Catalytic asymmetric synthesis of quaternary carbon centers. Exploratory investigations of intramolecular heck reactions of (E)-α,β-unsaturated 2-haloanilides and analogues to form enantioenriched spirocyclic products

Article abstract of DOI:10.1021/ja980786p

The effect of chiral diphosphine structure, method of catalyst generation, reaction solvent, and HI scavenger on the formation of enantioenriched 3,3-disubstituted 2-oxindole 5 from asymmetric Heck cyclization of 4 was studied (eq 1). Depending upon wheth

Full text of DOI:10.1021/ja980786p

J. Am. Chem. Soc. 1998, 120, 6477-6487
6477
Catalytic Asymmetric Synthesis of Quaternary Carbon Centers.
Exploratory Investigations of Intramolecular Heck Reactions of
(E)-R,â-Unsaturated 2-Haloanilides and Analogues To Form
Enantioenriched Spirocyclic Products
Atsuyuki Ashimori,1a Benoit Bachand,1b Larry E. Overman,* and Daniel J. Poon1c
Contribution from the Department of Chemistry, 516 Physical Sciences 1, UniVersity of California,
IrVine, California 92697-2025
ReceiVed March 9, 1998
Abstract: The effect of chiral diphosphine structure, method of catalyst generation, reaction solvent, and HI
scavenger on the formation of enantioenriched 3,3-disubstituted 2-oxindole 5 from asymmetric Heck cyclization
of 4 was studied (eq 1). Depending upon whether the HI scavenger was a silver salt or a basic tertiary amine,
either enantiomer of 5 could be formed with good selectivity using the same enantiomer of BINAP. Using
Pd-BINAP as catalyst, a variety of enantioenriched 3,3-disubstituted oxindoles, indolines, and dihydroben-
zofurans was prepared from (E)-R,â-unsaturated 2-haloaniline substrates (Table 5). With but one exception,
cyclizations conducted in the presence of Ag3PO4 or 1,2,2,6,6-pentamethylpiperidine (PMP) afforded opposite
enantiomers of the spirocyclic product. Which HI acceptor results in highest enantioselection is substrate
dependent. These studies demonstrate, for the first time, that asymmetric Heck reactions of halide substrates
can proceed with useful levels of enantioselectivity in the absence of silver or thallium salts.
Introduction
ligands for bimolecular Heck reactions,7 asymmetric Heck
reactions were first described only in 1989.8,9 Although only
modest enantiocontrol was described in the initial disclosures
from Shibasaki’s and our laboratories, rapid progress in this
area has been made; many asymmetric Heck reactions proceed-
ing with enantioselectivities of >90% have now been described.6
Since our first disclosure of the exceptional facility with which
fully substituted carbon centers can be constructed by intramo-
lecular Heck reactions, our investigations in this area have
centered on Heck cyclizations that form quaternary carbons.4b,10
In 1989, we reported the first example of directly creating a
quaternary center by an asymmetric Heck cyclization, in this
case asymmetric bis-cyclization of a trienyl triflate.9 We report
herein details of our subsequent investigations of asymmetric
Heck cyclizations of alkenyl aryl halides to prepare enantioen-
riched heterocycles. A variety of heterocycles are produced with
moderate to high levels of enantiomeric purity. Moreover, these
investigations led to the unanticipated discovery that depending
upon how HI is scavenged, either enantiomer of the spirocyclic
product could be formed with good selectivity using the same
enantiomer of a chiral diphosphine ligand (Figure 1). These
studies demonstrated, for the first time, that asymmetric Heck
reactions not proceeding via cationic intermediates (vide infra)
can occur with high (>90%) enantioselectivity.11 In two
accompanying papers, we further elaborate the scope of these
Although first reported more than 25 years ago,2 it is only
within the past decade that the enormous potential of the Heck
reaction in organic synthesis has been revealed.3 When
employed intramolecularly, Heck reactions succeed in many
contexts,3c including insertions into trisubstituted and even
tetrasubstituted double bonds.4 The ability of intramolecular
Heck reactions to reliably fashion carbon-carbon bonds in
polyfunctional molecules has led to wide application of this
reaction at the strategy level for the synthesis of complex natural
products.5
One of the most important developments in this area is the
increasing success being realized in effecting catalytic asym-
metric Heck reactions using enantiopure ligands.6 Undoubtedly
due to early reports that chelating diphosphines were unsuitable
(1) Current addresses: (a) The Green Cross Corporation, Research
Division, 2-25-1, Shodai-Ohtani, Hirakata, Osaka 573-1153, Japan. (b)
BioChem Therapeutique Inc., 275, Boul, Armand-Frappier, Laval, Quebec,
H7V 4A7, Canada. (c) Department of Chemistry, Colorado State University,
Fort Collins, CO 80523-1872.
(2) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(3) One indication of the importance of the Heck reaction is seen in the
large number of recent reviews. For selected examples, see: (a) de Meijere,
A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (b) Jeffery,
T. In AdVances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI:
Greenwich, 1996; pp 249-252. (c) Gibson, S. E.; Middleton, R. J. Contemp.
Org. Synth. 1996, 3, 447. (d) Bra¨se, S.; de Meijere, A. In Metal-catalyzed
Cross-coupling Reactions; Diederick, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 3.
(6) For recent reviews, see: (a) Shibasaki, M. In AdVances in Metal-
Organic Chemistry; Liebeskind, L. S., Ed.; JAI: Greenwich, 1996; pp 119-
151. (b) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53,
7371.
(4) (a) Grigg, R.; Sridharan, V.; Stevenson, P.; Worakan, T. J. Chem.
Soc., Chem. Commun. 1986, 1697. (b) Abelman, M. M.; Oh, T.; Overman,
L. E. J. Org. Chem. 1987, 52, 4130.
(5) The application of intramolecular Heck reactions in natural products
synthesis has been recently reviewed: Link, J. T.; Overman, L. E. In Metal-
catalyzed Cross-coupling Reactions; Diederick, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998; Chapter 6.
(7) Heck, R. F. Organic Reactions 1982, 27, 345-390.
(8) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738.
(9) Carpenter, N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989,
54, 5846.
(10) Overman, L. E.; Abelman, M. M.; Kucera, D. J.; Tran, V. D.; Ricca,
D. J. Pure Appl. Chem. 1992, 64, 1813. (b) Overman, L. E. Pure Appl.
Chem. 1994, 66, 1423.
S0002-7863(98)00786-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/20/1998

6478 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Ashimori et al.
Figure 1.
Scheme 1
Figure 2.
Scheme 2
Table 1. Asymmetric Heck Cyclization of 4 to Spirooxindole 5a
reactions,12,13 report initial mechanistic investigations,12,14 and
illustrate the utility of “neutral” asymmetric Heck reactions for
asymmetric synthesis of 3a-substituted pyrroloindolines, includ-
ing pharmacologically important Calabar alkaloids.15
ligand
solvent time, h yield, % abs config ee, %
(-)-DIOP
(-)-DIOP
(+)-DIOP
PPFA
PPFA
BPPFA
AMPHOS
AMPHOS
(S)-(-)-BINAP toluene
(S)-(-)-BINAP THF
(S)-(-)-BINAP MeCN
(S)-(-)-BINAP NMP
toluene
MeCN
NMP
toluene
NMP
NMP
toluene
NMP
8
22
6
4
8
24
24
25
23
12
28
23
76
racb
9
58c
91
S
racb
26
23
26
5
87
81
S
S
R
S
Results and Discussion
39c
45c
34c
47c
79
Initial Exploratory Studies. To avoid potentially complicat-
ing double bond isomerization of the Heck product, 2-iodo-N-
(1,4-dioxaspiro[4.5]dec-7-en-8-ylcarbonyl)-N-methylaniline (4)
was chosen for our initial studies. This anilide was readily
synthesized on multigram scales as summarized in Scheme 1.
Aldehyde 116 was first converted to carboxylic acid 2 by
Lindgren oxidation17 and then coupled, via the acid chloride
derivative, with 2-iodoaniline to give 3. Finally, deprotonation
of anilide 3 with NaH followed by reaction with excess MeI in
refluxing THF provided 4 in 41% overall yield from 1.
R
R
R
R
20
38
20
51
33c
70
a Conditions: 10 mol % Pd(OAc)2, 10 mol % bisphosphine, 2 equiv
of Ag3PO4, 0.1 M substrate, 80 °C. b Racemic. c Anilide 4 was not fully
consumed.
As did other early workers in this field,8,18 we initially
assumed that iodide would have to be scavenged to achieve
good selectivity in Heck cyclizations of 4 carried out in the
presence of enantiopure diphosphine ligands (eq 1). This
presumption followed from the expectation that the migratory
insertion step 6 f 7 would proceed from a four-coordinate
intermediate, which would accommodate a bidentate ligand only
if iodide was removed from the palladium coordination sphere
(Scheme 2). Our inaugural experiments were guided by recent
disclosures from the Shibasaki group that Ag3PO4 was the
optimal halide scavenger for asymmetric Heck cyclizations that
formed tertiary centers.19 Results obtained from our initial study
of the cyclization of iodide 4 to form 3-spiro-2-oxindole 5 using
Pd(OAc)2, commercially available enantiopure chiral disphos-
(11) Early parts of these investigations were described in a preliminary
communication: Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57,
4571.
(12) Ashimori, A.; Bachand, B.; Govek, S.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6488-6499.
(13) For a preliminary communication, see: Ashimori, A.; Matsuura,
T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58, 6949.
(14) For a preliminary communication, see: Overman, L. E.; Poon, D.
J. Angew. Chem., Int. Ed. Engl. 1997, 36, 518.
(15) Matsuura, T.; Overman, L. E.; Poon, D. J. Am. Chem. Soc. 1998,
120, 6500-6503.
(16) Iio, H.; Isobe, M.; Kawai, T.; Goto, T. Tetrahedron 1979, 35, 941.
(17) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
(b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2901.
phines (Figure 2), and excess Ag3PO4 are presented in Table 1.
Enantiomeric purity was determined by integrating the N-methyl
signals of 5 in 1H NMR spectra (CDCl3) measured in the
presence of tris[3-(trifluoromethylhydroxymethylene)-(+)-cam-
phorato]ytterbium(III), Yb(tfc)3.
The rate of cyclization of 4 varied considerably with ligand
structure: DIOP∼PPFA>BINAP>AMPHOS. With all ligands,
Heck cyclizations in MeCN were particularly slow. As is
apparent in Table 1, BINAP was the most promising ligand.
(18) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417.
(19) Sato, Y.; Sodeoka, M.; Shibasaki, M. Chem. Lett. 1990, 1953.

(E)-R,â-Unsaturated 2-Haloanilides and Analogues
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6479
Table 2. Forming (S)-Spirooxindole 5 Using Pd(R)-BINAP
Table 3. Effect of Silver and Thallium Salts on Asymmetric Heck
Cyclization of 4 with Pd(R)-BINAP to Form (S)-5a
Generated from Tris(dibenzylideneacetone)dipalladium(0)a
entry
solvent
temp, °C
time, h
yield,b %
ee,b %
entry
silver salt
conversion,b %
yield, %
ee, %
1
2c
3c
4d
5
6
7
NMP
NMP
DMPU
THF
MeCN
DMA
DMF
DMSO
DMA
DMA
DMA
80
80
80
80
80
80
80
80
60
110
80
26
26
26
26
26
26
26
26
88
4
86
70
1
2
3
4
5
6
7
8
Ag3PO4
Ag2CO3
Ag2O
100
100
100
62
14
7
86
83
79
38
4
4
4
c
c
86
6
70
68
64
22
11
0
78-80
68-70
84
42
81
69
67
78
86
68-69
49-53
22
63
71
70
42
71
67
AgOAc
AgOBz
AgO2CCF3
AgNO3
AgOTf
AgBF4
Tl2CO3
none
6
0
8
9
73
70
100
19
9
10
10d
11
48
11e
4
90
65
68e
a Pd2(dba)3 (5 mol %) was treated with (R)-BINAP (11 mol %) in
the presence of Ag3PO4 (2 equiv) at room temperature for 40 min
(unless noted otherwise) before the addition of 4. The reaction was
then maintained at 80 °C. b A range is reported for reactions run in
duplicate. c Same as a with a pretreatment time of 20 min. d Same as
a with a pretreatment time of 90 min. e Same as a with 10 mol %
Pd2(dba)3 and 22 mol % (R)-BINAP.
a A mixture of 5 mol % Pd2(dba)3, 11 mol % (R)-BINAP, and 2
equiv of a silver salt was stirred in NMP under Ar at room temperature
for 40 min prior to adding 4. The reaction was then maintained at 80
°C for 26 h. b By capillary GC analysis. c Loss of 4 was determined
by capillary GC analysis, but no 5 was detected by TLC analysis. d The
solvent was DMA and reaction time was 2.5 h. e The absolute
configuration of the predominant enantiomer was R.
Enantioselectivities realized in cyclizations of 4 in the presence
of (S)-(-)-BINAP were solvent dependent, with the highest ee’s
being realized in N-methylpyrrolidine (NMP).
(AgNO3, AgOTf, and AgBF4) virtually no spirooxindole 5 was
formed, although anilide 4 was slowly consumed to provide a
complex mixture of products in the presence of AgOTf and
AgBF4. Most revealing was the observation that 4 cyclized,
albeit inefficiently, in the absence of silver salts to produce (R)-5
in a remarkable 68% ee (entry 11). We assumed that the low
yield of 5 realized in cyclizations of 4 carried out in the absence
of a silver salt, or in the presence of silver salts with weakly
basic or nonbasic counterions, reflected the inability to regener-
ate a competent Pd(0) catalyst from “HPdI”. Nonetheless, it
was particularly provocative that the opposite enantiomer of 5
was formed in good ee when no HI scaVenger was present.
To further pursue the effect of additives on enantioselection,
Heck reactions of 4 with Pd(R)-BINAP were carried out in the
presence of other bases that would not specifically scavenge
iodide. As summarized in Table 4, cyclizations in NMP in the
presence of 2 equiv of Na3PO4, (n-Bu)4NH2PO4, K2CO3, or
KHCO3 took place within 2-26 h in high yield, although little
enantioselection was realized (entries 4-7). Cyclizations in the
presence of 2 equiv of CaHPO4 or Na2HPO4 occurred slowly
at 80 °C in NMP producing the R enantiomer of 5 in 65-68%
ee (entries 1 and 2). With this latter base, raising the reaction
temperature to 110 °C in DMA resulted in some decrease in
enantioselection (entry 3).
Since incomplete ligation of Pd(0) with BINAP would result
in an achiral metal species being present (and potentially
catalyzing the formation of racemic 5), we next examined in
situ generation of Pd(BINAP) from other palladium precatalysts.
Using Cl2Pd-BINAP as the precatalyst, enantioselectivities
realized in the 4 f 5 conversion were not reproducible, while
ee’s were no higher if bis(acetonitrile)palladium(II)chloride
[PdCl2(MeCN)2]20 was employed as the precatalyst. However,
higher enantioselectivities were obtained using tris(dibenzylide-
neacetone)dipalladium(0) [Pd2(dba)3],21 which is known to
rapidly exchange dibenzylideneacetone ligands with phosphines.
The results summarized in Table 2 were obtained when the
catalyst was generated by stirring Pd2(dba)3 (5 mol %) under
an Ar atmosphere with (R)-BINAP (11 mol %) in the presence
of 2 equiv of Ag3PO4 in various solvents at room temperature
for 20-90 min prior to adding a solution of 4. Enantioselection
was again found to be quite solvent dependent, with the polar
solvents NMP, N,N-dimethylacetamide (DMA), and DMF
giving (S)-5 in highest ee (68∼71%). Doubling the catalyst
generation time in NMP (entries 1 and 2) had no effect on
enantioselectivity. Enantioselectivity was also not changed,
within experimental error, when the cyclization temperature was
varied from 60 to 110 °C in DMA (entries 6, 9, and 10).
Doubling the catalyst loading also had little effect on ee;
however, as expected cyclization was faster (entry 11). At this
stage, Pd2(dba)3 was chosen as the optimal palladium source,
and NMP and DMA were selected as solvents for further studies.
The effect of varying the silver salt in Heck cyclizations of
4 with Pd(R)-BINAP, generated in situ from Pd2(dba)3, was
studied next. Cyclizations carried out at 80 °C for 26 h in the
presence of 2 equiv of Ag2CO3, Ag2O, or Ag3PO4 provided
(S)-5 in high yield and 64-70% ee (Table 3, entries 1-3).
Qualitatively similar results were observed in the presence of
Tl2CO3 (entry 10). Cyclizations of 4 were much slower in the
presence of silver carboxylate salts (AgOAc, AgOBz, and AgO2-
CCF3) and took place with low or no asymmetric induction
(entries 4-6). With silver salts of even less basic anions
The best combination of rate and enantioselectivity was
realized with tertiary amine bases. Although cyclizations of 4
in the presence of 5-15 equiv of Et3N and 10 mol % Pd(R)-
BINAP were slow, the rate was approximately doubled by use
of the more basic tertiary amine, 1,2,2,6,6-pentamethylpiperidine
(PMP) (entries 8-10). Doubling the catalyst loading to 20 mol
% provided (R)-5 in 65% yield and 66% ee, although the
reaction time was still not practical (entry 11). However, when
the reaction temperature was raised to 110 °C, Heck cyclization
was complete in 8 h, and (R)-5 was isolated in 71% yield
without significant diminution of enantiomeric purity (entry 12).
Two other strongly basic amines, 1,8-bis(dimethylamino)-
naphthalene (PS)22 and 1,1,2,3,3-pentaisopropylguanidine (PIG),23
were screened and also afforded (R)-5 in good yield within hours
at 110 °C, although enantioselection was slightly lower than
that obtained in the presence of PMP (entries 12-14).
(20) Lebedinskiˆı, V. V.; Simanovskiˆı, P. V.; Slutsker, O. D. IzVest.
Sektora Platiny i Drugikh Blagorodnykh Metal., Inst. Obshcheˆı Neorg.
Khim., Akad. Nauk S.S.S.R. 1948, 43. Chem. Abstr. 1950, 44, 9293.
(21) (a) Ukai, T.; Kawazura, H.; Ishii, Y. J. Organomet. Chem. 1974,
65, 253. (b) Pierpont, C. G.; Mazza, M. C. Inorg. Chem. 1974, 13, 1891.
(22) Quast, H.; Risler, W.; Doellscher, G. Synthesis 1972, 558.
(23) (a) Barton, D. H. R.; Elliott, J. D.; Gero, S. D. J. Chem. Soc., Perkin
Trans. 1 1982, 2085. (b) Corey, E. J.; Jardine, P. D. S.; Mohri, T.
Tetrahedron Lett. 1988, 29, 6409.

6480 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Ashimori et al.
Table 4. Effect of Inorganic and Organic Bases on Asymmetric Heck Cyclizations of 4 with Pd(R)-BINAP To Form (R)-5a
oxindole(R)-5
entry
additiveb
solvent
Pd2(dba)3, %
(R)-BINAP, %
time, h
convc
yield, %
ee, %
1
2
CaHPO4
Na2HPO4
Na2HPO4
Na3PO4
TBAPe
K2CO3
KHCO3
Et3N
NMP
NMP
DMA
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMA
DMA
DMA
DMA
5
5
10
5
5
5
5
5
5
5
10
10
10
10
11
11
22
11
11
11
11
11
11
11
22
22
22
22
26
26
9
26
26
3
1.7
26
192
26
138
8
14
34
53
100
100
100
100
16
62
30
84
100
100
100
8
12
32
77
76
85
86
8
37
22
65
71
70
76
68
65
51
7
3d
4
5
6
7
8
25
8f
4f
65
48
57
66
63
46
56
9
Et3Ng
10
11
12d
13d
14d
PMPh
PMPh
PMPh
PSi
11
4
PIGj
a The catalyst was generated as detailed in Table 3 prior to adding 4. The final concentration of 4 was 0.1 M, and reactions were conducted at
80 °C unless noted otherwise. b Unless indicated otherwise, 2 equiv of inorganic bases and 5 equiv of organic bases were employed. c By capillary
GLC analysis. d Reaction temperature was 110 °C. e (n-Bu)4NH2PO4. f The S enantiomer predominates. g 15 equiv. h PMP ) 1,2,2,6,6-pentameth-
ylpiperidine. i PS ) 1,8-bis(dimethylamino)naphthalene. j PIG ) 1,1,2,3,3-pentaisopropylguanidine.
Scheme 3
Although enantiomeric purity of a sample allylic acetal (+)-5
(68% ee, obtained from (R)-BINAP cyclization in the presence
of Ag2CO3) could not be enhanced by recrystallization, the
corresponding enone 8 was enriched to 92% ee by recrystalli-
zation from Et2O (Scheme 3). To prepare a derivative suitable
for determining absolute configuration by single-crystal X-ray
analysis, 8 was brominated by reaction with trimethylphenyl-
ammonium tribromide in THF, and the product was dehydro-
brominated by exposure to Et3N to give levorotatory R-bromo
enone 9 in good yield. This product provided single crystals
that were suitable for determining absolute configuration by
X-ray diffraction.24
Scope of Asymmetric Heck Cyclizations of (E)-r,â-
Unsaturated 2-Haloaniline Derivatives. A. Preparation of
Cyclization Substrates. The scope of asymmetric Heck
cyclizations using Pd-BINAP was surveyed with the series of
(E)-R,â-unsaturated 2-haloaniline derivatives depicted in Figure
3. Anilides 10 and 11 were obtained from secondary amide 3
by alkylation of the sodium salt with BnBr or SEM-Cl, while
tert-butoxycarbonyl derivative 12 was obtained by coupling of
3 with di-tert-butyl dicarbonate in the presence of Et3N and
4-(dimethylamino)pyridine (DMAP) (Scheme 4). The synthesis
of the bromo analogues of anilides 14, 16, and 17 has been
described,4 and the iodide derivatives were prepared in similar
fashion. Anilides 13 and 20 were prepared from 2-iodoaniline
Figure 3.
and the corresponding R,â-unsaturated acid; details are provided
in Supporting Information. The allylic carbamate 18 and allylic
ether 19 were obtained from allylic chloride 24 and 2-iodoaniline
or 2-iodophenol in straightforward fashion as summarized in
Scheme 4.
The synthesis of R-methyl (E)-butenanilide 21 is summarized
in Scheme 5. The Wittig reagent derived from methyl 2-bro-
mopropionate (26) was condensed with glyoxylic acid mono-
hydrate in MeCN to give (E)-acid 27 with high stereoselectively
(>98%).25 Reduction of this carboxylic acid with BH3‚THF26
followed by TBDMS protection provided 29 in 58% overall
yield from 27. Condensation of 29 with the reagent prepared
from 2-iodoaniline and Me3Al27 gave the corresponding anilide,
which, again without purification, was methylated to provide
21.
The corresponding R-tert-butyl (E)-buteneanilide 22 was
prepared in related fashion (Scheme 6). Reductive iodination28
of 4,4-dimethylpent-2-yn-1-ol (30),29 which is available from
(24) (a) Absolute configuration was assigned by the method of Rogers:
Rogers, D. Acta Crystallogr. 1981, A37, 734. (b) The authors have deposited
atomic coordinates for this structure with the Cambridge Crystallographic
Data Centre. The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, UK.
(25) Zumbrunn, A.; Uebelhart, P.; Eugster, C. H. HelV. Chim. Acta 1985,
68, 1519.
(26) Kende, A. S.; Fludzinski, P. Org. Synth. 1986, 64, 104.
(27) Lipton, M. F.; Basha, A.; Weinreb, S. M. Org. Synth. 1978, 59, 49.
(28) Kim, K. D.; Magriotis, P. A. Tetrahedron Lett. 1990, 31, 6137.

(E)-R,â-Unsaturated 2-Haloanilides and Analogues
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6481
Scheme 4
coupling of 37 with the phenylzinc chloride, generated in situ
by transmetalation of phenylmagnesium bromide with ZnCl2,
afforded 38. Aminolysis of this ester following the Weinreb
procedure27 provided (E)-amide 39, which was contaminated
with ∼8% of the corresponding Z isomer. Removal of the minor
stereoisomer by column chromatography and subsequent N-
methylation then furnished 23.
B. Scope of Asymmetric Heck Cyclizations. The scope
of asymmetric Heck cyclizations of (E)-R,â-unsaturated 2-ha-
loaniline derivatives was surveyed using two reaction condi-
tions: (1) silver-promoted cyclizations were conducted with 5
mol % Pd2(dba)3 and 11 mol % (R)-BINAP in the presence of
2 equiv of Ag3PO4 in DMA or NMP at 60-80 °C, and (2)
amine-promoted cyclizations employed 10 mol % Pd2(dba)3 and
22 mol % (R)-BINAP with 5 equiv of PMP in the same solvents
at 100-120 °C. The results of these investigations are
summarized in Table 5. Enantiomer ratios were determined
1
either by H NMR analysis of the spirocyclic products in the
presence of chiral shift reagents or by HPLC analysis using a
chiral stationary phase. In four cases (entries 4, 13, 15, 23,
and 24), enantiomeric purity was determined by both methods;
agreement between the two methods was (2-5%. Absolute
configuration is specified when it was rigorously established
(vide infra); in other cases the sign of rotation at the sodium D
line is reported. Yields of spirooxindole products were typically
good (60-95%). With all anilide substrates except 22, Ag3PO4-
and PMP-promoted cyclizations occurred with opposite enan-
tioselection.
Scheme 5
The nature of the nitrogen protecting group had some effect
(entries 1-10), particularly in the case of the N-BOC derivative
12. Heck cyclization of this latter substrate in the presence of
Ag3PO4 occurred slowly and took place with lower enantiose-
lection, while attempted cyclizations of 12 in the presence of
PMP at 100 °C resulted in cleavage of the BOC group. That
the acetal substituent at the homoallylic carbon had little effect
was apparent in the nearly identical stereoselection observed
in cyclizations of 4 and 13 (entries 1-3, 11 and 12).
Cyclizations of unsubstituted five-, six-, and seven-membered
cycloalkenyl analogues 14, 16, and 17 provided the known4
oxindoles 44-46, accompanied with varying amounts of double
bond regioisomers (see Table 5). The excellent enantioselec-
tivity (up to 95% ee) observed in forming (R)-44 is undoubtedly
due to preferential double bond migration of the initially
generated palladium hydride complex of the minor S enantiomer.
Enantiomeric enrichment by this type of kinetic resolution was
first seen by Hayashi and co-workers in a bimolecular Heck
reaction.18 Consistent with this explanation, the enantiomeric
excess of the ∆3,4 isomer 53, which was isolated in 44% yield
from the cyclization summarized in entry 15, was only 31%
(the R enantiomer predominated). The enantiomeric purity of
(R)-53 (obtained by PMP-promoted cyclization) was determined
by oxidation with CrO3‚(pyridine)2 to afford enone (R)-8 in low
yield (eq 2).33 The PMP-promoted Heck cyclization of the
corresponding cyclohexenyl aryl bromide 15 occurred at a
convenient rate only at 120 °C and provided (R)-44 in low ee.
Cyclizations of cycloheptenyl anilide 16 and cyclopentenyl
anilide 17 occurred with no meaningful stereoinduction in the
presence of Ag3PO4, whereas the corresponding PMP-promoted
cyclizations provided 45 in 88% ee and 46 in 56% ee. We
presume that enantioselection in forming 45 is also enhanced
by subsequent kinetic resolution, since the ∆3,4 and ∆4,5 isomers
of 45 were obtained in 40% and 4% yields, respectively.
the hydroxymethylation of 3,3-dimethylbutyne,30 followed by
protection of the resulting alcohol as a TIPS ether afforded 31
in 74% yield. Carboxylation of iodide 31 by sequential
treatment with tert-butyllithium and CO2 afforded (Z)-carboxylic
acid 32, which was converted to the corresponding methyl ester
33 by reaction with MeI and DBU.31 Condensation of 33 with
the trimethylaluminum derivative of 2-iodoaniline27 provided
a single amide product 34 in 32% yield. That the alkene had
completely isomerized, presumably by conjugate addition-
elimination, to the more stable E configuration was apparent
by comparison of 34 with the corresponding Z isomer, which
had been prepared in a stereochemically unambiguous fashion.12
N-Methylation of 34 then provided tertiary amide 22 in high
yield.
The synthesis of R-phenyl (E)-buteneanilide 23 began with
stannylation of readily available ester 35 to give an 8:1 mixture
of vinylstannane 36 and a regioisomer (Scheme 7). Iodination
of this mixture and removal of the minor isomer by chroma-
tography provided iodide 37 in 75% yield, as described for the
tert-butyldimethylsilyl analogue.32 Palladium(0) catalyzed cross-
(29) MacInnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987,
1077.
(30) Collier, W. L.; Macomber, R. S. J. Org. Chem. 1973, 38, 1367.
(31) Koji, A.; Ono, N.; Saito, T.; Tanaka, K.; Yamada, T. Bull. Chem.
Soc. Jpn. 1978, 51, 2401.
(33) Dauben, W. G.; Lorber, M.; Fullerton, D. S. J. Org. Chem. 1969,
34, 3587.
(32) Rossi, R.; Carpita, A.; Cossi, P. Tetrahedron 1992, 48, 8801.

6482 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Ashimori et al.
Chart 1
Scheme 6
Scheme 7
That the factors controlling enantioselection are varied and
subtle is seen in cyclizations of acyclic (E)-acrylolyl 2-iodoa-
nilides 20-23. For example, changing the â-substituent from
Me to CH2OTBDMS results in a decrease in enantioselectivity
of the Ag3PO4-promoted Heck cyclization but an increase in
enantioselection in the corresponding PMP-promoted reaction.
More dramatic are the changes occasioned by changing the
R-substituent (entries 27-32). Although low enantioselection
is seen in cyclizations conducted with both Ag3PO4 and PMP,
when this group is methyl (entries 27 and 28), the t-Bu substrate
22 provides (R)-51 in 72% ee in the presence of Ag3PO4 (entry
29). In contrast, phenyl analogue 23 cyclizes with poor
enantioselectivity in the presence of PMP and provides the
opposite enantiomer 52 in 73% ee in the presence of Ag3PO4
However, in this case we did not establish that these isomers
were enriched in the S enantiomer.
Allylic carbamate 18 and allylic ether 19 underwent Heck
cyclizations to give the corresponding spirocyclic products 47
and 48 in moderate ee in the presence of Ag3PO4. However,
nearly racemic products were obtained in the presence of PMP
(Table 5, entries 21-24).

(E)-R,â-Unsaturated 2-Haloanilides and Analogues
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6483
Table 5. Scope of Asymmetric Heck Cyclizations of
(E)-R,â-Unsaturated 2-Haloanilides with Pd(R)-BINAP
Scheme 8
reaction conditions
Heck product
HX
convnm scavenger solvent
time, temp, yield,
abs
h
°C
%
ee, % configa
1
2
3
4
Ag3PO4 DMA 26
4 f 5 Ag3PO4 NMP 26
80 81 71c
80 86 70c
S
S
R
S
S
R
S
S
R
S
+
-
S
PMP
DMA
8
110 71 66c
80 91 41-51c,d
80 91 50c
Ag3PO4 DMA 11
5 10 f 40 Ag3PO4 NMP 13
6
7
PMP
DMA
4.5 100 66 66c
Ag3PO4 DMA 52
80 76 65c
80 78 58c
8 11 f 41 Ag3PO4 NMP 29
PMP DMA
10 12 f 42 Ag3PO4 DMA 72
9
6.5 100 68 75c
80 65 42c,e
80 99 72c
11
12
13
Ag3PO4 DMA
3.5
1
13 f 43
PMP
DMA
100 89 71c
Ag3PO4 DMA 25
60 74f 79-81c,d
60 70g 80c
14 14 f 44 Ag3PO4 NMP 25
15
16 15 f 44 PMP
S
Scheme 9
PMP
DMA
DMA
1.5 100 45h 89-95c,d
9
R
R
b
b
b
120 51i 32c
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Ag3PO4 DMA
7.5
80 62j
0
16 f 45
17 f 46
18 f 47
19 f 48
20 f 49
21 f 50
22 f 51
23 f 52
PMP
Ag3PO4 DMA 23
PMP DMA
1.3 100 96 56c
Ag3PO4 NMP 24
60 90 64c
PMP DMA 100 51
8c
Ag3PO4 NMP 24
60 91 49-55c,d
PMP DMA 100 66
0-7c,d
Ag3PO4 DMA 27
80 88 59c
PMP DMA
1.3 100 91 25c
Ag3PO4 DMA
PMP DMA
Ag3PO4 DMA
PMP DMA
Ag3PO4 DMA
PMP
DMA
1.5 100 50k 88c
60 81
7c
+
-
+
-
S
R
S
R
R
R
l
7
6
2
1
4
2
80 80 45d
100 85 38d
120 41 72d
120 90 27d
80 93 73d
100 74 35d
2.5
DMA 14
l
a For compounds for which absolute configuration are not deter-
correlation with 50. The absolute configuration of t-Bu
congener 51 was established by chemical correlation with (S)-
5612 (Scheme 10). First, the absolute configuration of (S)-56
was secured by decarbonylation using Wilkinson’s catalyst,35
followed by hydrolysis of the resulting acetal, to provide (S)-
(+)-50 in 27% overall yield. The preparation of tert-butyl
derivative 61 from 56 was considerably more involved. Alkyl-
ation of the N-cyclohexylimine derivative of (S)-56 by sequential
treatment with LDA, MeI, and hot aqueous NH4Cl gave
monomethylated aldehyde 57. Unfortunately, the monomethy-
lated imine intermediate could not be deprotonated with LDA,
lithium diethylamide, or lithium pyrrolidide in THF (with or
without DMPU) precluding direct dimethylation of the imine
intermediate. Nevertheless, 57 could be methylated under phase
transfer conditions36 to provide a 2:1 mixture of 58 and enol
ether 59 in 50% combined yield. However, all attempts to
reductively deoxygenate aldehyde 58 to provide the correspond-
ing tert-butyl derivative failed.37 The desired conversion of 58
f 61 was finally accomplished in an indirect fashion. Aldehyde
58 was first homologated to 60 by reaction with methoxy-
methyltriphenylphosphorane38 followed by hydrolysis. Alde-
hyde 60 was then decarbonylated using Wilkinson’s catalyst to
afford acetal 61 in low yield. Hydrolysis of this intermediate
provided (S)-51. Since only a small amount of (S)-51 (∼1 mg)
was obtained from this multistep correlation, comparison of the
corresponding alcohol derivative 62 with this derivative of the
mined, sign of optical rotation is shown instead. b Not determined.
c Determined by 1H NMR analysis in the presence of Eu(tfc)3, Eu(hfc)3
or Yb(tfc)3. d Determined by HPLC analysis using a Chiralcel OD, OJ
or OB-H column. e Determined by analysis of the 1-unsubstituted
oxindole prepared by treatment of 42 with TFA. f The ∆3,4 isomer was
formed also (8% yield). g The ∆3,4 isomer was formed also (14% yield).
h The ∆3,4 isomer was formed also (44% yield). i The ∆3,4 isomer was
formed also (36% yield). j The ∆3,4 and ∆4,5 isomers were formed also
(13% and 17% yields, respectively). k The ∆3,4 and ∆4,5 isomers were
formed also (40% and 4% yields, respectively). l The PMP- and
Ag3PO4-promoted cyclizations produced opposite enantiomersd of
unknown absolute configuration. The major enantiomer formed in the
PMP-promoted reaction elutes first on a Chiracel OJ column (85:15
hexane-2-propanol). m Structures are shown in Chart 1.
(entries 31 and 32). The cyclization of 22 f 51 is also notable
in that it is the only Heck cyclization of an (E)-R,â-unsaturated
anilide that affords the same enantiomer in the presence of PMP
and Ag3PO4.
The absolute configurations of spirooxindole acetals 40-42
were established by the straightforward chemical correlations
summarized in Scheme 8. The absolute configuration of 44
was determined by allylic oxidation33 to give, in the case of
the product formed in the presence of Ag3PO4, (S)-8 in 52%
yield (Scheme 9). This intermediate was also employed to
confirm the configuration assigned to 53. Thus, conversion of
(S)-8 to the corresponding tosylhydrazone 55, followed by
reduction with catecholborane,34 provided an authentic sample
of (S)-53.
(35) Ohno, K.; Tsuji. J. Synthesis 1969, 157.
(36) Brannock, K. C.; Dietl, H. K. Tetrahedron Lett. 1973, 1273.
(37) Barton deoxygenation of the xanthate derivative and Wolf-Kishner
reduction of the tosylhydrazone derivative failed. Attempts to prepare the
tosylate or iodide derivative of the corresponding primary alcohol, as a
prelude to reduction, were also unsuccessful.
(38) Claremon, D. A.; Magolda, R. L.; Nicolaou, K. C. J. Am. Chem.
Soc. 1980, 102, 2, 1404.
The absolute configuration of 50 was assigned by conversion
to physostigmine derivative (+)-esermethole,12 while the con-
figuration of 49 was assigned by straightforward chemical
(34) Kabalka, G. W.; Hutchins, R.; Natale, N. R.; Yang, D. T. C.; Broach,
V. Organic Syntheses; Wiley: New York, 1988; Collect. Vol. VI, p 293.

6484 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Ashimori et al.
Scheme 10
R,â-unsaturated 2-iodoanilides using Pd(R)-BINAP produce the
S enantiomer of the oxindole when the HI acceptor is Ag3PO4
and the R enantiomer when 1,2,2,6,6-pentamethylpiperidine
(PMP) is the HI scavenger (see Figure 1).
Which HI acceptor is optimal for achieving highest enanti-
oselection is substrate dependent. For example, allylic carbam-
ate 18 and allylic ether 19 cyclized with moderate enantiose-
lection in the presence of Ag3PO4, yet provided racemic products
in the presence of PMP. On the other hand, with anilide
substrates 14, 16, and 17 enantioselectivities were higher in the
presence of PMP than Ag3PO4. With (Z)-R,â-unsaturated
2-iodoanilide substrates, whose asymmetric Heck cyclizations
are reported in the accompanying paper, enantioselection in Pd-
BINAP catalyzed cyclizations is much higher in the presence
of PMP. Although the origin of these trends is only partially
understood at this time, the ability to carry out asymmetric Heck
cyclizations in two distinct ways provides additional opportuni-
ties for reaction optimization.
The high enantioselectivities realized in asymmetric Heck
cyclizations carried out in the absence of halide scavengers
dispels the notion that a halide counterion cannot be present
for high enantioselection in asymmetric Heck reactions using
chiral diphosphine catalysts to be achieved. Investigations
aimed at further defining this novel halide-containing (neutral)
asymmetric Heck reaction manifold are presented in the
following paper.12
Conclusion
Enantioenriched 3,3-disubstituted oxindoles, indolines, and
dihydrobenzofurans can be prepared by Pd-BINAP-catalyzed
intramolecular Heck reactions of o-iodoarenes tethered to (E)-
trisubstituted alkenes. Enantioselectivities are typically moder-
ate (55-75% ee); however, in cases where the major enantiomer
can be enriched by in situ kinetic resolution (e.g., oxindoles 44
and 45) or recrystallization (e.g., oxindole 8), asymmetric Heck
cyclizations provide convenient access to heterocycles of high
(>90%) enantiomeric purity.
These investigations led to the unprecedented discovery that
depending upon how HX is scavenged, either enantiomer of
the Heck product can be formed with good selectivity using a
single enantiomer of a chiral diphosphine ligand (Figure 1).
Moreover, these studies demonstrate that the presence of a halide
scavenger is not obligatory for realizing high enantioselection
in (diphosphine)palladium-catalyzed asymmetric Heck insertions
of some halide substrates.
The two accompanying papers report (a) intramolecular Heck
reactions of related substrates containing (Z)-trisubstituted
alkenes, which in the absence of halide scavengers proceed with
high enantioselectivity,12,13 (b) our initial mechanistic investiga-
tions of this unusual “neutral” asymmetric Heck pathway,12,14
and (c) one illustration of the utility of “neutral” asymmetric
Heck reactions for natural products construction.15
product produced from Heck cyclization of 22 was utilized to
establish absolute configuration.
Discussion
A variety of 3,3-disubstituted 2-oxindoles can be prepared
in moderate enantiomeric purity (typically 55-75% ee) by
cyclization of N-alkyl-2-iodoanilide derivatives of (E)-R,â-
unsaturated acids. At the time these results were first reported,11
they represented the highest enantioselectivities obtained in
asymmetric Heck reactions that directly form chiral quaternary
carbon centers. In cases where the major enantiomer can be
enriched, either by in situ kinetic resolution (e.g., oxindoles 44
and 45) or recrystallization (e.g., oxindole 8), asymmetric Heck
cyclizations using Pd-BINAP provide convenient access to 3,3-
disubstituted 2-oxindoles of high (>90%) enatiomeric purity.
The exploratory investigations reported here reveal the
important role the HX scavenger plays in determining both rate
and enantioselection in asymmetric Heck cyclizations.
A
moderately strong proton base must be present to obtain useful
catalytic rates. This requirement is seen in Heck cyclizations
conducted in the presence of silver salts, where salts having
weakly basic counterions (e.g., OTf-, NO3-, BF4-) do not
effectively promote Heck cyclization. This trend of higher
reaction rate in the presence of more basic proton acceptors is
also seen in Heck cyclizations carried out in the presence of
inorganic or tertiary amine bases (Table 4). Both observations
suggest that the turnover-limiting step is regeneration of an
active Pd(0) catalyst from a hydridopalladium(II) halide inter-
mediate.
Experimental Section39
1,4-Dioxaspiro[4.5]dec-7-ene-8-carboxylic Acid (2). A solution
of NaClO2 (10.1 g, 89.3 mmol), NaH2PO4 (7.0 g, 58 mmol), and H2O
(70 mL) was added dropwise at room temperature to a solution of
(39) Chromatography was carried out on silica gel as described by Still
and co-workers40 and is abbreviated as sgc. Tetrahydrofuran was purified
by distillation from sodium and benzophenone and N,N-dimethylacetamide
(DMA) was purified by distillation from CaH2 at 20 mm. Pd2(dba)3 and
BINAP were purchased from Aldrich Chemical Co. High-resolution mass
spectra were measured on a MicroMass Analytical 7070E spectrometer (EI
or CI-isobutane); uncertainty (s) in mass measurements is 1.0 millimass
unit (molecular weight < 400) or 1.5 millimass units (molecular weight
400-1000). Other general experimental details have been described: Deng,
W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.
Certainly the most provocative result of these investigations
is the unprecedented observation that either enantiomer of a
Heck product can be obtained using the same enantiomer of a
chiral ligand. In all cases but one, Heck cyclizations of (E)-

(E)-R,â-Unsaturated 2-Haloanilides and Analogues
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6485
aldehyde 116 (12.0 g, 71.4 mmol), t-BuOH (355 mL), and 2,3-dimethyl-
2-butene (85 mL).17 The mixture was stirred at room temperature for
24 h and then concentrated. The resulting aqueous solution was basified
to pH 10 with 6 M NaOH, diluted with H2O (470 mL), and then washed
with hexanes (2 × 350 mL). The aqueous solution was acidified to
pH 3 with 6 M HCl and then extracted with Et2O (5 × 250 mL). The
extract was washed with brine (250 mL), dried (MgSO4), and
concentrated. The residue was recrystallized from hexanes-EtOAc
7.29 (td, J ) 7.7, 1.2 Hz, 1H), 7.25 (d, J ) 7.6 Hz, 1H), 7.05 (td, J )
7.5, 0.9 Hz, 1H), 6.84 (d, J ) 7.8 Hz, 1H), 5.96 (d, J ) 10.0 Hz, 1H),
5.49 (d, J ) 10.0 Hz, 1H), 4.14-3.95 (m, 4H), 2.44 (ddd, J ) 13.7,
10.1, 3.5 Hz, 1H), 2.22 (dddd, J ) 13.0, 9.0, 3.6, 0.5 Hz, 1H), 2.10-
1.95 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.0, 143.1, 132.8, 131.1,
129.9, 128.3, 123.8, 122.6, 108.0, 104.3, 64.7, 64.6, 49.2, 30.6, 29.7,
26.4; IR (CCl4) 1719, 1613 cm-1; MS (EI) m/z 271.1194 (271.1208
calcd for C16H17NO3). Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32;
N, 5.16. Found: C, 70.71; H, 6.35; N, 5.13.
1
to give 10.6 g (81%) of 2 as colorless scales: mp 105-105.5 °C; H
1
NMR (250 MHz, CDCl3) δ 7.00 (m, 1H), 3.99 (s, 4H), 2.6-2.4 (m,
4H), 1.80 (t, J ) 6.4 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 172.1,
139.1, 129.3, 107.1, 64.5, 36.3, 30.6, 23.1; IR (CCl4) 2956, 2883, 1692,
1650 cm-1; MS (EI) m/z 184.0718 (184.0736 calcd for C9H12O4). Anal.
Calcd for C9H12O4: C, 58.69; H, 6.55. Found: C, 58.79; H, 6.61.
Determination of Enantiomeric Excess of 5 by H NMR Using
Yb(tfc)3. Yb(tfc)3 was stored and weighed in a glovebox, and the
CDCl3 was stored over 4 Å molecular sieves and K2CO3. Oxindole 5
was dissolved in CDCl3 (5-6 mg in 0.5 mL). A solution of Yb(tfc)3
(10 mg/mL) and CDCl3 was added dropwise (10-14 drops) to the NMR
tube and the N-methyl singlet at 3.21 ppm split into two singlets (3.6-
3.8 ppm) which could be integrated. Addition of too much Yb(tfc)3
caused the N-methyl signals to overlap with signals of the ethylene
ketal.
2-Iodo-N-(1,4-dioxaspiro[4.5]dec-7-en-8-ylcarbonyl)-N-methyla-
niline (4). A solution of 2 (10.1 g, 54.6 mmol) and THF (72 mL) was
added dropwise to a suspension of NaH (60%, 2.41 g, 60.3 mmol) and
THF (90 mL) with ice bath cooling. The resulting mixture was stirred
at room temperature for 2 h and recooled in an ice bath, and then SOCl2
(4.38 mL, 60.1 mmol) was added dropwise over 6 min. After having
been stirred at room temperature for 2.5 h a solution of 2-iodoaniline
(11.9 g, 54.3 mmol), Et3N (7.92 mL, 56.8 mmol), and THF (54 mL)
was added dropwise at room temperature. The resulting mixture was
heated at reflux for 5 h, allowed to cool to room temperature, diluted
with Et2O (750 mL), and then washed successively with 250 mL of
H2O, saturated aqueous NaHCO3, and brine. After drying (MgSO4),
the organic layer was concentrated, and the residue was purified by
sgc (3:2 hexanes-EtOAc) to give 13.1 g (62%) of 3 as a yellow oil:
1H NMR (250 MHz, CDCl3) δ 8.33 (dd, J ) 8.3, 1.5 Hz, 1H), 7.84 (d,
1H, J ) 0.7 Hz), 7.77 (dd, J ) 7.9, 1.4 Hz, 1H), 7.34 (td, J ) 7.9, 1.4
Hz, 1H), 6.83 (td, J ) 7.7, 1.5 Hz, 1H), 6.76 (m, 1H), 4.02 (s, 4H),
2.68 (m, 2H), 2.50 (m, 2H), 1.89 (t, J ) 6.5 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 165.3, 138.7, 138.2, 133.1, 132.4, 129.2, 125.7, 121.6,
Typical Procedure for Asymmetric Heck Cyclization Using Pd2-
(dba)3, (R)-BINAP and PMP in DMA. Preparation of (R)-(-)-1′,2′-
Dihydro-1′-methyl-2′-oxospiro[1,4-dioxaspiro[4.5]dec-6-ene-8,3′-
3′H-indole] [(R)-5]. A mixture of Pd2(dba)3 (23.2 mg, 0.0253 mmol),
(R)-BINAP (33.9 mg, 0.0544 mmol), and DMA (1 mL) was stirred at
room temperature for 40 min, and then a solution of 4 (100 mg, 0.251
mmol), PMP (0.23 mL, 1.27 mmol), and DMA (1.5 mL) was added.
After having been stirred at 110 °C for 8 h, the resulting mixture was
worked up as decribed for the cyclization using Ag3PO4 and purified
by sgc to give 48.1 mg (71%) of (R)-(-)-5 (63% ee) as a colorless
solid, [R]25 -2.1° (c 0.74, MeOH).
D
(S)-(-)-1′,2′-Dihydro-1′-methyl-2′-oxo-4-oxospiro[cyclohex-2-ene-
1,3′-3′H-indole] [(S)-(-)-8]. To a solution of (+)-5 (68% ee, 552 mg,
2.07 mmol) and THF (20 mL) at 0 °C, 1 M HCl (20 mL) was added,
and the resulting solution was allowed to warm to room temperature
over 40 min and then was poured into 30% aqueous K2CO3 (30 mL).
This mixture was extracted with CH2Cl2 (60 mL, 2 × 45 mL), and the
extract was washed with brine (30 mL) and dried (MgSO4). Concen-
tration followed by sgc (1:1 EtOAc-hexanes) gave 462 mg (∼100%)
107.0, 89.9, 64.5, 36.0, 30.7, 23.8; IR (CCl4) 3398, 1689, 1645 cm-1
;
MS (EI) m/z 385.0166 (385.0176 calcd for C15H16INO3).
A solution of 3 (12.9 g, 33.4 mmol) and THF (55 mL) was added
dropwise at 0 °C to a stirring suspension of NaH (60%, 2.01 g, 50.3
mmol) and THF (35 mL). The resulting mixture was stirred at 0 °C
for 40 min, and then MeI (5.20 mL, 84.0 mmol) was added. The
reaction mixture was then heated at reflux for 75 min, allowed to cool
to room temperature, diluted with Et2O (750 mL), and washed
successively with 100 mL of H2O, saturated aqueous NaHCO3, and
brine. After drying (MgSO4), the organic layer was concentrated, and
the residue was purified by sgc (3:2 hexanes-EtOAc) to give 10.9 g
of (S)-(-)-8 as a pale yellow solid, 60% ee: [R]25 -31.8° (c 0.51,
D
MeOH); 1H NMR (500 MHz, CDCl3) δ 7.37 (t, J ) 7.7 Hz, 1H), 7.21
(d, J ) 7.3 Hz, 1H), 7.11 (t, J ) 7.8 Hz, 1H), 6.92 (d, J ) 7.8 Hz,
1H), 6.48 (d, J ) 10.0 Hz, 1H), 6.27 (d, J ) 10.0 Hz, 1H), 3.26 (s,
3H), 3.13 (ddd, J ) 17.3, 9.8, 5.3 Hz, 1H), 2.63 (ddd, J ) 17.3, 7.1,
5.1 Hz, 1H), 2.42 (ddd, J ) 13.2, 6.5, 6.5 Hz, 1H), 2.29 (ddd, J )
14.0, 9.5, 4.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 197.9, 176.2,
146.2, 143.1, 131.4, 131.2, 129.1, 123.6, 123.0, 108.6, 49.6, 33.1, 32.0,
26.6; IR (CHCl3) 1711, 1678, 1612 cm-1; MS (EI) m/z 227.0943
(227.0946 calcd for C14H13NO2). Anal. Calcd for C14H13NO2: C,
73.99; H, 5.77; N, 6.16. Found: C, 74.06; H, 5.80; N, 6.14.
1
(82%) of 4 as pale yellow crystals: mp 109-110 °C; H NMR (300
MHz, CDCl3) δ 7.87 (dd, J ) 7.9, 1.3 Hz, 1H), 7.35 (td, J ) 7.7, 1.4
Hz, 1H), 7.15 (d, J ) 7.5 Hz, 1H), 6.99 (td, J ) 7.7, 1.4 Hz, 1H),
5.9-5.7 (br m, 1H), 3.86 (s, 4H), 3.23 (s, 3H), 2.6-1.9 (br m, 4H),
1.8-1.4 (br m, 2H); 13C NMR (75 MHz, CDCl3) δ 171.3, 147.0, 140.0,
133.5, 129.7, 129.3, 129.1, 128.9, 106.9, 98.9, 64.2, 37.1, 35.5, 30.7,
25.3; IR (CCl4) 1662, 1640 cm-1; MS (EI) m/z 399.0320 (399.0332
calcd for C16H18INO3). Anal. Calcd for C16H18NO3: C, 48.14; H, 4.54;
N, 3.51. Found: C, 48.22; H, 4.51; N, 3.45.
Recrystallization of a 360 mg sample from Et2O three times afforded
67 mg of (S)-(-)-8 as colorless crystals which were 92% ee.
(S)-(-)-1′,2′-Dihydro-1′-methyl-2′-oxo-3-bromo-4-oxospiro[cyclo-
hex-2-ene-1,3′-3′H-indole] [(S)-(-)-9]. A solution of PhNMe3Br3 (107
mg, 0.285 mmol) and THF (0.8 mL) was added dropwise to a solution
of (S)-(-)-8 (92% ee, 58.9 mg, 0.259 mmol) and THF (0.8 mL) at
-10 °C. The resulting mixture was stirred at -10 °C for 1.5 h, at 0
°C for 5 h, and at room temperature for 1.5 h and then recooled to 0
°C, and Et3N (0.054 mL, 0.39 mmol) was added. After stirring at room
temperature for 75 min, the reaction mixture was diluted with Et2O
(20 mL) and then washed with H2O (7 mL). The aqueous layer was
back-extracted with Et2O (2 × 10 mL), and the combined extracts were
washed with 7 mL of saturated aqueous NaHCO3 and brine. After
drying (MgSO4), the organic layer was concentrated, and the residue
was purified by sgc (3:2 hexanes-EtOAc) to give 51.4 mg (65%) of
(S)-(-)-9 as a colorless solid. Recrystallization from acetone-hexanes
gave colorless single crystals, which were suitable for X-ray crystal-
Typical Procedure for Asymmetric Heck Cyclization Using Pd2-
(dba)3, (R)-BINAP and Ag3PO4 in DMA. Preparation of (S)-(+)-
1′,2′-Dihydro-1′-methyl-2′-oxospiro[1,4-dioxaspiro[4.5]dec-6-ene-
8,3′-3′H-indole] [(S)-5]. Under an Ar atmosphere, a mixture of
Pd2(dba)3 (11.5 mg, 0.0126 mmol), (R)-BINAP (16.8 mg, 0.0270
mmol), Ag3PO4 (210 mg, 0.501 mmol), and DMA (1 mL) was stirred
at room temperature for 40 min, and then a solution of 4 (100 mg,
0.251 mmol) and DMA (1.5 mL) was added. After stirring at 80 °C
for 26 h, the mixture was diluted with Et2O (20 mL) and washed with
saturated aqueous NaHCO3 (7 mL). The aqueous layer was further
extracted with Et2O (2 × 10 mL), and the combined organic extracts
were washed with brine (7 mL) and dried (MgSO4). Concentration
followed by sgc (1:1 EtOAc-hexanes) gave 54.4 mg (80%) of (S)-
1
lographic analysis: mp 176-177 °C; H NMR (CDCl3, 500 MHz) δ
(+)-5 (71% ee) as a colorless solid, [R]25 +3.8° (c 0.54, MeOH).
7.38 (t, J ) 7.7 Hz, 1H), 7.24 (d, J ) 7.4 Hz, 1H), 7.13 (t, J ) 7.5 Hz,
1H), 6.93 (s, 1H), 6.92 (d, J ) 7.8 Hz, 1H), 3.37 (ddd, J ) 16.6, 9.6,
7.0 Hz, 1H), 3.26 (s, 3H), 2.79 (dt, J ) 17.2 Hz, 5.5 Hz, 1H), 2.46-
2.34 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ 190.0, 174.7, 146.6,
142.9, 130.3, 129.5, 126.8, 123.7, 123.3, 108.8, 52.2, 33.4, 32.0, 26.7;
D
Recrystallization from toluene-hexanes gave (S)-(+)-5 as off-white
crystals: mp (racemate) 124-126 °C; 1H NMR (300 MHz, CDCl3) δ
(40) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

6486 J. Am. Chem. Soc., Vol. 120, No. 26, 1998
Ashimori et al.
IR (CHCl3) 1712, 1614, 1601 cm-1; MS (CI) m/z 308.0093 (308.0109
3.20 (s, 3H), 2.62-2.50 (m, 1H), 2.40-2.30 (m, 1H), 2.16-2.06 (m,
1H), 2.06-1.96 (m, 1H), 1.95-1.75 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 179.6, 142.6, 135.5, 131.0, 129.4, 127.7, 123.9, 122.3, 107.9,
55.3, 36.1, 34.6, 28.2, 26.2, 24.6; IR (CHCl3) 1701, 1612 cm-1; MS
(CI) m/z 227.1297 (227.1310 calcd for C15H17NO). ∆3,4 isomer: 1H
NMR (500 MHz, CDCl3) δ 7.57 (d, J ) 7.4 Hz, 1H), 7.28 (td, J )
7.7, 1.1 Hz, 1H), 7.01 (t, J ) 7.4 Hz, 1H), 6.86 (d, J ) 7.7 Hz, 1H),
6.10 (m, 1H), 5.69 (m, 1H), 3.21 (s, 3H), 2.85 (ddd, J ) 14.6, 3.0, 1.8
Hz), 2.45-2.33 (m, 2H), 2.19 (ddd, J ) 13.4, 12.1, 1.7 Hz), 2.01 (ddd,
J ) 14.5, 8.4, 0.9 Hz, 1H), 1.87-1.70 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 180.8, 142.9, 134.3, 133.7, 127.5, 125.6, 121.6, 107.8, 47.9,
38.6, 33.8, 28.8, 26.2, 21.0; IR (CHCl3) 1697, 1612 cm-1; MS (CI)
m/z 228.1357 (228.1388 calcd for C15H18NO).
81
calcd for C14H1381BrNO2), 307.0056 (307.0030, calcd for C14H12
-
BrNO2). Anal. Calcd for C14H12BrNO2: C, 54.92; H, 3.94; N, 4.57.
Found: C, 54.79; H, 4.00; N, 4.52.
(S)-(-)- and (R)-(+)-1′-Benzyl-1′,2′-dihydro-2′-oxospiro[1,4-
dioxaspiro[4.5]dec-6-ene-8,3′-3′H-indole] [(S)-(-)- and (R)-(+)-40]:
1
a slightly yellow oil; H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m,
6H), 7.17 (t, J ) 7.7 Hz, 1H), 7.01 (t, J ) 7.5 Hz, 1H), 6.72 (d, J )
7.8 Hz, 1H), 6.00 (d, J ) 9.9 Hz, 1H), 5.55 (d, J ) 9.9 Hz, 1H), 4.95
and 4.87 (ABq, J ) 15.7 Hz, 2H), 4.2-4.0 (m, 4H), 2.50 (ddd, J )
13.5, 10.0, 3.3 Hz, 1H), 2.28 (ddd, J ) 13.4, 9.2, 3.8 Hz, 1H), 2.4-
2.0 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.1, 142.1, 135.8, 132.9,
131.4, 129.9, 128.8, 128.3, 127.6, 127.2, 123.9, 122.6, 109.1, 104.4,
64.8, 64.7, 49.2, 43.7, 30.8, 29.8; IR (CHCl3) 1709, 1612 cm-1; MS
(EI) m/z 347.1529 (347.1521 calcd for C22H21NO3).
(+)- and (-)-1′,2′-Dihydro-1′-(methoxycarbonyl)spiro[1,4-dioxa-
spiro[4.5]dec-6-ene-8,3′-3′H-indole] [(+)- and (-)-47]: a colorless
solid; mp (racemate) 135.5-136 °C (toluene-hexanes); 1H NMR (500
MHz, CDCl3) δ 7.87 (br s, 1H), 7.23 (t, J ) 7.4 Hz, 1H), 7.13 (d, J )
7.4 Hz, 1H), 6.99 (t, J ) 7.7 Hz, 1H), 5.80 (d, J ) 9.9 Hz, 1H), 5.78
(d, J ) 10.1 Hz), 4.10-3.95 (m, 5H), 3.83 (br s, 3H), 3.76 (d, J )
11.2 Hz, 1H), 2.40-1.80 (m, 4H); 13C NMR (125 MHz, CDCl3) δ
153.5, 141.4, 136.9, 135.6, 129.1, 128.3, 123.8, 122.8, 114.9, 104.6,
Table 5, entry 5: (S)-(-)-40, 50% ee, [R]25D -1.9° (c 0.50, MeOH);
entry 6 (R)-(+)-40 66% ee, [R]25 +9.6° (c 0.71, CHCl3).
D
(S)-(-)- and (R)-(+)-1′,2′-Dihydro-2′-oxo-1′-(2-trimethylsilyl-
ethoxymethyl)spiro[1,4-dioxaspiro[4.5]dec-6-ene-8,3′-3′H-indole] [(S)-
(-)- and (R)-(+)-41]: off-white crystals; mp (racemate) 108-109 °C
1
(toluene-hexanes); H NMR (500 MHz, C6D6) δ 7.11 (d, J ) 7.3 Hz,
64.6, 64.5, 58.9, 52.5, 44.6, 34.1, 30.5; IR (CHCl3) 1702, 1600 cm-1
;
1H), 7.00 (td, J ) 8.2, 0.9 Hz, 1H), 6.88 (d, J ) 7.8 Hz, 1H), 6.78 (t,
J ) 7.3 Hz, 1H), 5.95 (d, J ) 9.9 Hz, 1H), 5.40 (d, J ) 9.9 Hz, 1H),
4.98 and 4.92 (ABq, J ) 11.0 Hz, 2H), 3.6-3.45 (m, 6H), 2.66 (ddd,
J ) 13.8, 10.4, 3.3 Hz, 1H), 2.33 (ddd, J ) 13.6, 9.3, 3.8 Hz, 1H),
2.11-2.0 (m, 2H), 0.86 (app qt, J ) 14.1, 7.6 Hz, 2H), -0.10 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 178.4, 141.5, 132.5, 131.4, 129.8, 128.4,
123.8, 123.1, 109.7, 104.3, 69.5, 64.8, 64.7, 49.5, 31.0, 29.7, 17.8, -1.5;
IR (CHCl3) 1719, 1613 cm-1; MS (EI) m/z 387.1852 (387.1866 calcd
for C21H29NO4Si).
MS (EI) m/z 301.1310 (301.1314 calcd for C17H19NO4). Anal. Calcd
for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.78; H, 6.40;
N, 4.64.
Table 5, entry 21: (+)-47 64% ee, [R]25D +17.0° (c 0.64, MeOH);
entry 22: (-)-49, 8% ee, [R]25 -0.5° (c 0.56, MeOH).
D
Spiro[1,4-dioxaspiro[4.5]dec-6-ene-8,3′(2H)-benzofuran]: a color-
less oil; 1H NMR (500 MHz, CDCl3) δ 7.16 (td, J ) 7.6, 1.4 Hz, 1H),
7.14 (d, J ) 7.4 Hz, 1H), 6.88 (t, J ) 7.4 Hz, 1H), 6.82 (d, J ) 8.0
Hz, 1H), 5.84 (d, J ) 9.9 Hz, 1H), 5.78 (d, J ) 10.0 Hz, 1H), 4.42 and
4.25 (ABq, J ) 8.9 Hz, 2H), 4.10-3.97 (m, 4H), 2.07-1.96 (m, 3H),
1.90-1.81 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 159.4, 135.1, 133.5,
129.3, 128.7, 123.9, 120.7, 109.9, 104.7, 81.0, 64.6, 47.1, 33.2, 30.7;
IR (film) 1650, 1608 cm-1; MS (CI) m/z 245.1175 (245.1178 calcd
for C15H17O3).
Table 5, entry 7: (S)-(-)-41, 65% ee, [R]25D -5.0° (c 0.61, MeOH);
entry 9: (R)-(+)-4, 68% ee, [R]25 +5.9° (c 0.68, MeOH).
D
(S)-(-)-1′-(tert-Butoxycarbonyl)-1′,2′-dihydro-2′-oxospiro[1,4-
dioxaspiro[4.5]dec-6-ene-8,3′-3′H-indole] [(S)-(-)-42]: colorless crys-
tals; mp (racemate) 147-147.5 °C (toluene-hexanes); 1H NMR (300
MHz, CDCl3) δ 7.85 (d, J ) 8.2 Hz, 1H), 7.31 (td, J ) 7.8, 1.4 Hz,
1H), 7.24 (dd, J ) 7.5, 1.4 Hz, 1H), 7.15 (td, J ) 7.4, 0.9 Hz, 1H),
5.98 (d, J ) 9.9 Hz, 1H), 5.54 (d, J ) 10.0 Hz, 1H), 4.1-3.95 (m,
4H), 2.45 (ddd, J ) 13.5, 10.2, 3.4 Hz, 1H), 2.24 (dddd, J ) 13.5, 7.5,
3.4, 0.6 Hz, 1H), 2.07 (ddd, J ) 13.7, 10.5, 3.4 Hz, 1H), 1.98 (dddd,
J ) 13.3, 7.5, 3.4, 0.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 176.1,
149.3, 138.9, 131.9, 131.8, 129.4, 128.5, 124.6, 123.7, 115.0, 104.1,
Table 5, entry 23: (+)-48, 55% ee, [R]25D +59.7° (c 0.96, MeOH).
(-)- and (+)-3-Ethenyl-1,2-dihydro-1,3-dimethyl-2-oxo-3H-indole
1
[(-)- and (+)-49]: a pale yellow oil; H NMR (500 MHz, CDCl3) δ
7.30 (t, J ) 7.7 Hz, 1H), 7.19 (d, J ) 7.2 Hz, 1H), 7.09 (t, J ) 7.4 Hz,
1H), 6.87.(d, J ) 7.8 Hz, 1H), 5.95 (dd, J ) 17.2, 10.4 Hz, 1H), 5.14
(d, J ) 9.2 Hz, 1H), 5.13 (d, J ) 16.7 Hz, 1H), 3.21 (s, 3H), 1.49 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 178.6, 143.0, 138.1, 132.6, 128.0,
123.8, 122.4, 115.1, 108.2, 51.1, 26.3, 22.4; IR (film) 1717, 1702, 1635,
1612 cm-1; MS (EI) m/z 187.0991 (187.0997 calcd for C12H13NO).
Table 5, entry 25: (-)-49, 59% ee, [R]25D -32.1° (c 0.79, MeOH);
84.5, 64.9, 64.6, 49.4, 31.8, 29.4, 28.1; IR (CHCl3) 1660, 1626 cm-1
;
MS (EI) m/z 357.1560 (357.1576 calcd for C20H23NO5). Anal. Calcd
for C20H23NO5: C, 67.21; H, 6.49; N, 3.92. Found: C, 67.14; H,
6.52; N, 3.94.
entry 26: (+)-49, 25% ee, [R]25 +15.2° (c 0.79, MeOH).
Table 5, entry 10: 42% ee, [R]25 -11.8° (c 0.60, MeOH).
D
D
(R)- and (S)-1,2-Dihydro-1,3-dimethyl-2-oxo-3-(2-oxoethyl)-3H-
indole [(R)-and (S)-50]: a pale yellow oil; 1H NMR (300 MHz, CDCl3)
δ 9.52 (t, J ) 1.5 Hz, 1H), 7.28 (td, J ) 7.7, 1.2 Hz, 1H), 7.18 (dd, J
) 7.5, 0.7 Hz, 1H), 7.05 (td, J ) 7.6, 0.8 Hz, 1H), 6.88 (d, J ) 7.8
Hz, 1H), 3.26 (s, 3H), 2.99, 2.94 (app qd, J ) 17.2, 1.6 Hz, 2H), 1.42
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 198.7, 179.5, 143.1, 132.7,
128.3, 122.6, 122.4, 108.3, 50.5, 44.9, 26.4, 23.9; IR (film) 1716, 1702,
1635, 1615 cm-1; MS (CI) m/z 204.1014 (204.1024 calcd for C12H14-
NO2).
(-)- and (+)-1′,2′-Dihydro-1′-methyl-2′-oxo-4,4-dimethylspiro-
[cyclohex-2-ene-1,3′-3′H-indole] (43): a colorless solid; 1H NMR
(CDCl3, 500 MHz) δ 7.27 (t, J ) 7.8 Hz, 1H), 7.19 (d, J ) 7.4 Hz,
1H), 7.04 (t, J ) 7.5 Hz, 1H), 6.83 (d, J ) 7.7 Hz, 1H), 5.85 (d, J )
9.9 Hz, 1H), 5.15 (d, J ) 9.8 Hz, 1H), 3.21 (s, 3H,), 2.07 (ddd, J )
13.5, 9.5, 3.9 Hz, 1H), 1.98 (dddd, J ) 12.9, 9.3, 4.4, 1.6 Hz, 1H),
1.78-1.66 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 179.6, 143.0, 141.7, 134.5, 127.9, 123.7, 122.4, 122.3, 107.8,
49.5, 32.8, 31.0, 29.9, 29.5, 29.2, 26.3; IR (CHCl3) 1701, 1612 cm-1
;
Table 5, entry 27: 45% ee; entry 28: 38% ee.
MS (EI) m/z 241.1463 (241.1467 calcd for C16H19NO). Anal. Calcd
for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.47; H, 7.92;
N, 5.80.
(R)-3-(1,1-Dimethylethyl)-1,2-dihydro-1-methyl-2-oxo-3-(2-oxo-
ethyl)-3H-indole (51): a beige semisolid; 1H NMR (300 MHz, CDCl3)
δ 9.19 (d, J ) 2.6 Hz, 1H), 7.26 (td, J ) 7.7, 1.0 Hz, 1H), 7.12 (dd,
J ) 7.5, 0.8 Hz, 1H), 6.98 (td, J ) 7.5, 1.1 Hz, 1H), 6.90 (dd, J ) 7.7,
0.8 Hz, 1H), 3.23 (s, 3H), 3.19 (d, J ) 17.0 Hz, 1H), 3.03 (dd, J )
17.0, 2.6 Hz, 1H), 0.97 (s, 9H); 13C NMR (75 Mz, CDCl3) 199.1, 178.4,
144.4, 129.8, 128.1, 124.5, 121.6, 107.6, 53.9, 45.2, 36.3, 25.9, 24.9;
IR (neat, melted) 1728, 1708, 1611 cm-1. Anal. Calcd for C15H19-
NO2: C, 73.44; N, 5.71; H, 7.81. Found: C, 73.21; N, 5.69; H, 7.78.
Table 5, entry 29: 72% ee (determined by HPLC analysis of the
corresponding primary alcohol on a Chiralcel OD column, 9:1 hexane-
Table 5, entry 11: 72% ee, [R]25 +18.0° (c 0.61, MeOH); entry
D
12: 71% ee, [R]25 -17.9° (c 0.66, MeOH).
D
1′,2′-Dihydro-1′-methyl-2′-oxospiro[cyclohept-2-ene-1,3′-3′H-in-
dole] (45) and Its ∆3,4 and ∆4,5 Isomers. Anilide 16 (88.5 mg, 0.249
mmol) was cyclized with Pd-(R)-BINAP in the presence of PMP as
described for the formation of (-)-5 to give after repeated sgc (4:1
hexanes-EtOAc, four times; 5:1 hexanes-EtOAc, once) 30.3 mg
(54%) of a 93:7 mixture of 45 (88% ee) and its ∆4,5 isomer as a colorless
oil and 22.6 mg (40%) of the corresponding ∆3,4 isomer also as a
2-propanol); [R]24 -9.0° (c 0.75, benzene).
1
colorless oil: 45 H NMR (500 MHz, CDCl3) δ 7.28 (t, J ) 7.5 Hz,
D
1H), 7.28-7.25 (m, 1H), 7.05 (t, J ) 7.6 Hz, 1H), 6.83 (d, J ) 7.7
Hz, 1H), 6.03 (dt, J ) 11.7, 5.8 Hz, 1H), 5.30 (d, J ) 11.7 Hz, 1H),
(R)- and (S)-1,2-Dihydro-1-methyl-2-oxo-3-(2-oxoethyl)-3-phenyl-
3H-indole (52): a colorless semisolid; 1H NMR (300 MHz, CDCl3) δ

(E)-R,â-Unsaturated 2-Haloanilides and Analogues
J. Am. Chem. Soc., Vol. 120, No. 26, 1998 6487
9.53 (s, 1H), 7.34-7.23 (m, 7H), 7.10 (app t J ) 7.5 Hz, 1H), 6.93 (d,
J ) 7.8 Hz, H), 3.41 and 3.40 (ABq, J ) 2.5 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 198.6, 177.7, 144.0, 138.7, 131.0, 128.9, 127.8, 126.6,
124.6, 122.9, 108.7, 52.6, 50.7, 26.7. Anal. Calcd for C17H15NO2: C
76.95; H 5.70; N 5.28. Found: C 76.75; H 5.76; N 5.25.
Table 5, entry 31: 73% ee (determined by HPLC analysis of the
corresponding primary alcohol on a Chiralcel OJ column); Table 5,
entry 32: 35% ee of the other enantiomer.
DOEd through a GAANN Predoctoral Fellowship to D.J.P., and
from Merck, Pfizer, Roche Biosciences, and SmithKline Bee-
cham is gratefully acknowledged. NMR and mass spectra were
determined at Irvine using instruments acquired with the
assistance of NSF and NIH Shared Instrumentation Programs.
Supporting Information Available: Experimental proce-
dures and characterization data for new compounds not de-
scribed in the Experimental Section (20 pages, print/PDF). See
any current masthead page for ordering and Web access
instructions.
Acknowledgment. This research was supported NIH Grant
GM-30859 and the Green Cross Corporation. Additional support
from the National Science and Engineering Research Council
of Canada through a Postdoctoral Fellowship to B.B., the U.S.
JA980786P