Improved catalysts for the palladium-catalyzed synthesis of oxindoles by amide α-arylation. Rate acceleration, use of aryl chloride substrates, and a new carbene ligand for asymmetric transformations

Article abstract of DOI:10.1021/jo005761z

Catalysts comprised Pd(OAc)₂ and either PCy₃ or sterically hindered N-heterocyclic carbene ligands provide fast rates for a palladium-catalyzed synthesis of oxindoles by amide α-arylation. This catalyst system allowed for room-temperature reactions in some cases and reactions of aryl chlorides at 70 °C. Most important, reactions occurred in high yields under mild conditions to form the quaternary carbon in α,α-disubstituted oxindoles. The combined inter- and intramolecular reaction afforded an efficient synthetic method for formation of α-aryloxindole derivatives. Surprisingly, catalysts containing tert-butylphosphine ligands, which have been most reactive for ketone arylations, were less active than those containing PCy₃. Use of new, optically active heterocyclic carbene ligands gave substantial enantioselectivity in formation of an α,α-disubstituted oxindole. In contrast, a variety of optically active phosphine ligands that were tested gave poor enantioselectivity. Mechanistic studies showed that the reaction involves rate-limiting oxidative addition of aryl halide. Base-induced formation of and reductive elimination from an arylpalladium enolate intermediate were both faster than oxidative addition. Deprotonation of the tethered amide appeared to be faster than reductive elimination of the resulting palladium enolate to form the oxindole product.

Full text of DOI:10.1021/jo005761z

3402
J . Org. Chem. 2001, 66, 3402-3415
Im p r oved Ca ta lysts for th e P a lla d iu m -Ca ta lyzed Syn th esis of
Oxin d oles by Am id e r-Ar yla tion . Ra te Acceler a tion , Use of Ar yl
Ch lor id e Su bstr a tes, a n d a New Ca r ben e Liga n d for Asym m etr ic
Tr a n sfor m a tion s
Sunwoo Lee and J ohn F. Hartwig*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107
john.hartwig@yale.edu
Received December 7, 2000
Catalysts comprised Pd(OAc)2 and either PCy3 or sterically hindered N-heterocyclic carbene ligands
provide fast rates for a palladium-catalyzed synthesis of oxindoles by amide R-arylation. This catalyst
system allowed for room-temperature reactions in some cases and reactions of aryl chlorides at
70 °C. Most important, reactions occurred in high yields under mild conditions to form the
quaternary carbon in R,R-disubstituted oxindoles. The combined inter- and intramolecular reaction
afforded an efficient synthetic method for formation of R-aryloxindole derivatives. Surprisingly,
catalysts containing tert-butylphosphine ligands, which have been most reactive for ketone
arylations, were less active than those containing PCy3. Use of new, optically active heterocyclic
carbene ligands gave substantial enantioselectivity in formation of an R,R-disubstituted oxindole.
In contrast, a variety of optically active phosphine ligands that were tested gave poor enantiose-
lectivity. Mechanistic studies showed that the reaction involves rate-limiting oxidative addition of
aryl halide. Base-induced formation of and reductive elimination from an arylpalladium enolate
intermediate were both faster than oxidative addition. Deprotonation of the tethered amide appeared
to be faster than reductive elimination of the resulting palladium enolate to form the oxindole
product.
In tr od u ction
Oxindoles are important substructures in many bio-
logically active molecules.11,12 A number of methods for
the synthesis of oxindoles have been reported. Friedel-
Crafts cyclizations of R-haloacetanilides and variations
on the Fischer indole synthesis are the classical methods
of oxindole synthesis.13 Cyclizations of 2-haloacryloyl-
anilide derivatives by a variety of radical initiators have
been reported more recently.14-19 Metal-catalyzed routes
to oxindoles include palladium-catalyzed cyclocarbony-
lations of 2-aminostyrenes,20 rhodium-catalyzed carbo-
nylations of 2-alkynylanilines,21 rhodium- and Nafion-
H-catalyzed cyclizations of R-diazoamides,22,23 and intra-
molecular Heck couplings of 2-haloacryloylanilides.24,25
The palladium-catalyzed R-arylation of carbonyl com-
pounds is emerging as a simple and useful method for
conducting what has been traditionally a difficult
transformation.1-7 Electrophilic main group aryl com-
pounds have been used in the past as an alternative
method, but they are often toxic, deliver only one of
several aryl groups, and require synthesis and isolation
of the main group reagent.8-10 We recently reported the
palladium-catalyzed R-arylation of amides.5 The intramo-
lecular R-arylation of amides to form oxindoles was
particularly effective, and the highest yields were ob-
served for the synthesis of R,R-disubstituted oxindoles,
which are the most difficult to construct by traditional
routes. However, the reactions required high tempera-
tures and relatively high catalyst loadings.
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10.1021/jo005761z CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3403
Photochemical,11,26 Ullmann-type,27 and radical-promoted
cyclizations of saturated 2-haloanilide derivatives28 have
also been reported.
Ta ble 1. Effect of Liga n d s on P d -Ca ta lyzed Cycliza tion
of Br om oa n ilid e 1a
Although there are a variety of methods for synthesiz-
ing these structures, methods that form oxindoles with
complete regioselectivity are rare. Friedel-Crafts meth-
ods and more recent variations do not allow control of
arene regiochemistry.13,27 Most other methodologies in-
volve cyclization by addition of reactive intermediates to
olefin or alkynyl moieties. Often, these additions occur
with poor regioselectivity to produce mixtures of oxindole
and 3,4-dihydroquinolin-2-one products.1-7 One of the
more attractive methods to form these structures is
intramolecular Heck chemistry. However, mixtures of
olefin products are often observed.29
The authors’ laboratory and others have shown re-
cently that the use of catalysts containing sterically
hindered alkylphosphines accelerate a number of cross-
coupling reactions.6,30-41 We first showed that this class
of ligand accelerates R-arylation,6 and Buchwald’s group
has shown that aryldialkylphosphines can be highly
reactive catalysts for ketone substrates, as well as for
substrates with pKa’s lower than those in ketones.7 We
were interested in using sterically hindered alkylphos-
phines and related heterocyclic carbene ligands to ac-
celerate the rates for cyclizations to form oxindoles and
to allow the reactions to be conducted under mild
conditions. We report that the most hindered of the
alkylphosphines are not effective for these reactions, but
that the slightly less sterically demanding PCy3 provides
fast rates. In addition, we have found that heterocyclic
carbene ligands generate active catalysts for these reac-
tions, and we have designed the first optically active
carbene ligand that gives substantial enantioselectivity
for any transformation.
time
(h)
convn
(%)
yieldb
(%)
entry
Pd
ligand
T (°C)
1
2
3
4
5
6
7
8
9
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
BINAP
3
4
PCy3
PtBu3
PCy3
PCy3
PtBu3
5
100
100
100
100
100
50
50
50
50
50
3
4
5
1
5
3
3
3
3
3
3
3
95
100
100
100
100
93
100
72
24
53
42
41
62
62
82
99
21
11
67
99
99
10
11
12
6
7
8
83
100
100
50
50
a
b
Reactions run with 0.3 mmol substrate. Yields determined
Resu lts a n d Discu ssion
by GC.
Cycliza tion of Ar yl Br om id e Su bstr a tes. Tables 1
and 2 summarize our results from screening a variety of
monophosphine and carbene ligands for four model
substrates that undergo cyclizations to form oxindoles (eq
1). Several trends are readily apparent. First, the most
(25) Arumugam, V.; Routledge, A.; Abell, C.; Balasubramanian, S.
Tetrahedron Lett. 1997, 38, 6473-6476.
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102, 3646-3647.
(27) Kametani, T.; Ohsawa, T.; Ihara, M. Heterocycles 1980, 14,
277-280.
general ligand for the reaction is PCy3, which was not
particularly effective for ketone or malonate arylations
reported previously.6 The use of this ligand allowed for
lower reaction temperatures (50 °C) and catalyst loadings
than previous work using BINAP as ligand.5 The com-
bination of Pd(0) precursors and PtBu3, which were highly
active for ketone arylation, did not provide mild reactions
for the formation of oxindoles. Second, reactions employ-
ing sterically hindered alkyl bis-phosphines required
temperatures that were similar to those published previ-
ously with BINAP5 (Table 1, entries 2 and 3). Third,
monodentate ligands were not suitable for cyclizations
at an unhindered secondary C-H bond (Table 2, entries
7-12). Fourth, the optimal ligand in some cases de-
pended on the particular substrate. For example, reaction
of substrate 13 occurred in low yield when using PCy3,
but gave high yields when the carbene ligands 7 and 8
were used. Finally, and perhaps most important, several
ligand systems were suitable for the formation of the
quaternary carbon in R,R-disubstituted oxindoles. Both
carbene ligands and PCy3 provided high yields.
(28) Beckwith, A. L. J .; Storey, J . M. D. J . Chem. Soc., Chem.
Commun. 1995, 977-978.
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P.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 4369-4378.
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1998, 120, 9722-9723.
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39, 617-620.

3404 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 2. Op tim iza tion of Liga n d s on P d -Ca ta lyzed Cycliza tion of Br om oa n ilid ea
Lee and Hartwig
a
b
Reaction run with 0.3 mmol of substrate, 5 mol % Pd(OAc)2, 5 mol % ligand, 1.5 equiv of base at 50 °C for 10 h. Determined by GC
after quenching with NH4Cl. c Determined by GC/MS with authentic sample.
To find the most effective palladium precursor in the
oxindole synthesis, we conducted the catalytic reaction
with substrate 1 by using Pd(dba)2/PCy3 and Pd(OAc)2/
PCy3. When using 5 mol % Pd(dba)2/PCy3, the reaction
rate was faster than that when using 5 mol % Pd(OAc)2/
PCy3, but the conversion was only 93%. When using Pd-
(OAc)2/PCy3, the initial reaction rate was slower than
when using Pd(dba)2/PCy3, but the substrate was com-
pletely converted to product. The cause of the slow initial
reaction rate catalyzed by Pd(OAc)2/PCy3 might be due
to an induction period for the conversion of Pd(II) to
Pd(0).
Cycliza tion of Ar yl Ch lor id e Su bstr a tes. The suc-
cessful use of alkylphosphines led us to evaluate cycliza-
tions of chloroarene substrates. The substrates for cy-
clizations in these cases are derived from inexpensive
chloroanilines. Traditionally, chloroarenes have required
high temperatures for oxidative addition, but the use of
sterically hindered alkylphosphines and heterocyclic car-
bene ligands has now allowed for reactions of chloroarene
substrates under mild conditions.7,31,32,35,39,40,42-46 Table
4 summarizes our results for oxindole synthesis using
this class of substrate. The chloroarene substrates re-
acted at 70 °C to form oxindoles in good yields. These
temperatures and the catalyst loadings are lower than
those required for previous reactions of even bromoarene
substrates using BINAP as ligand; reaction yields are
similarly high. N-Methyl substrates and N-benzyl sub-
strates reacted at similar rates and yields.
Th e Com bin ed In tr a - a n d In ter m olecu la r Ar yla -
tion of Am id es. The intermolecular R-arylation of
amides5 was combined with the intramolecular process
to prepare 3-aryloxindoles in a simple fashion. We postu-
lated that the intermolecular R-arylation of an acetani-
lide would be slower than the intramolecular R-aryla-
tion of oxindole itself. Thus, we devised a route that
would utilize initial cyclization followed by intermolecular
arylation of indole. Moreover, we expected that the rate
of oxidative addition of a bromoarene to Pd(0) would be
faster than that of a chloroarene. Thus, we sought to
construct 3-aryl oxindoles in one step from simple ma-
terials by reacting bromo-substituted acetamide 9 with
a chloroarene. As shown in Table 5, the process occurred
in good yields when using PCy3 as ligand. This yield is
particularly high considering that the yield of the cy-
clization of substrate 9 was 62%.
Table 3 summarizes the scope of the reaction with the
ligand that provides the highest yield for each substrate.
The functional group compatibility and potential elec-
tronic dependence of the reaction were evaluated with
the substrates in entries 7 and 8. Reactions of substrates
with electronically varied aryl groups, although a small
set, showed good yields in all cases. The effect of het-
eroatom substitution R to the carbonyl was evaluated
with oxygen substituents. Reactions with cyclic ethers
occurred smoothly when using PCy3 as catalyst (Table
3, entry 16). However, reaction of phenoxy-substituted
system 37 did not occur, even at high temperatures. In
previous work, reactions of substrates with R-aryl groups
occurred more slowly than those with purely aliphatic
groups when using BINAP as ligand.5 However, cycliza-
tion of substrates with R-aryl groups occurred rapidly
when using PCy3. This reaction also occurred in good
yield for substrates with an R-aryl group and secondary
R-C-H bonds (Table 3, entry 5). One might predict this
result because the lack of â-hydrogens in the presumed
intermediate enolate complex prevents â-hydrogen elimi-
nation as a competing pathway. However, the absence
of this reaction does not appear to distinguish the
reactivity of one substrate from another. The major side
product that is formed from reaction of substrate 11,
which does not contain an R-aryl group and could undergo
â-hydrogen elimination, is simply the hydrodehalogena-
tion product; no hydrodehalogenation product containing
the expected R,â-unsaturated carbonyl group from â-hy-
drogen elimination was observed. The origin of the
hydrogen in these cases is unclear.
(42) Stauffer, S.; Hauck, S. I.; Lee, S.; Stambuli, J .; Hartwig, J . F.
Org. Lett. 2000, 2, 1423-1426.
(43) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S. P. J . Org. Chem.
1999, 64, 3804-3805.
(44) Bei, X.; Crevier, T.; Guram, A. S.; J andeleit, B.; Powers, T. S.;
Turner, H. W.; Uno, T.; Weinberg, W. H. Tetrahedron Lett. 1999, 40,
3855-3858.
(45) Bei, X.; Uno, T.; Norris, J .; Turner, H. W.; Weinberg, W. H.;
Guram, A. S. Organometallics 1999, 18, 1840-1853.
(46) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H.
Tetrahedron Lett. 1999, 40, 1237-1240.

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3405
Ta ble 3. F or m a tion of Oxin d oles fr om 2-Br om oa n ilid esa
a
b
Reaction conditions: 5 mol % Pd(OAc)2, 5 mol % PCy3, 1.5 equiv of NaOtBu, 1,4-dioxane (0.1 M) at 50 °C. Reaction times were not
optimized. c Isolated yields are an average of at least two runs. All compounds were fully characterized spectroscopically (1H and 13C
NMR, FTIR, and LRMS) and are consistent with previously reported values. Ligand 8 was used instead of PCy3.
d
Asym m etr ic Oxin d ole Syn th esis. The successful
formation of R,R-disubstituted oxindoles led us to seek a
catalyst system for the asymmetric formation of such
oxindoles. In particular, we sought formation of R-meth-
yl, R-aryl systems that could not be formed by intra-
molecular Heck reactions.29,47 Our initial studies focused
on a number of different commercially available phos-
phine ligands, including arylphosphines. Reactions em-
ploying resolved BINAP gave enantioselectivities that
were much lower than those observed for ketone aryla-
tions.48 Even after optimization, only 46% ee was ob-
served. Reactions with 19 different mono- and bisphos-
phines all provided products that showed modest enan-
tiomeric excess or were racemic (Table 6). Only the
bisphosphine 5749 gave significant enantioselectivity.
However, slow reactions were observed in this case, even
with 10 mol % catalyst. It was notable that the neomen-
thyl monophosphine 62 gave significant selectivity, al-
though the selectivities were still too low for any syn-
thetic purposes. Thus, this cyclization is difficult to
conduct with good enantioselectivity and a new ligand
system was necessary.
The success of carbene ligands in these reactions led
us to prepare homochiral, heterocyclic carbene ligands
for use in the asymmetric variant of the cyclization. We
initially prepared versions of carbene 8 that contained
backbone chirality. The ligand 70 in Figure 1 that
contains a trans-diaminocyclohexane backbone was pre-
(47) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J . J . Am.
Chem. Soc. 1998, 120, 6477-6487.
(48) Ahman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.; Buch-
wald, S. L. J . Am. Chem. Soc. 1998, 120, 1918-1919.
(49) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J . Am. Chem. Soc. 1994, 116, 4062-4066.

3406 J . Org. Chem., Vol. 66, No. 10, 2001
Lee and Hartwig
Ta ble 5. Com bin ed In tr a - a n d In ter m olecu la r
Ta ble 4. F or m a tion of Oxin d oles fr om 2-Ch lor oa n ilid esa
P d -Ca ta lyzed Ar yla tion of Am id es
a
Reaction conditions: 5 mol % Pd(OAc)2, 5 mol % PCy3, 1.5
equiv of NaOtBu, 1,4-dioxane (0.1 M) at 70 °C. Reaction times
b
a
Isolated yields are an average of at least two runs.
were not optimized. c Isolated yields are an average of at least two
runs. All compounds were fully characterized spectroscopically (1H
and 13C NMR, FTIR, and LRMS) and are consistent with previ-
The imidazolidene ligands were again prepared readily
by standard methods. The two carbene ligands that were
prepared from these amines display complementary
orientation of amine and R-methyl groups, potentially
creating two ligands that would provide the opposite
absolute stereochemistry of the oxindole product.
Reactions of the R-naphthyl, R-methyl substrate 25a
catalyzed by palladium complexes of these two ligands
occurred at room temperature. Reactions using 72 were
particularly rapid and allowed for enantioselective pro-
cesses to be conducted below room temperature. Reac-
tions using carbene 71 were slower than those using 72,
but still provided useful rates at 25 °C. Studies that were
conducted with ligand 71 to optimize the enantioselec-
tivity are summarized in Table 7. These experiments
showed that base, counterion, and solvent were all
important in controlling enantioselectivity. Ligand-to-
metal ratio was not. Sodium tert-butoxide as base in DME
solvent gave the highest selectivities.
d
ously reported values. Ligand 8 was used instead of PCy3.
pared by modification of the standard protocol for prepa-
ration of these imidazolidine ligands.50 Unfortunately,
this ligand provided enantioselectivities that were similar
to those obtained when using phosphines.
Thus, we sought a carbene with chiral substituents at
nitrogen that would be readily available. Carbenes
derived from phenethylamine have been prepared previ-
ously,51 but reactions catalyzed by complexes of them
showed low enantioselectivity. We felt that these ligands
did not contain the appropriate steric properties to
provide fast reaction rates and/or suitable transfer of
chirality for the oxindole synthesis. Thus, we prepared
carbene ligands 71 and 72 derived from (-)-isopinocam-
pheylamine and (+)-bornylamine, respectively (Figure 1).
(50) Arduengo, A. J ., III; Rasika Dias, H. V.; Harlow, R. L.; Kline,
M. J . Am. Chem. Soc. 1992, 112, 5530-5534.
(51) Herrmann, W. A.; Goossen, L. J .; Kocher, C.; Artus, G. R. J .
Angew. Chem. 1996, 35, 2805-2807.
Table 8 summarizes our results on enantioselective
reactions using carbene ligands 71 and 72 using this

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3407
Ta ble 6. Liga n d Effect of P d -Ca ta lyzed Asym m etr ic
Oxin d ole Syn th esis
F igu r e 1. Chiral carbene ligands used for enantioselective
formation of oxindoles.
Ta ble 7. Op tim iza tion of P a lla d iu m Sou r ce, Solven t,
Tem p er a tu r e, a n d Ba se on Asym m etr ic Syn th esis of
Oxin d ole fr om 25a Usin g Liga n d 71
T
time
yieldb
%
entry
Pd
base
solvent (°C) (h) convna (%) eec
1d Pd(OAc)2 NaOtBu
dioxane
dioxane
THF
toluene
DME
diglyme
m-xylene 50
DME
DME
DME
70
50
50
50
50
50
20
12
14
14
14
14
14
16
36
36
14
16
14
88
100
100
100
100
100
100
100
17
35
56
55
50
64
61
60
89
5
20
56
57
93
4
34
42
34
55
51
28
59
11
50
48
6
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2 NaOtBu
Pd(OAc)2 NaOtBu
Pd(OAc)2 NaOtBu
Pd(OAc)2 NaOtBu
Pd(OAc)2 NaOtBu
Pd(OAc)2 NaOtBu
Pd(dba)2 NaOtBu
Pd(dba)2 KOtBu
Pd(dba)2 LiOtBu
50
50
50
50
50
25
61
Pd(dba)2 NaHMDS DME
Pd(dba)2 KHMDS DME
100
100
100
Pd(dba)2 NaOtBu
DME
67
a
b
Determined by GC. Isolated yield. c Determined by HPLC
d
with Chiral Daicel OD-H. Ligand 70 used instead of ligand 71.
and observe higher enantioselectivity. Cyclization with
10% catalyst at 10 °C gave 76% ee. As expected, the
products formed from reaction of the ligands 71 and 72
displayed opposite absolute stereochemistry. These enan-
tioselectivities are similar to those observed from in-
tramolecular Heck reactions reported previously.47
To determine if the identity of the halide influenced
enantioselectivity, reactions of N-methyl bromide sub-
strate 25a were compared to those of the chloride and
iodide analogues 25b and 25c. With both ligands, reac-
tions of bromo-substituted 25a occurred with similar
enantioselectivity to those of chloro-substituted 25b.
These data may suggest that that the halide is not
present on the complex during the enantiodiscriminating
step with these substrates. However, reaction of iodo-
substituted 25c gave product that was either racemic or
low in enantiomeric excess. Either the enantiodiscrimi-
nating step is different for reactions of 25c, or the steric
and electronic properties of the halide do affect the
selectivity.
In many reactions, catalysts bearing monophosphines
provide faster rates than those bearing bisphosphines.
Thus, a long-standing problem in enantioselective ca-
talysis is the development of chiral monophosphines that
provide good selectivities.52-54 Our results with carbene
ligands 71 and 72 provide an alternative approach to this
problem.
Mech a n istic Stu d ies. The mechanism of the cycliza-
tion reactions presumably involves oxidative addition of
the aryl halide, followed by formation of an arylpalladium
amide enolate intermediate and reductive elimination
(Figure 2). To determine the relative rates for the
different steps, we have evaluated the relative rates for
T
(°C)
time convna yieldb
opt.
entry
ligand
(h)
(%)
(%)
% eec rot.d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(R)-BINAP 100
3
24
12
24
24
24
24
6
24
14
12
9
24
36
36
24
3
100
100
100
100
100
100
100
100
78
100
100
100
100
57
49
72
72
66
57
67
70
55
56
24
60
75
82
37
18
49
63
45
50
46
6
2
(-)
(-)
(-)
(+)
(+)
(+)
(+)
(-)
(+)
(+)
(-)
(+)
(-)
(+)
(-)
(+)
0
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
100
100
70
16
38
41
61
31
61
38
15
53
20
4
5
7
0
18
2
70
100
100
100
100
100
70
50
100
100
100
50
100
100
50
56
100
100
89
3
24
(-)
(-)
a
b
Determined by GC. Isolated yield after column chromatog-
raphy. c Determined by HPLC with Chiral Daicel OD-H. Mea-
d
sured in CH2Cl2.
solvent and base. Cyclization of 25a using 5 mol % of a
1:1 ratio of Pd(dba)2 and carbene ligand 71 as catalyst
at 25 °C gave 67% ee. The analogous reaction using
carbene 72 occurred with 71% enantioselectivity. How-
ever, the higher reactivity of catalysts bearing ligand 72
allowed us to conduct reactions at lower temperatures
(52) Amold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865-2878.
(53) van den Berg, M.; Minnaard, A. J .; Schudde, E. P.; van Esch,
J .; de Vries, A. H. M.; de Vries, J . G.; Feringa, B. L. J . Am. Chem. Soc.
2000, 122, 11539-11540.
(54) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333-6336.

3408 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 8. Asym m etr ic Oxin d ole Syn th esis fr om 2-Ha loa n ilid es
Lee and Hartwig
a
b
Pd(dba)2 was used as palladium source. Isolated yield after column chromatography. c Determined by HPLC with Chiral Daicel
OD-H.
eq 2, while reaction with Pd(PCy3)2 formed the bisphos-
phine complex 73b in eq 3. The monophosphine complex
F igu r e 2. Proposed mechanism for the cyclization to form
oxindoles.
73a was isolated in 60% yield, while the bisphosphine
complex 73b was obtained in 60% yield. Both compounds
were characterized by standard spectroscopic methods
and microanalysis. We formulate complex 73a as a
monomer with a coordinated carbonyl oxygen for several
reasons. First, a similar monomeric complex was formed
with P(o-tol)3 as ligand;57 second, the carbonyl carbon
displayed 31P-13C coupling in the 13C NMR spectrum;
third, Signer solution molecular weight analysis58 of the
product yielded a molecular weight (589) that was within
10% of the calculated weight of the monomer (643).
stoichiometric oxidative addition of aryl halide, formation
of the enolate, and reductive elimination of oxindole.
Oxidative addition of bromo isobutyramide substrate
1 occurred more rapidly to the palladium complex formed
from a 1:1 ratio of Pd(dba)2 than it did to Pd(PCy3)2.55,56
Complete consumption of 1 occurred at room temperature
after 20 h when reacting it with the 1:1 ratio of ligand
and Pd(dba)2 but required 48 h at room temperature
when reacting it with Pd(PCy3)2. Moreover, the two
reactions formed different products. Reaction with the
1:1 mixture formed the monophosphine complex 73a in
(55) Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J . Am.
Chem. Soc. 1976, 98, 5850-5858.
(56) Yoshida, T.; Otsuka, S. 1985, 28, 113-119.
(57) Vicente, J .; Abad, J .-A.; Martinez-Vivente, E.; de Arellano, M.
C. R.; J ones, P. G. Organometallics 2000, 19, 752.
(58) Signer, R. Annalen 1930, 478, 246.

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3409
To compare the rates for formation and reaction of the
arylpalladium enolates, we reacted the isolated enolate
complexes with NaOtBu. Reaction of arylpalladium halide
complex 73a and 73b with NaOtBu occurred rapidly at
room temperature. When monophosphine complex 73a
was treated with NaOtBu, the 31P NMR resonance of the
starting complex disappeared immediately. However, the
oxindole product was formed in only 20% yield at this
time. From these two results one might expect to observe
an arylpalladium amide complex; however, no new
soluble palladium(II) phosphine complex was observed.
A quantitative yield of oxindole was obtained after
allowing the suspension to stand for 8 h. These results
suggest that deprotonation of 73a is rapid and that this
deprotonation forms an insoluble sodium or palladium
enolate that forms oxindole product over the course of 8
h. In a similar fashion, the bisphosphine palladium
complex 73b reacted rapidly with NaOtBu, but high-yield
formation of oxindole (99%) required 9 h. Although slower
than deprotonation, comparison of these times for forma-
tion of oxindole with those for oxidative addition of the
halide substrate shows that reductive elimination of
oxindole was measurably faster than the initial oxidative
addition of the bromoarene substrate.
To observe the catalyst resting state and confirm that
the oxidative addition is rate-determining, we monitored
by 31P NMR spectroscopy reactions containing Pd(dba)2/
PCy3 or Pd(PCy3)2 as catalyst. When the reaction was
conducted using Pd(dba)2/PCy3, Pd(PCy3)2 (δ40) was
observed throughout the reaction. However, we also
observed a signal at 26.3 ppm, and at the middle of the
reaction time this resonance was the largest signal. As
the reaction proceeded the material corresponding to this
resonance at 26.3 ppm was converted to Pd(PCy3)2.
The same experiment using Pd(PCy3)2 as catalyst
showed that Pd(PCy3)2 was the major species throughout
the reaction and that the compound with a chemical shift
of 26.3 ppm was absent. A minor signal at 23.6 ppm was
observed, which never exceeded 20% of the palladium-
phosphine complex in solution. This compound appeared
to correspond to a catalyst decomposition product. It was
never converted to Pd(PCy3)2 and did not react with PhBr
added at the end of the reaction We have been unable to
prepare independently a complex displaying a 31P NMR
shift of 26.3 or 23.6 ppm. These complexes are not formed
by adding dba to either Pd(PCy3)2, 73a or 73b. They are
also not formed from reaction of Pd(dba)2 and PCy3 in a
1:1 ratio. This reaction, in the absence of substrate,
generates a broad set of signals at 34.2-28.5 ppm.
The reason the reaction rates are faster when using a
1:1 ratio of ligand to palladium is unclear at this point,
but similar observations have been made in amination,
ketone arylation, and Suzuki reactions catalyzed by a 1:1
ratio of PtBu3:Pd(dba)2.6,31,36 Oxidative addition to bis-
phosphine Pd(0) complexes containing sterically hindered
ligands occurs by a preequilibrium involving ligand
dissociation.59 Thus, the generation of free phosphine
retards the reaction rates for this step, which is turn-
over limiting. Perhaps the 1:1 ratio ensures that the
concentration of free ligand remains low, even after some
palladium precipitates or decomposes to a monophos-
phine species.
catalyst. No resonance at 26.3 ppm was observed at any
point during the reaction. Signals at 49.7, 45.6, and 40.0
ppm were observed at various times. However, Pd(PCy3)2
was always the major palladium-phosphine complex
present in solution. These results are expected for reac-
tions of chloroarenes and even bromoarenes when oxida-
tive addition is the turnover-limiting step for the reaction.
Con clu sion : Effect of Liga n d P r op er ties. It was
unexpected that a less hindered alkylphosphine would
provide reaction rates that are faster than those observed
with the more hindered PtBu3. We assume that the steric
demands of the substrates for cyclization to form oxin-
doles accounts for this trend. A smaller Pd(0) reactive
intermediate would be able to react more readily with
the Ar-X linkage of a hindered substrate. Thus, it may
be necessary in some cross-coupling processes to match
the size of the substrate with the size of the ligand to
observe the maximum rate.60
Exp er im en ta l Section
Gen er a l Con sid er a tion s. All coupling reactions were
assembled in a drybox under nitrogen and were conducted in
sealed reaction flasks. Pd(dba)2,61 54,62 63,63 64,64 66,65 and
69,66 were prepared by literature procedures. PCy3, PtBu3, 5,
6, (R)-BINAP, 52, 53, 55-62, 65, 67, 68, and NatOBu were
obtained from commercial sources and used as received.
Anhydrous grade dioxane was purchased from Aldrich and was
used and stored in a nitrogen glovebox. 2-Bromo-N-methyl-
aniline and 2-chloro-N-methylaniline were prepared from 2-
bromoaniline and 2-chloroaniline, respectively.11 2-Chlorophe-
nyl-N-methylacetamide and 2-chorophenyl-N-benzylacetamide
were prepared according to the previously published proce-
dures and were characterized by 1H and 13C NMR spectros-
copy.11 The 2-bromoanilide substrates (23, 25, 27, 29, 31, 33,
1
35, and 37) displayed major and minor isomers by H and 13C
NMR at room temperature due to slow rotation.67 Naphthalene
was used as a standard in quantitative GC experiments using
response factors determined from isolated products. Melting
points were measured on a Thomas-Hoover capillary melting
point apparatus and were uncorrected. Optical rotations were
measured at 589 nm (sodium D line). Specific rotations are
reported in degrees per decimeter at room temperature, and
the concentration is given in grams per 100 mL of the specified
solvent. 1H and 13C NMR data were reported in ppm downfield
of TMS and were referenced to residual solvent protons or
internal TMS. Low-resolution mass spectral data were ob-
tained on a Hewlett-Packard 5890 A mass spectrometer.
Electron impact ionization was used for all samples. Elemental
analyses were performed by Robertson Microlit Laboratories,
Inc., Madison, NJ .
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Br om o-,
2-Iod o-, a n d 2-Ch lor oa n ilid e Su bstr a tes. 2-Bromoaniline,
2-iodoaniline, or 2-chloroaniline (1.0 equiv) was added to a
mixture of the appropriate acid chloride (1.2 equiv) and
triethylamine (1.5 equiv) in CH2Cl2 (0.3 M) at room temper-
ature. The reaction was allowed to stir for 6 h. The reaction
(59) Hartwig, J . F.; Paul, F. J . Am. Chem. Soc. 1995, 117, 5373-
5374.
(60) Littke, A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122,
4020-4028.
(61) Kadin, S. B. J . Org. Chem. 1973, 38, 1349-1350.
(62) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566-568.
(63) Chen, Z.; J iang, Q. Z., G.; Xiao, D.; Cao, P.; Guo, C.; Zhang, X.
J . Org. Chem. 1997, 62, 4521-4523.
(64) Richter, W. J . Chem. Ber. 1984, 117, 2328-2336.
(65) Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J . Org. Chem.
1993, 58, 1945-1948.
For reactions of chloro-substituted isobutyrylanilide
substrate 44, Pd(PCy3)2 was the major species observed
by 31P NMR spectrometry when the reactions were
conducted with either Pd(dba)2/PCy3 or Pd(PCy3)2 as
(66) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374-2376.
(67) Siddall, T. H., III; Stewart, W. E. J . Org. Chem. 1969, 34, 2927-
2933.

3410 J . Org. Chem., Vol. 66, No. 10, 2001
Lee and Hartwig
was then diluted with Et2O and quenched with a saturated
aqueous solution of NH4Cl. The organic phase was washed
with a saturated NaCl solution, dried over MgSO4, filtered,
and concentrated at reduced pressure. The resulting crude
product was purified by chromatography on silica gel. The
product was eluted with 20% ethyl acetate in hexanes.
N -(2-Br om op h e n yl)-N -m e t h yl-2-cycloh e xylp r op a n -
a m id e (13). 2-Bromo-N-methylaniline (744 mg, 4.00 mmol)
was coupled with cyclohexylacetyl chloride68 (771 mg, 4.80
mmol) to give 1.10 g (3.55 mmol, 89%) of 13 as a white solid
after chromatography. Recrystallization from hexanes gave a
white solid (mp 72-73 °C). 1H NMR (400 MHz, CDCl3): δ 7.61
(dd, J ) 7.4, 1.6 Hz, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 3.12 (s,
3H), 1.81-1.73 (m, 3H), 1.63-1.52 (m, 5H), 1.17 (m, 2H), 0.97
(m, 1H), 0.68 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 172.75,
143.33, 134.26, 130.46, 130.01, 129.28, 123.92, 41.85, 36.14,
33.73, 33.56, 26.64, 26.54, 26.52. MS (EI): 230 (M+ - Br, 100),
185 (54), 148 (75), 105 (11), 77 (14), 55 (20). Anal. Calcd for
(m), 36.94 (m), 30.89 (M), 20.96 (m), 20.67 (M). FTIR (KBr
pellet): 1665 cm-1. MS (EI): 369 (10), 367 (10), 288 (32), 212
(40), 155 (100), 128 (10), 117 (13). Anal. Calcd for C20H18
-
BrNO: C, 65.23; H, 4.93; N, 3.80. Found: C, 65.41; H, 4.81;
N, 3.72.
N-(2-Ch lor op h en yl)-N-m et h yl-2-(1-n a p h t h yl)p r op a n -
a m id e (25b). 2-Chloro-N-methylaniline (930 mg, 3.04 mmol)
was coupled with 2-(1-naphthyl)propanoyl chloride69 (797 mg,
3.65 mmol) to give 767 mg (2.37 mmol, 78%) of 25b after
chromatography. Recrystallization from hexanes gave a white
solid (mp 116-117 °C). 1H NMR (400 MHz, CDCl3): δ 7.75 (d,
J ) 8.0 Hz, 1H), 7.68 (m 1H), 7.51 (d, J ) 6.9 Hz, 1H), 7.45-
7.31 (m, 3.3H), 7.26 (m, 1H), 7.18 (m, 1H), 7.05 (t, J ) 7.3 Hz,
0.3H), 6.97 (t, J ) 7.3 Hz, 0.7H), 6.79 (d, J ) 7.9 Hz, 0.3H),
6.5 (t, J ) 7.4 Hz, 0.7H), 6.09 (t, J ) 7.7 Hz, 0.7H), 4.49 (quart,
J ) 6.7 Hz, 0.3H), 4.18 (quart, J ) 6.8 Hz, 0.7H), 3.21 (s, 3H),
1.54 (d, J ) 6.7 Hz, 0.9H), 1.53 (d, J ) 6.8 Hz, 2.1H). 1H NMR
(300 MHz, 100 °C, toluene-d8): δ 7.69-7.60 (m, 2H), 7.54 (d,
J ) 8.5 Hz, 1H), 7.40 (m, 0.7H), 7.28-7.01 (m, 4.9H), 6.63 (m,
1H), 6.20 (m, 0.7H), 6.02 (m, 0.7H), 4.48 (m, 0.3H), 4.30 (m,
0.7H), 3.13 (s, 3H), 1.68 (d, J ) 6.9 Hz, 3H). 13C NMR (100
MHz, CDCl3, M ) major conformer, m ) minor conformer): δ
174.88 (M), 174.76 (m), 141.06 (m), 140.80 (M), 139.13 (M),
137.36 (m), 134.35 (m), 134.25, 133.23 (M), 131.26 (m), 131.16
(m), 131.10 (M), 131.05 (M), 130.65 (M), 130.46 (m), 129.80
(m), 129.63 (M), 129.19, 128.46 (m), 128.01 (M), 127.73 (M),
127.67 (m), 126.36 (M), 126.27 (m), 126.17, 126.09 (m), 125.86
(M), 125.57 (m), 125.03 (M), 122.58 (m), 122.53 (M), 40.00 (M),
39.41 (m), 36.86 (M), 36.72 (m), 20.79 (m), 20.60 (M). FTIR
(KBr pellet): 1664 cm-1. MS (EI): 323 (20), 288 (35), 168 (90),
155 (100), 128 (22), 111 (7), 77 (21), 51 (7). Anal. Calcd for
C
15H20BrNO: C, 58.07; H, 6.50; N, 4.51. Found: C, 58.30; H,
6.28; N, 4.50.
N-Ben zyl-N-(2-b r om op h en yl)-2-(1-n a p h t h yl)p r op a n -
a m id e (23). 2-Bromo-N-benzylaniline (460 mg, 1.74 mmol)
was coupled with 2-(1-naphthyl)propanoyl chloride (457 mg,
2.09 mmol) to give 540 mg (1.22 mmol, 70%) of 23 after
chromatography. Recrystallization from hexanes gave a white
solid (mp 99.5-100 °C). 1H NMR (400 MHz, CDCl3): δ 7.74
(d, J ) 8.0 Hz, 1H), 7.68 (d, J ) 8.0 Hz, 1H), 7.62 (d, J ) 7.2
Hz, 1H), 7.54 (d, J ) 7.2 Hz, 1H), 7.41-7.17 (m, 9H), 6.85 (m,
1H), 6.26 (m, 1H), 5.83 (d, J ) 14.8 Hz, 0.2H), 5.71 (d, J )
14.0 Hz, 0.8H), 5.56 (d, J ) 6.4 Hz, 1H), 4.45 (m, 0.2H), 4.20
(m, 0.8H), 4.02 (d, J ) 14.0 Hz, 0.8H), 3.91 (d, J ) 14.8 Hz,
0.2H), 1.59 (d, J ) 6.8 Hz, 3H). 1H NMR (300 MHz, 100 °C,
toluene-d8): δ 8.58-8.37 (br m, 3H), 7.67-7.70 (m, 11.6H), 6.74
(br s, 0.7H), 6.45 (br s, 0.7H), 6.02 (br s, 1H), 4.42-4.33 (br s,
1H), 4.12-4.01 (br s, 1H), 1.74 (br s, 3H). 13C NMR (100 MHz,
CDCl3, M ) major conformer, m ) minor conformer): δ 174.64
(M), 174.41 (m), 140.49 (m), 140.34 (M), 138.98 (M), 137.78
(m), 137.69 (M), 137.27 (m), 134.50 (m), 134.38 (m), 134.26
(M), 133.76 (M), 132.56, 132.19 (m), 131.50 (m), 131.10 (M),
129.99 (M), 129.84 (M), 129.68, 129.27 (m), 129.14 (M), 128.96
(m), 128.84, 128.51 (m), 128.08 (m), 127.97 (M), 127.78 (M),
126.38, 126.14 (m), 126.08 (M), 125.89 (M), 125.59 (m), 125.01,
124.35, 122.64 (m), 122.50 (M), 52.41 (M), 52.00 (m), 40.48 (M),
39.35 (m), 21.16 (M), 21.35 (m). FTIR (KBr): 1668 cm-1. MS
(EI): 444 (M+, 5), 364 (5), 217 (18), 155 (100), 128 (10), 91
(73), 65 (10), 51 (1). Anal. Calcd for C26H22BrNO: C, 70.28; H,
4.99; N, 3.15. Found: C, 70.12; H, 5.02; N, 3.04.
C
20H18ClNO: C, 74.18; H, 5.60; N, 4.33. Found: C, 74.12; H,
5.63; N, 4.29.
N -(2-Iod op h e n yl)-N -m e t h yl-2-(1-n a p h t h yl)p r op a n -
a m id e (25c). 2-Iodoaniline (1.00 g, 4.56 mmol) was added to
the mixture of Et3N (552 mg, 15.5 mmol) and 2-(1-naphthyl)-
propanoyl chloride69 (1.20 g, 15.5 mmol) to give 1.32 g (3.28
mmol, 72%) of N-(2-iodophenyl)-N-2-(1-naphthyl)propanamide
after chromatography. 1H NMR (400 MHz, CDCl3): δ 8.14 (dd,
J ) 8.2, 1.0 Hz, 1H), 8.01 (d, J ) 8.0 Hz, 1H), 7.82 (m, 1H),
7.77 (d, J ) 8.2 Hz, 1H), 7.57 (d, J ) 7.0 Hz, 1H), 7.48-7.41
(m 4H), 7.28 (br s, 1H), 7.19 (m, 1H), 6.64 (td, J ) 8.6, 1.5
Hz, 1H), 4.45 (quart, J ) 7.2 Hz, 1H), 1.78 (d, J ) 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 173.82, 139.29, 138.68,
136.40, 134.93, 132.57, 129.74, 129.70, 129.40, 127.68, 126.83,
126,40, 126.34, 126.17, 123.99, 122.03, 89.88, 45.80, 18.20.
N-(2-Iodophenyl)-N-2-(1-naphthyl)propanamide (1.32 g, 3.28
mmol) was added to a mixture of NaH (78.7 mg, 3.28 mmol)
and THF (30 mL). The resulting mixture was stirred for 12 h
at room temperature. MeI (558 mg, 3.94 mmol) was then
added, and the reaction was stirred for 12 h at room temper-
ature. Saturated aqueous ammonium chloride was added, and
the reaction mixture was extracted with Et2O. The combined
organic extracts were dried over MgSO4, filtered, and concen-
trated in vacuo. The resulting crude product was purified by
flash chromatography on silica gel to give 722 mg (1.74 mmol,
53%) of 25c. Recrystallization from hexanes gave a white solid
N-(2-Br om op h en yl)-N-m et h yl-2-(1-n a p h t h yl)p r op a n -
a m id e (25a ). 2-Bromo-N-methylaniline (1.77 g, 9.52 mmol)
was coupled with 2-(1-naphthyl)propanoyl chloride69 (2.49 g,
11.4 mmol) to give 3.02 g (8.20 mmol, 86%) of 25a after
chromatography. Recrystallization from hexanes gave a white
1
solid (mp 120-120.5 °C). H NMR (400 MHz, CDCl3): δ 7.76
(d, J ) 8.4 Hz, 1H), 7.69 (d, J ) 8.4 Hz, 1H), 7.62 (d, J ) 8.4
Hz, 0.7H), 7.53 (d, J ) 7.2 Hz, 0.7H) 7.47 (d, J ) 7.6 Hz, 0.3H),
7.42-7.34 (m, 2.3H), 7.24-7.16 (m, 2.6H), 7.04 (m, 0.3H), 6.89
(m, 0.7H), 6.49 (t, J ) 7.6 Hz, 0.7H), 6.09 (d, J ) 8.0 Hz, 0.7H),
4.48 (quart, J ) 6.8 Hz, 0.3H), 4.18 (quart, J ) 6.8 Hz, 0.7H),
3.22 (s, 0.9H), 3.21 (s, 2.1H), 1.55 (d, J ) 6.8 Hz, 0.9H), 1.53
(d, J ) 6.8 Hz, 2.1H). 1H NMR (300 MHz, 100 °C, toluene-d8):
δ 7.69-7.62 (m, 2H), 7.54 (d, J ) 7.8 Hz, 0.7H), 7.36-7.02 (m,
6.2H), 6.51 (br m, 0.7H), 6.22 (br m, 0.7H), 6.02 (br m. 0.7H),
1
(mp 136-137 °C). H NMR (400 MHz, CDCl3): δ 7.77 (dd, J
) 8.9, 1.3 Hz, 0.8H), 7.66 (d, J ) 8.2 Hz, 1H), 7.60 (d, J ) 8.1
Hz, 1H), 7.43 (dd, J ) 7.2, 0.9 Hz, 1H), 7.39 (dd, J ) 7.1, 1.0
Hz, 0.2H), 7.32-7.25 (m, 2.2H), 7.09-7.05 (m, 2.2H), 6.83 (td,
J ) 7.9, 1.4 Hz, 0.2H), 6.19 (td, J ) 7.9, 1.6 Hz, 0.8H), 6.40
(td, J ) 7.7, 1.4 Hz, 0.8H), 5.97 (dd, J ) 7.9, 1.6 Hz, 0.8H),
4.37 (quart, J ) 6.9 Hz, 0.2H), 4.06 (quart, J ) 6.9 Hz, 0.8H),
3.12 (s, 0.6H), 3.09 (s, 2.4H), 1.45 (d, J ) 6.9 Hz, 2.4H), 1.44
(d, J ) 6.9 Hz, 0.6H). 1H NMR (300 MHz, 100 °C, toluene-d8):
δ 7.70 (d, J ) 7.2 Hz, 1H), 7.62 (m, 1.8H), 7.54 (d, J ) 8.5 Hz,
1H), 7.37 (m, 1H), 7.28-7.16 (m, 3.2H), 6.82 (m, 0.2H), 6.62
(m, 0.2H), 6.51 (m, 0.2H), 6.33 (m, 0.8H), 6.25 (m, 0.8H), 6.01
(m. 0.8H), 4.46 (m, 0.2H), 4.26 (m, 0.8H), 3.15 (s, 0.6H), 3.10
(s, 2.4H), 1.73 (d, J ) 6.9 Hz, 2.4H), 1.64 (d, J ) 6.9 Hz, 0.6H).
13C NMR (100 MHz, CDCl3, M ) major conformer, m ) minor
conformer): δ 174.44 (m), 174.24 (M), 146.18 (m), 145.41 (M),
140.93 (m), 139.92 (M), 138.79 (M), 137.23 (m), 134.33 (m),
134.05 (M), 131.53 (m), 130.88 (M), 130.24 (M), 129.95 (m),
4.30 (br m, 1H), 3.12 (br s, 3H), 1.70 (br d J ) 8.4 Hz, 3H). 13
C
NMR (100 MHz, CDCl3, M ) major conformer, m ) minor
conformer): δ 174.76 (M), 174.69 (m), 142.78 (m), 142.33 (M),
139.13 (M), 137.38 (m), 134.58 (m), 134.38 (m), 134.28 (M),
133.87 (M), 131.47 (m), 131.22 (M), 131.10 (M), 130.63 (m),
130.00 (m), 129.85 (M), 129.29 (m), 129.21 (M), 128.71, 127.77,
126.41, 126.23, 126.16 (m), 125.89 (M), 125.60 (m), 125.10 (M),
124.73 (m), 123.93 (M), 122.66 (m), 122.57 (M), 40.23 (M), 39.25
(68) Wamser, C. C.; Wagner, W. R. J . Am. Chem. Soc. 1981, 103,
7232-7234.
(69) Pirkle, W. H.; McCune, J . E. J . Chromatogr. 1989, 469, 67-
75.

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3411
129.73 (m), 129.72 (m), 129.65 (M), 129.40 (M), 129.12 (m),
128.96 (M), 127.69 (m), 127.53 (M), 126.50 (m), 126.41 (m),
126.26 (M), 126.01, 125.65 (M), 125.42 (m), 124.88 (M), 122.51
(m), 122.31 (M), 100.31, 30.37 (M), 38.70 (m), 37.06 (m), 36.73
(M), 20.89 (m), 20.48 (M). FTIR (KBr pellet): 1663 cm-1. MS
(EI): 415 (10), 288 (54), 260 (50), 231 (8), 203 (7), 182 (6), 155
(100), 133 (17), 128 (19), 104 (17), 77 (16), 63 (7), 51 (7). Anal.
Calcd for C20H18INO: C, 57.85; H, 4.37; N, 3.37. Found: C,
57.84; H, 4.33; N, 3.32.
7.06-6.94 (br m, 4H), 6.78 (br m, 2H), 6.54 (br s, 1H), 3.53-
3.42 (br s, 1H), 3.11 (s, 3H), 2.41 (d, J ) 6.9 Hz, 2H), 1.84
(sept, J ) 6.6 Hz, 1H), 1.58 (br s, 3H), 0.93 (d, J ) 6.6 Hz,
6H). 13C NMR (100 MHz, CDCl3, M ) major conformer, m )
minor conformer): δ 174.76 (m), 174.64 (M), 143.15 (m), 142.80
(M), 140.69, 139.55 (M), 138.40 (m), 134.64 (m), 134.12 (M),
131.60 (M), 130.77 (m), 130.31 (m), 130.26 (M), 129.75 (M),
129.61 (m), 129.23 (m), 129.04 (M), 128.28 (m), 127.77 (M),
124.93 (m), 124.32 (M), 45.69 (m), 45.63 (M), 44.37 (M), 43.62
(m), 36.84 (M), 36.81 (m), 30.87 (m), 30.85 (M), 23.08 (m), 23.05
(M), 22.98, 21.25 (M), 20.76 (m). FTIR (neat, NaCl plate): 1669
cm-1. MS (EI): 294 (M+ - Br, 100), 212 (40), 188 (10), 161
(10), 145 (12), 117 (40), 91 (32), 77 (20), 57 (5). Anal. Calcd for
N-(2-Br om op h en yl)-N-m et h yl-2-p h en ylp r op a n a m id e
(27). 2-Bromo-N-methylaniline (1.78 g, 6.34 mmol) was coupled
with 2-phenylpropanoyl chloride70 (1.28 g, 7.61 mmol) to give
1.49 g (4.68 mmol, 74%) of 27 as a colorless oil after chroma-
tography. 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J ) 8.0, 1.6
Hz, 0.7H), 7.49 (d, J ) 7.6 Hz, 0.3H), 7.35 (td, J ) 7.8, 1.2 Hz,
0.3H), 7.28 (dd, J ) 8.0, 2.0 Hz, 0.3H), 7.20-7.07 (m, 3.8H),
6.93 (m, 0.3H), 6.88 (m, 2.3H), 6.63 (dd, J ) 7.6, 1.6 Hz, 1H),
3.45 (quart, J ) 6.8 Hz, 0.3H), 3.27 (quart, J ) 7.2 Hz, 0.7H),
3.11 (s, 0.9H), 3.09 (s, 2.1H), 1.35 (d, J ) 7.2 Hz, 2.1H), 1.33
(d, J ) 6.8 Hz, 0.9H). 1H NMR (300 MHz, 100 °C, toluene-d8):
δ 7.32 (br s, 1H), 7.21-6.88 (br m, 5H), 6.69 (br s, 2.3H), 6.40
(br s, 0.7H), 3.44-3.34 (br s, 1H), 3.00 (s, 3H), 1.46 (d, J ) 8.4
Hz, 3H). 13C NMR (100 MHz, CDCl3, M ) major conformer, m
) minor conformer): δ 174.58 (m), 174.39 (M), 143.09 (m),
142.85 (M), 142.28 (M), 141.21 (m), 134.65 (m), 134.18 (M),
131.49 (M), 130.72 (m), 130.39 (m), 130.33 (M), 129.31 (m),
129.10 (M), 129.02 (M), 128.83 (m), 128.66 (m), 128.07 (M),
127.39 (m), 127.32 (M), 124.84 (m), 124.30 (M), 44.68 (M), 43.90
(m), 36.83 (M), 36.81 (m), 21.29 (M), 20.75 (m). FTIR (neat,
NaCl plate): 1668 cm-1. MS (EI): 238 (M+-Br, 100), 214 (25),
185 (17), 155 (4), 132 (4), 105 (100), 77 (38), 51 (10). Anal. Calcd
for C16H16BrNO: C, 60.39; H, 5.07; N, 4.40. Found: C, 60.53;
H, 4.93; N, 4.16.
C
20H24BrNO: C, 64.18; H, 6.46; N, 3.74. Found: C, 64.44; H,
6.41; N, 3.81.
N -(2-Br om op h e n yl)-N -m e t h yl-2-cycloh e xylp r op a n -
a m id e (33). 2-Bromo-N-methylaniline (1.21 g, 6.51 mmol) was
coupled with 2-cyclohexylpropanoyl chloride72 (1.36 g 7.81
mmol) to give 1.93 g (5.96 mmol, 92%) of 33 as a colorless oil
after chromatography. 1H NMR (400 MHz, CDCl3): δ 7.67 (m,
1H), 7.38 (m, 1H), 7.26 (m, 2H), 3.20 (d, J ) 1.2 Hz, 1.7H),3.19
(d, J ) 1.2 Hz, 1.3H), 1.84 (m, 1H), 1.76-1.49 (m, 6H), 1.26-
1.13 (m, 2H), 1.08 (dd, J ) 6.8, 0.8 Hz, 1.7H), 1.04 (m, 1H),
1.03 (dd, J ) 6.8, 0.8 Hz, 1.3H), 0.84 (m, 1H), 0.66 (m, 1H). 1H
NMR (300 MHz, 100 °C, toluene-d8): δ 7.40 (d, J ) 8.0 Hz,
1H), 7.06-6.96 (br m, 2H), 6.77 (m, 1H), 3.15 (s, 3H), 2.05 (br
s, 1H), 1.82-1.62 (m, 6H), 1.25-1.13 (br m, 7H), 0.81 (m, 1H).
13C NMR (100 MHz, CDCl3, M ) major conformer, m ) minor
conformer): δ 177.54 (m), 177.33 (M), 143.55 (M), 143.46 (m),
134.73 (m), 134.51 (M), 131.36, 130.46 (m), 130.16 (M), 129.26
(M), 129.22 (m), 124.13 (M), 123.60 (m), 43.59 (m), 43.42 (M),
42.12 (M), 40.98 (m), 36.54 (M), 36.46 (m), 33.23 (m), 32.78
(M), 30.26 (M), 30.05 (m), 27.09 (M), 27.03 (m), 27.00, 26.92,
16.21 (m), 16.03 (M). FTIR (neat, NaCl plate): 1661 cm-1. MS
(EI): 244 (M+ - Br, 100), 185 (50), 162 (100), 147 (5), 111 (59),
69 (75), 55 (41). Anal. Calcd for C16H22BrNO: C, 59.27; H, 6.84;
N, 4.32. Found: C, 59.19; H, 6.95; N, 4.26.
N-(2-Br om oph en yl)-N-m eth yltetr ah ydr o-2-fu r an cabox-
a m id e (35). 2-Bromoaniline (3.01 g, 17.5 mmol) was added to
the mixture of DCC (4.33 g, 21.0 mmol) and tetrahydro-2-
furancarboxylic acid (2.44 g, 21.0 mmol) in DMF (80 mL) at
room temperature. The resulting solution was allowed to stir
for 12 h. The reaction mixture was poured into water and
extracted with Et2O. The organic phase was washed with
brine, dried over MgSO4, filtered, and concentrated at reduced
pressure. The resulting crude product was purified by flash
chromatography on silica gel to give 1.95 g (41%) of N-(2-
bromophenyl)tetrahydro-2-furancaboxamide. 1H NMR (300
MHz, CDCl3): δ 9.17 (br s, 1H), 8.41 (m, 1H), 7.54 (m, 1H),
7.31 (m, 1H), 7.00 (m, 1H), 4.51 (m, 1H), 4.13 (m, 1H), 4.00
(m, 1H), 2.35 (m, 1H), 2.20 (m, 1H), 1.98 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 172.52, 135.88, 132.95, 129.02, 125.80,
122.02, 114.28, 79.48, 70.54, 31.00, 26.22.
N-(2-Bromophenyl)tetrahydro-2-furancaboxamide (1.78 g,
6.59 mmol) was added to a mixture of NaH (237 mg, 9.88
mmol) and THF (40 mL). The resulting mixture was stirred
for 12 h at room temperature. MeI (0.82 mL, 13.2 mmol) was
then added, and the reaction was stirred for 12 h at room
temperature. Saturated aqueous ammonium chloride was
added, and the reaction mixture was extracted with Et2O. The
combined organic extracts were dried over MgSO4, filtered, and
concentrated in vacuo. The resulting crude product was
purified by flash chromatography on silica gel to give 1.37 g
(4.82 mmol, 73%) of 35, which was obtained as a colorless oil.
1H NMR (300 MHz, CDCl3): δ 7.67 (m, 1H), 7.37 (m, 2H), 7.25
(m, 1H), 4.14 (m, 0.6H), 4.11 (m, 0.4H), 4.03-3.93 (m, 1H),
3.76 (m, 1H), 3.19 (s, 3H), 2.14-1.92 (m, 2H), 1.86-1.68 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 173.74 (m), 172.97 (M),
142.56 (M), 142.42 (m), 134.58 (m), 134.29 (M), 131.06, 130.77
(m), 130.48 (M), 129.58 (m), 129.32 (M), 124.33 (m), 123.80
(M), 76.23 (m), 75.59 (M), 70.28 (m), 69.94 (M), 36.83, 31.13
N -(2-B r o m o p h e n y l)-N -m e t h y l-2-(o-t o ly l)p r o p a n -
a m id e (29). 2-Bromo-N-methylaniline (1.16 g, 6.23 mmol) was
coupled with 2-(o-tolyl)propanoyl chloride (1.36 g 7.48 mmol)
to give 1.75 g (5.27 mmol, 84%) of 29 as a colorless oil after
1
chromatography. H NMR (400 MHz, CDCl3): δ 7.59 (dd, J )
8.0, 1.4 Hz, 0.8H), 7.40 (dd, J ) 8.1, 1.4 Hz, 0.2H), 7.34-7.30
(m, 0.4H), 7.26 (m, 0.8H), 7.14-7.00 (m, 2.2H), 6.97 (m, 1H),
6.91 (m, 0.8H), 6.83 (m, 1H), 6.03 (dd, J ) 11.8, 1.5 Hz, 0.8H),
3.77 (quart, J ) 6.8 Hz, 0.2H), 3.44 (quart, J ) 6.8 Hz, 0.8H),
3.13 (s, 0.6H), 3.09 (s, 2.4H), 1.41 (s, 0.6H), 1.38 (s, 2.4H), 1.26
1
(d, J ) 6.8 Hz, 3H). H NMR (300 MHz, 100 °C, toluene-d8):
δ 7.50 (m, 1H), 7.25 (m, 0.8H), 7.05-6.57 (m, 5.4H), 6.15 (m,
0.8H), 3.70-3.54 (m, 1H), 3.00 (s, 3H), 1.41 (m, 6H). 13C NMR
(100 MHz, CDCl3, M ) major conformer, m ) minor con-
former): δ 174.46, 142.78 (m), 142.34 (M), 140.93 (M), 139.36
(m), 135.38 (M), 135.23 (m), 134.54 (m), 133.71 (M), 131.20
(M), 130.77 (m), 130.40 (M), 130.28 (m), 129.86 (M), 129.06
(m), 128.78 (M), 128.01 (m), 126.92, 126.86, 126.77, 124.64 (m),
124.25 (M), 40.76 (M), 39.36 (m), 36.62 (m), 36.58 (M), 20.29
(m), 19.67 (M), 18.64 (m), 18.60 (M). FTIR (neat, NaCl plate):
1668 cm-1. MS (EI): 333 (10), 331 (7), 252 (80), 212 (20), 185
(17), 155 (5), 119 (100), 91 (47), 77 (47), 51 (10). Anal. Calcd
for C17H18BrNO: C, 61.46; H, 5.46; N, 4.22. Found: C, 61.67;
H, 5.47; N, 3.94.
N-(2-Br om op h en yl)-N-m eth yl-2-(4-isobu tyl)p h en ylp r o-
p a n a m id e (31). 2-Bromo-N-methylaniline (372 mg, 2.00
mmol) was coupled with 2-(4-isobutylphenyl)propanoyl chlo-
ride71 (571 mg 2.4 mmol) to give 531 mg (1.42 mmol, 71%) of
31 as a colorless oil after chromatography. 1H NMR (400 MHz,
CDCl3): δ 7.72 (dd, J ) 8.0, 1.2 Hz, 0.7H), 7.57 (dd, J ) 8.0,
1.2 Hz, 0.3H), 7.44 (m, 0.3H), 7.37 (m, 0.3H), 7.26 (m, 0.3H),
7.23 (m, 0.7H), 7.16 (m, 0.7H), 6.97 (d, J ) 7.6 Hz, 2H), 6.89-
6.85 (m, 2H), 6.71 (dd, J ) 7.8, 1.2 Hz, 0.7H), 3.52 (quart, J )
7.2 Hz, 0.3H), 3.33 (quart, J ) 6.8 Hz, 0.7H), 3.20 (m, 0.9H),
3.18 (m, 2.1H), 2.43 (d, J ) 6.8 Hz, 1.4H), 2.40 (d, J ) 6.8 Hz,
0.6H), 1.82 (m, 1H), 1.42 (m, 3H), 0.91 (m, 3H), 0.89 (m, 3H).
1H NMR (300 MHz, 100 °C, toluene-d8): δ 7.48 (br m, 1H),
(70) Bly, R. S.; Zhong, Z.; Kane, C.; Bly, R. K. Organometallics 1994,
13, 899-905.
(71) Welch, S. C.; Hagan, C. P.; Kim, J . H.; Chu, P. S. J . Org. Chem.
1977, 42, 2879-2887.
(72) Schlessinger, R. H.; Tata, J . R.; Springer, J . P. Tetrahedron Lett.
1987, 28, 5423-5426.

3412 J . Org. Chem., Vol. 66, No. 10, 2001
Lee and Hartwig
1
(m), 30.05 (M), 26.68 (M), 26.33 (m). FTIR (neat, NaCl plate):
1674 cm-1. MS (EI): 285 (1), 283 (1), 204 (35), 176 (40), 71
(100). Anal. Calcd for C12H14BrNO2: C, 50.72; H, 4.97; N, 4.93.
Found: C, 51.00; H, 5.14; N, 5.19.
give 1.05 g (3.66 mmol, 97%) of 45 after chromatography. H
NMR (400 MHz, CDCl3): δ 7.41 (dd, J ) 8.0, 1.2 Hz, 1H),
7.21-7.15 (m, 4H), 7.11-7.09 (m, 2H), 7.05 (ddd, J ) 7.8,
7.6, 1.6 Hz, 1H), 6.72 (dd, J ) 7.6, 1.2 Hz, 1H), 5.52 (d,
J ) 14.0 Hz, 1H), 3.96 (d, J ) 14.0 Hz, 1H), 2.18 (sept, J )
6.8 Hz, 1H), 1.03 (d, J ) 6.8 Hz, 3H), 0.94 (d, J ) 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 178.02, 139.98, 137.94,
133.98, 131.70, 131.22, 130.04, 129.77, 128.99, 128.17, 128.04,
N -(2-B r o m o p h e n y l)-N -m e t h y l-2-p h e n o x y p r o p a n -
a m id e (37). 2-Bromo-N-methylaniline (730 mg, 3.92 mmol)
was coupled with 2-phenoxypropanoyl chloride (868 mg 4.70
mmol) to give 1.07 g (3.20 mmol, 82%) of 37 as a colorless oil
after chromatography. 1H NMR (400 MHz, CDCl3): δ 7.56 (m,
1H), 7.25 (m, 0.4H), 7.16-7.04 (m, 5H), 6.93 (m, 0.4H), 6.84
(m, 0.6H), 6.69 (d, J ) 8.0 Hz, 0.6H), 6.56 (d, J ) 7.6 Hz, 1H),
4.54 (quart, J ) 6.8 Hz, 0.4H), 4.50 (quart, J ) 6.4 Hz, 0.6H),
3.17 (s, 1.2H), 3.16 (s, 1.8H), 1.38 (d, J ) 6.8 Hz, 1.2H), 1.37
(d, J ) 6.4 Hz, 1.8H). 1H NMR (300 MHz, 100 °C, toluene-d8):
δ 7.36-7.30 (m, 2H), 7.20 (m, 2H), 6.94-6.82 (m, 3H), 6.75-
6.63 (m, 2H), 4.73 (br s, 1H), 3.18 (s, 3H), 1.57 (s, 3H). 13C
NMR (100 MHz, CDCl3, M ) major conformer, m ) minor
conformer): δ 171.67 (m), 171.00 (M), 157.68 (m), 157.63 (M),
142.07, 134.70 (m), 134.37 (M), 131.16, 130.57 (M), 130.54 (m),
129.98 (M), 129.89 (m), 129.49 (M), 129.22 (m), 123.95 (m),
123.63 (M), 122.36 (M), 122.14 (m), 116.99 (M), 116.76 (m),
72.84 (m), 72.40 (M), 37.47 (m), 37.07 (M), 18.66 (m), 17.72
(M). FTIR (neat, NaCl plate): 1678 cm-1. MS (EI): 335 (2),
333 (2), 254 (M+ - Br, 25), 211 (25), 184 (20), 161 (50), 146
51.95, 34.43, 20.70, 19.89. MS (EI): 287 (M+, 10), 252 (M+
Cl, 100), 217 (50), 180 (10), 152 (7), 138 (11), 91 (100), 65 (8),
51 (5).
-
N-(2-Ch lor op h en yl)-N-m eth ylcycloh exa n eca r ba m id e
(47). 2-Chloro-N-methylaniline (789 mg, 5.60 mmol) was
coupled with cyclohexylcarbonyl chloride (985 mg, 6.72 mmol)
to give 1.26 g (5.01 mmol, 89%) of 47. Recrystallization from
hexanes gave a white solid (mp 87-88 °C). 1H NMR (300 MHz,
CDCl3): δ 7.52 (m, 1H), 7.34 (m, 2H), 7.27 (m, 1H), 3.18 (s,
3H), 1.95 (m, 1H), 1.74-1.44 (m, 8H), 1.20 (m, 1H), 0.97 (m,
1H). 13C NMR (75 MHz, CDCl3): δ 176.51, 141.51, 133.17,
130.73, 129.76, 129.42, 128.20, 41.91, 35.38, 29.78, 29.06,
25.69, 25.64, 25.46. FTIR (KBr): 1663 cm-1. MS (EI): 216 (M+
- Cl, 80), 141 (100), 83 (90), 55 (70). Anal. Calcd for C14H18
ClNO: C, 66.79; H, 7.21; N, 5.56. Found: C, 66.68; H, 7.09;
N, 5.36.
-
(15), 121 (100), 93 (20), 77 (76), 51 (26). Anal. Calcd for C16H16
-
Gen er a l P r oced u r e for th e Syn th esis of Oxin d oles
fr om 2-Br om oa n ilid e or 2-Ch lor oa n ilid e Su bstr a tes Us-
in g P Cy3 or Liga n d 8. In the drybox, Pd(OAc)2 (11.2 mg,
0.0500 mmol), PCy3 (14.0 mg, 0.0500 mmol), or carbene ligand
8 (23.9 mg, 0.0500 mmol) was combined with NaOtBu (144
mg, 1.50 mmol) in a small round-bottom flask. 1,4-Dioxane
(10 mL) was added, and the flask was sealed with a septum.
The resulting mixture was allowed to stir for 1 min, at which
time the 2-bromo or 2-chloroanilide substrate was added. After
being removed from the drybox, the flask was placed in an oil
bath at the appropriate temperature (see Tables 3 and 4) until
the starting material was consumed, as determined by GC and
TLC. The reaction was poured into 20 mL of saturated aqueous
ammonium chloride and extracted (3 × 20 mL) with Et2O. The
combined ether extracts were washed with brine (60 mL), dried
over MgSO4, and filtered. The solvent was removed under
vacuum, and the resulting crude product was purified by flash
chromatography on silica gel. The product was eluted with 15%
ethyl acetate in hexanes. The products (2, 10, 12, 16, 18, 20,
BrNO2: C, 57.50; H, 4.83; N, 4.19. Found: C, 57.44; H, 4.86;
N, 4.19.
N-(2-Ch lor oph en yl)-N-m eth ylpr opan am ide (41).11 2-Chlo-
ro-N-methylaniline (980 mg, 6.95 mmol) was coupled with
propionyl chloride (771 mg 8.34 mmol) to give 1.25 g (6.34
mmol, 91%) of 41 as colorless oil after chromatography. 1H
NMR (400 MHz, CDCl3): δ 7.35 (m, 1H), 7.18 (m, 2H), 7.12
(m, 1H), 3.05 (s, 3H), 1.82 (quart, J ) 7.6 Hz, 2H), 0.89 (t, J )
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 174.39, 141.80,
133.61, 131.25, 130.41, 130.08, 128.87, 36.31, 27.74, 9.97. MS
(EI): 162 (M+ - Cl, 100), 141 (100), 111 (20), 90 (10), 77 (55),
57 (43), 51 (14).
N-(2-Ch lor oph en yl)-N-m eth ylcycloh exylacetam ide (42).
2-Chloro-N-methylaniline (1.10 g, 7.80 mmol) was coupled with
cyclohexylacetyl chloride (1.50 g, 9.34 mmol) to give 1.93 g
(7.28 mmol, 93%) of 42 as a colorless oil after chromatography.
Recrystallization from hexanes gave a white solid (mp 74-75
°C). 1H NMR (300 MHz, CDCl3): δ 7.51 (m, 1H), 7.33 (m, 2H),
7.26 (m, 1H), 3.20 (s, 3H), 1.85 (m, 2H), 1.69 (m, 6H), 1.23 (m,
2H), 1.18 (m, 1H), 0.76 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 172.57, 141.51, 133.13, 130.71, 130.07, 129.44, 128.20, 41.33,
35.78, 34.84, 33.31, 33.21, 26.29, 26.19, 26.16. FTIR (KBr):
1666 cm-1. MS (EI), 230 (M+-Cl, 100), 183 (50), 168 (10), 148
(100), 141 (100), 125 (10), 111 (10), 97 (35), 77 (47), 67 (9), 55
(80). Anal. Calcd for C15H20ClNO: C, 67.79; H, 7.58; N, 5.27.
Found: C, 67.81; H, 7.76; N, 5.17.
1
22, and 40) were characterized by comparison of their H NMR
and 13C NMR spectra to those reported previously; their purity
was confirmed by GC analysis.5
1-Ben zyl-3-(1-n a p h th yl)-3-m eth yloxin d ole (24). Sub-
strate 23 (133 mg, 0.300 mmol), Pd(OAc)2 (3.3 mg, 0.015
mmol), PCy3 (4.2 mg, 0.015 mmol), and NaOtBu (43.2 mg,
0.450 mmol) were used. Reaction at 50 °C for 12 h gave 98 mg
(90%) of 24 after silica gel chromatography. Recrystallization
from hexanes gave a white solid (mp 142-143.5 °C). 1H NMR
(400 MHz, CDCl3): δ 7.77 (d, J ) 7.6 Hz, 1H), 7.73 (d, J ) 8.0
Hz, 1H), 7.69 (d, J ) 8.0 Hz, 1H), 7.43 (m, 3H), 7.30-7.19 (m,
4H), 7.09 (dd, J ) 8.0, 7.6 Hz, 1H), 6.91 (d, J ) 7.6 Hz, 1H),
6.86 (dd, J ) 7.8, 7.2 Hz, 1H), 6.79-6.70 (m, 3H), 5.12 (d, J )
15.2 Hz, 1H), 4.88 (d, J ) 15.2 Hz, 1H), 1.85 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 180.78, 141.71, 137.22, 136.52, 135.53,
134.80, 131.76, 129.62, 129.46, 129.30, 128.78, 128.35, 128.21,
126.79, 126.62, 125.77, 125.54, 124.48, 123, 53, 123.37, 110.06,
52.92, 44.78, 27.54. FTIR (KBr): 1715 cm-1. MS (EI): 363 (M+,
64), 272 (100), 254 (22), 215 (20), 153 (10), 116 (55), 91 (80),
65 (12). Anal. Calcd for C26H21NO: C, 85.92; H, 5.82; N,3.85.
Found: C, 85.68; H, 6.05; N, 3.77.
1,3-Dim eth yl-3-(1-n a p h th yl)oxin d ole (26). Substrate 25a
(184 mg, 0.500 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), PCy3
(7.0 mg, 0.025 mmol), and NaOtBu (72.0 mg, 0.750 mmol) were
used. Reaction at 50 °C for 12 h gave 139 mg (97%) of 26 after
silica gel chromatography. Recrystallization from hexanes gave
a white solid (mp 127-128 °C). 1H NMR (400 MHz, CDCl3):
δ 7.91 (d, J ) 7.2 Hz, 1H), 7.87 (d, J ) 8.4 Hz, 1H), 7.84 (d, J
) 8.0 Hz, 1H), 7.60 (dd, J ) 7.8, 7.6 Hz, 1H), 7.35 (m, 2H),
7.21 (m, 1H), 7.08 (d, J ) 7.6 Hz, 1H), 6.96 (m, 2H), 6.87 (d, J
) 7.2 Hz, 1H), 3.48 (s, 3H), 1.96 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 180.97, 142.65, 137.19, 135.57, 134.85, 131.82,
N-(2-Ch lor op h en yl)-N-m eth ylp h en yla ceta m id e (43).11
2-Chloro-N-methylaniline (1.02 g, 7.23 mmol) was coupled with
phenylacetyl chloride (1.34 g 8.68 mmol) to give 1.12 g (4.32
mmol, 60%) of 43 as a colorless oil after chromatography.1H
NMR (400 MHz, CDCl3): δ 7.42 (dd, J ) 7.6, 1.6 Hz, 1H),
7.27-7.19 (m, 2H), 7.15-7.10 (m, 3H), 7.07 (dd, J ) 7.6, 2.0
Hz, 1H), 6.95 (m, 2H), 3.35 (d, J ) 14.8 Hz, 1H), 3.24 (d, J )
14.8 Hz, 1H), 3.13 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
171.60, 141.60, 135.52, 133.77, 131.28, 130.86, 130.29, 129.78,
128.88, 128.75, 127.24, 41.57, 36.69. MS (EI): 224 (M+ - Cl,
100), 168 (18), 141 (63), 91 (70), 77 (18), 51 (7).
N-(2-Ch lor op h en yl)-N-m et h yl-2-m et h ylp r op a n a m id e
(44).11 2-Chloro-N-methylaniline (758 mg, 5.38 mmol) was
coupled with isobutyryl chloride (688 mg, 6.46 mmol) to give
1.09 g (5.17 mmol, 96%) of 44 as colorless oil after chroma-
tography. 1H NMR (400 MHz, CDCl3): δ 7.43 (m, 1H), 7.27
(m, 2H), 7.20 (m, 1H), 3.12 (s, 3H), 2.21 (sept, J ) 6.8 Hz, 1H),
0.98 (d, J ) 6.8 Hz, 3H), 0.93 (d, J ) 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 178.09, 141.96, 133.70, 131.30, 130.32,
130.03, 128.82, 36.48, 32.11, 20.51, 19.97. MS (EI): 176 (M+
- Cl, 100), 141 (68), 111 (5), 77 (20), 51 (5).
N-Ben zyl-N-(2-ch lor op h en yl)-2-m et h ylp r op a n a m id e
(45).11 2-Chloro-N-benzylaniline (820 mg, 3.78 mmol) was
coupled with isobutyryl chloride (483 mg, 4.53 mmol) to

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3413
129.64, 129.56, 128.41, 126.79, 126.77, 125.75, 125.59, 123.96,
123.59, 123.33, 109.13, 52.96, 27.33, 27.21. FTIR (KBr): 1716
cm-1. MS (EI): 287 (M+, 100), 262 (69), 256 (7), 244 (20), 215
(20), 202 (10), 160 (9), 127 (7), 101 (6), 77 (6). Anal. Calcd for
C20H17NO: C, 83.60; H, 5.96; N, 4.87. Found: C, 83.46; H, 5.77;
N, 4.77.
36.55, 27.09, 26.72. FTIR (neat, NaCl plate): 1723 cm-1. MS
(EI): 203 (M+, 67), 159 (100), 133 (75), 117 (40), 77 (40), 51
(11). Anal. Calcd for C12H13NO2: C, 70.91; H, 6.45; N, 6.89.
Found: C, 70.73; H, 6.57; N, 6.77.
3-Cycloh exyl-1-m eth yloxin d ole (14). Substrate 42 (265
mg, 1.00 mmol), Pd(OAc)2 (11.2 mg, 0.0500 mmol), PCy3 (14.0
mg, 0.0500 mmol), and NaOtBu (144 mg, 1.500 mmol) were
used. Reaction at 70 °C for 24 h gave 149 mg (65%) of 14 after
silica gel chromatography. Recrystallization from hexanes gave
1,3-Dim eth yl-3-p h en yloxin d ole (28). Substrate 27 (159
mg, 0.500 mmol), Pd(OAc)2 (5.6 mg, 0.025 mmol), PCy3 (7.0
mg, 0.025 mmol), and NaOtBu (72.0 mg, 0.750 mmol) were
used. Reaction at 50 °C for 14 h gave 118 mg (99%) of 28 as a
colorless oil after silica gel chromatography. 1H NMR (400
MHz, CDCl3): δ 7.26-7.20 (m, 5H), 7.16 (m, 1H), 7.10 (m, 1H),
7.01 (ddd, J ) 7.6, 6.4, 1.2 Hz, 1H), 6.83 (d, J ) 7.6 Hz, 1H),
1
a white solid (mp 80-81 °C). H NMR (300 MHz, CDCl3): δ
7.28 (m, 2H), 7.05 (t, J ) 7.68 Hz, 1H), 6.82 (d, J ) 8.0 Hz,
1H), 3.35 (d, J ) 3.0 Hz, 1H), 3.20 (s, 3H), 2.16 (m, 1H), 1.78-
1.66 (m, 4H), 1.48-1.07 (m, 6H). 13C NMR (75 MHz, CDCl3):
δ 178.08, 145.45, 128.39, 125.07, 122.72 (2C), 108.42, 52.21,
41.64, 31.05, 29.05, 27.38, 27.00, 26.78, 26.66. FTIR (KBr):
1710 cm-1. MS (EI): 229 (M+, 13), 147 (100), 118 (9), 91 (9),
77 (5), 55 (10). Anal. Calcd for C15H19NO: C, 78.56; H, 8.35;
N, 6.11. Found: C, 78.41; H, 8.25; N, 5.98.
3.15 (s, 3H), 1.71 (s, 3H). 13C NMR (400 MHz, CDCl3):
δ
180.06, 143.83, 141.39, 135.42, 129.16, 128.73, 127.85, 127.26,
124.81, 123.41, 108.93, 52.76, 27.11, 24.37. FTIR (neat, NaCl
plate): 1716 cm-1. MS (EI): 237 (M+, 93), 222 (100), 207 (10),
194 (15), 178 (7), 165 (10), 152 (8), 130 (4), 117 (5), 102 (2), 91
(4), 77 (5), 51 (4). Anal. Calcd for C16H15NO: C, 80.98; H, 6.37;
N, 5.90. Found: C, 80.75; H, 6.40; N, 5.74.
Gen er a l P r oced u r e for th e Syn th esis of Oxin d oles
fr om N-(2-Br om op h en yl)-N-m eth yla ceta m id e a n d Ar yl
Ch lor id e Usin g P Cy3 a s Liga n d . In the drybox, Pd(OAc)2
(22.4 mg, 0.100 mmol), PCy3 (28.0 mg, 0.100 mmol), and
NaOtBu (288 mg, 3.00 mmol) were combined in a small round-
bottom flask. 1,4-Dioxane (3.0 mL) was added, and the flask
was sealed with a septum. The resulting mixture was allowed
to stir for 1 min, at which time the N-(2-bromophenyl)-N-
methylacetamide 9 (235 mg, 1.03 mmol) and aryl chloride
substrate (1.0 mmol) were added. After being removed from
the drybox, the flask was placed in an oil bath at 70 °C until
the starting material was consumed, as determined by GC and
TLC. The reaction was poured into 10 mL of saturated aqueous
ammonium chloride and extracted (3 × 20 mL) with Et2O. The
combined ether extracts were washed with brine (60 mL), dried
over MgSO4, and filtered. The solvent was removed under
vacuum, and the resulting crude product was purified by flash
chromatography on silica gel. The product was eluted with 20%
ethyl acetate in hexanes.
1,3-Dim eth yl-3-(o-tolyl)oxin d ole (30). Substrate 29 (332
mg, 1.00 mmol), Pd(OAc)2 (11.2 mg, 0.0500 mmol), PCy3 (14.0
mg, 0.0500 mmol), and NaOtBu (144 mg, 1.500 mmol) were
used. Reaction at 50 °C for 12 h gave 250 mg (99%) of 30 as
colorless oil after silica gel chromatography. 1H NMR (400
MHz, CDCl3): δ 7.57 (d, J ) 7.8 Hz, 1H), 7.18 (m, 2H), 7.11
(m, 1H), 6.96-6.88 (m, 2H), 6.83 (d, J ) 7.6 Hz, 1H), 6.77 (d,
J ) 7.2 Hz, 1H), 3.24 (s, 3H), 1.69 (s, 3H), 1.53 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 179.64, 142.59, 137.48, 136.45,
134.69, 131.31, 127.42, 127.06, 127.00, 125.63, 122.58, 122.52,
107.67, 51.94, 26.09, 25.41, 18.81. FTIR (neat, NaCl plate):
1716 cm-1. MS (EI): 251 (100), 236 (10), 193 (42), 179 (40),
130 (5), 115 (12), 91 (10), 63 (9). Anal. Calcd for C17H17NO: C,
81.24; H, 6.82; N, 5.57. Found: C, 81.05; H, 6.74; N, 5.43.
1,3-Dim eth yl-3-(4-isobu tylp h en yl)oxin d ole (32). Sub-
strate 31 (112 mg, 0.300 mmol), Pd(OAc)2 (3.3 mg, 0.015
mmol), PCy3 (4.2 mg, 0.015 mmol), and NaOtBu (43.2 mg, 0.450
mmol) were used. Reaction at 50 °C for 14 h gave 66 mg (75%)
of 32 as colorless oil after silica gel chromatography. 1H NMR
(400 MHz, CDCl3): δ 7.23 (td, J ) 7.8, 1.2 Hz, 1H), 7.12 (m,
3H), 7.01 (d, J ) 7.2 Hz, 1H), 6.97 (d, J ) 8.4 Hz, 2H), 6.82 (d,
J ) 7.6 Hz, 1H), 3.15 (s, 3H), 2.33 (d, J ) 7.2 Hz, 2H), 1.73
(m, 1H), 1.69 (s, 3H), 0.79 (d, J ) 6.4 Hz, 3H), 0.78 (d, J ) 6.8
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 180.08, 143.64, 141.07,
138.43, 135.40, 129.68, 128.43, 126.74, 124.63, 123.14, 108.68,
52.31, 45.37, 30.56, 26.89, 24.24, 22.84, 22.82. FTIR (neat,
NaCl plate): 1717 cm-1. MS (EI): 293 (M+, 100), 268 (80), 250
(45), 222 (35), 207 (30), 160 (20), 130 (7), 91 (8), 77 (5), 51 (3).
Anal. Calcd for C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found:
C, 81.62; H, 8.12; N, 4.58.
1-Meth yl-3-(o-tolyl)oxin d ole (48). o-Tolyl chloride (127
mg, 1.00 mmol) was used. Reaction at 70 °C for 12 h gave 134
mg (56%) of 48 after silica gel chromatography. Recrystalli-
1
zation from hexanes gave a white solid (mp 131-132 °C). H
NMR (400 MHz, CDCl3): δ 7.24 (m, 1H), 7.17-6.93 (m, 6H),
6.82 (d, J ) 7.8 Hz, 1H), 4.76 (br s, 1H), 3.19 (s, 3H), 2.29 (br
s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.58, 144.77, 137.60,
135.81, 131.40, 129.61, 128.64 (2C), 128.08, 126.74, 124.98,
123.15, 108.48, 50.64, 26.84, 20.17. FTIR (KBr): 1709 cm-1
.
MS (EI): 237 (M+, 100), 208 (38), 194 (37), 179 (30), 165 (28),
152 (11), 118 (10), 91 (11), 51 (4). Anal. Calcd for C16H15NO:
C, 80.98; H, 6.37; N, 5.90. Found: C, 80.72; H, 6.11; N, 5.78.
1-Meth yl-3-(p-tolyl)oxin d ole (49). p-Tolyl chloride (127
mg, 1.00 mmol) was used. Reaction at 70 °C for 12 h gave 132
mg (55%) of 49 after silica gel chromatography. Recrystalli-
zation from hexanes gave a white solid (mp 95-96 °C). 1H
NMR (400 MHz, CDCl3): δ 7.35 (m, 1H), 7.17 (m, 3H), 7.08
(m, 3H), 6.92 (d, J ) 7.8 Hz, 1H), 4.60 (s, 1H), 3.28 (s, 3H),
2.35 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.82, 145.12,
137.88, 134.21, 130.21, 129.68, 128.96, 128.90, 125.63, 123.33,
108.75, 52.33, 27.09, 21.76. FTIR (KBr): 1716 cm-1. MS (EI):
237 (M+, 100), 208 (56), 194 (48), 165 (15), 151 (10), 118 (10),
91 (8), 51 (2). Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N,
5.90. Found: C, 80.73; H, 6.09; N, 5.86.
3-Cycloh exyl-1,3-d im et h yloxin d ole (34). Substrate 33
(324 mg, 1.00 mmol), Pd(OAc)2 (11.2 mg, 0.0500 mmol), PCy3
(14.0 mg, 0.0500 mmol), and NaOtBu (144 mg, 1.500 mmol)
were used. Reaction at 50 °C for 14 h gave 156 mg (64%) of 34
1
as colorless oil after silica gel chromatography. H NMR (400
MHz, CDCl3): δ 7.18 (m, 1H), 7.12 (d, J ) 8.8 Hz, 1H), 6.96
(ddd, J ) 8.0, 7.6, 0.8 Hz, 1H), 6.74 (d, J ) 8.0 Hz, 1H), 3.12
(s, 3H), 1.75-1.65 (m, 3H), 1.52 (m, 2H), 1.40 (m, 1H), 1.27 (s,
3H), 1.18-1.04 (m, 3H), 0.92 (m, 1H), 0.69 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 181.63, 144.16, 134.27, 128.10, 124.06,
122.72, 108.28, 52.29, 46.09, 28.07, 27.68, 27.29, 26.94, 26.81,
26.57, 21.59 ppm. FTIR (neat, NaCl plate): 1715 cm-1. MS
(EI): 243 (13), 161 (100), 130 (7), 117 (10), 77 (7), 55 (9). Anal.
Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.75. Found: C,
78.69; H, 8.83; N, 5.47.
1-Met h yl-3-(2-sp ir ot et r a h yd r ofu r a n yl)oxin d ole (36).
Substrate 35 (142 mg, 0.500 mmol), Pd(OAc)2 (5.6 mg, 0.025
mmol), PCy3 (7.0 mg, 0.025 mmol), and NaOtBu (72.0 mg, 0.750
mmol) were used. Reaction at 50 °C for 24 h gave 99.5 mg
(98%) of 36 as a colorless oil after silica gel chromatography.
1H NMR (400 MHz, CDCl3): δ 7.33 (m, 2H), 7.08 (ddd, J )
7.6, 7.4, 0.8 Hz, 1H), 6.80 (d, J ) 7.6 Hz, 1H), 4.32 (m, 1H),
4.26 (m, 1H), 3.17 (s, 3H), 2.47 (m, 1H), 2.37 (m, 1H), 2.25 (m,
1H), 2.14 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 178.53,
144.20, 131.18, 130.21, 124.05, 123.65, 108.86, 83.39, 70.97,
1-Meth yl-3-(2-m eth oxyp h en yl)oxin d ole (50). 2-Chloro-
anisole (142 mg, 1.00 mmol) was used. Reaction at 70 °C for
12 h gave 152 mg (60%) of 50 after silica gel chromatography.
Recrystallization from hexanes gave a white solid (mp 106-
107 °C). 1H NMR (400 MHz, CDCl3): δ 7.21-7.16 (m, 2H),
6.99 (m, 2H), 6.90 (m, 1H), 6.85-6.78 (m, 3H), 4.81 (s, 1H),
3.66 (s, 3H), 3.22 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ
177.47, 158.15, 144.94, 130.66, 130.46, 129.54, 128.47, 126.63,
124.77, 123.06, 121.61, 112.10, 108.36, 56.45, 48.56, 27.07.
FTIR (KBr): 1715 cm-1. MS (EI): 253 (M+, 100), 238 (80), 210
(50), 194 (24), 181 (20), 165 (20), 152 (21), 139 (10), 127 (5),
115 (8), 102 (3), 91 (5), 77 (5), 63 (4), 51 (3). Anal. Calcd for
C
16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.59; H,
5.75; N, 5.44.

3414 J . Org. Chem., Vol. 66, No. 10, 2001
Lee and Hartwig
3-(1,3-Ben zodioxol-5-yl)-1-m eth yloxin dole (51). 5-Chloro-
1,3-benzodioxole (127 mg, 1.00 mmol) was used. Reaction at
70 °C for 12 h gave 134 mg (56%) of 51 after silica gel
chromatography. Recrystallization from hexanes gave a white
solid (mp 131-132 °C). 1H NMR (400 MHz, CDCl3): δ 7.34
(m, 1H), 7.17 (d, J ) 7.3 Hz, 1H), 7.08 (m, 1H), 6.90 (d, J )
8.0 Hz, 1H), 6.78 (d, J ) 8.0 Hz, 1H), 6.72 (dd, J ) 6.4, 1.7 Hz,
1H), 6.64 (d, J ) 1.7 Hz, 1H), 5.92 (s, 2H), 4.52 (s, 1H), 3.25
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 176.56, 148.55, 147.63,
144.91, 130.73, 129.41, 129.00, 125.51, 123.29, 122.45, 109.22,
13C NMR (100 Hz, CDCl3): δ 161.79, 76.05, 51.39, 49.16, 46.07,
37.91, 29.15, 28.77, 20.33, 19.42, 14.18.
The reduction of the diimine (515 mg, 1.57 mmol) with
NaBH(OAc)3 (827 mg, 3.92 mmol) gave the corresponding
diamine (308 mg, 0.928 mmol). 1H NMR (400 MHz, CDCl3): δ
2.71 (m, 4H), 2.57 (m, 2H), 2.08 (m, 2H), 1.71 (m, 2H), 1.61
(m, 2H), 1.53 (m, 2H), 1.18 (m, 4H), 1.10 (m, 2H), 0.80 (s, 6H),
0.78 (s, 12H), 0.73 (dd, J ) 12.4, 4.4 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 63.34, 49.10 (2C), 48.64, 45.41, 38.61, 28.84,
27.78, 20.27, 19.08, 14.72.
Reaction of the diamine (308 mg, 0.928 mmol) with triethyl
orthoformate (137 mg, 0.928 mmol) and ammonium tetrafluo-
roborate (97.3 mg, 0.928 mmol) gave 72 (366 mg, 0.853 mmol,
92%). Recrystallization from ethanol gave a white solid (mp
280-282 °C). [R]24D ) +14.0° (c ) 0.73, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ 7.84 (s, 1H), 4.06 (m, 2H), 3.94 (m, 2H), 3.90
(m, 2H), 2.27 (m, 2H), 1.76 (m, 2H), 1.71 (m, 2H), 1.43 (m,
2H), 1.35-1.17 (m, 6H), 0.89 (s, 6H), 0.87 (s, 6H), 0.83 (s, 6H).
13C NMR (100 MHz, CDCl3): δ 157.77, 65.12, 51.09, 50.55,
49.40, 44.72, 32.78, 28.44, 28.20, 20.02, 18.81, 14.60. Anal.
Calcd for C23H39BF4N2: C, 64.19; H, 19.13; N, 6.51. Found:
C, 63.90; H, 9.17; N, 6.23.
109.04, 108.73, 101.65, 52.18, 26.99. FTIR (KBr): 1716 cm-1
.
MS (EI): 267 (M+, 100), 232 (61), 209 (33), 152 (30), 139 (25),
118 (20), 76 (22), 51 (10). Anal. Calcd for C16H13NO3: C, 71.90;
H, 4.90; N, 5.24. Found: C, 71.67; H, 4.69; N, 5.09.
Liga n d 70. Ligand 70 was prepared by literature methods
using (+)-diaminocyclohexane instead of the racemic diamine.
[R]24 ) +29.8° (c ) 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3):
D
δ 8.45 (s, 1H), 7.27 (s, 2H), 7.00 (s, 2H), 4.12 (m, 2H), 2.36 (s,
6H), 2.31 (s, 12H), 2.02 (m, 4H), 1.78 (m, 2H), 1.42 (m, 2H).
13C NMR (75 MHz, CDCl3): δ 161.15, 140.61, 136.15, 134.68,
130.33, 130.12, 128.99, 70.87, 27.47, 23.76, 21.11, 18.59, 17.89.
N,N′-Diisop in oca m p h eylim id a zolin iu m Tetr a flu or o-
bor a te (71). A round-bottom flask was charged with (-)-
isopinocamphenylamine (1.796 g, 11.71 mmol) in 10 mL of
CH2Cl2. Aqueous glyoxal (40%, 849 mg, 5.86 mmol) was added
at 0 °C. The resulting solution was allowed to warm to room
temperature and to stir for 5 h. The reaction was diluted with
Et2O, and the organic phase was washed with water, dried
over MgSO4, filtered, and dried in vacuo. The crude product
(1.92 g, 5.86 mmol) was used in the following reaction without
further purification. 1H NMR (400 MHz, CDCl3): δ 7.79 (s,
2H), 3.38 (m, 2H), 2.34 (m, 2H), 2.19 (m, 2H), 2.00 (m, 2H),
1.91 (m, 2H), 1.80 (m, 4H), 1.17 (s, 6H), 1.11 (m, 2H), 0.97 (s,
6H), 0.93 (d, J ) 7.3 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
159.82, 70.39, 47.80, 43.70, 41.90, 39.20, 36.05, 34.28, 28.36,
23.93, 20.23.
The diimine (1.92 g, 5.86 mmol) was dissolved in dichlo-
romethane in a round-bottom flask, and NaBH(OAc)3 (3.104
g, 14.65 mmol) was added. The resulting mixture was allowed
to stir for 24 h at room temperature. The reaction mixture was
quenched by adding aqueous saturated NH4Cl, and the product
was extracted with Et2O. The organic phase was washed with
brine, dried over MgSO4, filtered, and concentrated at reduced
pressure. The resulting crude product was purified by flash
chromatography on silica gel (EtOAc/hexane ) 1:1). A colorless
oil (1.05 g, 3.16 mmol) was obtained. 1H NMR (300 MHz,
CDCl3): δ 2.84 (m, 4H), 2.71 (m, 2H), 2.36 (m, 4H), 1.94 (m,
2H), 1.79 (m, 4H), 1.62 (m, 4H), 1.21 (s, 6H), 1.11 (d, J ) 7.2
Hz, 6H), 0.98 (s, 6H), 0.94 (s, 2H). 13C NMR (75 MHz, CDCl3):
δ 56.88, 48.03, 47.72, 45.20, 41.84, 38.65, 36.93, 33.89, 27.93,
23.48, 21.91.
A 10 mL round-bottom flask charged with triethyl ortho-
formate (486 mg, 3.16 mmol) ammonium tetrafluoroborate
(331 mg, 3.16 mmol) and diamine (1.05 g, 3.16 mmol) was
heated at 120 °C in an oil bath for 2 h. The ethanol formed
during the reaction was removed in vacuo. The crude product
was crystallized from absolute ethanol to give 870 mg (2.02
mmol, 64%) of white needles (mp >330 °C dec). [R]D ) -36.7°
(c ) 0.52, CH2Cl2). 1H NMR (400 MHz, CD2Cl2): δ 8.23 (s, 1H),
4.22 (m, 2H), 3.93 (m, 4H), 2.40 (m, 4H), 2.01 (ddd, J ) 7.8,
7.6, 1.6 Hz, 2H), 1.96 (m, 2H), 1.84-1.76 (m, 4H), 1.17 (s, 6H),
1.06 (d, J ) 7.2 Hz, 6H), 0.96 (s, 6H), 0.75 (d, J ) 9.6 Hz, 2H).
13C NMR (100 MHz, CD2Cl2): δ 157.78, 58.65, 47.84, 44.29,
41.96, 40.84, 39.13, 35.35, 32.62, 28.35, 23.84, 20.56. Anal.
Calcd for C23H39BF4N2: C, 64.19; H, 9.13; N, 6.51. Found: C,
63.90; H, 8.84; N,6.39.
Asym m etr ic Syn th esis of Oxin d oles. The same method
was followed as was described in the general synthesis of
racemic oxindoles, except Pd(dba)2 and optically active ligands
were used in monoglyme solvent. The enantiomeric excess was
determined by 1H NMR spectroscopy using the chiral shift
reagent Eu(hfc)3 and by HPLC analysis with a chiral column
(Chiral Daicel OD-H; 25 cm × 0.46 cm; hexane/i-PrOH ) 98:
2, UV-vis 254 nm).
1-Ben zyl-3-(1-n a p h th yl)-3-m eth yloxin d ole (24). A mix-
ture of 24 (10.8 mg, 0.0300 mmol) and Eu(hfc)3 (7.1 mg, 0.0059
mmol) in CDCl3 (0.8 mL) showed two separate peaks at 5.56
ppm ((-)-24) and 5.48 ppm ((+)-24) in the 1H NMR spec-
trum for the N-methylene group of the two enantiomers.
HPLC analysis gave two separate peaks (flow rate: 2.0 mL/
min, tR ) 10.42 min ((+)-24), 23.04 min ((-)-24)). Reactions
employing ligand 71 gave 67% ee (HPLC), [R]24 ) +30.8° (c
D
) 1.00, CH2Cl2), and reactions employing ligand 72 gave 76%
ee (HPLC), [R]24 ) -32.2° (c ) 1.55, CH2Cl2).
D
1,3-Dim eth yl-3-(1-n a p h th yl)oxin d ole (26). A mixture of
26 (7.7 mg, 0.027 mmol) and Eu(hfc)3(3.0 mg, 0.0025 mmol)
in CDCl3 (0.8 mL) showed two separate peaks at 3.85 ppm-
((+)-26) and 3.74 ppm((-)-26) in the 1H NMR spectrum for
the N-methyl group of the two enantiomers. HPLC analysis
gave two separate peaks (flow rate: 1.5 mL/min, tR ) 15.32
min ((-)-26), 39.67 min ((+)-26)). Reactions employing ligand
71 gave 67% ee (HPLC), [R]24D ) -3.5° (c ) 0.62, CH2Cl2), and
reactions employing ligand 72 gave 69% ee (HPLC), [R]24
+7.7° (c ) 1.30, CH2Cl2).
)
D
1,3-Dim eth yl-3-p h en yloxin d ole (28). A mixture of 28
(10.5 mg, 0.0443 mmol) and Eu(hfc)3 (4.4 mg, 0.0037 mmol)
in CDCl3 (0.8 mL) showed two separate peaks at 3.76 ppm
((-)-28) and 3.67 ppm ((+)-28) in the 1H NMR spectrum for
the N-methyl group of the two enantiomers. HPLC analysis
gave two separate peaks (flow rate: 2.0 mL/min, tR ) 5.48 min
((-)-28), 6.55 min ((+)-28)). Reactions employing ligand 71
gave 34% ee (HPLC), [R]24 ) -27.7° (c ) 2.97, CH2Cl2), and
D
reactions employing ligand 72 gave 57% ee (HPLC), [R]24
+41.1° (c ) 0.84, CH2Cl2).
)
D
1,3-Dim eth yl-3-(o-tolyl)oxin d ole(30). A mixture of 30
(25.1 mg, 0.100 mmol) and Eu(hfc)3 (11.8 mg, 0.0099 mmol)
in CDCl3 (0.8 mL) showed two separate peaks at 3.83 ppm
((-)-30) and 3.78 ppm ((+)-30) in the 1H NMR spectrum for
the N-methyl group of the two enantiomers. HPLC analysis
gave two separate peaks (flow rate: 2.0 mL/min, tR ) 6.44 min
((+)-30), 9.53 min ((-)-30)). Reactions employing ligand 75
N,N′-Dibor n ylim id a zolin iu m Tetr a flu or obor a te (72).
The same procedure as in the preparation of 74 was used. The
reaction of (+)-bornylamine (500 mg, 3.26 mmol) and glyoxal
(40%, 236 mg, 1.63 mmol) gave the corresponding diimine (515
gave 33% ee (HPLC), [R]24 ) +18.7° (c ) 1.23, CH2Cl2), and
D
reactions employing ligand 76 gave 42% ee (HPLC), [R]24
-23.9° (c ) 1.45, CH2Cl2).
)
D
1,3-Dim eth yl-3-(4-isobu tylp h en yl)oxin d ole (32). A mix-
ture of 32 (6.7 mg, 0.0228 mmol) and Eu(hfc)3 (2.6 mg, 0.0022
mmol) in CDCl3 (0.8 mL) showed two separate peaks at 3.80
1
mg, 1.57 mmol). H NMR (400 MHz, CDCl3): δ 7.95 (m, 2H),
3.42 (m, 2H), 2.18 (m, 2H), 2.03 (m, 2H), 1.79 (m, 2H), 1.73
(m, 2H), 1.37 (m, 2H), 1.34 (m, 2H), 1.28 (m, 2H), 0.95 (d, J )
1.2 Hz, 6H), 0.92 (d, J ) 1.6 Hz, 6H), 0.73 (d, J ) 2.0 Hz, 6H).
1
ppm ((-)-32) and 3.74 ppm ((+)-32) in the H NMR spectrum
for the N-methyl group of the two enantiomers. HPLC analysis

Pd-Catalyzed Synthesis of Oxindoles by Amide R-Arylation
J . Org. Chem., Vol. 66, No. 10, 2001 3415
gave two separate peaks (flow rate: 1.0 mL/min, tR ) 7.96 min
((-)-32), 8.77 min ((+)-32)). Reactions employing ligand 71
stirred in benzene for 48 h at room temperature. A white solid
precipitated from solution. The solid collected by filtration, and
was washed with Et2O and then dried in vacuo. Recrystalli-
zation from CH2Cl2/Et2O (1/1) gave a white solid 170 mg (0.184
gave 40% ee (HPLC), [R]24 ) -27.9° (c ) 2.97, CH2Cl2), and
D
reactions employing ligand 72 gave 50% ee (HPLC), [R]24
+39.9° (c ) 1.09, CH2Cl2).
)
D
1
mmol, 60%). H NMR (400 MHz, CD2Cl2): δ 7.58 (br s, 1H),
Syn th esis of P a lla d iu m Com p lex 73a . In the drybox, Pd-
(dba)2 (575 mg, 1.00 mmol), PCy3 (280 mg, 1.00 mmol) and 1
(358 mg, 1.40 mmol) were stirred in benzene for 20 h at room
temperature. A white solid precipitated from solution. The
solid was collected by filtration and was washed with Et2O
and then dried in vacuo. Recrystallization from CH2Cl2/Et2O
6.67 (br s, 2H), 6.59 (br s, 1H), 3.76 (br s, 3H), 2.72-2.47 (br
s, 1H), 2.03 (br s, 4H), 1.74 (br s, 12H), 1.48-1.36 (m, 30H),
0.94 (br s, 26H). 13C NMR (100 MHz, CD2Cl2): δ 179.11,
148.13, 142.58, 129.07, 127.57, 124.25, 123.35, 39.65, 35.54,
32.16, 30.98, 28.38, 27.18, 22.40, 19.45. 31P NMR (CD2Cl2, 162
MHz): δ 21.27 (s). FTIR (KBr pellet): 1651 cm-1. Anal. Calcd
for C47H80BrNOP2Pd: C, 54.17; H, 7.37; N, 2.17. Found: C,
53.87; H, 7.08; N, 1.99.
1
(1/1) gave a white solid 385 mg (0.600 mmol, 60%). H NMR
(400 MHz, CD2Cl2): δ 7.13 (m, 1H), 6.84 (m, 2H), 6.69 (m, 1H),
3.43 (s, 3H), 2.91 (sept, J ) 6.6 Hz, 1H), 2.05 (m, 3H), 1.44-
1.35 (m, 18H), 1.16 (br s, 6H), 1.06 (m, 6H), 0.69 (br s, 6H).
13C NMR (100 MHz, CD2Cl2): δ 181.71 (d, J c-p ) 2.7 Hz),
145.52 (d, J c-p ) 3.7 Hz), 141.76, 137.64 (d, J c-p ) 5.3 Hz),
127.69 (d, J c-p ) 3.7 Hz), 125.35, 117.74, 36.32, 36.10 (d, J c-p
) 24.4 Hz), 32.68, 30.86, 28.27 (d, J c-p ) 11.2 Hz), 27.20, 19.74.
31P NMR (CD2Cl2, 162 MHz): δ 51.89 (s). FTIR (KBr pellet):
1645 cm-1. Anal. Calcd for C29H47BrNOPPd: C, 54.17; H, 7.37;
N, 2.17. Found: C, 53.87; H, 7.08; N, 1.99.
Ack n ow led gm en t. We are grateful for support of
this work by NIH (GM R01-GM58108-02) and for
J ohnson Matthey for donation of palladium salts. S.L.
thanks the Korea Science and Engineering Foundation
(KOSEF) for a postdoctoral fellowship. We thank Sophia
Sarifidou for preliminary results on the rate acceleration
using PCy3.
Syn th esis of P a lla d iu m Com p lex 73b. In the drybox, Pd-
(PCy3)2 (205 mg, 0.307 mmol) and 1 (105 mg, 0.410 mmol) were
J O005761Z