6 f 5f 1 f 5 f 6 f 7 f 8 f 2.
For the Pd-catalyzed C-arylation reaction of oxindole with
aryl halides, transmetalation of a molecule of oxindole to the
L1Pd(Ar)(X) complex can provide multiple isomeric species.
Two of these isomers, namely, 1 and 2, would reductively
eliminate to provide the N-aryl and C3-aryl oxindole products,
respectively. The energy profile illustrating the reaction course
with the relative energies of the key intermediates and transition
states is shown in Figure 7. The C3-aryl product, which is
exclusively observed in the Pd-catalyzed reaction, must result
from a rapid reductive-elimination from the higher-energy
Pd-C-bound enolate, 2, as opposed to the more stable Pd-N-
bound amidate, 1. Therefore, the selectivity demonstrated by
the Pd-catalyzed reaction is kinetically governed according to
the Curtin-Hammett principle.22 The 2.4 kcal/mol difference
in energy between 1-TS and 2-TS is consistent with the
Discussion
In metal-catalyzed amidation reactions of aliphatic amides,
such as 2-pyrrolidinone, coordination and deprotonation of the
(16) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.
(17) Strieter, E. R. Mechanistic Studies on Metal-Catalyzed Carbon-
Nitrogen Bond Forming Reactions. Ph.D. Thesis, Massachusetts
Institute of Technology, Cambridge, MA, June 2005.
(18) Zhang, S. L.; Liu, L.; Fu, Y.; Guo, Q. X. Organometallics 2007, 26,
4546.
(19) Arai, S.; Hida, M.; Yamagishi, T. Bull. Chem. Soc. Jpn. 1978, 51,
277.
(21) (a) Eigen, M. Angew. Chem., Int. Ed. 1964, 3, 1. (b) Borwell, F. G.;
Boyle, W. J.; Hautala, J. A.; Yee, K. C. J. Am. Chem. Soc. 1969, 91,
4002. (c) Kresge, A. J. Acc. Chem. Res. 1975, 8, 354.
(22) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry,
3rd ed.; University Science Books: Sausalito, CA, 2006; pp 378-
379.
(20) (a) Jazdzewski, B. A.; Young, V. G., Jr.; Tolman, W. B. Chem.
Commun. (Cambridge, U.K.) 1998, 2521. (b) Na¨ther, C.; Beck, A.
Acta Crystallogr., Sect. E: Struct. Rep. Online 2004, 60, 1008. (c)
Blue, E. D.; Davis, A.; Conner, D.; Gunnoe, T. B.; Boyle, P. D.; White,
P. S. J. Am. Chem. Soc. 2003, 125, 9435.
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Cu- and Pd-Catalyzed N- and C-Arylation of Oxindole
A R T I C L E S
Figure 7. Energy diagram for XPhos ·Pd(Ph)(oxindolate) reductive-elimination.
Scheme 4. Mechanistic Considerations for Cu-Catalyzed N-Arylation of Oxindole
observed selectivity of the catalytic reaction. This difference in
energy is likely a reflection of the relative electronegativities
of nitrogen and carbon and the overlap of the relevant molecular
orbitals with those of Pd.23 Since the halide anion is not present
during the proposed selectivity-determining event of the cycle,
the change in identity of the electrophile from an aryl chloride
to a bromide or sulfonate ester does not have an effect on the
chemoselectivity observed in the catalytic reaction (e.g., Table
1, entries 11 and 12). However, the change in the nature of
the electrophile should have an effect on the relative rate of
reaction.
selectivity observed for the Cu-catalyzed N-arylation of oxindole
might be governed by two different factors: (1) aryl halide
activation from 13 proceeds faster than from 14 and/or (2) aryl
halide activation proceeds faster than the isomerization process.
If the first factor is selectivity-determining, there could be a
dynamic equilibrium in solution between 13 and 14. The nature
of the aryl halide activation step in Cu-catalyzed C-heteroatom
bond-forming substitution reactions of aryl halides is not
well-understood.17–19 Kinetic studies for the reaction of 2-pyr-
rolidinone with 5-iodo-m-xylene estimate ∆G+ to be 19.4 kcal/
mol.17 Therefore, it is plausible that the C-bound enolate does
exist in small portions in solution and that the selectivity is
governed by the aryl halide activation process (k3 > k4). If the
second factor is selectivity-determining, then the absence of a
low energy pathway for the interconversion of 13 and 14
controls the reaction’s outcome. A better understanding of the
mechanism of aryl halide activation is required to properly
For the Cu-catalyzed N-arylation reaction, the computational
studies of the relevant CyDMEDA-Cu(oxindolate) species
suggest that N-bound species 13 is favored by 14.1 kcal/mol
over the C-bound isomer 14 (Scheme 4). Therefore, the
(23) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
9
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A R T I C L E S
Altman et al.
Because of the size of the XPhos ·Pd complexes, geometry
optimization was first performed using a two-layered ONIOM26
calculation (B3LYP/6-31g(d):UFF) with oxindole, phenyl, Pd, and
P at a high level and the rest of the ligand at a low level. The
resulting structures were then reoptimized using all-atom DFT
B3LYP/6-31g(d) with the LANL2DZ basis set and the Hay-Wadt
effective core potential27 for Pd. To obtain the final ∆E values,
single-point energy calculations were performed with the 6-311g(d,p)
basis set with implicit solvation included. Frequency calculations
were performed on all optimized structures to confirm that the
minima had no negative frequencies and that transition states had
a single imaginary frequency. The Gibbs free energies were
calculated at 298.15 K and 1 atm.
estimate the transitions state energies for this step and to gain
a full understanding for the observed chemoselectivity of the
Cu-catalyzed reaction.
Conclusion
In summary, we reported efficient and complementary Pd-
and Cu-based catalyst systems for the C3- and N-arylation
reactions of unprotected oxindoles using aryl halides. The use
of a weak base allows for the presence of a wide variety of
functional groups and substitution patterns that are not tolerated
with stronger bases.7b,c Theoretical calculations suggest that for
both Pd- and Cu-based catalyst systems, the respective metal-
lated oxindoles have a strong preference for the oxindole moiety
to coordinate as an N-bound amidate as opposed to a C3-bound
enolate. For the Pd-based catalyst system, the energy difference
between the Pd-amide and Pd-enolate is ∼5 kcal/mol; however,
the selectivity is governed by rapid C-C reductive-elimination
as compared to C-N reductive-elimination based on calculated
transition state energies. For the Cu-based catalyst system, the
preference for the metal to bind at N1 is stronger (∼14 kcal/
mol). In this case, the selectivity might be governed by rapid
aryl halide activation from the diamine-Cu(I)-amidate complex
as compared to the diamine-Cu(I)-enolate. Alternatively, a low
energy pathway for Cu to isomerize from N to C may not exist,
and the C-bound enolate might never form. The implications
of this study should be useful for those chemists interested in
understanding the inherent differences between Pd- and Cu-
based catalyst systems for nucleophilic substitution reactions
of aryl halides.
Acknowledgment. We thank the National Institutes of Health
(NIH) (GM58160 and GM46059) for financial support of this
project. R.A.A. is grateful to Pfizer and the NIH (F31GM081905)
for predoctoral fellowships. A.M.H. thanks Aldrich for a Graduate
Student Innovation in Organic Chemistry Award. We thank Amgen,
Boehringer-Ingelheim, and Merck for additional unrestricted fi-
nancial contributions. XPhos used for this study was generously
provided by Saltigo. The NMR instruments used for this study were
furnished by funds from the National Science Foundation (CHE
9808061 and DBI 9729592).
Supporting Information Available: Experimental procedures
and characterization data for all new and known compounds,
computational data for complexes, and complete ref 24. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA803179S
Computational Methods
(25) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B: Condens. Matter Mater. Phys. 1988,
37, 785.
All calculations were performed with the Gaussian ′0324 suite
of programs. DFT calculations employed the B3LYP functional25
using the 6-31G(d) basis set for all atoms in the Cu complexes.
(26) (a) Svensson, M.; Humbel, S.; Froese, R. D. J.; Matsubara, T.; Sieber,
S.; Morokuma, K. J. Phys. Chem. 1996, 100, 19357. (b) Vreven, T.;
Morokuma, K.; Farkas, O.; Schlegel, H. B.; Frisch, M. J. J. Comput.
Chem. 2003, 24, 760.
(24) Frisch, M. J.; Gaussian 03, revision D.01; Gaussian Inc.: Wallingford,
CT, 2004.
(27) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
9
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