Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular Heck reactions

Article abstract of DOI:10.1021/ja034525d

A practical sequence involving three consecutive palladium (0)-catalyzed reactions has been developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors 10 and 11a-k are generated in one step by chemoselective

Full text of DOI:10.1021/ja034525d

Published on Web 04/23/2003
Catalytic Asymmetric Synthesis of Quaternary Carbons
Bearing Two Aryl Substituents. Enantioselective Synthesis of
3-Alkyl-3-Aryl Oxindoles by Catalytic Asymmetric
Intramolecular Heck Reactions
Amy B. Dounay, Keiko Hatanaka,1a Jeremy J. Kodanko, Martin Oestreich,1b
Larry E. Overman,* Lance A. Pfeifer,1c and Matthew M. Weiss
Contribution from the Department of Chemistry, 516 Rowland Hall, UniVersity of California,
IrVine, California 92697-2025
Received February 5, 2003; E-mail: leoverma@uci.edu
Abstract: A practical sequence involving three consecutive palladium(0)-catalyzed reactions has been
developed for synthesizing 3-alkyl-3-aryloxindoles in high enantiopurity. The Heck cyclization precursors
10 and 11a-k are generated in one step by chemoselective Stille cross-coupling of 2′-triflato-(Z)-2-stannyl-
2-butenanilide 9 with aryl or heteroaryl iodides. The pivotal catalytic asymmetric Heck cyclization step of
this sequence takes place in high yield and with high enantioselectivity (71-98% ee) with the Pd-BINAP
catalyst derived from Pd(OAc)2 to construct oxindoles containing a diaryl-substituted all-carbon quaternary
carbon center. A wide variety of aryl and heteroaryl substituents, including ones of considerable steric
bulk, can be introduced at C3 of oxindoles in this way (Table 4). The only limitations encountered to date
are aryl substituents containing ortho nitro or basic amine functionalities and the bulky N-alkyl-7-oxindolyl
group. Asymmetric Heck cyclization of butenalide 22 having an o-(N-acetyl-N-benzylamino)phenyl substituent
at C2 provided a ∼1:1 mixture of amide atropisomers 23 and 24 in high yield and high enantioselectivity.
These atropisomers are formed directly upon Heck cyclization of 22 at 80 °C, as they interconvert thermally
to only a small extent at this temperature.
pharmaceuticals.5 In this context, we described some years ago
efficient catalytic asymmetric syntheses of the Calabar alkaloids
physostigmine (1) and physovenine, the former of which is used
in the clinical practice of medicine (Scheme 1).5a,d
Introduction
As a result of extreme steric congestion, the construction of
carbon atoms having four carbon ligands, all-carbon quaternary
centers, is a formidable challenge for chemical synthesis. This
challenge is magnified when the central carbon is stereogenic.2
The most powerful extant method for enantioselective construc-
tion of stereogenic all-carbon quaternary centers is the catalytic
asymmetric intramolecular Heck reaction, first reported in
1989.3,4 A particular focus of our investigations in this area has
been enantioselective synthesis of chiral 3,3-disubstituted ox-
indoles, as these heterocycles have numerous potential applica-
tions in the synthesis of alkaloids, drug candidates, and clinical
Scheme 1
(1) Current addresses: (a) Fujisawa Pharmaceutical Co., Ltd., Medicinal
Chemistry Research Laboratories, Kashima 2-1-6, Yodogawa, Osaka 532-
8514, Japan. (b) Institute for Organic Chemistry und Biochemistry, Albert-
Ludwigs-University Freiburg, Albertstrasse 21, 79104 Freiburg im Breisgau,
Germany. (c) Eli Lilly and Co., Lilly Corporate Center, Drop Code-1513,
Indianapolis, IN 46285.
(2) For reviews, see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591-4597. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388-401.
(3) (a) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989,
54, 5846-5848. (b) The indirect formation of stereogenic quaternary
carbons by group selective asymmetric intramolecular Heck reactions was
also first described in 1989, see: (b) Sato, Y.; Sodeoka, M.; Shibasaki, M.
J. Org. Chem. 1989, 54, 4738-4739.
(4) For recent reviews of asymmetric Heck reactions, see: (a) Link, J. T. Org.
React. 2002, 60, 157-534. (b) Shibasaki, M.; Vogl, E. M. J. Organomet.
Chem. 1999, 1-15. (c) Donde, Y.; Overman, L. E. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; Chapter 8G.
(d) Shibasaki, M. In AdVances in Metal-Organic Chemistry; Liebeskind,
L. S., Ed.; JAI: Greenwich, 1996; pp 119-151. (d) Dounay, A. B.;
Overman, L. E. Chem. ReV. 2003, 103, in press.
Extension of this catalytic approach to asymmetric synthesis
of oxindoles containing an aryl substituent at C3 could expedite
enantioselective synthetic access to a broad range of indole
alkaloids and congeners that contain one or more diaryl-
(5) (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem.
1993, 58, 6949-6951. (b) Ashimori, A.; Bachand, B.; Overman, L. E.;
Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477-6487. (c) Ashimori, A.;
Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J.
Am. Chem. Soc. 1998, 120, 6488-6499. (d) Matsuura, T.; Overman, L.
E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500-6503. (e) Overman, L.
E.; Poon D. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 518-521. (f)
Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed. 2000, 39, 4596-
4599.
9
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J. AM. CHEM. SOC. 2003, 125, 6261-6271
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A R T I C L E S
Dounay et al.
triflato-N-benzyl-(Z)-4-methoxy-2-phenyl-2-butenanilide (10)
from 3-benzyl-3H-benzoxazol-2-one (7), the latter of which is
available in one high-yielding step from commercially available
2-benzoxazolinone (Scheme 2).10 Toward this end, lithiation of
methyl propargyl ether with n-BuLi at -78 °C, followed by
addition of benzoxazolinone 7 and subsequent quenching with
N-phenyltriflimide, provided amide 8 in 59% yield. Regiose-
lective palladium(0)-catalyzed hydrostannylation11 of the triple
bond of 8 delivered 2-stannyl-2-butenanilide 9. Chemoselective
Stille reaction of this intermediate and iodobenzene gave 2′-
triflato-(Z)-2-phenyl-2-butenanilide 10 in high yield. Coupling
to form 10 occurred optimally in N-methyl-2-pyrrolidone (NMP)
in the presence of catalytic amounts of Pd2dba3‚CHCl3 and tri-
2-furylphosphine12a and 1 equiv of CuI.12b This palladium(0)-
catalyzed hydrostannylation-Stille cross-coupling sequence left
the aryl triflate untouched and provided Heck cyclization
precursor 10 in three steps and 43% overall yield from
benzoxazolinone 7. HPLC analysis established that the isomeric
purity of 10 was >99%.13
Figure 1. Representative indole alkaloids containing diaryl-substituted
quaternary stereocenters.
Scheme 2
substituted quaternary stereocenters. Representative bioactive
indole alkaloids displaying this structural motif include the
epidithiodiketopiperazine alkaloid leptosin D (2),6 the polypyr-
rolidinoindoline alkaloid hodgkinsine (3),7 and the dodecacyclic
alkaloid psycholeine (4) (Figure 1).7
Our early investigations of the asymmetric intramolecular
Heck reaction focused only briefly on synthesis of oxindoles
having an aryl substituent at C3.5b,c Illustrative of these studies,
cyclization of 2′-iodo-(Z)-2-phenyl-2-butenanilide 5 was studied
under both cationic (Ag3PO4 as an additive) and neutral
(1,2,2,6,6-pentamethylpiperidine, PMP, as an additive) Heck
conditions using a catalyst system generated from Pd2dba3‚
CHCl3 and (R)-BINAP8 (eq 1). Only moderate to low enantio-
selection (65% ee under cationic conditions and 19% ee under
neutral conditions) was realized in the assembly of oxindole
6.5c The observation that the cationic variant of the Heck
cyclization of 5 was superior5b,c,9 encouraged us to investigate
the cyclization of analogous aryl triflates. In this paper, we
describe our development of an expeditious way to prepare 2′-
triflato-(Z)-2-aryl-2-butenanilides and the optimization of the
catalytic asymmetric Heck cyclization of these precursors to
furnish 3-alkyl-3-aryl oxindoles of high enantiopurity.
Stille cross-coupling of stannane 9 with various aromatic or
heteroaromatic iodides provided a series of 2′-triflato-(Z)-2-aryl
(or heteroaryl)-2-butenanilides (Table 1).14 These chemoselective
cross-coupling reactions were high yielding for all but one of
(8) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi, H.;
Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51, 629-
635.
(9) Similar results (73% ee under cationic conditions and 35% ee under neutral
conditions) were seen with the corresponding E stereoisomer.5b
(10) Ucar, H.; Vanderpoorten, K.; Cacciaguerra, S.; Spampinato, S.; Stables, J.
P.; Depovere, P.; Isa, M.; Masereel, B.; Delarge, J.; Poupaert, J. H. J. Med.
Chem. 1998, 41, 1138-1145.
(11) (a) Zhang, H. X.; Guibe´, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857-
1867. (b) Cochran, J. C.; Bronk, B. S.; Terrence, K. M.; Phillips H. K.
Tetrahedron Lett. 1990, 31, 6621-6624. (c) Betzer, J. F.; Delaloge, F.;
Muller, B.; Pancrazi, A.; Prunet, J. J. Org. Chem. 1997, 62, 7768-7780.
(12) (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-9595. (b)
Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364. Farina,
V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S. J. Org. Chem.
1994, 59, 5905-5911. Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem.
Soc. 1999, 121, 7600-7605.
Results
A. Synthesis of Heck Cyclization Precursors. Our inves-
tigations of the catalytic asymmetric construction of oxindoles
bearing diaryl-substituted quaternary carbon stereocenters began
with the development of a general route for assembling
cyclization precursors. Initial efforts focused on preparing 2′-
(13) An Alltech Alltima SiO2 5 µ column (98:2 n-hexane-2-propanol) provided
baseline separation of 10 and its E stereoisomer.
(14) Iodides that are not available from commercial sources were prepared by
literature procedures or are reported in the Supporting Information: (a)
Table 1, entry 6: Olah, G. A.; Lin, H. C. J. Am. Chem. Soc. 1974, 96,
2892-2898. (b) Table 1, entry 8: Witulski, B.; Buschmann, N.; Berg-
stra¨sser, U. Tetrahedron 2000, 56, 8473-8480. (c) Table 1, entry 9: Kelly,
T. A.; McNeil, D. W. Tetrahedron Lett. 1994, 35, 9003-9006. (d) Table
1, entry 10: Park, Y.; Lee, I.; Kim, Y. J. Heterocycl. Chem. 1994, 31,
1625-1630.
(6) Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki, H.;
Kushida, K. J. Chem. Soc., Perkin Trans. 1 1994, 1859-1864.
(7) For a recent review of polypyrrolidinoindoline alkaloids, see: Anthoni,
U.; Christophersen, C.; Nielsen, P. H. Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Permagnon: New York, 1999; Vol.
13, pp 163-236.
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6262 J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003

Synthesis of 3-Alkyl-3-Aryl Oxindoles
A R T I C L E S
Table 2. Effect of the Precatalyst on Heck Cyclization of 10a
Table 1. Stille Coupling of 9 with Aryl Iodides
b
c
entry
precatalyst
solvent
yield 12, %
ee (S)-13 %
1
2
3
4
Pd(OAc)2
Pd2dba3‚CHCl3
Pd(OAc)2
THF
THF
DMA
DMA
98
<5
94
80
ndd
84
82
Pd2dba3‚CHCl3
23
a Conditions: 10 mol % Pd(OAc)2/20 mol % (R)-BINAP or 5 mol %
Pd2dba3‚CHCl3/11 mol % (R)-BINAP, 4.0 equiv of PMP, 80 °C, THF, or
100 °C, N,N-dimethylacetamide (DMA) for 4 h, substrate concentration )
0.1 M. b Yield of the mixture of enol ethers 12 (E/Z ) 9-14:1).
c Enantiomeric excess ((1% ee) of (S)-13 was measured by HPLC using a
Chiralcel OJ column. d Not determined.
(Scheme 3). Reactions were conducted at a substrate concentra-
tion of 0.1 M, employed catalyst loadings of 10 mol % of
palladium, and were performed for a set time of 4 h. The
enantioselectivity of the Heck cyclization step was determined
by HPLC analysis using a chiral stationary phase17 after
converting the mixture of stereoisomeric oxindole enol ethers
12 to â-hydroxyethyl derivative (S)-13. Enantioselectivites
determined in this way were reproducible within (1% ee over
multiple runs.
Scheme 3
Initial experiments employed either 5 mol % of Pd2dba3‚
CHCl3 and 11 mol % of (R)-BINAP or 10 mol % Pd(OAc)2
and 20 mol % of (R)-BINAP (Table 2). Both conditions generate
10 mol % of a Pd(0)-diphosphine complex.18 To our surprise,
the Pd2dba3‚CHCl3/(R)-BINAP catalyst system, previously
reported by us to be optimal for the cyclization of 2′-iodo-(Z)-
2-methyl-2-butenanilides,5a,c was kinetically sluggish for cy-
clization of 10 (entries 2 and 4). Use of Pd(OAc)2 as the
precatalyst led to substantially higher reaction rates (entries 1
and 3). For example, only a trace of product was observed when
the intramolecular Heck reaction of 10 was conducted at 80 °C
using the catalyst derived from Pd2dba3‚CHCl3, whereas com-
plete conversion to 12 was achieved within 4 h with the catalyst
generated from Pd(OAc)2. Even at 100 °C, 10 was only partially
converted to 12 using the Pd2dba3‚CHCl3/(R)-BINAP catalyst
system (entry 4).
the aryl and heteroaryl iodides surveyed. A variety of function-
alities were tolerated, including nitro groups and basic amines
(entries 5-6, 10). The efficiency of this carbon-carbon bond-
forming reaction was also not sensitive to steric effects, as aryl
iodides containing bulky ortho substituents (entries 7, 9-11)
coupled in good to excellent yields (75-93%). The sole
exception was the coupling of stannane 9 with N-(tert-
butoxycarbonyl)-3-iodoindole14c (entry 8), which proceeded in
only 51% yield. The isomeric purity of the 2′-triflato-N-methyl-
(Z)-4-methoxy-2-aryl (or heteroaryl)-2-butenanilides prepared
in this way was judged to be >95% based on 1H NMR analysis
and by analogy with the high stereospecificity observed in the
preparation of triflate 10.15
B. Optimization of the Heck Cyclization Conditions. We
initially examined the catalytic asymmetric intramolecular Heck
reaction of 2′-triflato-N-benzyl-(Z)-2-phenyl-4-methoxy-2-bu-
tenanilide (10).16 These studies were carried out using various
palladium precatalysts, chiral bidentate phosphine ligands, and
1,2,2,6,6-pentamethylpiperidine (PMP) as the acid scavenger
Upon identification of Pd(OAc)2 as a suitable precatalyst for
Heck cyclization of 10, the use of alternative bidentate phos-
phine ligands was investigated (Table 3). In addition to (R)-
BINAP (14), (R)-Tol-BINAP (15), (S,S)-DIOP (16), and (S,S)-
(15) These butenanilides exist in solution as two amide bond rotamers, in ratios
ranging from 4:1 to >20:1 depending upon the 2 substituent. Geometric
purity was evaluated by inspection of the methyl ether region (3-4 ppm)
of 1H NMR spectra; in all cases only two singlets were observed.
(16) Other propargyl ethers were surveyed including triisopropylsilyl (TIPS)
and methoxymethyl ether (MOM) derivatives. The enantiopurity of (S)-13
prepared from these precursors was 20-30% lower than that obtained from
methyl ether congener 10.
(17) A Daicel Chiralcel OJ column (7:3 hexane-i-PrOH) provided baseline
resolution of enantiomers; chromatograms are provided in the Supporting
Information.
(18) Two equivalents of (R)-BINAP per equivalent of Pd(OAc)2 are required
because 1 equiv of the diphosphine is consumed in the reduction of Pd(II)
to Pd(0), see: (a) Amatore, C.; Jutand, A.; Thuilliez, A. Organometallics
2001, 20, 3241-3249. (b) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett.
1992, 2177-2180.
9
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A R T I C L E S
Dounay et al.
Table 3. Asymmetric Heck Cyclization of 10 to Oxindole 12a
6 h (entries 2, 4, 6, 8, and 10). This lower catalyst loading had
no appreciable effect on either the yield or the enantioselectivity
of the cyclizations surveyed. In the few cases where Heck
cyclizations were sluggish, longer reaction times (12-18 h) led
to high conversions to oxindole products (entries 13 and 14).
Substrates containing an o-nitrophenyl 2-substituent (entries 11
and 12) required extended reaction times and high catalyst
loadings, 30-40 mol % of Pd(OAc)2/60-80 mol % of (R)-
BINAP, for complete consumption of starting material. In these
cases, oxindole products 18e and 18f were isolated in only
moderate yield, albeit with high enantiopurity.
The absolute configurations of oxindole products 12 and 18i,
formed using the catalyst derived from Pd(OAc)2 and (R)-
BINAP, were verified by X-ray crystallographic analysis of
heavy atom derivatives 20 and 21, respectively.19 These
derivatives were accessed as follows: Oxindole 12 (Ar ) Ph)
was converted to dibromooxindole (S)-20 by the straightforward
sequence summarized in Scheme 4, whereas oxindole 18i (Ar
b
c
entry
ligand
solvent
yield, %
ee, %
abs conf
1
2
3
4
5
6
7
8
14
14
14
14
15
15
15
15
16
16
16
16
17
17
17
17
toluene
THF
MeCN
DMA
toluene
THF
MeCN
DMA
toluene
THF
MeCN
DMA
toluene
THF
93
98
96
94
89
92
95
96
95
97d
95
92
95
93d
94
96
78
80
85
84
82
84
87
88
32
49
19
48
24
31
39
25
S
S
S
S
S
S
S
S
S
S
S
S
R
R
S
R
9
10
11
12
13
14
15
16
MeCN
DMA
a Conditions: 20 mol % Pd(OAc)2, 40 mol % diphosphine, 4.0 equiv of
PMP, 0.1 M substrate, 80 °C (THF or MeCN) or 100 °C (toluene or N,N-
dimethylacetamide, DMA) for 4 h, unless otherwise noted. b Isolated yield
of enol ethers 12 (E/Z ) 8-20:1). c Enantiomeric excess was determined
by HPLC analysis of the E enol ether. d Reaction time was 22 h as a result
of incomplete conversion at 4 h.
Scheme 4
) 2-BocNHC6H4) was converted to tetracyclic bromohydrin 21
by sequential reaction with p-toluenesulfonic acid (PTSA) and
N-bromosuccinimide (NBS) in wet CH2Cl2 (eq 2). The absolute
configuration of additional oxindoles prepared during these
investigations was assigned by analogy with that established
for 12, 18i, and related examples reported previously.20 The
absolute configuration observed in all cases is consistent with
the model we previously advanced for absolute stereocontrol
in intramolecular Heck cyclizations of (Z)-2-alkyl-2-butenanil-
ides with Pd-BINAP.5c
Figure 2. Chiral bisphosphine ligands.
BDPP (17) were screened (Figure 2). The effect of changing
solvent polarity on the enantioselectivity and chemical efficiency
of the intramolecular Heck reaction of 10 was also examined.
As summarized in Table 3, catalysts having a DIOP or BDPP
ligand provided oxindole 12 in modest enantiopurity in each of
the solvents surveyed (entries 9-16), whereas catalysts contain-
ing (R)-BINAP or (R)-Tol-BINAP furnished oxindole 12 in high
enantiopurity (entries 1-8). In the case of the BINAP ligands,
increasing solvent polarity led to slight increases in enantiose-
lectivity.
C. Scope of the Heck Cyclization. The utility of this
asymmetric intramolecular Heck reaction was investigated using
aryl triflates 11a-j, in which the steric and electronic nature
of the aromatic or heteroaromatic 2 substituent varied consider-
ably (Table 4). Heck cyclization of triflates 11a-i to form 3-aryl
(or heteroaryl)-3-alkyloxindoles 18a-i proceeded cleanly and
with high enantioselectivity. In most cases, complete conversion
to the oxindole product was observed within 4 h at 80 °C using
the catalyst derived from 10 mol of % Pd(OAc)2 and 20 mol %
of (R)-BINAP (entries 1, 3, 5, 7, and 9). In an effort to enhance
the practicality of these transformations, the effect of decreasing
catalyst loading on reaction efficiency was also examined.
Lowering the catalyst loading to 5 mol % of Pd(OAc)2 and 10
mol % of (R)-BINAP required an increase in the initial substrate
concentration to 0.25 M to achieve complete conversion within
Heck cyclizations of substrates in which the 2 aryl substituent
is an o-aminophenyl derivative (entries 15 and 16) proved to
be quite sensitive to the nature of the protecting group on the
aniline nitrogen. When this group was tert-butoxycarbonyl
(Boc), the intramolecular Heck reaction proceeded efficiently
(19) Absolute configuration was assigned by analysis of the anomalous dispersion
using the Rogers’s η parameter, see: Flack, H. D. Acta Crystallogr. 1983,
A39, 876-881.
(20) The absolute configuration of three additional oxindoles formed by
asymmetric Heck cyclizations of 2′-triflato-(Z)-2-aryl-2-butenanilides using
Pd-BINAP has been verified, see: (a) Oestreich, M.; Dennison, P. R.;
Kodanko, J. J.; Overman, L. E. Angew. Chem., Int. Ed. 2001, 40, 1439-
1442. (b) Lebsack, A. L.; Link, J. T.; Overman, L. E.; Stearns, B. A. J.
Am. Chem. Soc. 2002, 124, 9008-9009.
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Synthesis of 3-Alkyl-3-Aryl Oxindoles
A R T I C L E S
Table 4. Asymmetric Heck Cyclizations
a Unless otherwise indicated, yield refers to the isolated yield of the E enol ether product; 1H NMR analysis of crude cyclization product mixtures shows
the Z enol ether to be a minor component (E/Z ) 10-20:1). b Unless otherwise indicated, enantiomeric excess was determined by HPLC analysis of the
primary alcohol derived from treatment of the cyclization product with 6 N HCl, then NaBH4. c Absolute configuration was assigned in analogy with 12 and
18i. d Isolated yield of mixture of E/Z isomers (∼10:1). e Enantiomeric excess was determined by HPLC analysis of E enol ether. f Enantiomeric excess of
the Z enol ether product was 88%.
to furnish the corresponding oxindole in high enantiopurity (98%
ee, Table 4, entry 15). In contrast, cyclization of triflate 11j
containing an o-(N-benzylamino)phenyl substituent at C2 (entry
16) proceeded in low yield and gave rise to racemic oxindole
product 18j. In this latter case, increasing the catalyst loading
or reaction time had little effect on the yield or enantioselectivity
of this reaction.
As the low yield and enantioselectivity observed in the Heck
cyclization of N-benzylaniline substrate 11j was atypical,
acetamide derivative 22 was prepared and studied to probe the
role of the basic nitrogen in undermining enantioselection in
the catalytic asymmetric cyclization of 11j (Scheme 5). Exposure
of 22 to 10 mol % of Pd(OAc)2 and 20 mol % of (R)-BINAP
for 4 h at 80 °C provided an equimolar mixture of two products
in high yield. Separation and characterization of these products
led to their eventual identification as amide atropisomers 23
and 24. The relative configuration of 23 was established by
single-crystal X-ray analysis (Figure 3); enantiomeric purity of
23 and 24 was determined by HPLC analysis using a chiral
stationary phase. Oxindole 24 is assigned as the atropisomer
9
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A R T I C L E S
Dounay et al.
Scheme 5
Table 5. Rate of Thermal Equilibration of 23
solvent
temp, °C
k, min-1
t1/2, min
THF
80
80
90
100
110
120
4 × 10-4
900
900
240
34.2
11.1
5.9
toluene
toluene
toluene
toluene
toluene
4 × 10-4
1.4 × 10-3
1.00 × 10-2
3.09 × 10-2
6.73 × 10-2
establishing that 23 and 24 have the same absolute configuration
at their quaternary stereocenters. The barrier for conversion of
23 to 24 was measured in toluene to be 36.9 kcal/mol (Ea, ∆Hq
) 36.3 kcal/mol) by Arrhenius analysis of the kinetic data in
Table 5. In toluene, the equilibrium ratio of 23:24 was 1.0:1.6.
Thermal conversion of atropisomer 23 to the 1.0:1.4 equilibrium
mixture of 23:24 occurred in THF at 80 °C with a half-life of
15 h. As equilibration of 23 and 24 would be only ∼10%
complete within 4 h at 80 °C (conditions of the Heck cyclization
to generate these products), both of these atropisomers must be
formed directly in the Heck cyclization of triflate 22.
Although triflate 22 cyclized cleanly and with high enantio-
selectivity to form oxindoles 23 and 24, strikingly different
results were observed with the structurally related oxindole
precursor 11k (Scheme 6). In this case, a high catalyst loading
(40 mol % of Pd(OAc)2/80 mol % of (R)-BINAP) was required
for complete consumption of triflate 11k within 24 h at 80 °C.
Cyclization of 11k under these conditions delivered a complex
mixture of products, in which quinolin-2-one 28a was one
component (∼20%). The presence of the exocyclic alkene
isomer 27a was suggested by the appearance of singlets at δ
6.56 and 5.41 ppm in the 1H NMR of the crude product
mixture.21 When the mixture of products formed from the Heck
cyclization of 11k was treated with DBU in toluene at 110 °C,
quinolin-2-one 28a was isolated in 50% yield. The structure of
28a was confirmed by single-crystal X-ray analysis.
resulting from hindered rotation about the aryl carbon-nitrogen
bond of the acetamide group based on the following observa-
1
tions: The H NMR spectrum of 23 reveals a one-hydrogen
doublet at δ 2.05 ppm, assignable to a benzylic hydrogen of
the N-benzyl substituent. The large upfield shift of these
methylene hydrogens is attributed to their shielding by the
aromatic ring of the oxindole, a conclusion that is supported
by the solid state structure of 23 (Figure 3). In contrast, the 1H
NMR spectrum of atropisomer 24 shows the N-benzyl methylene
hydrogens at a fairly typical chemical shift, whereas the three-
hydrogen singlet for the methyl group of the acetamide
substituent is observed at δ 0.71 ppm. The upfield shift of ∼1
ppm for this group would be expected if 24 were the amide
atropisomer of 23, as the acetamide methyl group of the former
would reside over the aromatic ring of the oxindole (see Figure
3).
Scheme 6
Quinolone 28a could be formed from triflate 11k either by
direct 6-endo Heck cyclization or by a multistep sequence
involving double-bond migration to form a â,γ-unsaturated
anilide, 6-exo Heck cyclization of this intermediate to give
exocyclic alkene product 27a, and ultimately migration of the
Figure 3. Chem 3D representations of the X-ray model of oxindole 23
and the proposed structure of 24. For clarity, only the acetyl and benzylic
hydrogens are shown.
Thermal interconversion of oxindoles 23 and 24 could be
achieved conveniently at temperatures > 80 °C, consistent with
these products being atropisomers (Table 5). This equilibration
proceeded without erosion of enantiomeric purity (95% ee), thus
(21) The exo-cyclic alkene 27a could not be separated from other components
of this complex mixture.
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6266 J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003

Synthesis of 3-Alkyl-3-Aryl Oxindoles
A R T I C L E S
Table 6. Heck Cyclization of 25: Percent Conversion vs Timea
catalyzed. To pursue this issue, 25 was exposed to 4 equiv of
PMP in d8-THF at 80 °C for 22 h. Enol ether 29 was not
detected by 1H NMR analysis, suggesting that the isomerization
of 25 to 29 is palladium-catalyzed. As 1,8-bis(dimethylamino)-
naphthalene (Proton-Sponge) has been shown to minimize
double-bond isomerizations caused by palladium(II) hydride
species,26 this base was substituted for PMP in the Heck
cyclization of triflate 25. Gratifyingly, the product of 5-exo
cyclization, oxindole 26b, was isolated in 88% yield, albeit in
60% ee, from this reaction (Scheme 8). Quinolinone product
27b or 28b was not detected by 1H NMR analysis of the crude
reaction mixture. Despite this success, these conditions failed
to subvert quinolone formation in the cyclization of N-benzyl
congener 11k.
b
b
b
b
entry
time, min
25, %
26b,%
27b,%
28b,%
27b:28b
1
2
3
4
5
6
7
8
0
15
30
45
60
75
90
105
150
180
240
100
68
50
42
33
22
12
6
0
0
3
0
0
3
6
9
11
13
17
22
23
30
0
0
0
0
0
2
3
5
8
7
10
12
16
21
28
30
38
5.5
4.3
3.4
2.8
2.6
1.9
9
10
11
0
0
0
9
16
a Conditions: 40 mol % Pd(OAc)2/80 mol % (R)-BINAP, 4.0 equiv of
PMP, o-tolualdehyde (internal standard, 1.14 equiv), 80 °C, d8-THF, 6 h.
1
b Percent conversion was measured by integration of diagnostic H NMR
signals (see Experimental Section for details) and was reproducible within
(1%.
Scheme 8
double bond of this latter product to yield 28a. Although direct
6-endo carbopalladation is documented in the literature for
several biased substrates, 5-exo cyclization is preferred in the
overwhelming majority of cases in which these two Heck
cyclization pathways are possible.4c,22
To probe the mechanism of quinolone formation, the Heck
reaction of N-methyl congener 25 was examined in detail
(Scheme 6).23 Heck cyclization of triflate 25 using 40 mol %
of Pd(OAc)2 and 80 mol % of (R)-BINAP proceeded within 6
h to give the 5-exo product 26b (38%) together with an
inseparable 2:1 mixture of quinolones 27b and 28b (46%).24
1
Monitoring the cyclization of triflate 25 by H NMR spectro-
scopy revealed that oxindole 26b and the exocyclic alkene
isomer 27b were formed more rapidly than quinolone 28b
(Table 6, entries 2-5). Furthermore, the ratio of 27b:28b
decreased with time (entries 6-11). The formation of 27b prior
to 28b and the approach of the ratio of 27b:28b toward
equilibrium25 during the reaction are consistent with quinolone
28b being formed by the sequence outlined in Scheme 7.
Discussion
Synthesis of Heck Cyclization Precursors. The chemose-
lective Stille cross-coupling of aryl triflate stannane 9 with
aromatic or heteroaromatic iodides provides an efficient, one-
step route to diversely functionalized 2′-triflato-(Z)-2-aryl (or
heteroaryl)-2-butenanilides.27 The faster rate of oxidative ad-
dition of iodides than triflates to Pd(0) is undoubtedly the origin
of the chemoselectivity observed in this reaction.28 In addition
to generating Heck precursors in high geometric purity, which
is critical to realizing good enantiocontrol,29 the mild conditions
of the coupling approach reported here allow for the incorpora-
tion of a wide variety of functional groups in the aryl or
heteroaryl fragment. For example, both basic amines (11g and
11j) and acidic NH substituents (11i) were tolerated in the ortho
position of the iodide coupling partner. Additionally, the
efficiency of this Stille cross-coupling step was not adversely
affected by neighboring substituents of considerable steric bulk
(e.g., 11g and 11k).
Scheme 7
Asymmetric Heck Cyclization. Heck cyclization of 2′-
triflato-(Z)-2-phenyl-2-butenanilide 10 was significantly faster
(25) The conversion of 27b to 28b was confirmed by exposing a 2:1 mixture
of 27b:28b to DBU at 80 °C in d8-THF.; complete conversion to quinolone
28b was observed within 1 h.
(26) Hii, K. K.; Claridge, T. D.; Brown, J. M. Angew. Chem., Int. Ed. Engl.
1997, 36, 984-987.
(27) This rapid assembly of substrates for the catalytic asymmetric Heck
synthesis of chiral 3-alkyl-3-aryloxindoles is a marked improvement to the
route we employed previously to access 2-phenyl-(Z)-2-butenanilides.5c
(28) Alcazar-Roman, L. M.; Hartwig, J. F. Organometallics 2002, 21, 491-
502, and references therein.
(29) Heck cyclizations of (E)- and (Z)-2′-iodo-2-phenyl-2-butenanilides under
cationic conditions (Ag salts as the HI scavenger) lead to opposite absolute
configurations at the newly formed quaternary carbon center.5b,c
In principle, deconjugation of Heck cyclization substrate 25
to form 29 (Scheme 7) could be base-promoted or palladium-
(22) 6-Endo Heck cyclization has been observed when 5-exo cyclization would
lead to a strained product, see: Dankwardt, J. W.; Flippin, L. A. J. Org.
Chem. 1995, 60, 2312-2313.
(23) Whereas the 1H NMR resonances of 11k are not resolved at 80 °C, the 1H
NMR resonances of 25 are resolved, making 25 a more suitable substrate
for this study.
(24) See Supporting Information for details of the structural assignments for
26b, 27b, and 28b.
9
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A R T I C L E S
Dounay et al.
when Pd(OAc)2 rather than Pd2dba3‚CHCl3 was used as the
precatalyst. Studies by Amatore, Jutand, and co-workers have
shown that the predominant species formed upon mixing Pd2-
dba3‚CHCl3 and BINAP is a neutral Pd(BINAP)dba complex.30
On the other hand, the anionic Pd0(dppp)OAc- complex results
from reaction of the bidentate phosphine dppp, 1,3-bis(diphe-
nylphosphino)propane, with 0.5 equiv of Pd(OAc)2.18a As
oxidative addition of PhI to Pd0(PPh3)2(OAc)- is 30 times faster
than oxidative addition to the neutral complex Pd0(PPh3)2-
(DMF),31 the rate increase observed in the cyclization of triflato
anilide 10 with the Pd(OAc)2-derived catalyst likely derives at
least in part from the faster oxidative addition of the anionic
Pd0(BINAP)OAc- complex with this substrate.32
The Heck cyclizations summarized in Table 4 illustrate that
the electronic and steric nature of the aryl or heteroaryl
substituent at C2 of the 2′-triflato-(Z)-2-butenanilide cyclization
substrate, not surprisingly, influences the enantioselectivity of
the reaction. Several trends are apparent. The degree of
enantioselection parallels electron density of the aromatic ring,
with electron-rich substrates cyclizing in the lowest ee: 11c
(4-NHAcC6H4, 72% ee) < 11a (4-MeOC6H4, 77% ee) < 10
(Ph, 83% ee) < 11b (3-pyridyl, 89% ee). Heck precursors
possessing large substituents at C2 cyclize in higher ee than
the 2-phenyl substrate 10. For example, naphthyl- and N-
benzylindoline-substituted butenanilides 11d and 11g cyclize
in 93% and 95% ee, respectively, as do substrates in which the
aryl 2 substituent bears a bulky ortho substituent: 11e (2-
NO2C6H4, 89% ee), 11i (2-BocNHC6H4, 98%), and 22 (2-Ac-
(Bn)NC6H4, 95%).
Plausible rationales of these observed trends in enantiose-
lectivity can be advanced. To begin with, stereoinduction in
the intramolecular Heck reaction of 2-butenanilides with Pd-
(BINAP) has been proposed to result from preferential migratory
insertion of the more stable of the two possible diastereomeric
Pd-olefin complexes.5c For the cases at hand, these are depicted
in Figure 4. Large aromatic or heteroaromatic 2-substituents
should further destabilize the disfavored olefin complex B
through nonbonding interactions between the 2-substituent of
the butenanilide and the cis pseudoaxial phenyl ring of BINAP.
On the other hand, electron-deficient aryl or heteroaryl substit-
uents could result in some shortening of the Pd-C bond lengths
in these electron-deficient cationic olefin complexes,33 which
could augment the steric interactions that energetically dif-
ferentiate complexes A and B.
The cyclization of substrate 11j, having an o-(N-benzylami-
no)phenyl substituent at C2, provided racemic Heck product in
low yield. All other substrates investigated in this survey
cyclized to give oxindole products of high enantiopurity. The
lack of enantioselectivity observed in the cyclization of 11j is
likely not an electronic effect, as other electron-rich, albeit more
sterically encumbered substrates, such as 11h (2-substituent )
N-benzyl-7-indolinyl) cyclized to give oxindole products of high
Figure 4. Models of the favored (A) and disfavored (B) diastereomeric
cationic square planar complexes formed from Pd-(R)-BINAP and 2′-triflato-
N-benzyl-(Z)-2-phenyl-2-butenanilide having the alkene π and aryl C-Pd
σ bonds nearly coplanar. For clarity, the naphthalene rings of BINAP and
the phenyl ring of the N-benzyl substituent are not shown.
ee. A more likely explanation is that the aniline nitrogen of 11j
is ligated to palladium during the carbopalladation step. Such
coordination would displace one of the phosphines from
palladium and would be expected to significantly erode
enantioselection.4,5c,34
Heck cyclization of acetamide 22 provided the isolable
atropisomers 23 and 24 in excellent yield and high ee. The
disparity in time periods required for Heck cyclization of 22 (4
h) and equilibration of 23 and 24 (>20 h) establishes that these
atropisomers were generated from the cyclization of different
rotamers about the aryl carbon-nitrogen bond of the acetamide
group of 22.35
One of the more notable attributes of the method reported
here for forming 3-alkyl-3-aryl oxindoles is the efficiency of
the cyclization even in cases where the aryl substituent projects
considerable steric bulk in the vicinity of the newly formed,
all-carbon quaternary stereocenter. Examples include the con-
versions of 11d f 18d (1-naphthyl), 11g f 18g (N-benzyl-7-
indolinyl), 22 f 23 and 24 [o-(N-benzyl-N-acylamino)phenyl)],
and 25 f 26b (1,3,3-trimethyl-7-oxindolyl). The last example
(30) Pd(BINAP)dba and Pd(BINAP) have both been implicated as reactive
species in oxidative addition reactions with iodobenzene, see: Amatore,
C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997, 119, 5176-
5185.
(31) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254-278.
(32) This rationale may be an oversimplification, as many steps are involved in
the Heck reaction with each palladium catalyst system.
(33) Small effects on Pd-olefin bond lengths are seen in X-ray analyses of a
series of para-substituted trans-â-nitrostyrene Pd(0) complexes, see: Stahl,
S. S.; Thorman, J. L.; Siva, N.; Guzei, I. A.; Clark, R. W. J. Am. Chem.
Soc. 2003, 125, 12-13.
(34) The coordination of amino substituents to palladium during Heck reactions
has been suggested occasionally; for a recent example, see: Nilson, P.;
Larhed, M.; Hallberg, A. J. Am. Chem. 2001, 123, 8217-8225.
(35) The N-benzylacetamide substituent is undoubtedly canted nearly perpen-
dicular to the arene in both amide rotamers of 22. This orientation is likely
responsible for the observation that enantioselection is essentially the same
in the cyclization of both amide rotamers.
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Synthesis of 3-Alkyl-3-Aryl Oxindoles
A R T I C L E S
Figure 5. Structurally related and sterically crowded intramolecular Heck
substrates.
appears to push the limit of steric encumberance that can be
tolerated, as a 40% catalyst loading was required to obtain useful
cyclization rates at 80 °C. Under these conditions, deconjugation
of the double bond of 25 was competitive with 5-exo Heck
cyclization. Moreover, enantioselection in forming 26b was poor
(60% ee), with good yields requiring the use of 1,8-bis-
(dimethylamino)naphthalene as the base (presumably by mini-
mizing palladium-catalyzed deconjugation of 25).26 Finally, the
limit of this method was defined in the cyclization of the
N-benzyl congener 11k, which did not provide useful amounts
of oxindole product even when Proton Sponge was used as the
base.
Although the asymmetric intramolecular Heck reactions of
substrates 11g, 22, and 3120a proceeded readily and with high
enantioselectivity, cyclizations of related oxindole substrates 11k
and 25 were problematic (Figure 5). We believe this discrepancy
in reactivity stems from the following: During the catalytic cycle
of the Heck reaction of the o-triflato-(Z)-2-aryl-(or heteroaryl)-
2-butenanilides described in this account, carbopalladation likely
occurs by a conformation wherein the 2-aryl or 2-heteroaryl
substituent and the alkene are nearly coplanar. If these two π
systems were orthogonal, a severe steric interaction between
the C2 aryl substituent and the aryl group of the anilide would
develop in a 5-exo carbopalladation process (see Figure 6, model
A). In the cases of oxindole substrates 11k and 25, having
N-alkyl substituents, conformations in which the alkene and
oxindole C2 substituents are coplanar would be destabilized by
severe nonbonding interactions between the N-alkyl substituent
of the oxindole and the acyl group of the buteneanilide fragment
(model B).36 This destabilizing interaction would be much less
severe in similar coplanar conformations of substrates 11g (C2
substituent ) N-benzyl-7-indolyl), 22 (C2 substituent ) o-(N-
benzyl-N-acylamino)phenyl), or 31 (C2 substituent ) 3-ethyl-
enedioxy-7-oxindoyl), all of which undergo smooth 5-exo Heck
cyclization. In the case of indoline 11g, the N-benzyl substituent
could be canted from the plane of the oxindole ring (model C),
whereas with acetamide 22, the N-benzyl and acetyl frag-
ments could be perpendicular to the plane of the C2 arene.37
The absence of a substituent on the oxindole nitrogen would
also mitigate destabilizing interactions in a coplanar cycliza-
tion conformation analogous to B, thus rationalizing the facile,
highly enantioselective 5-exo Heck cyclization of substrate
31.20a
Figure 6. Chem 3-D models of conformations for 5-exo carbopalladation
of Heck substrates 11k (A and B) and 11g (C). In A the alkene π bond and
the oxindole C2 substituent are perpendicular, whereas in B and C these
groups are coplanar. The palladium atom is displayed in yellow; for clarity,
the phenyl ring of the acetanilide N-benzyl substituent has been removed.
Conclusions
A practical sequence involving three consecutive palladium-
(0)-catalyzed reactions has been developed for synthesizing
3-alkyl-3-aryloxindoles in high enantiopurity. The 2′-triflato-
(Z)-2-aryl-2-butenanilide Heck cyclization precursors are gener-
ated in one step from easily accessible (Z)-2-stannyl-2-
butenanilide 9 and aryl or heteroaryl iodides. The pivotal
catalytic asymmetric Heck cyclization step of this sequence takes
place in high yield and with high enantioselectivity to forge
the new diaryl-substituted all-carbon quaternary carbon center
of the oxindole products. Of particular note is the wide variety
of aryl and heteroaryl substituents, including ones of consider-
able steric bulk, that can be introduced into an oxindole in this
(36) The alkene and oxindole C2 substituent are perpendicular in the solid state
conformation of 11k.
(37) Such an orientation of the N-benzylacetamide group is observed in the X-ray
structure of oxindole Heck product 23; see Figure 3.
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A R T I C L E S
Dounay et al.
NMR (125 MHz, CDCl3) δ 153.4, 145.6, 135.8, 133.6, 132.6, 130.4,
129.1, 128.9, 128.7, 128.6, 128.0, 122.4, 88.9, 79.5, 59.6, 57.6, 51.5;
IR (film) 1654 cm-1; HRMS (CI) calcd for C19H17F3NO5S (M + H)+:
428.0779, found: 428.0782.
way. The only limitations encountered to date are aryl substit-
uents containing ortho nitro or basic amine functionalities and
the extremely bulky N-alkyl-7-oxindolyl group. In terms of both
reaction rate and enantioselectivity, the Pd-BINAP catalyst
derived from Pd(OAc)2 is far superior to that formed from Pd2-
dba3‚CHCl3.
This asymmetric synthesis of 3-aryl or 3-hetroaryl oxindoles
should find particular use for the enantioselective synthesis of
a range of indole alkaloids and congeners that contain one or
more diaryl-substituted quaternary stereocenters. A compelling
example of the utility of this chemistry is found in our recent
asymmetric total syntheses of quadrigemine C and psycholeine
(4).20b In the key step of these syntheses (32 f 33), two new
oxindole rings, each having exceedingly bulky C-3 heteroaryl
substituents, were formed in useful yield and high enantiose-
lectivity (eq 3).
Trifluoromethanesulfonic Acid 2-(Benzyl-[2-tributylstannanyl-
4-methoxy-but-2-enoyl]amino)phenyl Ester (9). A solution of amide
8 (600 mg, 1.40 mmol) and THF (15 mL) was deoxygenated by
bubbling Ar through a submerged needle for 15 min. This solution
was cooled to 0 °C, and Pd(PPh3)4 (80 mg, 0.070 mmol) was added. A
solution of Bu3SnH (0.38 mL, 1.4 mmol) and THF (2 mL) then was
added by syringe over 40 min. The reaction was maintained at 0 °C
under Ar for an additional 2 h, then concentrated without external
heating. The residue was purified by silica gel chromatography (1:9-
2:8 EtOAc-hexanes) to provide 9 (860 mg, 84%) as a clear oil: 1H
NMR and 13C NMR are complex due to slow rotation of the amide
group on the NMR time scale; copies of these spectra are included in
the Supporting Information; IR (thin film) 1646, 1215 cm-1. HRMS
(ESMS, MeOH) calcd for C31H44F3NO5SSnNa (M + Na)+: 742.1817,
found: 742.1839.
General Procedure for Stille Coupling: Preparation of Trifluo-
romethanesulfonic Acid 2-[Benzyl-(4-methoxy-2-phenylbut-2-enoyl)-
amino]phenyl Ester (10). A stirred mixture of Pd2dba3‚CHCl3 (6 mg,
0.006 mmol), P(2-furyl)3 (12 mg, 0.051 mmol), and freshly distilled
N-methylpyyrolidinone (NMP, 2 mL) was deoxygenated by bubbling
Ar through a submerged needle for 1 h, during which time a bright
yellow solution resulted. A deoxygenated solution of stannane 9 (200
mg, 0.28 mmol), iodobenzene (52 mg, 0.25 mmol), and NMP (5 mL)
was then added via syringe. Copper(I) iodide (46 mg, 0.28 mmol) was
then added, and the resulting mixture was flushed with a stream of Ar
for 15 min and then maintained at room temperature for 24 h. After
diluting the reaction with EtOAc (100 mL), the resulting solution was
washed with 5% aqueous NH4OH (3 × 10 mL) and brine (3 × 10
mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate
was concentrated. The residue was purified by flash chromatography
(1:9-3:7 EtOAc-hexanes) to give 10 as a viscous, nearly colorless
oil (110 mg, 87%): E/Z ratio ) 0.9:99.1, HPLC (Alltech, Alltima SiO2
5 µ, column temperature 23 °C, n-98:2 hexane-2-propanol, flow rate
1.0 mL‚min-1) 9.8 min (major Z stereoisomer), 11.5 min (minor E
stereoisomer); 1H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 5H),
7.19-6.99 (m, 5H), 6.83 (dd, J ) 7.2, 1.2 Hz, 2H), 6.80 (dd, J ) 7.6,
1.6 Hz, 1H), 6.25 (dd, J ) 8.0, 1.2 Hz, 1H), 5.96 (d, J ) 14.4 Hz,
1H), 5.81 (t, J ) 6.4 Hz, 1H), 4.23 (d, J ) 6.4 Hz, 2H), 3.95 (d, J )
14.4 Hz, 1H), 3.38 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.7,
145.4, 139.5, 136.8, 136.6, 133.4, 132.4, 131.5, 129.6, 129.3, 128.4,
Experimental Section38,39
TrifluoromethanesulfonicAcid2-(Benzyl-[4-methoxybut-2-ynoyl]-
amino)phenyl Ester (8). A solution of methyl propargyl ether (3.00
g, 42.8 mmol) and THF (200 mL) was cooled to -78 °C and treated
dropwise with a THF solution of n-BuLi (2.3 M, 20.5 mL, 47 mmol).
After 1 h at -78 °C, 3-benzyl-3H-benzooxazol-2-one (7, 9.63 g, 42.8
mmol)10 was added and the resulting solution was maintained at -25
°C. After 6 h, PhNTf2 (22.5 g, 64.2 mmol) was added, and the resulting
solution was allowed to warm to room temperature. After 15 min, the
reaction mixture was combined with EtOAc (500 mL), and this solution
was washed with brine (3 × 100 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by silica gel chromatography
(1:9-3:7 EtOAc-hexanes) to give 8 (11.6 g, 59%) as a yellow oil:
1H NMR (500 MHz, CDCl3) δ 7.42-7.16 (m, 8H), 6.99 (dd, J ) 8.0,
1.5 Hz, 1H), 5.60 (d, J ) 14.5 Hz, 1H), 4.19 (d, J ) 14.5 Hz, 1H),
1
128.2, 128.1, 127.8, 127.6, 125.6, 121.0, 118.2 (q, JCF ) 255 Hz),
69.9, 58.3, 51.7; IR (film) 1660 cm-1. Anal. Calcd for C25H22F3NO5S:
C, 59.40; H, 4.39; N, 2.77. Found: C, 59.18; H, 4.44; N, 2.69.
General Procedure for Intramolecular Asymmetric Heck Cy-
clizations. Preparation of (S)-1-Benzyl-3-(2-methoxyvinyl)-3-phenyl-
1,3-dihydroindol-2-one, (S)-12. A base-washed and oven-dried 10 mL
sealable tube equipped with a magnetic stir bar was charged with 10
(98 mg, 0.19 mmol, 1.0 equiv), PMP (0.14 mL, 0.78 mmol, 4.0 equiv),
and THF (0.8 mL). This solution was deoxygenated by bubbling Ar
through a submerged needle for 20 min, and Pd(OAc)2 (2.2 mg, 9.7
µmol, 5 mol %) and (R)-BINAP (12 mg, 19 µmol, 10 mol %) were
then added. Deoxygenation and vigorous stirring were continued for
15 min, during which time a red solution resulted. The tube then was
sealed and heated at 80 °C for 6 h. After cooling to room temperature,
the solution was diluted with EtOAc (10 mL) and washed with NaHCO3
(3 × 10 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated. The residue was purified by flash chromatography (9:1
hexanes-ethyl acetate) to give (S)-12 as an amorphous, colorless solid
(59 mg, 0.17 mmol, 86%): 1H NMR (400 MHz, CDCl3) δ 7.36-7.23
(m, 10H), 7.18 (dd, J ) 7.6, 7.6 Hz, 1H), 7.12 (d, J ) 7.2 Hz, 1H),
7.02 (dd, J ) 7.2, 7.6 Hz, 1H), 6.78 (d, J ) 8.0 Hz, 1H), 6.43 (d, J )
12.8 Hz, 1H), 5.36 (d, J ) 12.8 Hz, 1H), 5.00 (d, J ) 15.6 Hz, 1H),
4.00 (d, J ) 16.9 Hz, 1H), 3.93 (d, J ) 16.9 Hz, 1H), 2.95 (s, 3H); 13
C
(38) General experimental details have been described: Minor, K. P.; Overman,
L. E. J. Org. Chem. 1997, 62, 6379-6387.
(39) Crystallographic data for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication nos. CCDC-200985 (20), CCDC-200986 (28a), CCDC-
200987 (23), CCDC-200988 (11k), and CCDC-200989 (21). Copies of the
data can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (+44)1223-336-033; e-mail
deposit@ccdc.cam.ac.uk.).
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Synthesis of 3-Alkyl-3-Aryl Oxindoles
A R T I C L E S
4.95 (d, J ) 15.6 Hz, 1H), 3.61 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 177.4, 149.8, 141.7, 140.8, 135.6, 132.2, 128.4, 128.3, 127.8, 127.3,
127.0, 126.9, 126.8, 124.9, 122.4, 109.3, 103.5, 56.1, 55.8, 43.4; IR
(film) 2915, 1711, 1611 cm-1; HRMS (CI) calcd for C24H21NO2 (M)+:
355.1572, found: 355.1573. Anal. Calcd for C24H21NO2: C, 81.10; H,
5.96; N, 3.94. Found: C, 81.16; H, 6.03; N, 3.98.
2.43 (dt, J ) 13.9, 6.0 Hz, 1H), 1.85 (s, 1H); 13C NMR (125 MHz,
CDCl3) δ 179.2, 142.8, 140.1, 135.8, 132.0, 128.8, 128.7, 128.3, 127.3,
126.7, 122.8, 109.6, 59.5, 55.0, 44.1, 40.1; IR (film) 1695, 1610 cm-1
;
LRMS (CI) m/z 343 (M)+; HRMS (CI) calcd for C23H21NO2: 343.1572,
found: 343.1575.
Acknowledgment. This research was supported by NIH grant
GM-12389 and postdoctoral fellowships to A.B.D. (F32
CA94471-01), M.O. (Emmy Noether-Stipendium from the
Deutsche Forschungsgemeinschaft, Oe 249/1-1), L.A.P. (NIH
grant GM-20589-01), and M.M.W. (NIH grant GM-64217-01).
We thank Scott Savage for preliminary studies and Christopher
Douglas and Donald Watson for helpful discussions. NMR and
mass spectra were determined at UCI with instrumentation
purchased with the assistance of the NSF and NIH shared
instruments programs.
General Procedure for Converting Heck Products to the Corr-
sponding 2-Hydroxyethyl Derivatives: Preparation of (S)-1-Benzyl-
3-(2-hydroxyethyl]-3-phenyl-1,3,3a,7a-tetrahydroindole-2-one, (S)-
13. A solution of oxindole enol ethers 12 (83 mg, 0.230 mmol), 6 M
HCl (1 mL), and THF (2 mL) was maintained at room temperature for
1 h, then combined with saturated aqueous NaHCO3 (25 mL) and
extracted with EtOAc (3 × 10 mL). The organic extracts were dried,
filtered, and concentrated. The crude residual aldehyde was suspended
in EtOH (3 mL), and NaBH4 (90 mg, 2.3 mmol) was added at room
temperature. After 1 h at room temperature, the mixture was combined
with 0.5 M NaOH (20 mL), and the aqueous layer was extracted with
EtOAc (3 × 10 mL). The organic extracts were combined, dried, and
filtered, and the filtrate was concentrated. The residue was purified by
silica gel chromatography (Et2O) to provide alcohol (S)-13 (70 mg,
89%, 84% ee) as an amorphous, colorless solid: HPLC (Daicel Chiracel
OJ column, column temperature 23 °C, 7:3 n-hexane-2-propanol, flow
rate 1.0 mL‚min-1) 12.2 min (major enantiomer), 24.2 min (minor
enantiomer); mp 97 °C (hexanes-Et2O); 1H NMR (500 MHz, CDCl3)
δ 7.16-7.38 (m, 12H), 7.04 (t, J ) 7.5 Hz, 1H), 6.76 (d, J ) 7.9 Hz,
1H), 4.92 (s, 2H), 3.45-3.53 (m, 2H), 2.81 (dt, J ) 13.9, 7.0 Hz, 1H),
Supporting Information Available: Experimental procedures
and characterization data for new compounds not described in
the Experimental Section, HPLC traces used to determine
enantiopurity, Arrhenius analysis for the atropisomerization of
23 to 24, measurements of the equilibrium constant, and details
of the experiments reported in Table 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA034525D
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J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003 6271