Copper(II)-and palladium(II)-catalyzed enantioselective claisen rearrangement of allyloxy-and propargyloxy-indoles to quaternary oxindoles and spirocyclic lactones

Article abstract of DOI:10.1021/jo302039n

In this Article, a strategy to obtain highly enantioselective catalysts for the Claisen rearrangement of allyloxy-and propargyloxy-indoles is outlined. Ultimately, copper BOX and palladium BINAP or PHOX catalysts were discovered as superior in catalyzing Claisen rearrangements of allyloxy-or proparyloxy-substituted indoles to generate oxindoles bearing allyl-or allenyl-substituted quaternary centers. This method proved to be tolerant of a broad range of functional groups. Tandem reactions of the silyl-allene products provide rapid access to a variety of spirocyclic oxindoles in one operation.

Full text of DOI:10.1021/jo302039n

Article
pubs.acs.org/joc
Copper(II)- and Palladium(II)-Catalyzed Enantioselective Claisen
Rearrangement of Allyloxy- and Propargyloxy-Indoles to Quaternary
Oxindoles and Spirocyclic Lactones
Trung Cao, Elizabeth C. Linton, Joshua Deitch, Simon Berritt, and Marisa C. Kozlowski*
Department of Chemistry and Penn-Merck High Throughput Experimentation Laboratory, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: In this Article, a strategy to obtain highly enantio-
selective catalysts for the Claisen rearrangement of allyloxy-
and propargyloxy-indoles is outlined. Ultimately, copper BOX
and palladium BINAP or PHOX catalysts were discovered
as superior in catalyzing Claisen rearrangements of allyloxy- or
proparyloxy-substituted indoles to generate oxindoles bearing
allyl- or allenyl-substituted quaternary centers. This method
proved to be tolerant of a broad range of functional groups.
Tandem reactions of the silyl-allene products provide rapid
access to a variety of spirocyclic oxindoles in one operation.
available at the quaternary center. For example, ester/allyl
combinations, which map onto many natural products, are not
available in high enantioselectivity. By exploiting sigmatropic
rearrangements, we theorized that a number of structures could
be achieved that would be difficult or impossible to obtain via
other routes including ester/allyl combinations, generation of
two adjacent quaternary centers, and formation of allenes from
the propargyl alcohols.
INTRODUCTION
■
The oxindole framework bearing a C3-quaternary stereocenter
is a privileged heterocyclic motif, which is present in a large
number of biologically active natural products.1 Many of these
natural products, including physostigmine,2 flustramine B,3
pseudophrynaminol,4 and mollenine,5 contain an allyl chain at
the C3-position (Figure 1). This chain could easily be installed
in an asymmetric fashion utilizing Claisen rearrangement
methodology. Notably, syntheses have not been described for
mollenine and notamides,6 novel alkaloids derived from marine
sources, which incorporate this motif.
The oxindole moiety is also a popular fragment for drug
discovery, and several reports describe its incorporation into
compounds with potent biological activity (Figure 1).7−9 The
apparent clinical significance of the spirocyclic quaternary
center at the C3 position of oxindoles10 has led to a demand for
efficient methods for their enantioselective synthesis.11 The
topology of this moiety allows functionalization of all four faces
of a tetrahedron centered on the spirocyclic center, creating an
ideal environment for structural diversity.
To facilitate the synthesis of natural products and related
analogues for biological evaluation and structure−activity relation-
ships, catalytic asymmetric syntheses of oxindoles with a quaternary
center have been of intense interest (Figure 2).1e,2,11,12 For
example, Overman generated such oxindoles via an asymmetric
Heck reaction with very good enantioselectivity.13 Later, Fu
developed an enantioselective intramolecular acyl transfer of
benzofurans and indoles, which requires an unusual carbonate.14
Recognizing that oxindoles can be enolized readily, Trost
developed an asymmetric π-allylation to yield oxindole
variants.15 For most of these methods, several steps are needed
to prepare the precursors. Moreover, in all cases, N-masked
indoles are used. Also, not all substituent combinations are
The Claisen rearrangement of allyl vinyl ethers is a [π2s +
σ2s + π2s] sigmatropic isomerization process. This transforma-
tion is a key entry to generate the γ,δ-unsaturated carbonyl
moiety.16 Despite the utility of these compounds, the
development of asymmetric catalysts has proven difficult for
this transformation.17,18 As we have previously reported, we
identified palladium complexes that affect the asymmetric
catalytic Meerwein−Eschenmoser Claisen18a or Saucy−Marbet
Claisen18b rearrangements to produce a range of oxindoles
bearing a quaternary stereocenter. In this Article, we provide a
complete account of our development of allyloxy or propargyloxy
indoles as precursors for the generation of oxindoles and
spirocylic variants bearing a tetrasubstituted stereocenter using
palladium systems.
RESULTS AND DISCUSSION
■
We employed allyl- or propargyl-substituted indoles 3 or 4,
which were obtained from indole 1 and allylic or propargyl
alcohols 2 (Scheme 1).18,19 Although a few of these substrates
were found to rearrange spontaneously at low temperatures
(rt to 40 °C), care in the isolation provided indole substrates
that could be stored up to a year at −20 °C.
Received: September 20, 2012
Published: November 20, 2012
© 2012 American Chemical Society
11034
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Figure 1. Natural products and pharmaceutical agents incorporating an oxindole.
Figure 2. Catalytic asymmetric synthesis of oxindoles bearing a C3 quaternary stereocenter.
Scheme 1. Synthesis of Indole Series
Scheme 2. Claisen Rearrangement of 3-Nitrile Indole
the aim of identifying a catalyst that would activate the
substrate via interaction with the ethereal oxygen. The nitrile
served as an electron-withdrawing group that would decelerate
the Claisen rearrangement and allow isolation of 3a and 3b in
pure form.20 The substituents at C2′ are known to affect the
rate of the rearrangement, so both allyloxy and methallyloxy
groups were incorporated. Evaluation of C3-nitrile substituents
with representative Brønsted and Lewis acids revealed that
these catalysts did not facilitate the Claisen rearrangement.
1. Monodentate Indoles. The first substrates that were
investigated bore a nitrile at the C3-position (Scheme 2) with
11035
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
2. Bidentate Indoles. 2.1. Allyloxy Indoles. Because of the
lack of success with the monodentate substrate, an ester group
was added to the C3-position. It was envisioned that either a
Brønsted acid (BA) or a Lewis acid (LA) could coordinate to
both the sp3 oxygen of the allyl chain, as well as the sp2 oxygen
of a carbonyl substituent (Scheme 3), and that this double
activation would accelerate the reaction.
Scheme 5. Copper Complex Counterion and Ligand
Screening
Scheme 3. Coordination of Catalyst to a Bidentate Substrate
Scheme 4. Brønsted Acid Screening
dramatically affected the enantioselectivity. When copper
triflate was used with the tert-butyl bisoxazoline ligand L1,
only 34% ee was achieved. However, with the less-coordinating
hexafluoroantimonate counterion, the selectivity increased to
58% ee. This trend was consistent regardless of the ligand used,
with the hexafluoroantimonate copper complexes always giving
higher enantioselectivity. Apparently, substrate binding to the
Lewis acidic copper is weak; either the catalyzed reaction is
quicker with the more Lewis acidic species resulting in higher
enantioselectivity due to less competing thermal background
reaction or the more tightly bound complex brings the asymmetric
environment of the ligand into closer proximity of the reacting
partners, amplifying the intrinsic asymmetric induction. Overall,
the selectivity could be improved up to 81% ee with Cu(SbF6)2
and the indanol bisoxazoline L4.
For further optimization, a variety of solvents were evaluated
(Table 1). It was necessary to use distilled solvents as trace HCl
could catalyze the rearrangement.23 Dichloromethane allowed
complete conversion to product 5c with 81% ee (entry 1). 1,2-
Dichloroethane gave comparable results; however, when chloro-
form or toluene was used, both the selectivity and the conversion
were lower (entries 2−4). Interestingly, THF gave no conversion
to product either with (entry 6) or without catalyst (entry 5).
Because THF appears to inhibit the background reaction that
occurs in in CH2Cl2 at room temperature, it was thought that a
small amount of THF might inhibit the background reaction
while allowing the enantioselective rearrangement to proceed.
Unfortunately, any amount of THF resulted in no conversion to
product (entry 7). Last, acetonitrile caused decomposition of the
starting material (entry 8).
Brønsted Acid Catalyst Survey. Brønsted acid catalysts were
screened first (Scheme 4). Bisamidinium catalyst C121 gave
complete conversion and 16% enantiomeric excess, while 80%
conversion and racemic product were observed with
sulfonamide C2. Urea C3 also gave 80% conversion, with 6%
enantiomeric excess. The low selectivity issue arises due to the
competing background reaction, with 60% conversion being
observed without catalyst over the same time frame.
Lewis Acid Catalyst Survey. Lewis acid catalysts, which have
a much broader reactivity range, were investigated next. To
diminish the background reaction and allow a gauge of the
inherent selectivity of the catalysts, initial screens were
conducted with stoichiometric bisoxazoline copper complexes
(Scheme 5).22 The substitution on the oxazoline portion of
the ligand, as well as the counterion on the copper, both
With the copper complexes, the steric environment around
the coordinating carbonyl proved to be an important factor to
control the selectivity. Larger ester groups led to lower
selectivity (Scheme 6) with the ethyl and benzyl esters 5d
and 5e resulting in 79% ee and 73% ee, respectively. The
11036
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Table 1. Copper Catalyst Solvent Screening
Scheme 7. Effect of Methyl Ketone at C3 Position
a
entry
solvent
CH2Cl2
R
conv. (%)
t
ee (%)
1
2
3
4
indanol
indanol
indanol
indanol
100
100
35 min
35 min
4 h
81
78
Cl(CH2)2Cl
CHCl3
60
69
PhCH3
80
5 h
70
b
5
THF
SM
18 h
18 h
18 h
18 h
NA
NA
NA
NA
6
7
8
THF
t-Bu
SM
2:1 CH2Cl2/THF
MeCN
Ph
SM
t-Bu
decomp.
a
b
Conversion measured by TLC. No catalyst was used.
Scheme 6. Substrate Scope with Copper Indanol
Bisoxazoline
Scheme 8. Use of C3-Amide Derivative
generated by reaction with N-chlorosuccinimide and allyl alcohol.
Disappointingly, copper(II) was unable to promote the rearrange-
ment with high enantioselectivity. It appears that allylic strain (see
Scheme 8) destabilizes coordination mode 7, which is necessary
for good asymmetry transfer from the catalyst to the product.
To further optimize the rearrangement of the ester substrates,
a range of loadings of the copper species were investigated
(Table 2). When 200 mol % loading was used, there was no
improvement in enantioselectivity (entries 1,2). When the
loading was lowered to 50 mol %, almost complete conversion
was observed with only a small loss in enantioselectivity.
Decreasing the loading to 25 mol % lowered conversion (78%)
and selectivity (76% ee), indicating that thermal rearrangement
was intervening during the relatively slow turnover.
Because of poor turnover with substoichiometric copper(II),
additional metals were examined for superior turnover (Table 3).
The bisoxazoline metal complexes were screened as stoichiometric
promoters for the rearrangement with the goal of selectively
stabilizing the starting material complex 3c and destabilizing the
product−metal adduct 5c. Copper provided the highest
enantioselectivities and complete conversion. Both nickel and
zinc resulted in lower conversion to product, as well as lower
selectivity. Interestingly, when zinc was employed, the opposite
enantiomer of the product was formed, which is consistent with a
change from square planar to tetrahedral coordination geometry.24
Encouragingly, the palladium adduct exhibited reactivity at the
isopropyl ester 5f decreased the selectivity further to 65% ee.
The large substrate 5g, with a tert-butyl ester, provided only
42% ee. Conversely, the small methyl ester 5c gave the best
result with 81% ee.
It was hypothesized that replacing the methyl ester with a
methyl ketone 3h might improve the selectivity (Scheme 7) as
smaller esters afforded better enantioselectivities (Scheme 6).
Unfortunately, rearranged product 5h was not stable. The
methyl ketone was cleaved, presumably via a facile retro-Claisen
condensation of the more electrophilic ketone, affording only
product 6. In principle, this route to monosubstituted oxindoles
such as 6 could be subject to asymmetric induction using a
chiral protonation catalyst. However, this exchange of methyl
ketone for an allyl was not investigated further.
Installation of an amide at the 3-position of the indole
provided another possible substrate (Scheme 8). In a fashion
analogous to that of the ester series, the C3-amide was
11037
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Table 2. Catalyst Loading with Copper Indanol Complex
Scheme 9. Initial Screening of Diphosphine Palladium
Complexes
a
entry cat. loading (mol %) T (°C) conv. (%)
t
ee (%)
1
2
3
4
5
200
100
100
50
10
10
rt
100
90
10 min
5 h
82
80
81
77
76
100
93
35 min
2 h
rt
25
rt
78
2.5 h
a
Conversion measured by NMR.
Table 3. Metal Screening
a
entry
M
conv. (%)
t
ee (%)
1
2
3
4
5
CuCl2
CuBr2
ZnCl2
NiBr2
PdCl2
100
100
30
35 min
75 min
2 h
81
80
24
47
73
Scheme 10. Effect of Pd Counterion on Enantioselectivity
b
50
2 h
100
1 h
a
b
Conversion measured by TLC. Opposite enantiomer.
same level as the copper adduct, along with moderate levels of
selectivity (73% ee).
Palladium Catalysts. Attention turned to the palladium
complexes because palladium can accommodate a wider array
of ligands (diamines, aminophosphines, and diphosphines),
offering more opportunity for catalyst optimization. A number
of diphosphine ligands were screened (Scheme 9), building on
the promising 73% ee with [Pd(S,S)-Ind-box](SbF6)2. BINAP
(L5) gave a promising 45% ee and exceedingly fast reactions
(complete conversion to product in just 5 min at room
temperature). Lowering the temperature only slowed the rate of
conversion to product and did not increase the selectivity. More
sterically encumbered ligands such as tol-BINAP (L6) and xylyl-
BINAP (L7) were used without any appreciable change in the
enantioselectivity. DifluoroPhos (L8), which has a smaller bite
angle than that of BINAP, increased the selectivity to 56% ee.25
Finally, BIPHEP (L9) gave moderate selectivity.
a
Table 4. Effect of Pd Catalyst Loading on Enantioselectivity
Changing the palladium counterion did little to affect the
enantioselectivity. In the case of triflate or acetate, the product
formed very slowly (Scheme 10). Presumably, strongly coordinat-
ing counterions inhibit the coordination of the substrate.26
Lowering the loading to 20 mol % showed no drop in
selectivity, and complete conversion to product was observed in
10 min at room temperature (Table 4). Decreasing the loading
further to 5 mol % provided 5g with the same enantioselectivity
at 82% ee, and did not substantially reduce the rate.
entry
mol %
T (°C)
t (min)
ee (%)
1
2
3
4
100
20
20
5
0
rt
0
10
10
80
80
84
82
85
82
rt
Two proposed transition states (Figure 3), which are in accord
with those computed27 for the copper-catalyzed reactions of
Conversion measured by TLC.
a
11038
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Scheme 11. Substrate Scope with Palladium-BINAP Catalyst
Figure 3. Stereochemical model of the Pd-BINAP-catalyzed rearrange-
ment.
substrates containing a similar coordination array,17a,b illustrate
the C2-symmetric BINAP-derived catalyst coordinating to the
indole starting material 3j (the BINAP backbone is removed for
clarity).28 In TS2, there are steric interactions between the ester
and the pseudoequatorial phenyl group, as well as between the
allyl group and the pseudoequatorial phenyl group on the other
phosphorus center. These interactions suggest that increasing the
steric bulk of the ester might further destabilize TS2 and increase
the enantioselectivity.
To test this theory, a series of esters were screened using the
palladium-BINAP catalyst (Scheme 11). Notably, the selectivity
was improved when the steric bulk of the C3-ester increased, as
the isopropyl and tert-butyl esters (5f and 5g) of the methylallyl
derivative furnished the product in 63% ee and 85% ee,
respectively, relative to the 48% ee of the methyl ester (5c).
Similar results were seen with both the isopropyl and the benzyl
esters (5l and 5m) in the allyl series. Decreasing the steric bulk
at R1 on the allyl group also improved the selectivity, in
accordance with the above hypothesis. While the ethallyl
derivative 5k afforded only 35% ee, the allyl derivative 5j
provided a much higher 71% ee. The tert-butyl ester with allyl
substitution 5i gave the best selectivity with 89% ee. Moreover,
the turnover problems observed with copper catalysts were not
seen with the palladium catalysts.
Scheme 12. Crystal Structure of the Derivatized Oxindole
To understand how the catalyst conveys asymmetry in the
reaction, it was necessary to determine the absolute configura-
tion of the quaternary stereocenter that is formed during the
course of the reaction. In an effort to obtain an X-ray crystal
structure, attempts were made to synthesize a hydrazone
derivative of the oxindole product over two steps by sulfonylation
of the tert-butyl ester 5i and condensation with 2,4-
dinitrophenylhydrazine (2,4-DNPH) (Scheme 12). The trans-
esterified methyl ester 5′i was observed, rather than the expected
hydrazone. An X-ray crystal structure was obtained showing that
5′i was the (S)-configuration. All other structures were assigned
by analogy from this result.
substoichiometric catalyst loadings had been achieved, the
substrate scope of this reaction was limited. High enantio-
selectivity was only observed when unsubstituted allyl alcohol was
used, with the exception of compound 5g (Scheme 11). New
ligands were investigated to further optimize the reaction with the
aim of expanding the substrate scope. The phosphinooxazo-
line (PHOX) ligands were screened because they combine the
Although the goal of establishing a Meerwein−Eschenmoser
Claisen rearrangement with high enantioselectivity using
11039
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Scheme 13. Substrate Screening with PHOX Pd Catalysts
Scheme 14. Substrate Scope with t-BuPHOX Pd Catalyst
scaffolds of both the diphosphine ligands and the bisoxazoline
ligands (Scheme 13). Only moderate enantioselectivities were
observed with the phenyl- and benzyl-phosphinooxazoline
ligands (L10, L11). Indanol ligand L12, as well as the isopropyl
ligand L13, provided the product 5c in good selectivity. The
tert-butyl-phosphinooxazoline ligand L14 generated the highest
selectivity (89% ee).
tert-Butyl-phosphinooxazoline ligand afforded high selectiv-
ities over a range of substrates (Scheme 14). While methyl ester
with allyl alcohol 5j afforded the product in 83% ee, methyl allyl
alcohol 5c and ethyl allyl alcohol 5k provided 89% and 92% ee,
respectively. The enantioselectivity (91% ee) and yield (95%)
improved when the reaction was performed on a 1 mmol scale.
Contrary to results with the BINAP ligand, the use of the tert-butyl
ester 5g lowered both enantioselectivity and yield. Interestingly, the
smaller methyl ester provided high enantioselectivity regardless of
the electronics of the aromatic ring (5n−5p).
Scheme 15. [3,3′] versus [1′,3] Rearrangement
Mechanism. Because copper(II), zinc(II), nickel(II), and
palladium(II) complexes all promote the Meerwein−Eschenmoser
Claisen, a Lewis acid activation pathway seemed plausible.28
With the same ligand, the selectivity of copper(II) and
palladium(II) was virtually identical (Table 3, entries 1 and 5),
which is consistent with the square planar coordination
environments of these Lewis acids. As would be expected with a
large change in coordination environment, zinc(II), which forms
tetrahedral complexes, was much less selective (Table 3, entry 3).
The major difference between copper(II) and palladium(II) lies in
the turnover, which is ascribed to the larger size and weaker
O-coordinating ability of the palladium. To determine if reduced
palladium(0) was forming and causing to a π-allyl cation pathway,
a deuterium atom was installed on the allyl group of the indole
starting material 3q (Scheme 15). This substrate was subjected to
the reaction conditions, and only the [3,3′] rearranged product 5q
1
was observed by H NMR, resulting in 80% isolated yield and
92% ee.
A further study of the mechanism of the formation of
allyloxindole from the indole precursor was undertaken,
11040
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Scheme 16. Crossover Mechanism Experiment
Scheme 17. Comparison of t-BuPHOX Ligand with BINAP
Ligand
utilizing two different substrates with unique substitution on
the allyl and indole fragments (Scheme 16). If discrete π-allyl
species were forming, four products arising from both allyl
fragments combining with both indole fragments should be
observed. There is also literature precedent for alkene activation
with palladium(II) catalysts.29 However, these cases do not
possess an alternate strong coordination site for the palladium
as shown in Scheme 3. If reaction via alkene coordination was
occurring, substrates lacking the ester coordination group should
also be viable, which is not the case (Scheme 2 and ref 29b).
Finally, the Lewis acid activation28 models explain the sense
and trends in the stereochemcial induction (see Figure 3 and
discussion above). Overall, the evidence supports the concerted
Meerwein−Eschenmoser Claisen rearrangement illustrated in
Figure 3.
In summary, the palladium-catalyzed enantioselective
Meerwein−Eschenmoser Claisen rearrangement is a useful tool
to give access to oxindole products bearing an allyl-substituted
quaternary stereocenter. While the BINAP (L5) provided higher
selectivities with large esters and small allyl alcohols, tert-
butyl-phosphinooxazoline (L14) afforded the best selectivity
with the smaller C3-methyl ester and the larger allyl alcohols
(Scheme 17). The rearrangement has proven to be general, as
substrates with either electron-withdrawing or electron-donating
groups on the indole framework work well. In addition, catalyst
loadings as low as 5 mol % can be used. The absolute configura-
tions of the products were established through crystal structures
(see the Supporting Information) and are in accord with the
proposed stereochemical models.
2.2. Propargyloxy Indoles. With the goal of expanding this
methodology from allyl ethers to propargyl ethers, we investi-
gated the Saucy−Marbet rearrangement. Very few catalytic
asymmetric methods of forming allenes exist,30 as most
transformations to allenes commence with enantioenriched
precursors.31 Notably, enantioenriched allenes have many
potential applications.32 In asymmetric catalysis, the trans-
formations of propargyl vinyl ethers to provide β-substituted
allenyl carbonyls remain highly challenging, as evidenced by
the fact that no catalytic asymmetric Saucy−Marbet Claisen re-
arrangements were reported prior to our effort.18,33 Examina-
tion of simple models revealed that the alkyne sp centers
significantly perturb the sigmatropic rearrangement transition
state. In addition, cylindrically symmetric alkyne gives no
opportunity for facial discrimination. On the basis of the
success of palladium catalysts for the transformation of allyloxy
indoles to allyl oxindoles, a stereochemical model of the
Pd(t-BuPHOX) catalyst with the propargyl substituted indoles
was proposed (Figure 4). This model suggested that the ester
group, which most likely coordinates to the palladium metal,
could interact with larger alkyne terminal substituents,
suppressing the pathways to one of the enantiomers.
Palladium Catalyst Survey. In line with this hypothesis,
increasing the size of the terminal alkyne substituents did result
in enhanced selectivity with the Pd(t-BuPHOX) catalyst
(Table 5, entries 1−5). In particular, very high levels of enantio-
selectivity (96−98% ee) were observed with alkynes having
ortho-substituted aryl groups at R2. In addition, the reactivity of
these compounds with the catalyst was significantly higher.
For example, complete conversion to product was observed in
8 h at −15 °C with just 5 mol % catalyst loading (entries 5−9).
Other alkynes with large groups, such as TMS, tert-butyl, and
N-methyliminodiacetic acid (MIDA) boronates, provided lower
selectivity (entries 10−12).
In an effort to improve the enantioselection of nonaryl alkynes,
alternative ligands were evaluated. Trends similar to Pd(t-
BuPHOX) catalyst (i.e., better selectivity for large substituents)
were also observed with BINAP-derived complexes (Table 6).
Methyl ester with propargyl alcohol 4d afforded 4% ee (entry 2),
while tert-butyl-substituted propargyl alcohol 4k provided 76% ee
(entry 3). Among a series of biaryl diphosphine ligands,
DifluoroPHOS proved the most effective, providing tert-butyl-
substituted allene 8k with 90% yield and 86% ee (entry 4). Most
surprising was the poor selectivity of the TMS-substituted alkyne
(entry 6). A significant improvement with a return to BINAP
(44% vs 77% ee, entries 6−7) suggested that trace fluoride from
the DifluoroPHOS interferes with the rearrangement. While
elevated temperature (rt vs 0 °C) allowed for good conversion of
TBS substrates (entry 9), it also led to lower selectivity, which
limited the utility of this system for large silyl-substituted terminal
alkynes. However, this problem could be solved by modifying the
reaction solvent. A screen of CH2Cl2, C6H5CF3, THF, toluene,
C6H5Cl, and several mixtures thereof revealed that a toluene−
C6H5Cl mixture afforded good conversion and enantioselectivity
(89% ee, entry 10) with the TBS substrate.
11041
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Figure 4. Proposed transition states with the t-BuPHOX Pd catalyst.
Table 5. Substrate Scope with Palladium t-BuPHOX
Table 6. Diphosphine Ligand Screening in the
Saucy−Marbet Rearrangement
mol %
cat.
T
(°C)
yield
(%)
ee
(%)
entry
4
R1
R2
t
a
1
2
a
b
c
d
e
f
t-Bu
H
20
20
20
20
5
0
0
10 min
15 min
10 min
15 min
8 h
100
100
100
100
96
0
4
a
a
a
t-Bu Me
3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
0
14
45
78
98
96
98
98
14
45
70
4
Me
Ph
0
5
−15
−15
−15
−15
−15
0
6
o-MePh
o-BrPh
1-Nap
5
8 h
95
entry
L
4
R2
mol % cat.
t
yield (%) ee (%)
7
g
h
i
5
8 h
93
8
5
8 h
95
1
2
L5
L5
L5
L8
L15
L8
L5
L5
L5
L5
c
H
20
20
10 min
30 min
2 d
100
100
40
8
4
9
o-MeOPh
TMS
5
8 h
90
d
k
k
k
j
Me
10
11
j
20
20
20
90 min
2 d
15
3
t-Bu
t-Bu
t-Bu
TMS
TMS
TMS
TBS
20
76
86
83
44
77
60
78
89
a
k
l
t-Bu
0
100
60
4
100
100
100
100
20
10 h
10 h
10 h
4 h
90
b
12
MIDA-B
45
2 d
5
90
a
b
6
95
Conversion (%) measured by TLC. MIDA boronate; see ref 34.
7
j
90
Solvent: 1:5:5 MeCN:C6H5Cl:CH2Cl2.
8
j
4 d
100
100
90
a
b
9
m
m
100
20
14 h
5 d
Gratifyingly, the Pd-(R)-BINAP complex afforded high sel-
ectivities with a range of TES- or TBS-substrates (Table 7).
Both electron-withdrawing and electron-donating groups were
tolerated on the indole framework. However, lower catalyst
loadings translated into unacceptably long reaction times and
lower enantioselectivity. To maintain the enantioselectivity for
a 5 mol % catalyst reaction, we discovered that degassing of
solvents was critical (Table 7, entry 4). To increase the rate of
this reaction, a similar diphosphine ligand bearing an electron-
withdrawing group was theorized to result in a more Lewis-
acidic and reactive catalyst. BIPHEP (L9, entry 5) was indeed
better in terms of reaction time but worse than BINAP (L5,
entry 4) in terms of enantioselectivity. The (R)-configuration of
the products was established through crystal structure (see the
Supporting Information).
10
TBS
a
b
Room temperature. Reaction condition: 1:1 C6H5Cl:C6H5CH3 at
room temperature.
for the allyloxy substrates (see Scheme 16), no crossover was
observed in the reaction, and the products arising from a [3,3′]-
sigmatropic rearrangement were isolated in high isolated yield
and enantioselectivity. This result ruled out a stepwise ionic
mechanism and confirmed a concerted Saucy−Marbet Claisen
rearrangement to generate the enantioenriched allenes.
Parallel Microscale Screening. The main drawback with the
palladium catalysts remained the long reaction times. In an
attempt to resolve this issue, a number of different metals
were complexed with BINAP and examined (Table 8).
Although 100 mol % catalyst was used, the reactions with Ag,
Cu, Pt were very slow and resulted in decomposition (entries 1−3).
Among metal complexes, Ni catalyst gave highest selectivity, but
poor turnover (entries 4,5). On the other hand, the reaction
Mechanism. A further study of the mechanism of the
formation of allene 8 from 4 was undertaken by utilizing two
different substrates, each containing unique propargyl and
indole fragments, in one reaction (Scheme 18). As was the case
11042
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Using 1 mL vials with 100 μL reaction volumes at a 0.1 M
concentration, 192 chiral mono- and bidentate phosphine ligands
were screened in 96-well plates. A control experiment on larger
scale showed that the AgCl formed during the generation of the
gold catalyst did not affect the enantioselectivity; this result was
crucial as it is very difficult to remove the AgCl precipitate at the
microscale level. However, we were disappointed with the poor
selectivity of substrates (R2 = TBS, 0−67% ee) seen with either
Au(III) or Au(I) catalysts. Use of a larger silyl group (TIPS,
Table 9, entry 4) or smaller groups (TMS and Me, entries 6−8)
did not result in retention of the selectivity. Unfortunately, the
enantioselectivity could not be improved using different solvents
(entry 3) or counteranions (entry 5). As a result, we determined
that the palladium(II) catalyst is the most efficient catalyst for the
Saucy−Marbet Claisen rearrangement, providing both sufficient
reactivity and high enantioselectivity.
2.3. Spirocyclization with Propargyloxy Indoles. Higher
temperatures (40 °C vs rt) were required when the optimized
conditions using catalytic palladium were applied to the larger
TIPS substrates. Under these conditions, an entirely different
product, spirocyclic lactone 9s, was observed as the major
product (eq 1). Only a few examples of the racemic, saturated
versions of these spirooxindoles have been reported.7,36
Because of the broad utility of tandem reactions and the
interesting structures of the spirocyclic lactones, further study
of this tandem cyclization was undertaken.
Table 7. Substrate Scope in the Saucy−Marbet
Rearrangement
entry
4
R1
R2
R3
t (d) yield (%)
ee (%)
1
2
3
4
5
6
7
8
n
m
o
o
o
p
q
r
Me
Me
Et
TES
TBS
TBS
TBS
TBS
TBS
TBS
H
H
6
5
78
90
87
76
65
82
91
85
90
89
90
7-Me
7-Me
7-Me
5-OMe
7-OMe
5-Br
5
a
Et
10
6
90
ab
,
Et
86
93
93
90
Et
5
Et
6
Et
TBS
6
a
b
5 mol % L*Pd(SbF6)2. BIPHEP L9 was used.
Scheme 18. Mechanism Study
To determine the cause of the cyclization, the allene was
investigated as a potential intermediate (Figure 5). Notably, the
cyclization is not catalyzed by Brønsted acid, and the Pd
catalyst is necessary to generate the spirolactone from the allene
(Figure 5). Specially, TIPS-substituted 8s (89% ee) was isolated
at lower temperature and then resubjected to the reaction con-
ditions, resulting in full conversion to 9s (90% ee). Hypothesiz-
ing that the spirocyclic compounds 9 arose from hydration of
allenes 8 and subsequent Lewis acid-induced cyclization, β-silyl
ketone 10 was generated (see below). Upon subjection of this
ketone to the palladium catalyst, the spirocyclic lactone 9o was
obtained as the sole product.
Table 8. Metal Screening
entry
M
R2
cat. mol %
t
yield (%)
ee (%)
We also observed that nonsilyl substrates reluctantly formed
the spirolactone. The mechanism most consistent with all of
the data is the formation of allene 8 followed by hydration
and a palladium-catalyzed cyclization to generate lactone 9
(Scheme 19). A key component of this mechanism is carboca-
tion intermediate 11, which is stabilized via the β-silyl effect,37
and explains why nonsilyl substrates cyclize slowly.
1
2
3
4
5
6
Ag(I)
t-Bu
t-Bu
t-Bu
t-Bu
TIPS
100
100
100
100
100
20
4 d
4 d
2 d
4 d
4 d
2 h
0
0
NA
NA
NA
87
Cu(II)
Pt(II)
Ni(II)
Ni(II)
Au(III)
decomp.
30
a
90
66
b
TBS
b
100
60
a
Temperature: 45 °C. R3 = 5-MeO. Reaction conditions: Au(III)
To selectively generate the allene 8 at elevated temperature
(vs spirocyclic lactone 9), efforts were directed at removing
trace water and acid from the reaction mixtures (Table 10).
Water absorbents such as 3 or 4 Å MS, MgO, and MgSO4 were
used, which stopped the cyclization process to some extent
(entries 1−4). It was exciting to find that the use of 2,4,6-tri-
tert-butylpyridine or (TMEDA)Zn(SbF6)2 prevented the
cyclization entirely (entries 5 and 7).
catalyst, C6H5Cl, 0 °C.
with Au(III) proceeded at a much faster rate but with modest
selectivity (entry 6).35
Encouraged by the reactivity of the gold(III) catalyst (Table 9,
entries 1 and 3), we undertook a parallel microscale screen
with resources that became available at this point in the project.
11043
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Table 9. Gold Catalyst Optimization
entry
n
X
R1
R2
R3
T (°C)
t
conv. (%)
ee (%)
−
−
−
−
1
2
3
4
5
6
7
8
3
1
3
3
3
3
3
1
SbF6
SbF6
SbF6
SbF6
Me
Me
Me
Me
Me
i-Pr
Me
Me
TBS
TBS
TBS
TIPS
TIPS
TMS
Me
5-MeO
rt
rt
0
2 h
100
100
100
100
50
60
47
5-MeO
3 h
6 h
a
5-MeO
60
H
H
H
H
H
rt
rt
0
18 h
36
10
6
−
BF4
14 h
−
SbF6
SbF6
SbF6
1 h
100
100
100
−
−
0
30 min
30 min
3
Me
0
7
a
Solvent: C6H5Cl.
Table 10. Additives Screening
entry
additives
1 equiv of MgO
yield (%)
8s:9s
1
2
3
4
65
85
1:0.8
1:4.4
NA
1 equiv of MgSO4
MS 3 Å or 4 Å
0−5
100
NaHCO3
1:2.2
a
5
10 mol % tri-tert-butylpyridine
10 mol % N(TMS)3
10 mol % Zn(TMEDA)(SbF6)2
80 (10 d)
50 (10 d)
55
1:0 (82% ee)
6
NA
1:0 (94% ee)
a
7
a
30 mol % palladium catalyst.
Table 11. Tandem Rearrangement-Cyclization
Figure 5. Formation of the spirocyclic lactone.
Scheme 19. Proposal Mechanism for the Formation of
Spirocyclic Lactones
yield
(%)
ee
a
entry
4
R1
Me
R2
R3
t (d) solvent
(%)
b
1
2
3
4
5
6
7
8
s
TIPS
TIPS
TIPS
TIPS
H
H
H
H
4.5
4
C
C
C
C
B
A
C
B
B
78
90
90
87
92
96
91
92
92
86
t
Et
95
90
95
93
81
90
82
95
u
v
CH2CF3
Bn
4
4
w
x
Et
TIPS 7-Me
TIPS 5-OMe
TIPS 7-OMe
TIPS 5-Br
6
Et
5
y
Et
6
z
Et
6
c
9
m
Me
TBS
H
5
a
Solvents: (A) CH2Cl2, (B) 1:1 C6H5Cl:C6H5CH3, (C) C6H5Cl.
Performed with 0.5 mmol of substrate. Reaction conducted at room
b
c
temperature.
In line with the proposed mechanism (Scheme 19), addition
of water shifted the reaction outcome entirely to the spiro-
lactone 9. A range of substrates was readily transformed to the
corresponding spirooxindole lactones (Table 11). Substrates
with different esters or indole substituents were well tolerated,
11044
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
acetone-d6 2.05 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
broad, m = multiplet), coupling constants, and number of protons.
Mass spectra were obtained from a TOF mass spectrometer with an
ionization mode of either CI or ES. Optical rotations are reported as
follows [α]23 (c g/mL × 100, solvent).
providing the lactone in good yields and enantioselectivities.
Reactions on a larger scale also proceeded well (Table 11, entry 1).
The allenyl products were found to be useful in a number of
transformations (Scheme 20). Hydration of the allene 8o with
RepresenDtative Procedure (A) for Installation of an Allyl
Alcohol to Indole Substrates. Methyl 2-(2-Methylallyloxy)-1H-
indole-3-carboxylate (3c). To a flame-dried round-bottom flask
was added methyl indole-3-carboxylate (3.0 g, 17.13 mmol). CH2Cl2
(15 mL) was added, and upon cooling to 0 °C, distilled 1,4-
dimethylpiperazine (1.29 mL, 9.60 mmol) and recrystallized
N-chlorosuccinimide (2.52 g, 19.02 mmol) were added. The resulting
solution was stirred at 0 °C for 2 h. In a separate flame-dried round-
bottom flask, methallyl alcohol (2.9 mL, 34.26 mmol) and trichloro-
acetic acid (0.67 g, 4.11 mmol) were dissolved in CH2Cl2 (15 mL).
The solution was cooled to 0 °C and transferred via cannula to the
indole solution. This mixture was stirred for 2 h at 0 °C, at which time
the reaction mixture was concentrated under vacuum. It was then
loaded onto a base-washed SiO2 column (1% Et3N, 24% EtOAc, 75%
hexanes) and eluted with 25% EtOAc/hexanes to afford 3c (2.5 g) in
Scheme 20. Transformations of Allenyl Compounds
1
60% yield as a white solid: mp 92−94 °C; H NMR (500 MHz,
CDCl3) δ 8.63 (bs, 1H), 8.03 (d, J = 7.7 Hz, 1H), 7.23−7.14 (m, 3H),
5.18 (s, 1H), 5.05 (s, 1H), 4.81 (s, 2H), 3.93 (s, 3H), 1.86 (s, 3H); 13C
NMR (90 MHz, THF-d8) δ 164.5, 156.9, 141.4, 131.0, 127.2, 121.5,
121.4, 121.1, 113.1, 110.6, 89.9, 76.8, 49.9, 19.0; IR (film) 3231, 2949,
1660, 1552, 1475 cm−1; HRMS (ES) m/z = 268.0949 calcd for
C14H15NO3Na [MNa]+, found 268.0957.
2-(Allyloxy)-1H-indole-3-carbonitrile (3a). Following the general
procedure, compound 3b was obtained in 38% yield. Because of the
difficulty in separating compound 3a from the indole-3-nitrile, the
isolated yield was calculated from the mixture of compound 3a and
indole-3-nitrile. As the consequence, compound 3a was only assessed
by H NMR experiment and mass spectrum. H NMR (500 MHz,
CDCl3) δ 8.53 (bs, 1H), 7.55−7.53 (m, 1H), 7.26−7.14 (m, 3H), 5.54
(dd, J = 1.2, 17.2 Hz, 1H), 5.40 (dd, J = 1.1, 10.5 Hz, 1H), 5.10 (dt, J =
1.3, 5.5 Hz, 2H); HRMS (CI) m/z = 199.0871 calcd for C12H11N2O
[MH]+, found 199.0878.
Hg(O2CCF3)2 provided α-silyl ketone 10. This ketone could
easily undergo Brook rearrangement to form silyl enol ether 12
or cylization to form lactone 9o. The silyl group on 8n was
effectively removed by TBAF to provide the simplest congener
8c, a compound that was not directly accessible with good
selectivity via the Saucy−Marbet Claisen rearragement (see
Table 5, entry 3).
1
1
CONCLUSION
■
2-(2-Methylallyloxy)-1H-indole-3-carbonitrile (3b). Following the
general procedure (A), 3b (0.056 g, 0.26 mmol) was obtained in 38%
yield as a white solid: mp 104−106 °C; 1H NMR (500 MHz, CDCl3)
δ 8.05 (bs, 1H), 7.58 (d, J = 3.7 Hz, 1H), 7.24−7.18 (m, 3H), 5.20 (s,
1H), 5.10 (s, 1H), 5.03 (s, 2H), 1.89 (s, 3H); 13C NMR (90 MHz,
THF-d8) δ 157.0, 139.7, 130.1, 127.3, 121.7, 121.1, 117.4, 114.8, 113.1,
110.5, 107.7, 75.0, 18.3; IR (film) 3223, 3173, 2926, 2212, 1563, 1471
cm−1; HRMS (CI) m/z = 213.1028 calcd for C13H13N2O [MH]+,
found 213.0994.
Ethyl 2-(2-Methylallyloxy)-1H-indole-3-carboxylate (3d). Follow-
ing the general procedure (A), 3d (0.06 g, 0.23 mmol) was obtained in
47% yield as beige solid: mp 90−91 °C; 1H NMR (500 MHz, CDCl3)
δ 9.16 (bs, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.24−7.12 (m, 3H), 5.15 (s,
1H), 5.00 (s, 1H), 4.77(s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.81 (s, 3H),
1.47 (t, J = 7.1 Hz, 3H); 13C NMR (90 MHz, THF-d8) δ 164.0, 156.8,
141.4, 131.0, 127.3, 121.4, 121.3, 121.2, 113.0, 110.5, 90.2, 76.9, 58.9,
19.1, 14.7; IR (film) 3231, 2980, 1660, 1552, 1471 cm−1; HRMS (CI)
m/z = 260.1287 calcd for C15H18NO3 [MH]+, found 260.1299.
Benzyl 2-(2-Methylallyloxy)-1H-indole-3-carboxylate (3e). Fol-
lowing the general procedure (A), 3e (0.073 g, 0.23 mmol) was
obtained in 45% yield as a brown oil: 1H NMR (500 MHz, CDCl3) δ
8.30 (bs, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.40−7.31 (m, 4H), 7.23−7.14
(m, 4 H), 5.41 (s, 2H), 5.15 (s, 1H), 5.05 (s, 1H), 4.81 (s, 2H), 1.85
(s, 3H); 13C NMR (90 MHz, THF-d8) δ 163.9, 157.1, 141.2, 138.4,
131.1, 128.6, 128.3, 127.9, 127.3, 121.6, 121.4, 121.1, 113.2, 109.9,
89.7, 76.7, 64.9, 19.1; IR (film) 3250, 2926, 1660, 1552, 1475, 1455
cm−1; HRMS (ES) m/z = 344.1263 calcd for C20H19NO3Na [MNa]+,
found 344.1270.
In this Article, highly enantioselective catalytic processes are
described for the Meerwein−Eschenmoser and Saucy−Marbet
Claisen rearrangements using BINAP or t-BuPHOX palladium
catalysts to construct a range of oxindoles bearing an allyl- or
allenyl-substituted quaternary center. Mechanistic evidence firmly
established the intermediacy of a [3,3′]-sigmatropic rearrange-
ment versus ionic or stepwise processes. Indole substrates with
functional groups at different positions can be utilized, which
allow for further functionalization of the resultant oxindole
products. Tandem reactions of silyl-allene indoles provide rapid
access to a variety of spirocyclic oxindoles in one operation.
In summary, a wide range of structurally rich chiral oxindoles is
readily accessible via the catalytic transformations described
herein.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all nonaqueous
reactions were carried out under an atmosphere of dry N2 in dried
glassware. When necessary, solvents and reagents were dried prior to
use. THF was distilled from sodium benzophenone ketyl. CH3CN,
CH2Cl2, TMEDA, and toluene were distilled from CaH2. The
alcohols38 and some indole precursors17−19,39 were prepared following
the literature protocols.
When necessary, the column was prewashed with 1% Et3N in the
eluent system. Enantiomeric excesses were determined using analytical
high performance liquid chromatography (HPLC) or supercritical
fluid chromatography (SFC) with UV detection at 254 nm, using
analytical OD, AS AD, IA, OJ-H columns (0.46 cm × 25 cm).
Chemical shifts are reported in ppm from tetramethylsilane (0 ppm)
or from the solvent resonance (CDCl3 7.26 ppm, THF-d8 3.58 ppm,
Isopropyl 2-(2-Methylallyloxy)-1H-indole-3-carboxylate (3f). Fol-
lowing general procedure (A), 3f (0.191 g, 0.70 mmol) was obtained
1
in 55% yield as a white solid: mp 88−90 °C; H NMR (500 MHz,
CDCl3) δ 8.36 (bs, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.25−7.12 (m, 3H),
11045
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
5.31−5.28 (m, 1H), 5.19 (s, 1H), 5.06 (s, 1H), 4.83 (s, 2H), 1.88 (s,
3H), 1.43 (d, J = 6.2 Hz, 6H); 13C NMR (90 MHz, THF-d8) δ 163.7,
156.8, 141.4, 130.9, 127.4, 121.4, 121.3, 121.2, 113.0, 110.5, 90.5, 76.8,
65.9, 22.2, 19.1; IR (film) 3227, 2980, 2937, 1656, 1552, 1471, 1374
cm−1; HRMS (ES) m/z = 296.1263 calcd for C16H19NO3Na [MNa]+,
found 296.1268.
δ 8.36 (bs, 1H), 8.01 (d, J = 7.0 Hz, 1H), 7.25−7.13 (m, 3H), 6.15−
6.02 (m, 1H), 5.46 (dd, J = 17.2, 1.4 Hz, 1H), 5.33 (dd, J = 10.4, 1.2
Hz, 1H), 4.92 (m, 2H), 1.66 (s, 9H); 13C NMR (90 MHz, THF-d8) δ
163.9, 156.7, 134.0, 130.9, 127.4, 121.4 (2), 121.3, 117.7, 110.6, 92.1,
81.6, 74.6, 28.6; IR (film) 3229, 2981, 2881, 1661, 1552, 1468, 1367,
1251, 1174, 1097 cm−1; HRMS (ES) m/z = 274.1443 calcd for
C16H20NO3 [MH]+, found 274.1435.
tert-Butyl 2-(2-Methylallyloxy)-1H-indole-3-carboxylate (3g). Fol-
lowing the general procedure (A), 3g (0.12 g, 0.418 mmol) was
obtained in 34% yield as a pale yellow solid: mp 105−107 °C; H
Isopropyl 2-(Allyloxy)-1H-indole-3-carboxylate (3l). Following the
general procedure (B), 3l (0.15 g, 0.59 mmol) was obtained in 80%
yield as an off-white oil: 1H NMR (300 MHz, CDCl3) δ 8.22 (bs, 1H),
8.05 (d, J = 7.0 Hz, 1H), 7.25−7.19 (m, 3H), 6.18−6.05 (m, 1H), 5.49
(ddd, J = 1.4, 2.9, 17.2 Hz, 1H), 5.36 (ddd, 1.4, 2.9, 10.4 Hz, 1H), 5.35
(septet, J = 6.3 Hz, 1H), 4.96 (ddd, J = 1.3, 2.7, 5.7 Hz, 2H), 1.42 (d,
J = 6.3 Hz, 6H); 13C NMR (90 MHz, THF-d8) δ 163.9, 156.9, 133.8,
131.5, 127.4, 121.5 (2), 121.3, 117.7, 110.7, 90.9, 74.4, 66.2, 22.3; IR
(film) 3229, 2981, 2935, 1738, 1661, 1552, 1468, 1375, 1244, 1097
cm−1; HRMS (ES) m/z = 260.1287 calcd for C15H18NO3 [MH]+,
found 260.1281.
1
NMR (500 MHz, CDCl3) δ 8.20 (bs, 1H), 7.96 (d, J = 8.7 Hz, 1H),
7.15−7.08 (m, 3H), 5.13 (s, 1H), 5.01 (s, 1H), 4.77 (s, 2H), 1.82 (s,
3H), 1.60 (s, 9H); 13C NMR (90 MHz, THF-d8) δ 163.8, 156.6, 141.0,
129.9, 127.4, 121.2 (2), 121.1, 113.1, 110.4, 91.6, 78.6, 76.8, 28.6, 19.1;
IR (film) 3237, 2976, 1656, 1552, 1459, 1366 cm−1; HRMS (ES) m/z
= 310.1419 calcd for C17H21NO3Na [MNa]+, found 310.1411.
Methyl 2-(2-Methylenebutoxy)-1H-indole-3-carboxylate (3k).
Following the general procedure (A), 3k (0.257 g, 0.99 mmol) was
1
obtained in 43% yield as a yellow oil: H NMR (300 MHz, CDCl3) δ
8.30 (bs, 1H), 8.04 (d, J = 7.4 Hz, 1H), 7.26−7.15 (m, 3H), 5.23 (s,
1H), 5.09 (s, 1H), 4.89 (s, 2H), 3.93 (s, 3H), 2.23 (q, J = 7.0 Hz, 2H),
1.13 (t, J = 7.4 Hz, 3H); 13C NMR (90 MHz, THF-d8) δ 165.1, 157.5,
147.4, 131.5, 127.7, 122.0, 121.9, 121.6, 111.8, 111.1, 90.4, 76.4, 50.4,
26.6, 12.5; IR (film) 3229, 2966, 2881, 1668, 1552, 1468, 1352, 1267
cm−1; HRMS (ES, negative ion) m/z = 258.1130 calcd for C15H16NO3
[M − H]−, found 258.1123.
Benzyl 2-(Allyloxy)-1H-indole-3-carboxylate (3m). Following the
general procedure (B), 3m (0.121 g, 0.39 mmol) was obtained in 66%
yield as a yellow oil: 1H NMR (360 MHz, THF-d8) δ 10.87 (bs, 1H),
8.07 (m, 1H), 7.53 (d, J = 7.3 Hz, 2H), 7.37−7.20 (m, 4H), 7.11−7.06
(m, 2H), 6.14−6.04 (m, 1H), 5.45 (dd, J = 1.6, 17.2 Hz, 1H), 5.39 (s,
2H), 5.24 (dd, J = 1.3, 10.5 Hz), 4.92 (m, 2H); 13C NMR (90 MHz,
THF-d8) δ 164.1, 157.2, 138.4, 133.5, 131.2, 128.7, 128.2, 128.0, 127.3,
121.7, 121.6, 121.2, 118.0, 110.8, 90.1, 74.2, 64.9; IR (film) 3229,
3090, 3035, 2950, 2881, 1661, 1552, 1460, 1352, 1259, 1213 cm−1;
HRMS (ES) m/z = 308.1287 calcd for C19H18NO3 [MH]+, found
308.1285.
Methyl 2-(1-Deutero-2-methylenebutoxy)-1H-indole-3-carboxyl-
ate (3q). Following the general procedure (A), 3q (0.036 g, 0.14
1
mmol) was obtained in 17% yield as a yellow resin: H NMR (300
MHz, CDCl3) δ 8.22 (bs, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.26−7.16
(m, 3H), 5.23 (t, J = 1.1 Hz, 1H), 5.09 (s, 1H), 4.86 (s, 1H), 3.91 (s,
3H), 2.23 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (90
MHz, THF-d8) δ 164.5, 157.0, 147.0, 131.1, 127.3, 121.5, 121.4, 121.2,
111.5, 110.6, 90.0, 75.8 (t, J = 22.3 Hz), 49.9, 26.2, 12.3; IR (film)
3229, 3090, 2935, 2881, 1668, 1552, 1468, 1328, 1244 cm−1; HRMS
(ES) m/z = 283.1169 calcd for C15H16DNO3Na [MNa]+, found
283.1165.
2-(Allyloxy)-N,N-dimethyl-1H-indole-3-carboxamide (7). Follow-
ing the general procedure (A), compound 7 (0.145 g, 0.59 mmol) was
obtained in 59% yield as a beige solid: 1H NMR (500 MHz, CDCl3) δ
8.85 (bs, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.07
(m, 2H), 5.94 (m, 1H), 5.32 (d, J = 17.0, Hz, 1H), 5.24 (d, J = 10.5
Hz, 1H), 4.65 (d, J = 5.5 Hz, 2H), 3.11 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 167.2, 150.2, 132.5, 129.9, 126.3, 120.9, 120.7, 119.0, 118.6,
110.3, 91.2, 73.1, 38.6; IR (film) 3460, 3182, 3066, 2943, 2765, 1776,
1707, 1591, 1514, 1468, 1429, 1352, 1182 cm−1; HRMS (ES) m/z =
245.1290 calcd for C14H17N2O2 [MH]+, found 245.1285.
Methyl 2-(2-Methylallyloxy)-5-methoxy-1H-indole-3-carboxylate
(3n). Following the general procedure (B), 3n (0.03 g, 0.11 mmol)
1
was obtained in 22% yield as an off-white oil: H NMR (300 MHz,
CDCl3) δ 8.44 (bs, 1H), 7.59 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.78
(d, J = 8.6 Hz, 1H), 5.19 (s, 1H), 5.06 (s, 1H), 4.79 (s, 2H), 3.90 (s,
3H), 3.83 (s, 3H), 1.89 (s, 3H); 13C NMR (90 MHz, THF-d8) δ
164.6, 157.1, 156.3, 141.5, 128.2, 125.6, 113.1, 111.2, 110.1, 104.2,
90.2, 76.8, 55.4, 49.9, 19.1; IR (film) 3244, 2950, 1668, 1591, 1552,
1468, 1352, 1274, 1205 cm−1; HRMS (ES) m/z = 298.1055 calcd for
C15H17NO4Na [MNa]+, found 298.1066.
Methyl 2-(2-Methylallyloxy)-5-bromo-1H-indole-3-carboxylate
(3o). Following the general procedure (B), 3o (0.07 g, 0.22 mmol)
1
was obtained in 55% yield as an off-white oil: H NMR (300 MHz,
CDCl3) δ 8.23 (bs, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.26 (m, 1H), 7.09
(d, J = 8.5 Hz, 1H), 5.20 (s, 1H), 5.10 (s, 1H), 4.85 (s, 2H), 3.93 (s,
3H), 1.90 (s, 3H); 13C NMR (90 MHz, THF-d8) δ 164.2, 157.6, 141.1,
134.6, 129.1, 124.3, 123.5, 115.1, 113.4, 112.4, 89.7, 76.8, 50.7, 19.1; IR
(film) 3221, 2950, 1668, 1552, 1483, 1352, 1251, 1213 cm−1; HRMS
(ES) m/z = 346.0055 calcd for C14H14BrNO3Na [MNa]+, found
346.0045.
Methyl 2-(2-Methylallyloxy)-7-methoxy-1H-indole-3-carboxylate
(3p). Following general procedure (B), 3p (0.086 g, 0.31 mmol) was
obtained in 43% yield as a white resin: 1H NMR (500 MHz, CDCl3) δ
8.45 (bs, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.66
(d, J = 7.9 Hz, 1H), 5.21 (s, 1H), 5.08 (s, 1H), 4.83 (s, 2H), 3.94 (s,
3H), 3.90 (s, 3H), 1.90 (s, 3H); 13C NMR (90 MHz, THF-d8) δ
164.0, 156.0, 145.4, 141.1, 127.5, 121.9, 121.3, 113.5, 112.6, 101.9,
90.5, 77.0, 54.6, 49.3, 18.6; IR (film) 3221, 1950, 2842, 1668, 1552,
1475, 1367, 1282, 1220 cm−1; HRMS (ES) m/z = 298.1055 calcd for
C15H17NO4Na [MNa]+, found 298.1057.
Representative Procedure for Installation of a Propargyl
Alcohol to Indole Substrates. Methyl 2-((4,4-Dimethylpent-2-yn-
1-yl)oxy)-1H-indole-3-carboxylate (4k). To a solution of methyl
indole-3-carboxylate (200 mg, 1.14 mmol) in CH2Cl2 (10 mL) cooled
to 0 °C was added 1,4-dimethylpiperazine (0.085 mL, 0.64 mmol),
followed by recrystallized N-chlorosuccinimide (167 mg, 1.26 mmol).
The resultant solution was stirred at 0 °C for 3 h. A solution of
the propargyl alcohol (127 mg, 1.14 mmol) and trichloroacetic acid
(45 mg, 0.27 mmol) in CH2Cl2 (1 mL) at 0 °C was transferred via
cannula to the indole solution. This mixture was stirred for 12 h at
0 °C, at which time the reaction mixture was concentrated and
Representative Procedure (B) for Installation of an Allyl
Alcohol to Indole Substrates. Methyl 2-(Allyloxy)-1H-indole-3-
carboxylate (3j). To a flame-dried round-bottom flask was added
methyl indole-3-carboxylate (0.30 g, 1.71 mmol). After that was dis-
solved in CH2Cl2 (4 mL) and cooled to 0 °C, 1,4-diazobicyclo[2.2.0]-
octane (DABCO) (0.108 g, 0.96 mmol) was added followed by
recrystallized N-chlorosuccinimide (0.253 g, 1.90 mmol). The
resultant solution was stirred at 0 °C for 30 min, followed by addition
of allyl alcohol (0.23 mL, 3.42 mmol) and methanesulfonic acid
(0.016 mL, 0.24 mmol). This mixture was stirred for 30 min at 0 °C, at
which time the reaction mixture was concentrated under vacuum and
chromatographed on a base-washed SiO2 column (1% Et3N, 24%
EtOAc, 75% hexanes) using 25% EtOAc/hexanes as the eluent to
afford 3j (0.224 g, 0.97 mmol) in 57% yield as an off-white oil: mp
1
80−82 °C; H NMR (300 MHz, CDCl3) δ 8.21 (bs, 1H), 8.05 (m,
1H), 7.22−7.18 (m, 3H), 6.13−6.05 (m, 1H), 5.49 (d, J = 17.2 Hz,
1H), 5.36 (d, J = 10.4 Hz, 1H), 4.95 (d, J = 5.7 Hz, 2H), 3.94 (s, 3H);
13C NMR (90 MHz, THF-d8) δ 164.7, 157.0, 133.7, 131.0, 127.3,
121.6, 121.5, 121.2, 117.8, 110.7, 90.3, 74.4, 50.0; IR (film) 3229,
2997, 2950, 1668, 1552, 1468, 1328, 1251, 1213 cm−1; HRMS (ES)
m/z = 254.0799 calcd for C13H13NO3Na [MNa]+, found 254.0797.
tert-Butyl 2-(Allyloxy)-1H-indole-3-carboxylate (3i). Following the
general procedure (A), 3i (0.53 g, 1.94 mmol) was obtained in 77%
yield as a white solid: mp 124−126 °C; 1H NMR (300 MHz, CDCl3)
11046
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
chromatographed on a base-washed SiO2 column using 15% ethyl
ether/hexane to afford 4k (131 mg, 0.456 mmol) in 40% yield as a
white resin: 1H NMR (360 MHz, CDCl3) δ 8.55 (bs, 1H), 8.05 (d, J =
7.9 Hz, 1H), 7.26−7.16 (m, 3H), 5.03 (s, 2H), 3.92 (s, 3H), 1.19 (s,
9H); 13C NMR (90 MHz, CDCl3) δ 165.1, 155.8, 129.8, 126.1,
122.33, 122.3, 121.31, 110.5, 99.3, 91.4, 73.1, 62.0, 51.1, 30.8, 27.8; IR
(film) 3236, 2974, 2873, 2248, 1668, 1552, 1468, 1352, 1267, 1205,
1104 cm−1; HRMS (ES) m/z = 308.1263 calcd for C17H19NO3Na
[MNa]+, found 308.1259.
130.5, 130.0, 127.4, 125.9, 125.7, 123.9, 122.4, 122.3, 121.3, 110.8,
91.5, 87.9, 87.6, 61.9, 51.2; IR (film) 3253, 2954, 2233, 1671, 1550,
1466, 1344, 1204, 1104, 1017 cm−1; HRMS (ES) m/z = 406.0055
calcd for C19H14NO3NaBr [MNa]+, found 406.0051.
Methyl 2-((3-(Naphthalen-1-yl)prop-2-yn-1-yl)oxy)-1H-indole-3-
carboxylate (4h). Following the general procedure, compound 4h
1
was obtained as a colorless resin in 17% yield: H NMR (500 MHz,
CDCl3) δ 8.48 (bs, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 8.4 Hz,
1H), 7.82 (t, J = 8.5 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.0
Hz, 1H), 7.39 (t, J = 7.3 Hz, 1H), 7.29−7.19 (m, 5H), 5.51 (s, 2H),
3.96 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.4, 155.6, 133.3,
133.2, 130.9, 129.9, 129.7, 128.4, 127.2, 126.7, 126.1, 125.9, 125.2,
122.5, 122.3, 121.4, 119.5, 110.9, 92.0, 87.9, 87.5, 62.6, 51.2; IR (film)
3245, 3061, 2225, 1671, 1549, 1466, 1333, 1205, 1102 cm−1; HRMS
(ES) m/z = 378.1106 calcd for C23H17NO3Na [MNa]+, found
378.1106.
tert-Butyl 2-(Prop-2-yn-1-yloxy)-1H-indole-3-carboxylate (4a).
Following the general procedure, compound 4a was obtained as a
1
white solid in 30% yield: H NMR (500 MHz, CDCl3) δ 8.55 (bs,
1H), 8.03 (d, J = 7.0 Hz, 1H), 7.30−7.17 (m, 3H), 5.07 (d, J = 2.5 Hz,
2H), 2.58 (t, J = 2.5 Hz, 1H), 1.66 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 164.1, 155.1, 129.7, 126.0, 122.4, 122.2, 121.5, 110.8, 93.5,
80.5, 78.3, 77.4, 61.7, 28.8; IR (film) 3283, 2974, 2124, 1653, 1552,
1468, 1367, 1328, 167, 1213, 1174, 1097 cm−1; HRMS (ES) m/z =
294.1106 calcd for C16H17NO3Na [MNa]+, found 294.1104.
tert-Butyl 2-(But-2-yn-1-yloxy)-1H-indole-3-carboxylate (4b). Fol-
lowing the general procedure, compound 4b was obtained as a white
solid in 44% yield: 1H NMR (500 MHz, CDCl3) δ 8.45 (bs, 1H), 8.02
(d, J = 8.0 Hz, 1H), 7.26−7.15 (m, 3H), 5.02 (q, J = 2.4 Hz, 2H), 1.86
(t, J = 2.4 Hz, 3H), 1.65 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
164.2, 155.6 129.7, 126.2, 122.1, 121.4, 110.6, 100.2, 92.9, 86.2, 80.2,
73.8, 62.0, 28.9, 3.9; IR (film) 3221, 2974, 2927, 2240, 1661, 1552,
1468, 1352, 1213, 1174, 1097 cm−1; HRMS (ES) m/z = 308.1263
calcd for C17H19NO3Na [MNa]+, found 308.1266.
Methyl 2-(Prop-2-yn-1-yloxy)-1H-indole-3-carboxylate (4c). Fol-
lowing the general procedure, compound 4c was obtained as a white
resin in 45% yield: 1H NMR (500 MHz, CDCl3) δ 8.31 (bs, 1H), 8.05
(d, J = 7.0 Hz, 1H), 7.30−7.19 (m, 3H), 5.13 (d, J = 2.5 Hz, 2H), 3.93
(s, 3H), 2.62 (t, J = 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
165.2, 155.4, 129.8, 125.9, 122.6, 122.4, 121.3, 110.9, 91.7, 78.0, 77.6,
61.7, 51.23; IR (film) 3283, 2950, 2132, 1676, 1552, 1468, 1344, 1267,
1205, 1104 cm−1; HRMS (ES) m/z = 252.0637 calcd for
C13H11NO3Na [MNa]+, found 252.0634.
Methyl 2-(But-2-yn-1-yloxy)-1H-indole-3-carboxylate (4d). Fol-
lowing the general procedure, compound 4d was obtained as a white
resin in 47% yield: 1H NMR (500 MHz, CDCl3) δ 8.37 (bs, 1H), 8.05
(d, J = 8.0 Hz, 1H), 7.26−7.15 (m, 3H), 5.04 (q, J = 2.5 Hz, 2H),
3.92(S, 3H), 1.87 (t, J = 2.4 Hz, 5H); 13C NMR (125 MHz, THF-d8)
δ 163.5, 155.3, 129.9, 126.0, 120.7, 120.5, 120.3, 109.8, 90.0, 83.5, 73.3,
60.9, 49.0, 1.8; IR (film) 3229, 2950, 2240, 1668, 1552, 1468, 1344,
1267, 1213, 1097 cm−1; HRMS (ES) m/z = 244.0974 calcd for
C14H14NO3 [MH]+, found 244.0963.
Methyl 2-((3-(2-Methoxyphenyl)prop-2-yn-1-yl)oxy)-1H-indole-3-
carboxylate (4i). Following the general procedure, compound 4i was
obtained in 15% yield. Because of the difficulty in separating com-
pound 4i from the methylindole-3-carboxylate and the instability of
this material at ambient temperature, the isolated yield was calculated
from the mixture of compound 4i and methylindole-3-carboxylate
1
(1.4:1). As a consequence, compound 4i was only assessed by H
1
NMR experiment and mass spectrum. H NMR (500 MHz, THF-d8)
δ 7.99−7.97 (m, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.21−7.05 (m, 4H),
6.90 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 8.3 Hz, 1H), 5.36 (s, 2H), 3.82
(s, 3H), 3.68 (s, 3H); HRMS (ES) m/z = 358.1055 calcd for
C20H17NO4Na [MNa]+, found 358.1055.
Methyl 2-((3-(Trimethylsilyl)prop-2-yn-1-yl)oxy)-1H-indole-3-car-
boxylate (4j). Following the general procedure, compound 4j was
obtained as a white resin in 26% yield: 1H NMR (360 MHz, CDCl3) δ
8.48 (bs, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.27−7.17 (m, 3H), 5.06 (s,
2H), 3.93 (s, 3H), 0.16 (s, 9H); 13C NMR (90 MHz, CDCl3) δ 165.0,
155.3, 129.7, 126.0, 122.6, 122.4, 121.5, 110.6, 99.5, 95.7, 91.8, 62.5,
51.2, −0.2; IR (film) 3236, 2958, 2186, 1668, 1552, 1468, 1344, 1251,
1205, 1104, 1035 cm−1; HRMS (ES) m/z = 324.1032 calcd for
C16H19NO3NaSi [MNa]+, found 324.1041.
8-(3-((3-(Methoxycarbonyl)-1H-indol-2-yl)oxy)prop-1-yn-1-yl)-4-
methyl-2,6-dioxohexahydro-[1,3,2]oxazaborolo[2,3-b][1,3,2]-
oxazaborol-4-ium-8-uide (4l). Following the general procedure, to a
solution of methyl indole-3-carboxylate (61 mg, 0.35 mmol) in CH2Cl2
(2 mL) cooled to 0 °C was added 1,4-dimethylpiperazine (0.026 mL,
0.20 mmol), followed by recrystallized N-chlorosuccinimide (58 mg,
0.44 mmol). The resultant solution was stirred at 0 °C for 3 h. A
solution of the propargyl alcohol (30 mg, 0.14 mmol) and tri-
chloroacetic acid (14 mg, 0.08 mmol) in THF (0.5 mL) at 0 °C was
transferred via cannula to the indole solution. This mixture was stirred
for 12 h at 0 °C, at which time the reaction mixture was concentrated
and chromatographed on a base-washed SiO2 column using 80% ethyl
acetate/hexane to afford 4l (46 mg, 0.12 mmol) in 90% yield as a white
Methyl 2-((3-Phenylprop-2-yn-1-yl)oxy)-1H-indole-3-carboxylate
(4e). Following the general procedure, compound 4e was obtained as a
1
colorless oil in 28% yield: H NMR (500 MHz, CDCl3) δ 9.02 (bs,
1H), 8.07 (d, J = 8.0 Hz, 1H), 7.36−7.19 (m, 8H), 5.29 (s, 2H), 3.95
(s, 1H); 13C NMR (125 MHz, CDCl3) δ 165.4, 155.7, 132.0, 129.9,
129.2, 128.6, 126.0, 122.4, 122.3, 121.9, 121.3, 110.9, 91.5, 89.3, 83.1,
62.4, 51.2; IR (film) 3233, 2950, 2235, 1670, 1550, 1468, 1345, 1205,
1103, 1018 cm−1; HRMS (ES) m/z = 328.0950 calcd for
C19H15NO3Na [MNa]+, found 328.0948.
1
resin; H NMR (500 MHz, acetone-d6) δ 7.99−7.97 (m, 1H), 7.33−
7.91 (m, 1H), 7.16−7.11 (m, 2H), 5.21 (s, 2H), 4.21 (d, J = 17.0 Hz,
2H), 3.94 (d, J = 17.0 Hz, 2H), 3.84 (s, 3H), 2.94 (s, 3H); 13C NMR
(125 MHz, acetone-d6) δ 168.4, 165.1, 156.3, 131.2, 127.1, 122.7,
122.4, 121.6, 111.8, 91.7, 62.27, 62.25, 50.8, 48.2. The 13C NMR signals
for two alkynyl carbons were not seen in accord with prior reports;40 IR
(film) 3222, 2945, 2200, 1773, 1694, 1562, 1469, 1350, 1271, 1113,
1034 cm−1; HRMS (ES) m/z = 407.1027 calcd for C18H17BN2O7Na
[MNa]+, found 407.1033.
Methyl 2-((3-(o-Tolyl)prop-2-yn-1-yl)oxy)-1H-indole-3-carboxy-
late (4f). Following the general procedure, compound 4f was obtained
1
as a colorless oil in 31% yield: H NMR (500 MHz, CDCl3) δ 8.77
(bs, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.27−7.14
(m, 5H), 7.10 (t, J = 6.5 Hz, 1H), 5.36 (s, 2H), 3.94 (s, 3H), 2.27 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 165.3, 155.7, 140.7, 132.4,
129.8, 129.7, 129.3, 126.0, 125.8, 122.5, 122.3, 121.6, 121.3, 110.7,
91.7, 88.3, 86.8, 62.4, 51.2, 20.7; IR (film) 3227, 2949, 2221, 1671,
1551, 1472, 1343, 1210, 1101, 1010 cm−1; HRMS (ES) m/z =
320.1287 calcd for C20H18NO3 [MH]+, found 320.1281.
Methyl 2-((3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)oxy)-1H-
indole-3-carboxylate (4m). Following the general procedure,
compound 4m was obtained as a white solid in 43% yield: mp
1
128−129 °C; H NMR (500 MHz, CDCl3) δ 8.83 (bs, 1H), 8.06 (d,
J = 7.5 Hz, 1H), 7.26−7.17 (m, 3H), 5.07 (s, 2H), 3.94 (s, 3H), 0.86
(s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 165.2, 155.5,
129.8, 125.9, 122.4, 122.3, 121.3, 110.7, 100.0, 94.1, 91.6, 62.1, 51.2,
26.1, 16.5, −4.7; IR (film) 3190, 2958, 2858, 2186, 1661, 1552, 1468,
1259, 1097, 1027 cm−1; HRMS (ES) m/z = 344.1682 calcd for
C19H26NO3Si [MH]+, found 344.1690.
Methyl 2-((3-(2-Bromophenyl)prop-2-yn-1-yl)oxy)-1H-indole-3-
carboxylate (4g). Following the general procedure, compound 4g
1
was obtained as a colorless resin in 15% yield: H NMR (500 MHz,
CDCl3) δ 9.09 (bs, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 8.0 Hz,
1H), 7.38 (d, J = 7.7 Hz, 1H), 7.28−7.16 (m, 5H), 5.31 (s, 2H), 3.94
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.3, 155.6, 133.9, 132.6,
11047
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Ethyl 2-((3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)oxy)-7-me-
thoxy-1H-indole-3-carboxylate (4n). Following the general proce-
dure, compound 4n was obtained as a white solid in 50% yield: mp
98−99 °C; 1H NMR (500 MHz, CDCl3) δ 8.94 (bs, 1H), 8.06 (d, J =
7.5 Hz, 1H), 7.26−7.16 (m, 3H), 5.07 (s, 2H), 3.94 (s, 3H), 0.93 (t,
J = 8 Hz, 9H), 0.58 (q, J = 8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3)
δ 165.3, 155.6, 129.9, 125.9, 122.4, 122.3, 121.2, 110.7, 100.4, 93.3,
91.5, 62.1, 51.4, 7.46, 4.21; IR (film) 3259, 2958, 2881, 2186, 1668,
1552, 1468, 1205, 1104, 1012 cm−1; HRMS (ES) m/z = 344.1682
calcd for C19H26NO3Si [MH]+, found 344.1699.
129.9, 125.9, 122.2, 122.1, 121.2, 110.6, 101.1, 92.0, 91.7, 61.9, 59.8,
18.6, 14.7, 11.1; IR (film) 3244, 2943, 2866, 2178, 1668, 1552, 1460,
1375, 1274, 1205, 1097, 1020 cm−1; HRMS (ES) m/z = 422.2127
calcd for C23H33NO3SiNa [MNa]+, found 422.2125.
2,2,2-Trifluoroethyl 2-((3-(Triisopropylsilyl)prop-2-yn-1-yl)oxy)-
1H-indole-3-carboxylate (4u). Following the general procedure,
compound 4u was obtained as a white solid in 26% yield: mp 97−
98 °C; 1H NMR (500 MHz, CDCl3) δ 8.90 (bs, 1H), 8.00 (d, J = 8.0
Hz, 1H), 7.29−7.21 (m, 3H), 5.08 (s, 2H), 4.73 (q, J = 8.5 Hz, 2H),
1.06−0.98 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 162.7, 156.6,
129.9, 125.5, 123.8 (q, J = 275.1 Hz, 1C), 122.9, 122.8, 121.2, 110.7,
100.6, 93.1, 90.1, 61.8, 59.9 (q, J = 35 Hz, 1C), 18.6, 11.2; IR (film)
3267, 2950, 2873, 2178, 1684, 1552, 1460, 1282, 1166, 1104, 1022
cm−1; HRMS (ES) m/z = 476.1845 calcd for C23H30F3NO3SiNa
[MNa]+, found 476.1849.
Ethyl 2-((3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)oxy)-7-methyl-
1H-indole-3-carboxylate (4o). Following the general procedure,
compound 4o was obtained as a white solid in 31% yield: mp 117−
118 °C; 1H NMR (500 MHz, CDCl3) δ 8.55 (bs, 1H), 7.90 (d, J = 8.0
Hz, 1H), 7.15 (dd, J = 8.0, 7.0 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 5.08
(s, 2H), 4.40 (q, J = 7 Hz, 2H), 2.41 (s, 3H), 1.45 (t, J = 7 Hz, 3H),
0.87 (s, 9H), 0.09 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.8,
155.4, 129.2, 125.6, 123.2, 122.4, 119.7, 119.2, 100.3, 93.7, 92.5, 62.4,
59.8, 26.1, 16.5 (2C), 14.8, −4.8; IR (film) 3229, 2958, 2858, 2186,
1668, 1552, 1468, 1274, 1213, 1097 cm−1; HRMS (ES) m/z =
370.1838 calcd for C21H28NO4Si [M − H]−, found 370.1855.
Ethyl 2-((3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)oxy)-5-me-
thoxy-1H-indole-3-carboxylate (4p). Following the general proce-
dure, compound 4p was obtained as a white solid in 39% yield: mp
Benzyl 2-((3-(Triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-indole-3-
carboxylate (4v). Following the general procedure, compound 4v
1
was obtained as a white resin in 16% yield: H NMR (500 MHz,
CDCl3) δ 8.60 (bs, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.2 Hz,
2H), 7.40−7.31 (m, 3H), 7.21−7.15 (m, 3H), 5.40 (s, 2H), 5.09 (s,
2H), 1.05−0.95 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 164.4,
155.7, 137.0, 129.7, 128.7, 128.2, 128.1, 125.9, 122.4, 122.3, 121.5, 110.5,
101.2, 92.4, 91.7, 65.6, 62.1, 18.6, 11.2; IR (film) 3259, 2946, 2865,
2173, 1670, 1550, 1461, 1343, 1203, 1090, 1021 cm−1; HRMS (ES)
m/z = 484.2284 calcd for C28H35NO3NaSi [MNa]+, found 484.2292.
Ethyl 7-Methyl-2-((3-(triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-
indole-3-carboxylate (4w). Following the general procedure,
compound 4w was obtained as a white solid in 18% yield: mp 104−
105 °C; 1H NMR (300 MHz, CDCl3) δ 8.40 (bs, 1H), 7.89 (d, J = 7.8
Hz, 1H), 7.13 (dd, J = 7.8, 5.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 5.14
(s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.44 (t, J = 7.2 Hz,
3H), 1.08−0.93 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 164.8,
155.3, 129.1, 125.7, 123.2, 122.4, 119.6, 119.2, 101.4, 92.7, 91.8, 62.4,
59.8, 18.7, 16.5, 14.8, 11.4; IR (film) 3229, 2943, 2866, 2178, 1668,
1552, 1468, 1313, 1274, 1213, 1097, 1020 cm−1; HRMS (ES) m/z =
436.2284 calcd for C24H35NO3SiNa [MNa]+, found 436.2271.
Ethyl 5-Methoxy-2-((3-(triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-
indole-3-carboxylate (4x). Following the general procedure, com-
pound 4x was obtained as a white solid in 12% yield: mp 109−111 °C;
1H NMR (500 MHz, CDCl3) δ 8.48 (bs, 1H), 7.59 (d, J = 2.5 Hz,
1H), 7.08 (d, J = 8.5 Hz, 1H), 6.81 (dd, J = 8.5, 2.5 Hz, 1H), 5.08 (s,
2H), 4.39 (q, J = 7.5 Hz, 2H), 3.87 (s, 3H), 1.44 (t, J = 7.5 Hz, 3H),
1.08−0.97 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 164.7, 155.9,
155.6, 127.0, 124.4, 111.7, 111.3, 104.2, 101.3, 92.2, 92.1, 62.1, 59.8,
55.9, 18.7, 14.8, 11.1; IR (film) 3205, 2943, 2866, 2178, 1653, 1483,
1352, 1282, 1205, 1166, 1035 cm−1; HRMS (ES) m/z = 452.2233
calcd for C24H35NO4SiNa [MNa]+, found 452.2234.
Ethyl 7-Methoxy-2-((3-(triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-
indole-3-carboxylate (4y). Following the general procedure, com-
pound 4y was obtained as a colorless oil in 31% yield: 1H NMR (500
MHz, CDCl3) δ 8.81 (bs, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.13 (dd, J =
8.5, 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.09 (s, 2H), 4.39 (q, J =
7.0 Hz, 2H), 3.91 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.10−0.94 (m,
21H); 13C NMR (125 MHz, CDCl3) δ 164.5, 154.6, 145.1, 126.9,
122.3, 119.5, 113.7, 102.5, 100.9, 92.2, 92.0, 61.8, 59.5, 55.1, 18.8, 14.5,
10.9; IR (film) 3244, 2943, 2866, 2178, 1676, 1552, 1468, 1367, 1282,
1213, 1097, 1020 cm−1; HRMS (ES) m/z = 452.2233 calcd for
C24H35NO4SiNa [MNa]+, found 452.2234.
Ethyl 5-Bromo-2-((3-(triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-
indole-3-carboxylate (4z). Following the general procedure, com-
pound 4z was obtained as a light gray solid in 28% yield: mp 119−
120 °C; 1H NMR (500 MHz, CDCl3) δ 8.91 (bs, 1H), 8.16 (d, J = 2.0
Hz, 1H), 7.26 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 5.10
(s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7 Hz, 3H), 1.07−0.93
(m, 21H); 13C NMR (125 MHz, CDCl3) δ 164.4, 155.9, 128.4, 127.7,
125.2, 124.0, 115.7, 112.1, 100.7, 92.6, 91.7, 61.9, 60.1, 18.6, 14.7,
11.2; IR (film) 3229, 2943, 2866, 2178, 1668, 1552, 1468, 1328, 1251,
1205, 1097, 1027 cm−1; HRMS (ES) m/z = 500.1233 calcd for
C23H32BrNO3SiNa [MNa]+, found 500.1226.
1
145−146 °C; H NMR (500 MHz, CDCl3) δ 8.37 (bs, 1H), 7.60 (d,
J = 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.82 (dd, J = 2.0, 9.0 Hz,
1H), 5.05 (s, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.87 (s, 3H), 1.44 (t, J =
7.0 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 164.7, 156.0, 155.5, 126.9, 124.3, 111.8, 111.4, 104.2, 100.2, 94.0,
92.2, 62.4, 59.8, 55.9, 26.1, 16.6, 14.8, −4.7; IR (film) 3213, 2935,
2858, 2186, 1653, 1468, 1352, 1205, 1166, 1104, 1043 cm−1; HRMS
(ES) m/z = 388.1944 calcd for C21H30NO4Si [MH]+, found 388.1934.
Ethyl 2-((3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl)oxy)-7-me-
thoxy-1H-indole-3-carboxylate (4q). Following the general proce-
dure, compound 4q was obtained as a white solid in 16% yield: mp
1
107−108 °C; H NMR (500 MHz, CDCl3) δ 8.79 (bs, 1H), 7.62 (d,
J = 8.0 Hz, 1H), 7.12 (dd, J = 8.0, 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz,
1H), 5.03 (s, 2H), 4.37 (q, J = 7.5 Hz, 2H), 3.90 (s, 3H), 1.41 (t, J =
7.5 Hz, 3H), 0.86 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3)
δ 164.8, 154.9, 145.4, 127.1, 122.6, 119.8, 114.0, 102.8, 100.2, 94.2,
92.5, 62.1, 59.8, 55.5, 26.1, 16.5, 14.8, −4.8; IR (film) 3244, 2935,
2858, 2186, 1676, 1552, 1468, 1282, 1027 cm−1; HRMS (ES) m/z =
386.1788 calcd for C21H28NO4Si [M − H]−, found 386.1796.
Ethyl 5-Bromo-2-((3-(tert-butyldimethylsilyl)prop-2-yn-1-yl)oxy)-
1H-indole-3-carboxylate (4r). Following the general procedure,
compound 4r was obtained as a light gray solid in 28% yield: mp
1
155−156 °C; H NMR (500 MHz, CDCl3) δ 8.72 (bs, 1H), 8.15 (d,
J = 2.0 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.07 (d, J = 8.5 Hz,
1H), 5.05 (s, 2H), 4.37 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7 Hz, 3H),
0.82 (s, 9H), 0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 164.4,
155.9, 128.4, 127.7, 125.3, 124.1, 115.7, 112.1, 99.7, 94.4, 91.8, 62.2,
60.1, 26.1, 16.5, 14.8, −4.8; IR (film) 3221, 2958, 2858, 2186, 1668,
1552, 1475, 1328, 1251, 1205, 1104, 1027 cm−1; HRMS (ES) m/z =
458.0763 calcd for C20H26BrNO3SiNa [MNa]+, found 458.0781.
Methyl 2-((3-(Triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-indole-3-
carboxylate (4s). Following the general procedure, compound 4s
1
was obtained as a white solid in 59% yield: mp 92−93 °C; H NMR
(500 MHz, CDCl3) δ 9.56 (bs, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.27−
7.17 (m, 3H), 5.12 (s, 2H), 3.97 (s, 3H), 1.12−0.88 (m, 21H); 13C
NMR (125 MHz, CDCl3) δ 165.6, 155.6, 130.1, 125.9, 122.12, 122.07,
121.0, 110.8, 100.8, 91.9, 91.2, 61.6, 51.1, 18.5, 11.1; IR (film) 3259,
2950, 2866, 2178, 1668, 1552, 1460, 1344, 1274, 1205, 1104, 1020
cm−1; HRMS (ES) m/z = 386.2151 calcd for C22H32 NO3Si [MH]+,
found 386.2137.
Ethyl 2-((3-(Triisopropylsilyl)prop-2-yn-1-yl)oxy)-1H-indole-3-car-
boxylate (4t). Following the general procedure, compound 4t was
obtained as a white solid in 40% yield: mp 93−94 °C; 1H NMR (500
MHz, CDCl3) δ 9.03 (bs, 1H), 8.05 (d, J = 7.5 Hz, 1H), 7.24−7.17
(m, 3H), 5.11 (s, 2H), 4.41 (q, J = 7 Hz, 2H), 1.45 (t, J = 7 Hz, 3H),
1.09−0.86 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 164.9, 155.5,
11048
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
General Procedure for the Racemic Claisen Rearrangement.
3-Allyl-2-oxoindoline-3-carbonitrile (5a). To a solution of 3a (0.015 g,
0.081 mmol) in CH2Cl2 (0.50 mL) was added SiO2 (0.02 g, 0.32 mmol).
The resulting solution was allowed to stir at room temperature until the
starting material was consumed (2 days). The reaction mixture was
filtered to remove the SiO2 and then concentrated under vacuum to
afford the rearranged product 5a (0.014 g, 0.075 mmol) as a white resin
CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 13.0 min, tR(S) = 20.0 min.
(R)-Benzyl 3-(2-Methylallyl)-2-oxoindoline-3-carboxylate (5e).
Following the general procedure, using Cu(Ind-BOX L7)(SbF6)2
catalyst, compound 5e was obtained as a pale yellow resin in 73%
1
yield: [α]23 −22.00 (c 0.55, 73% ee, CH2Cl2); H NMR (500 MHz,
D
CDCl3) δ 8.25 (bs, 1H), 7.25−7.13 (m, 7H), 7.02 (t, J = 7.6 Hz, 1H),
6.88 (d, J = 7.8 Hz, 1H), 5.12 (s, 2H), 4.66 (s, 1H), 4.62 (s, 1H), 3.07
(d, J = 19.5 Hz, 1H), 3.03 (d, J = 19.5 Hz, 1H), 1.41 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 175.6, 168.9, 141.3, 139.4, 135.3, 129.1,
128.4, 128.2, 128.1, 127.4, 124.4, 122.6, 115.7, 110.0, 67.3, 60.0, 40.9,
23.7; IR (film) 3242, 2926, 2856, 1718, 1621, 1471 cm−1; HRMS (ES)
m/z = 344.1263 calcd for C20H19NO3Na [MNa]+, found 344.1264;
CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 17.8 min, tR(S) = 27.8 min.
1
in 93% yield. H NMR (500 MHz, CDCl3) δ 8.70 (bs, 1H), 7.41−7.35
(m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 5.77−5.69
(m, 1H), 5.24 (d, J = 10.5 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H), 3.04 (dd,
J = 6.4, 13.6 Hz, 1H), 2.82 (dd, J = 8.1, 13.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 172.2, 140.0, 130.4, 128.8, 125.3, 124.7, 123.7, 122.2,
116.4, 110.9, 46.9, 41.1, 22.7; IR (film) 3262, 2922, 2247, 1725, 1621,
1475 cm−1; HRMS (CI) m/z = 199.0871 calcd for C12H10N2O [MH]+,
found 199.0866; CSP HPLC (Chiralpak AD, 1.0 mL/min, 95:5
hexanes:i-PrOH): tR(ent-1) = 15.5 min, tR(ent-2) = 18.3 min.
(R)-Isopropyl 3-(2-Methylallyl)-2-oxoindoline-3-carboxylate (5f).
Following the general procedure, using Cu(Ind-BOX L7)(SbF6)2
catalyst, compound 5f was obtained as white resin in 100% yield:
[α]23D −22.00 (c 0.2, 65% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3)
δ 8.22 (bs, 1H), 7.25−7.21 (m, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.88 (d,
J = 8.0 Hz, 1H), 5.02−4.97 (m, 1H), 4.65 (s, 1H), 4.62 (s, 1H), 3.04
(d, J = 18.5 Hz, 1H), 3.01 (d, J = 18.5 Hz, 1H), 1.41 (s, 3H), 1.21 (d,
J = 6.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 175.6, 168.5, 141.2,
139.7, 128.9, 128.6, 124.2, 122.5, 115.5, 109.7, 69.7, 60.1, 40.9, 23.7,
21.4, 21.3; IR (film) 3250, 2984, 1733, 1621, 1475 cm−1; HRMS (ES)
m/z = 296.1263 calcd for C16H19NO3Na [MNa]+, found 296.1264;
CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 7.7 min, tR(S) = 11.8 min.
3-(2-Methylallyl)-2-oxoindoline-3-carbonitrile (5b). Following the
general procedure, 5b (0.011 g, 0.052 mmol) was obtained as a white
1
resin in 73% yield. H NMR (500 MHz, CDCl3) δ 8.41 (bs, 1H),
7.34−7.25 (m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H),
4.86 (t, J = 1.5 Hz, 1H), 4.68 (s, 1H), 2.92 (d, J = 13.5 Hz, 1H), 2.79
(d, J = 13.5 Hz, 1H), 1.61 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
172.0, 140.6, 137.6, 130.2, 125.0, 123.2, 117.9, 117.2, 110.7, 64.4, 46.6,
44.0, 23.4; IR (film) 3250, 2926, 2856, 2227, 1729, 1621, 1475 cm−1;
HRMS (CI): m/z = 213.1028 calcd for C13H13N2O [MH]+, found
213.1041; CSP HPLC (Chiralpak AD, 1.0 mL/min, 95:5 hexanes:i-
PrOH): tR(ent-1) = 13.9 min, tR(ent-2) = 16.1 min.
3-(2-Methylallyl)indolin-2-one (6). Following the general proce-
dure, compound 6 was obtained as a white resin: 1H NMR (500 MHz,
CDCl3) δ 8.12 (bs, 1H), 7.23 (m, 2H), 7.00 (dt, J = 0.5, 7.5 Hz, 1H),
6.89 (d, J = 8.0 Hz, 1H), 4.91 (s, 1H), 4.79 (s, 1H), 3.60 (dd, J = 4.5,
9.5 Hz, 1H), 2.83 (dd, J = 4.0, 14.5 Hz, 1H), 2.41 (dd, J = 10.0, 14.0
Hz, 1H), 1.83 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 179.7, 141.8,
141.1, 129.5, 127.9, 124.9, 122.1, 113.6, 109.5, 43.9, 38.9, 22.2; IR
(film) 3213, 3082, 2935, 1707, 1622, 1468, 1336, 1228 cm−1; HRMS
(ES) m/z = 210.0895 calcd for C12H13NONa [MNa]+, found 210.0879.
Typical Experimental Procedure for the Asymmetric
Meerwein−Eschenmoser Claisen Rearrangement. (S)-Methyl
3-(2-Methylallyl)-2-oxoindoline-3-carboxylate (5c). To a solution
of Pd(t-BuPHOX)Cl2 (0.004 g, 0.008 mmol) in CH2Cl2 (0.5 mL) was
added, via cannula, a solution of AgSbF6 (0.005 g, 0.014 mmol) in
CH2Cl2 (0.50 mL). The resulting solution was stirred in the absence
of light for 3 h, and filtered through a PTFE filter to remove the
precipitated AgCl. The resulting clear yellow solution was cooled to
0 °C, followed by addition of 3c (0.009 g, 0.038 mmol) in CH2Cl2
(1.0 mL) via cannula. The reaction mixture was stirred at 0 °C until
the starting material was completely consumed, as determined by
TLC. Filtration through a plug of SiO2 (5 mm × 2 cm) with 25%
EtOAc/hexanes and concentration of the solution under vacuum
(S)-tert-Butyl 3-(2-Methylallyl)-2-oxoindoline-3-carboxylate (5g).
Following the general procedure, using Pd(BINAP)(SbF6)2 catalyst,
compound 5g was obtained as a white resin in 100% yield: [α]23
D
+66.89 (c 0.90, 85% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 9.09
(bs, 1H), 7.23 (m, 2H), 7.02 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.7 Hz,
1H), 4.61 (s, 2H), 3.04 (d, J = 13.9 Hz, 1H), 2.97 (d, J = 13.9 Hz, 1H),
1.38 (s, 3H), 1.36 (s, 9H); 13C NMR (125 MHz, CDCl3) 175.6, 167.9,
141.1, 139.9, 129.0, 128.8, 124.1, 122.4, 115.3, 109.6, 82.5, 60.7, 40.8,
27.7, 23.7; IR (film) 3262, 2980, 2930, 1733, 1621, 1475 cm−1; HRMS
(ES) m/z = 310.1419 calcd for C17H21NO3Na [MNa]+, found
310.1416; CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5
hexanes:i-PrOH): tR(R) = 6.1 min, tR(S) = 9.2 min.
(S)-tert-Butyl 3-Allyl-2-oxoindoline-3-carboxylate (5i). Following
the general procedure, using Pd(BINAP)(SbF6)2 catalyst, compound
5i was obtained as a white resin in 60% yield: [α]23 +106.5 (c 0.30,
D
1
89% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.95 (bs, 1H),
7.26−7.23 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H),
5.50 (m, 1H), 5.06 (d, J = 17.0 Hz, 1H), 4.94 (d, J = 10.1 Hz, 1H),
2.98−2.90 (m, 2H), 1.31 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
175.9, 167.7, 141.2, 131.2, 128.8, 128.7, 123.7, 122.6, 119.5, 109.7,
82.5, 60.5, 38.2, 27.7; IR (film) 3252, 3090, 2981, 2927, 1722, 1622,
1475, 1251, 1159 cm−1; HRMS (CI) m/z = 274.1443 calcd for
C16H20NO3 [MH]+, found 274.1459; CSP HPLC (Chiralpak OD, 1.0
mL/min, 96.5:3.5 hexanes:i-PrOH): tR(R) = 7.2 min, tR(S) = 8.8 min.
(S)-Methyl 3-Allyl-2-oxoindoline-3-carboxylate (5j). Following the
yielded 5c (0.008 g, 0.033 mmol) in 89% yield as a white resin: [α]23
D
+79.25 (c 0.40, 89% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 8.84
(bs, 1H), 7.27−7.26 (m, 2H), 7.05 (t, J = 7.9, 1H), 6.94 (d, J = 7.7 Hz,
1H), 4.65 (s, 1H), 4.63 (s, 1H), 3.69 (s, 3H), 3.06 (s, 2H), 1.41 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 176.1, 169.6, 141.3, 139.4,
129.1, 128.3, 124.4, 122.6, 115.7, 110.1, 59.9, 53.1, 41.2, 23.6; IR (film)
3250, 2953, 1741, 1702, 1621, 1475 cm−1; HRMS (CI) m/z =
246.1130 calcd for C14H16NO3 [MH]+, found 246.1136; CSP HPLC
(Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH): tR(R) = 16.5
min, tR(S) = 20.3 min.
general procedure, compound 5j was obtained as a white resin in 100%
1
yield: [α]23 +51.30 (c 0.50, 83% ee, CH2Cl2); H NMR (500 MHz,
D
CDCl3) δ 8.20 (bs, 1H), 7.28−7.25 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H),
6.92 (d, J = 7.9 Hz, 1H), 5.49−5.41 (m, 1H), 5.08 (dd, J = 1.2, 17.0
Hz, 1H), 4.97 (d, J = 10.1 Hz, 1H), 3.71 (s, 3H), 3.04 (dd, J = 6.7, 13.8
Hz, 1H), 2.97 (dd, J = 7.9, 13.8 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 175.6, 169.3, 141.1, 130.8, 129.1, 128.0, 124.0, 122.8, 120.0,
110.0, 59.6, 53.1, 38.4; IR (film) 3252, 3090, 2958, 2858, 1715, 1622,
1475, 1437, 1336, 1236 cm−1; HRMS (ES) m/z = 254.0793 calcd for
C13H13NO3Na [MNa]+, found 254.0791; CSP HPLC (Chiralpak AD,
1.0 mL/min, 95.5 hexanes:i-PrOH): tR(S) = 18.4 min, tR(R) = 20.6 min.
(S)-Methyl 3-(2-Methylenebutyl)-2-oxoindoline-3-carboxylate
(5k). Following the general procedure, compound 5k was obtained
as a white resin in 82% yield: [α]23D +59.00 (c 0.45, 92% ee, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 8.12 (bs, 1H), 7.28−7.23 (m,
(R)-Ethyl 3-(2-Methylallyl)-2-oxoindoline-3-carboxylate (5d). Fol-
lowing the general procedure, using Cu(Ind-BOX L7)(SbF6)2 catalyst,
compound 5d was obtained as a white resin in 100% yield: [α]23
D
−48.44 (c 0.45, 79% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.93
(bs, 1H), 7.28−7.19 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 7.7
Hz, 1H), 4.67 (d, J = 16.6 Hz, 2H), 4.17 (m, 2H), 3.07 (d, J = 16.8 Hz,
1H), 3.03 (d, J = 16.8 Hz, 1H), 1.42 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 175.6, 169.1, 141.2, 139.6, 129.0,
128.5, 124.4, 122.6, 115.6, 109.8, 62.1, 59.9, 41.0, 23.7, 11.9; IR (film)
3250, 2980, 2922, 2853, 1718, 1621, 1475 cm−1; HRMS (ES)
m/z = 282.1106 calcd for C15H17NO3Na [MNa]+, found 282.1115;
2H), 7.05 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 4.66 (t, J =
1.4 Hz, 1H), 4.64 (s, 1H), 3.69 (s, 3H), 3.08 (d, J = 16.7 Hz, 1H),
11049
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
3.05 (d, J = 16.8 Hz, 1H), 1.68 (q, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 176.0, 169.7, 145.0, 141.3,
129.1, 128.3, 124.4, 122.6, 113.2, 110.0, 60.0, 53.1, 39.5, 29.7, 12.3; IR
(film) 3275, 2927, 2858, 1715, 1622, 1444, 1236 cm−1; HRMS (CI)
m/z = 260.1287 calcd for C15H18NO3 [MH]+, found 260.1287; CSP
HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 13.6 min, tR(S) = 15.8 min.
298.1057; CSP HPLC (Chiralpak AS, 1.0 mL/min, 96.5:3.5 hexanes:i-
PrOH): tR(R) = 21.3 min, tR(S) = 27.0 min.
(S)-Methyl 3-(2-(Deuteromethylene)butyl)-2-oxoindoline-3-car-
boxylate (5q). Following the general procedure, compound 5q was
obtained as a white resin in 80% yield: [α]23D +43.13 (c 0.40, 92% ee,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.04 (bs, 1H), 7.32−7.24
(m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 4.63 (s,
0.5 H, Z-deutero), 4.62 (s, 0.5 H, E-deutero), 3.70 (s, 3H), 3.07 (d, J =
16.3 Hz, 1H), 3.04 (d, J = 16.2 Hz, 1H), 1.68 (q, J = 7.3 Hz, 2H), 0.84
(t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.8, 169.9,
(S)-Isopropyl 3-Allyl-2-oxoindoline-3-carboxylate (5l). Following
the general procedure, using Pd(BINAP)(SbF6)2 catalyst, compound
5l was obtained as a white resin in 91% yield: [α]23 +44.20 (c 0.50,
D
145.1, 141.4, 129.3, 128.6, 124.7, 122.8, 113.1 (t, J1 = 23.6 Hz),
1
CD
74% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.04 (bs, 1H),
110.1, 60.2, 53.4, 39.7, 29.9, 12.5; IR (film) 3252, 3090, 2981, 2935,
1715, 1622, 1475, 1375, 1251, 1159 cm−1; HRMS (ES) m/z =
283.1169 calcd for C15H16DNO3Na [MNa]+, found 283.1173; CSP
HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 13.6 min, tR(S) = 15.8 min.
General Procedure for Preparing Catalysts. Pd[(R)-BINAP]-
(SbF6)2. To a flask of Pd[(R)-BINAP]Cl2 (4 mg, 0.005 mmol) in
CH2Cl2 (0.5 mL) was added a solution of AgSbF6 (3.3 mg, 0.0095
mmol) in CH2Cl2 (0.5 mL). The resulting solution was stirred in the
absence of light for 3 h, and filtered through a PTFE filter to remove
the precipitated AgCl. The resulting clear yellow solution was con-
centrated to afford Pd[(R)-BINAP](SbF6)2 as a yellow solid in 100%
yield.
Pd[(S)-t-BuPHOX](SbF6)2. To a flask of Pd[(S)-t-BuPHOX]Cl2
(2.8 mg, 0.005 mmol) in CH2Cl2 (0.5 mL) was added a solution of
AgSbF6 (3.3 mg, 0.0095 mmol) in CH2Cl2 (0.5 mL). The resulting
solution was stirred in the absence of light for 3 h, and filtered through
a PTFE filter to remove the precipitated AgCl. The resulting clear
yellow solution was concentrated to afford Pd[(S)-t-BuPHOX](SbF6)2
as a light yellow solid in 100% yield.
7.25−7.23 (m, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H),
5.50−5.41 (m, 1H), 5.07 (d, J = 17.0 Hz, 1H), 5.02 (m, 1H), 5.00 (d,
J = 10.1 Hz, 1H), 3.01 (dd, J = 6.7, 13.8 Hz, 1H), 2.95 (dd, J = 7.8,
13.8, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 175.5, 168.3, 141.1, 131.0, 128.9, 128.4,
123.9, 122.7, 119.8, 109.8, 69.7, 59.8, 38.3, 21.5, 21.3; IR (film) 3252,
3090, 2981, 2927, 2858, 1722, 1622, 1468, 1236 cm−1; HRMS (ES)
m/z = 282.1106 calcd for C15H17NO3Na [MNa]+, found 282.1091;
CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(R) = 11.8 min, tR(S) = 14.9 min.
(S)-Benzyl 3-Allyl-2-oxoindoline-3-carboxylate (5m). Following
the general procedure, using Pd(BINAP)(SbF6)2 catalyst, compound
5m was obtained as a white resin in 74% yield: [α]23D +51.38 (c 0.40,
1
72% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.28 (bs, 1H),
7.28−7.22 (m, 5H), 7.17−7.16 (m, 2H), 7.05 (td, J = 7.5, 0.9 Hz, 1H),
6.90 (d, J = 7.8 Hz, 1H), 5.50−5.41 (m, 1H), 5.16 (d, J = 15.5 Hz,
1H), 5.14 (d, J = 15.6 Hz, 1H), 5.08 (dd, J = 1.4, 16.9 Hz, 1H), 4.96
(dd, J = 1.7, 10.1 Hz, 1H), 3.05 (dd, J = 6.7, 13.9 Hz, 1H), 2.99 (dd,
J = 7.9, 13.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 175.3, 168.6,
141.2, 135.3, 130.8, 129.1, 128.4, 128.1, 128.0, 127.4, 124.0, 122.7,
120.0, 110.0, 67.3, 59.7, 38.2; IR (film) 3259, 3066, 2927, 1715, 1622,
1468, 1336 cm−1; HRMS (ES) m/z = 308.1263 calcd for C19H18NO3
[MH]+, found 308.1273; CSP HPLC (Chiralpak OD, 1.0 mL/min,
96.5:3.5 hexanes:i-PrOH): tR(R) = 20.7 min, tR(S) = 29.7 min.
(S)-Methyl 5-Methoxy-3-(2-methylallyl)-2-oxoindoline-3-carbox-
ylate (5n). Following the general procedure, compound 5n was
obtained as a white resin in 60% yield: [α]23D +40.83 (c 0.30, 91% ee,
CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.55 (bs, 1H), 6.88 (s, 1H),
6.80 (m, 2H), 4.70 (s, 1H), 4.65 (s, 1H), 3.79 (s, 3H), 3.70 (s, 3H),
3.05 (d, J = 19.5 Hz, 1H), 3.02 (d, J = 19.4 Hz, 1H), 1.42 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 175.6, 169.6, 155.9, 139.4, 134.5, 129.5,
115.7, 113.9, 111.3, 110.3, 60.2, 55.8, 53.2, 41.2, 23.7; IR (film) 3259,
2927, 2858, 1715, 1607, 1491, 1444, 1236 cm−1; HRMS (ES) m/z =
276.1236 calcd for C15H18NO4 [MH]+, found 276.1248; CSP HPLC
(Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH): tR(R) = 20.7
min, tR(S) = 23.8 min.
Typical Procedure for the Asymmetric Saucy−Marbet
Claisen Rearrangement. (R)-Ethyl 3-(1-(tert-Butyldimethylsilyl)-
propa-1,2-dien-1-yl)-5-methoxy-2-oxoindoline-3-carboxylate (8p).
To a solution of the Pd[(R)-BINAP](SbF6)2 complex (12 mg,
0.01 mmol, 20 mol %) in C6H5Cl (1 mL) was added a solution of 4p
(19.4 mg, 0.05 mmol) in toluene (1 mL) at ambient temperature. The
resulting solution was stirred in the absence of light at room temp-
erature until the starting material was completely consumed, as
determined by TLC. Filtration through a plug of SiO2 (5 mm × 2 cm)
with ethyl ether, concentration of the solution, and purification by
column chromatography using 50% ethyl ether/hexane afforded 8p as
a white resin in 82% yield: mp 136−137 °C; [α]23 +158.18 (c 0.17,
D
93% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.92 (bs, 1H), 6.89
(d, J = 2.0 Hz, 1H), 6.79−6.74 (m, 2H), 4.60 (d, J = 11.5 Hz, 1H),
4.41 (d, J = 11.5 Hz, 1H), 4.22 (qd, J = 7.5, 11.0 Hz, 1H), 4.13 (qd, J =
7.5, 11.0 Hz, 1H), 3.78 (s, 3H), 1.23 (t, J = 7.5 Hz, 3H), 0.92 (s, 9H),
0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 212.5,
174.8, 168.8, 155.7, 134.3, 129.7, 114.5, 113.2, 110.2, 100.2, 93.6, 74.1,
62.4, 56.1, 27.6, 19.4, 14.2, −4.0, −4.2; IR (film) 3252, 2958, 2858,
1931, 1746, 1622, 1468, 1259, 1089, 1027 cm−1; HRMS (ES) m/z =
386.1788 calcd for C21H28NO4Si [M − H]−, found 386.1776; CSP
HPLC (Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 14.0
min, tR(2) = 21.6 min.
(S)-Methyl 5-Bromo-3-(2-methylallyl)-2-oxoindoline-3-carboxyl-
ate (5o). Following the general procedure, compound 5o was
obtained as a white resin in 82% yield: [α]23 +38.67 (c 0.45, 87%
D
1
ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.34 (bs, 1H), 7.40 (m,
2H), 6.80 (d, J = 8.7 Hz, 1H), 4.70 (s, 1H), 4.63 (s, 1H), 3.72 (s, 3H),
3.05 (d, J = 19.8 Hz, 1H), 3.02 (d, J = 19.8 Hz, 1H), 1.46 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 175.3, 168.9, 140.2, 139.0, 132.0, 130.2,
127.7, 116.1, 115.2, 111.4, 59.9, 53.4, 41.2, 23.7; IR (film) 3252, 2958,
2858, 1738, 1614, 1475, 1228 cm−1; HRMS (ES) m/z = 324.0235
calcd for C14H15BrNO3 [MH]+, found 324.0240; CSP HPLC
(Chiralpak AS, 1.0 mL/min, 92.5:7.5 hexanes:i-PrOH): tR(R) = 15.1
min, tR(S) = 25.5 min.
(S)-tert-Butyl 2-Oxo-3-(propa-1,2-dien-1-yl)indoline-3-carboxyl-
ate (8a). Following the general procedure, using Pd(t-BuPHOX)-
(SbF6)2 catalyst and CH2Cl2 as the solvent, compound 8a was
1
obtained as a white solid in 100% yield: mp 140−141 °C; H NMR
(500 MHz, CDCl3) δ 8.78 (bs, 1H), 7.31−7.24 (m, 2H) 7.04 (t, J =
7.5 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.79 (t, J = 6.5 Hz, 1H) 4.87
(dd, 11.5, 6.5 Hz, 1H), 4.77 (dd, 11.5, 6.5 Hz, 1H), 1.38 (s, 9H); 13C
NMR (125 MHz, CDCl3) δ 208.5, 175.3, 167.1, 141.3, 129.2, 128.5,
125.0, 122.7, 110.3, 89.2, 83.3, 79.3, 60.2, 27.9; IR (film) 3221, 2927,
2858, 1962, 1668, 1738, 1622, 1468, 1259, 1159 cm−1; HRMS (ES)
m/z = 294.1106 calcd for C16H17NO3Na [MNa]+, found 294.1100;
CSP HPLC (Chiralpak AS, 1.0 mL/min, 90:10 hexanes:i-PrOH):
tR(1) = 18.3 min, tR(2) = 26.8 min.
(S)-Methyl 7-Methoxy-3-(2-methylallyl)-2-oxoindoline-3-car-
boxylate (5p). Following the general procedure, compound 5p was
obtained as a white resin in 95% yield: [α]23D +82.78 (c 0.450, 85% ee,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.65 (bs, 1H), 7.01 (t, J =
8.0 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.67 (s,
1H), 4.64 (s, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 3.04 (m, 2H), 1.43 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 174.7, 169.6, 143.8, 139.5,
130.1, 128.9, 123.1, 116.6, 115.6, 111.3, 60.5, 55.6, 53.1, 41.0, 23.7; IR
(film) 3229, 3090, 2958, 2850, 1715, 1622, 1498, 1228 cm−1; HRMS
(ES) m/z = 298.1055 calcd for C15H17NO4Na [MNa]+, found
(S)-tert-Butyl 3-(Buta-2,3-dien-2-yl)-2-oxoindoline-3-carboxylate
(8b). Following the general procedure, using Pd(t-BuPHOX)(SbF6)2
catalyst and CH2Cl2 as the solvent at 0 °C, compound 8b was
11050
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
1
obtained as a white solid in 100% yield: mp 119−120 °C; H NMR
(500 MHz, CDCl3) δ 9.01 (bs, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.24 (td,
J = 7.5, 1.0 Hz, 1H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.86 (d, J = 7.5 Hz,
1H), 4.77 (dq, J = 10.5, 3.0 Hz, 1H), 4.59 (dq, J = 10.5, 3.0 Hz, 1H),
1.90 (t, J = 3 Hz, 3H), 1.42 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
207.8, 175.3, 166.9, 141.3, 129.2, 128.0, 125.9, 122.4, 110.2, 97.6, 83.1,
77.8, 63.2, 27.9, 15.6; IR (film) 3213, 2927, 2858, 1962, 1738, 1622,
1475, 1259 cm−1; HRMS (ES) m/z = 308.1263 calcd for
C17H19NO3Na [MNa]+, found 308.1263; CSP HPLC (Chiralpak
AS, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH): tR(1) = 17.6 min, tR(2) =
21.9 min.
(S)-Methyl 3-(1-(2-Bromophenyl)propa-1,2-dien-1-yl)-2-oxoindo-
line-3-carboxylate (8g). Following the general procedure, the reaction
with 5 mol % Pd[(S)-t-BuPHOX](SbF6)2 catalyst and CH2Cl2 as the
solvent was conducted at −78 °C and slowly warmed to −15 °C.
Compound 8g was obtained as a white resin in 93% yield: [α]23
D
1
+44.44 (c 0.315, 96% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ
9.10 (bs, 1H), 7.55 (dd, J = 7.7, 1.6 Hz, 1H), 7.48 (dd, J = 8.0, 1.2 Hz,
1H), 7.26−7.14 (m, 3H), 7.06 (td, J = 7.5, 1.7 Hz, 1H), 6.94 (t, J = 7.7
Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 5.02 (d,
J = 12.0 Hz, 1H), 3.68 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 209.4,
174.7, 168.4, 141.4, 135.2, 132.9, 130.6, 129.6, 129.4, 127.4, 127.1,
126.5, 125.9, 122.6, 110.3, 101.9, 79.8, 62.5, 53.4; IR (film) 3272,
3062, 2954, 1951, 1742, 1614, 1474, 1235, 1029 cm−1; HRMS (ES)
m/z = 406.0055 calcd for C19H14NO3NaBr [MNa]+, found 406.0052;
CSP HPLC (Chiralpak IA, 1.0 mL/min, 90:10 hexanes:i-PrOH):
tR(1) = 15.07 min, tR(2) = 19.92 min.
(S)-Methyl 2-Oxo-3-(propa-1,2-dien-1-yl)indoline-3-carboxylate
(8c). Following the general procedure, using Pd[(S)-t-BuPHOX]-
(SbF6)2 catalyst and CH2Cl2 as the solvent at 0 °C, compound 8c was
obtained as a white solid in 100% yield: mp 128−129 °C; [α]23D +2.85
1
(c 0.175, 14% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 8.82 (bs,
1H), 7.30−7.26 (m, 2H) 7.06 (td, J = 7.5, 1.0 Hz, 1H), 6.95 (d, J = 7.5,
1H), 5.82 (t, J = 6.5 Hz, 1H), 4.91 (dd, J = 11.5, 6.5 Hz, 1H), 4.79 (dd,
J = 11.5, 6.5 Hz, 1H), 3.73 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
208.5, 174.9, 168.8, 141.1, 129.5, 127.8, 125.4, 122.9, 110.5, 83.1, 79.7,
59.2, 53.7; IR (film) 3252, 2935, 2889, 1962, 1746, 1475, 1244, 1189
cm−1; HRMS (ES) m/z = 230.0817 calcd for C13H12NO3 [MH]+,
found 230.0818; CSP HPLC (Chiralpak AD, 0.75 mL/min, 92.5:7.5
hexanes:i-PrOH): tR(1) = 20.5 min, tR(2) = 22.5 min.
(S)-Methyl 3-(1-(Naphthalen-1-yl)propa-1,2-dien-1-yl)-2-oxoin-
doline-3-carboxylate (8h). Following the general procedure, the
reaction with 5 mol % Pd[(S)-t-BuPHOX](SbF6)2 catalyst and CH2Cl2
as the solvent was conducted at −78 °C and slowly warmed to −15 °C.
Compound 8h was obtained as a white solid in 95% yield: decomposed
1
at 197 °C; [α]23 +59.22 (c 0.07, 98% ee, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 8.84 (bs, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 7.5
Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.44−7.37 (m, 3H), 7.30−7.20 (m,
2H), 7.11 (td, J = 7.7, 1.2 Hz, 1H), 6.83 (td, J = 7.7, 1.0 Hz, 1H), 6.71
(d, J = 7.7 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 5.04 (d, J = 12.0 Hz,
1H), 3.69 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 209.4, 174.6, 168.4,
141.1, 133.8, 132.4, 131.7, 129.5, 128.5, 128.3, 127.3, 126.6, 126.4,
126.1, 125.87, 125.86, 125.2, 122.6, 110.3, 100.1, 78.7, 63.9, 53.5; IR
(film) 3262, 3061, 2934, 1950, 1740, 1613, 1474, 1235, 1029 cm−1;
HRMS (ES) m/z = 378.1106 calcd for C23H17NO3Na [MNa]+, found
378.1109; CSP HPLC (Chiralpak IA, 1.0 mL/min, 90:10 hexanes:i-
PrOH): tR(1) = 14.3 min, tR(2) = 17.9 min.
(S)-Methyl 3-(Buta-2,3-dien-2-yl)-2-oxoindoline-3-carboxylate
(8d). Following the general procedure, using Pd[(S)-t-BuPHOX]-
(SbF6)2 catalyst and CH2Cl2 as the solvent at 0 °C, compound 8d was
obtained as a white solid in 100% yield: [α]23 +26.67 (c 0.075, 45%
D
1
ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.66 (bs, 1H), 7.33 (d,
J = 7.5 Hz, 1H), 7.26 (td, J = 7.5, 1.5 Hz, 1H), 7.05 (td, J = 7.5, 1.0 Hz,
1H), 6.87 (d, J = 7.5 Hz, 1H), 4.80 (dq, J = 11.0, 3.0 Hz, 1H), 4.64
(dd, J = 11.5, 3.0 Hz, 1H), 3.75 (s, 3H), 1.89 (t, J = 3.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 207.9, 173.9, 168.5, 140.8, 129.5, 127.6,
126.4, 122.8, 109.9, 97.5, 78.1, 62.4, 53.5, 15.5; IR (film) 3252, 3066,
2935, 2858, 1962, 1738, 1622, 1475, 1437, 1236, 1189 cm−1; HRMS
(ES) m/z = 244.0974 calcd for C14H14NO3 [MH]+, found 244.0962;
CSP HPLC (Chiralpak AD, 1.0 mL/min, 96.5:3.5 hexanes:i-PrOH):
tR(1) = 23.7 min, tR(2) = 26.7 min.
(S)-Methyl 2-Oxo-3-(1-phenylpropa-1,2-dien-1-yl)indoline-3-car-
boxylate (8e). Following the general procedure, the reaction with
5 mol % Pd[(S)-t-BuPHOX](SbF6)2 catalyst and CH2Cl2 as the
solvent was conducted at −78 °C and slowly warmed to −15 °C.
Compound 8e was obtained as a white solid in 96% yield: mp 149−
150 °C; [α]23D +98.57 (c 0.14, 78% ee, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 9.21 (bs, 1H), 7.42−7.39 (m, 2H), 7.36 (d, J = 7.5, Hz, 1H),
7.26−7.17 (m, 4H), 7.02 (td, J = 7.6, 1.0 Hz, 1H), 6.87 (d, J = 7.8 Hz,
1H), 5.11 (d, J = 12.5 Hz, 1H), 5.02 (d, J = 12.5 Hz, 1H), 3.69 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 210.0, 175.0, 168.6, 141.2,
133.9, 129.6, 128.4, 127.96, 127.91, 127.5, 126.3, 122.9, 110.5, 104.9,
80.3, 62.8, 53.5; IR (film) 3283, 3073, 2934, 1941, 1740, 1612, 1477,
1236, 1029 cm−1; HRMS (ES) m/z = 328.0950 calcd for
C19H15NO3Na [MNa]+, found 328.0944; CSP HPLC (Chiralpak
IA, 1.0 mL/min, 90:10 hexanes:i-PrOH): tR(1) = 16.47 min, tR(2) =
26.69 min.
(S)-Methyl 3-(1-(2-Methoxyphenyl)propa-1,2-dien-1-yl)-2-oxoin-
doline-3-carboxylate (8i). Following the general procedure, the
reaction of a mixture of compound 4i and methylindole-3-carboxylate
(1.4:1) with 5 mol % Pd[(S)-t-BuPHOX](SbF6)2 catalyst and CH2Cl2
as the solvent was conducted at −78 °C and slowly warmed to
−15 °C. Compound 8i was obtained as a colorless resin in 90% yield:
[α]23 +14.25 (c 0.035, 98% ee, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) δ 7.91 (bs, 1H), 7.32 (dd, J = 7.5, 1.7 Hz, 1H), 7.17−7.11 (m,
2H), 6.97 (d, J = 7.8 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.81−6.76 (m,
2H), 6.55 (d, J = 8.2 Hz, 1H), 5.15 (d, J = 11.5 Hz, 1H), 5.12 (d, J =
12.0 Hz, 1H), 3.73 (s, 3H), 3.41 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 210.7, 174.6, 169.0, 156.7, 141.2, 131.2, 129.4, 129.0, 127.4,
126.5, 124.0, 122.0, 120.6, 110.3, 109.2, 100.4, 78.4, 62.6, 54.7, 53.5; IR
(film) 3226, 2924, 2857, 1940, 1745, 1617, 1472, 1227, 1024 cm−1;
HRMS (ES) m/z = 358.1055 calcd for C20H17NO4Na [MNa]+, found
358.1063; CSP HPLC (Chiralpak IA, 1.0 mL/min, 90:10 hexanes:i-
PrOH): tR(1) = 22.93 min, tR(2) = 28.84 min.
(R)-Methyl 2-Oxo-3-(1-(trimethylsilyl)propa-1,2-dien-1-yl)-
indoline-3-carboxylate (8j). Following the general procedure, using
100 mol % Pd[(R)-BINAP](SbF6)2 and CH2Cl2 as the solvent at 0 °C,
compound 8j was obtained as a white solid in 90% yield: [α]23
D
+48.33 (c 0.06, 77% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.99
(bs, 1H), 7.31 (ddd, J = 7.5, 1.0, 0.5 Hz, 1H), 7.26 (td, J = 7.5, 1.0 Hz,
1H), 7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.87 (ddd, J = 7.5, 1.0, 0.5 Hz, 1H),
4.61 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.72 (s, 3H), 0.11
(s, 9H); 13C NMR (125 MHz, CDCl3) δ 211.3, 174.9, 169.2, 140.7,
129.5, 128.3, 126.6, 122.6, 109.9, 95.4, 73.3, 61.7, 53.3, −0.1; IR (film)
3275, 2958, 2858, 1931, 1746, 1622, 1475, 1244 cm−1; HRMS (ES)
m/z = 324.1032 calcd for C16H19NO3NaSi [MNa]+, found 324.1021;
CSP HPLC (Chiralpak AD, 0.75 mL/min, 92.5:7.5 hexanes:i-PrOH):
tR(1) = 12.6 min, tR(2) = 19.4 min.
(S)-Methyl 2-Oxo-3-(1-(o-tolyl)propa-1,2-dien-1-yl)indoline-3-
carboxylate (8f). Following the general procedure, the reaction
with 5 mol % Pd[(S)-t-BuPHOX](SbF6)2 catalyst and CH2Cl2 as the
solvent was conducted at −78 °C and slowly warmed to −15 °C.
Compound 8f was obtained as a white solid in 95% yield: mp 140−
141 °C ; [α]23D +58.50 (c 0.4, 98% ee, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 8.70 (bs, 1H), 7.22−7.18 (m, 3H), 7.10−7.09 (m, 2H),
7.03−7.00 (m, 1H), 6.95 (t, J = 7.5, Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H),
4.98 (d, J = 12.0 Hz, 1H), 4.95 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 2.20
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 208.5, 174.4, 168.3, 141.1,
137.7, 133.5, 130.4, 129.5, 128.7, 127.9, 127.5, 126.4, 125.8, 122.7,
110.2, 101.2, 78.4, 63.6, 53.4, 20.2; IR (film) 3268, 2954, 1949, 1742,
1613, 1477, 1235, 1106 cm−1; HRMS (ES) m/z = 342.1106 calcd for
C20H17NO3Na [MNa]+, found 342.1105; CSP HPLC (Chiralpak IA,
1.0 mL/min, 90:10 hexanes:i-PrOH): tR(1) = 10.65 min, tR(2) =
14.33 min.
(S)-Methyl 3-(4,4-Dimethylpenta-1,2-dien-3-yl)-2-oxoindoline-3-
carboxylate (8k). Following the general procedure, using Pd-
(difluoroPHOX)(SbF6)2 catalyst and CH2Cl2 as the solvent at 0 °C,
compound 8k was obtained as a white solid in 100% yield: [α]23
D
+51.20 (c 0.08, 86% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.58
(bs, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.27 (td, J = 7.5, 1.0 Hz, 1H),
11051
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
7.05 (td, J = 7.5, 1.0 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 4.94 (d, J =
11.0 Hz, 1H), 4.81 (d, J = 11.0 Hz, 1H), 3.71 (s, 3H), 1.06 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 209.7, 174.6, 168.8, 140.5, 129.5,
128.1, 128.0, 122.6, 110.7, 109.8, 79.3, 63.8, 53.5, 34.8, 31.1; IR (film)
3252, 2958, 1946, 1746, 1622, 1475, 1228 cm−1; HRMS (ES) m/z =
308.1263 for C17H19NO3Na [MNa]+, found 308.1255; CSP HPLC
(Chiralpak AD, 0.75 mL/min, 92.5:7.5 hexanes:i-PrOH): tR(1) = 15.4
min, tR(2) = 24.3 min.
procedure, compound 8q was obtained as a white solid in 91%
yield: [α]23D +172.80 (c 0.13, 93% ee, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.68 (bs, 1H), 6.98 (dd, J = 7.5, 7.5 Hz, 1H), 6.90 (d, J = 7.5
Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.37 (d,
J = 12.0 Hz, 1H), 4.20 (qd, J = 7.0, 11.0 Hz, 1H), 4.10 (qd, J = 7.0,
11.0 Hz, 1H), 3.86 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 0.92 (s, 9H), 0.14
(s, 3H), 0.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 212.4, 174.0,
168.9, 143.8, 129.9, 129.2, 122.7, 118.7, 111.5, 100.2, 93.5, 73.9, 62.3,
55.9, 27.6, 19.4, 14.2, −4.1, −4.2; IR (film) 3205, 2935, 2858, 1931,
1722, 1630, 1498, 1282, 1236, 1043 cm−1; HRMS (ES) m/z =
388.1944 calcd for C21H30NO4Si [MH]+, found 388.1954; CSP HPLC
(Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 11.5 min,
tR(2) = 25.2 min.
(S)-Methyl 3-(1-(6-Methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-
yl)propa-1,2-dien-1-yl)-2-oxoindoline-3-carboxylate (8l). Following
the general procedure, the reaction with 20 mol % Pd[(S)-t-
BuPHOX](SbF6)2 catalyst and MeCN:C6H5Cl:CH2Cl2 (1:5:5) as
the solvent was conducted at 45 °C for 2 days. Compound 8l was
obtained as a white solid in 60% yield: decomposed at 164 °C,
[α]23D +5.73 (c 0.035, 70% ee, MeCN); 1H NMR (500 MHz, acetone-
d6) δ 9.59 (bs, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H),
7.02 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 4.68 (d, J = 12.0 Hz,
1H), 4.53 (d, J = 12.0 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 4.21 (s, 2H),
4.07 (d, J = 17.5 Hz, 1H), 3.66 (s, 3H), 3.13 (s, 3H); 13C NMR (125
MHz, acetone-d6) δ 212.4, 174.6, 169.4, 168.3, 167.7, 141.9, 129.3,
128.9, 125.9, 122.0, 109.7, 109.6, 74.5, 63.8, 63.7, 61.4, 52.3, 48.3; IR
(film) 3208, 2960, 1944, 1743, 1617, 1464, 1244, 1042 cm−1; HRMS
(ES) m/z = 407.1027 calcd for C18H17N2O7NaB [MNa]+, found
407.1060; CSP SFC (Chiralpak IA, gradient 20−35% MeOH in CO2,
2−4 mL/min, 12 MPa): tR(1) = 7.94 min, tR(2) = 8.24 min.
(R)-Methyl 2-Oxo-3-(1-(triethylsilyl)propa-1,2-dien-1-yl)indoline-
3-carboxylate (8n). Following the general procedure, compound 8n
was obtained as a white solid in 78% yield: [α]23D +81.00 (c 0.05, 90%
ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 9.12 (bs, 1H), 7.34 (dd,
J = 7.5, 0.5 Hz, 1H), 7.25 (td, J = 8.0, 1.5 Hz, 1H), 7.03 (td, J = 7.5, 1.0
Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 11.5 Hz, 1H), 4.44 (d,
J = 11.5 Hz, 1H), 3.72 (s, 3H), 0.89 (t, J = 8.0 Hz, 9H), 0.67−0.54 (m,
6H); 13C NMR (125 MHz, CDCl3) δ 212.0, 175.8, 169.2, 141.1,
129.4, 128.4, 126.5, 122.5, 110.2, 92.2, 72.9, 62.0, 53.2, 7.5, 4.1; IR
(film) 3259, 2958, 2881, 1931, 1738, 1622, 1468, 1328, 1236, 1104
cm−1; HRMS (ES) m/z = 342.1525 calcd for C19H24NO3Si [M − H]−,
found 342.1537; CSP HPLC (Chiralpak IA, 1 mL/min, 95:5
hexanes:i-PrOH): tR(1) = 14.6 min, tR(2) = 18.4 min.
(R)-Ethyl 5-Bromo-3-(1-(tert-butyldimethylsilyl)propa-1,2-dien-1-
yl)-2-oxoindoline-3-carboxylate (8r). Following the general proce-
dure, compound 8r was obtained as a white solid in 85% yield: mp
1
133−134 °C; [α]23 +130.43 (c 0.12, 90% ee, CH2Cl2); H NMR
D
(500 MHz, CDCl3) δ 9.14 (bs, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36
(dd, J = 8.5, 2.0 Hz, 1H) 6.77 (d, J = 8.5 Hz, 1H), 4.63 (d, J = 12.0 Hz,
1H), 4.43 (d, J = 12.0 Hz, 1H), 4.23 (qd, J = 7.0, 10.5 Hz, 1H), 4.15
(qd, J = 7.0, 10.5 Hz, 1H), 1.25 (t, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.12
(s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 212.4, 175.4,
168.3, 140.1, 132.2, 130.4, 129.5, 115.0, 111.6, 93.3, 74.5, 62.7, 62.5,
27.5, 19.3, 14.2, −4.1, −4.2; IR (film) 3275, 2935, 2858, 1931, 1738,
1614, 1475, 1298, 1236, 1043 cm−1; HRMS (ES) m/z = 458.0756
calcd for C20H26BrNO3SiNa [MNa]+, found 458.0779; CSP HPLC
(Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 9.2 min,
tR(2) = 22.3 min.
(R)-4-(tert-Butyldimethylsilyl)-5-methyl-2H-spiro[furan-3,3′-indo-
line]-2,2′-dione (9m). Following the general procedure, the reaction
mixture was stirred at ambient temperature using C6H5Cl:C6H5CH3
(1:1) as the solvent until the starting material was completely
consumed, as determined by TLC (in 84 h). Next, 5 mol % H2O was
added, and the mixture was stirred at 40 °C for 36 h. Filtration
through a plug of SiO2 (5 mm × 2 cm) with ethyl ether, concentration
of the solution, and purification by column chromatography using
50% ethyl ether/hexane afforded 9m as a white resin in 95% yield:
[α]23D +21.66 (c 0.06, 86% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3)
δ 8.27 (bs, 1H), 7.31−7.26 (m, 1H), 7.06−6.93 (m, 2H), 6.92 (d, J =
7.5 Hz, 1H), 2.27 (s, 3H), 0.82 (s, 9H), −0.07 (s, 3H), −0.18 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 174.3, 173.6 163.2, 141.7, 130.2,
(R)-Methyl 3-(1-(tert-Butyldimethylsilyl)propa-1,2-dien-1-yl)-2-
oxoindoline-3-carboxylate (8m). Following the general procedure,
compound 8m was obtained as a white solid in 90% yield: mp 132−
1
133 °C; [α]23 +128.57 (c 0.07, 89% ee, CH2Cl2); H NMR (500
127.7, 124.8, 123.4, 110.8, 110.4, 66.5, 27.2, 18.2, 16.4, −4.92, −4.96;
IR (film) 3251, 2955, 2870, 1797, 1718, 1624, 1473, 1167, 995 cm−1;
HRMS (ES) m/z = 352.1345 calcd for C18H23NO3SiNa [MNa]+,
found 352.1337; CSP HPLC (Chiralpak IA, 1 mL/min, 90:10
hexanes:i-PrOH): tR(1) = 6.3 min, tR(2) = 10.0 min.
D
MHz, CDCl3) δ 7.87 (bs, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.22 (td, J =
7.5, 1.0 Hz, 1H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.83 (d, J = 7.5 Hz,
1H), 4.56 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.5 Hz, 1H), 3.69 (s, 3H),
0.89 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 212.6, 174.6, 169.3, 140.8, 129.4, 128.5, 126.8, 122.6, 109.7, 93.8,
74.0, 62.3, 53.2, 27.6, 19.4, −4.15, −4.18; IR (film) 3252, 2958, 2858,
1931, 1746, 1622, 1468, 1259, 1089, 1027 cm−1; HRMS (ES) m/z =
366.1501 calcd for C19H25NO3SiNa [MNa]+, found 366.1494; CSP
HPLC (Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 6.1
min, tR(2) = 11.0 min.
(R)-5-Methyl-4-(triisopropylsilyl)-2H-spiro[furan-3,3′-indoline]-
2,2′-dione (9s). Following the general procedure using 5 mol % H2O
and C6H5Cl as the solvent at 40 °C, compound 9s was obtained as
a white solid in 78% yield: mp 202−203 °C; [α]23D + 112.00 (c 0.025,
92% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 8.93 (bs, 1H), 7.27
(dd, J = 8.0, 1.0 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 7.03 (dd, J = 7.5,
1.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 2.28 (s, 3H), 1.03−1.01 (m,
12H), 0.89−0.87 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 174.4,
174.1, 163.0, 142.0, 130.3, 127.9, 124.8, 123.3, 110.9, 109.3, 67.6, 19.2,
18.9, 16.6, 12.5; IR (film) 3236, 2950, 2873, 1800, 1715, 1622, 1468,
1220, 1166 cm−1; HRMS (ES) m/z = 370.1839 calcd for C21H28NO3Si
[M − H]−, found 370.1807; CSP HPLC (Chiralpak IA, 1 mL/min,
98:2 hexanes:i-PrOH): tR(1) = 15.3 min, tR(2) = 39.0 min.
(R)-5,7′-Dimethyl-4-(triisopropylsilyl)-2H-spiro[furan-3,3′-indo-
line]-2,2′-dione (9w). Following the general procedure using 5 mol %
H2O and C6H5Cl:C6H5CH3 (1:1) as the solvent at 40 °C, compound
9w was obtained as a white solid in 93% yield: mp 239−240 °C;
[α]23D +73.53 (c 0.34, 96% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3)
δ 8.37 (bs, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.95 (dd, J = 7.5, 7.5 Hz,
1H), 6.90 (d, J = 7.5 Hz, 1H), 2.27 (s, 6H), 1.05−0.99 (m, 12H),
0.91−0.86 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 174.4, 173.6,
162.9, 140.5, 131.5, 127.5, 123.3, 122.2, 120.1, 109.3, 66.9, 19.2, 18.9,
16.68, 16.65, 12.6; IR (film) 3198, 2950, 2873, 1800, 1715, 1622, 1468,
1220, 1159, 1027 cm−1; HRMS (ES) m/z = 384.1995 calcd for
(R)-Ethyl 3-(1-(tert-Butyldimethylsilyl)propa-1,2-dien-1-yl)-7-
methyl-2-oxoindoline-3-carboxylate (8o). Following the general
procedure using 5 mol % Pd[(R)-BINAP](SbF6)2 as the catalyst,
compound 8o was obtained as a white solid in 76% yield: mp 135−
1
136 °C; [α]23 +137.43 (c 0.35, 90% ee, CH2Cl2); H NMR (300
D
MHz, CDCl3) δ 9.82 (bs, 1H), 7.09 (d, J = 7.5 Hz, 1H), 7.05 (d, J =
7.5 Hz, 1H), 6.93 (dd, J = 7.5, 7.5 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H),
4.36 (d, J = 11.5 Hz, 1H), 4.23 (qd, J = 7.0, 11.0 Hz, 1H), 4.11 (qd, J =
7.0, 11.0 Hz, 1H), 2.31 (s, 3H), 1.22 (t, J = 7.0 Hz, 3H), 0.94 (s, 9H),
0.17 (s, 3H), 0.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 212.3,
176.4, 169.2, 140.2, 130.6, 128.2, 123.6, 122.2, 119.7, 93.6, 74.0, 62.8,
62.2, 27.7, 19.4, 16.7, 14.2, −4.0, −4.1; IR (film) 3198, 2935, 2858,
1931, 1715, 1630, 1468, 1228, 1050 cm−1; HRMS (ES) m/z =
370.1838 calcd for C21H28NO3Si [M − H]−, found 370.1825; CSP
HPLC (Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 12.3
min, tR(2) = 13.8 min.
(R)-Ethyl 3-(1-(tert-Butyldimethylsilyl)propa-1,2-dien-1-yl)-7-me-
thoxy-2-oxoindoline-3-carboxylate (8q). Following the general
11052
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
C22H30NO3Si [M − H]−, found 384.1985; CSP HPLC (Chiralpak IA,
1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 8.9 min, tR(2) = 13.4 min.
(R)-5′-Methoxy-5-methyl-4-(triisopropylsilyl)-2H-spiro[furan-3,3′-
indoline]-2,2′-dione (9x). Following the general procedure using
5 mol % H2O and CH2Cl2 as the solvent at 40 °C, compound 9x was
obtained as a white solid in 81% yield: mp 147−148 °C; [α]23D +60.00
1H), 6.94 (dd, J = 7.5, 8.0 Hz, 1H), 5.25 (s, 1H), 4.17 (qd, J = 10.5,
7.0 Hz, 1H), 4.13 (qd, J = 10.5, 7.0 Hz, 1H), 2.28 (s, 3H), 1.47 (s,
3H), 1.17 (t, J = 7.0 Hz, 3H), 0.91 (s, 9H), 0.18 (s, 3H), 0.17 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 176.6, 169.5, 154.9, 139.8, 130.8,
130.4, 123.2, 121.8, 119.4, 105.1, 62.4, 59.8, 25.8, 19.7, 18.2, 16.7, 14.1,
−4.2, −4.3; IR (film) 3229, 2927, 2858, 1746, 1715, 1661, 1460, 1383,
1228, 1089, 1043 cm−1; HRMS (ES) m/z = 388.1944 calcd for
C21H30NO4Si [M − H]−, found 388.1941; CSP HPLC (Chiralpak
IA, 0.75 mL/min, 92.5:7.5 hexanes:i-PrOH): tR(1) = 7.9 min, tR(2) =
9.6 min.
N-Camphorsulfonyl Derivative of 5i (5′i). To a solution of 60%
NaH in oil (0. 003 g, 0.13 mmol) in THF (2 mL) at 0 °C was added 5i
(0.018 g, 0.07 mmol). After being stirred for 5 min, camphorsulfonyl
chloride (0.0180 g, 0.07 mmol) was added, and the mixture was
warmed to rt. After 2 h, H2O was added, and the aqueous layer was
extracted with CH2Cl2, dried over Na2SO4, and concentrated under
vacuum to give the camphorsulfonyl derivative in 47% yield as a
white solid (0.015 g, 0.03 mmol), which was used without further
purification.
The camphorsulfonyl derivative (0.015 g, 0.03 mmol) was treated
with a solution of 2,4-dinitrophenylhydrazine (0.26 mL, 0.12 M) in 1:1
H2SO4/MeOH. The resulting solution was allowed to stir for 10 min,
then cooled to 0 °C, whereupon formation of crystals was observed
after 24 h. Instead of obtaining the expected hydrazone, the
transesterified methyl ester product was observed. The configuration
obtained from the crystal structure was used to establish the absolute
stereochemistry of 5i. The remaining compounds were assigned by
analogy.
Cyclization of 10 To Form 9o. To a solution of 10 (21 mg, 0.053
mmol) in THF was added a solution of LDA in THF (0.065 mmol).
The reaction mixture was stirred for 4 h at 0 °C and quenched with
saturated aqueous NH4Cl. The aqueous layer was extracted with
diethyl ether, and the combined organic extracts were dried (MgSO4),
filtered, and concentrated. The residue was purified by flash column
chromatography (15% ethyl acetate/hexane) to afford 9o as a white
solid in 81% yield.
1
(c 0.05, 91% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.68 (bs,
1H), 6.83 (d, J = 1.5 Hz, 2H), 6.67 (s, 1H), 3.74 (s, 3H), 2.28 (s, 3H),
1.08−1.00 (m, 12H), 0.94−0.89 (m, 9H); 13C NMR (125 MHz,
CDCl3) δ 174.3, 172.9, 163.2, 156.4, 134.9, 128.9, 115.6, 111.4, 111.2,
109.3, 66.9, 56.0, 19.2, 18.9, 16.7, 12.6; IR (film) 3252, 2950, 2873,
1800, 1715, 1622, 1491, 1298, 1205, 1159, 1081, 1027 cm−1; HRMS
(ES) m/z = 424.1920 calcd for C22H31NO4SiNa [MNa]+, found
424.1910; CSP HPLC (Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH):
tR(1) = 11.0 min, tR(2) = 27.0 min.
(R)-7′-Methoxy-5-methyl-4-(triisopropylsilyl)-2H-spiro[furan-3,3′-
indoline]-2,2′-dione (9y). Following the general procedure using
5 mol % H2O and C6H5Cl as the solvent at 40 °C, compound 9y was
obtained as a white solid in 90% yield: mp 237−238 °C; [α]23D +64.00
1
(c 0.4, 92% ee, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.60 (bs,
1H), 7.00 (dd, J = 8.0, 7.5 Hz, 1H), 6.86 (d, J = 8.0, Hz, 1H), 6.71 (d,
J = 7.5 Hz, 1H), 3.88 (s, 3H), 2.26 (s, 3H), 1.05−0.99 (m, 12H),
0.91−0.87 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 174.2, 172.2,
163.0, 144.4, 130.7, 128.5, 123.9, 116.9, 112.4, 109.1, 67.0, 56.0, 19.2,
18.9, 16.7, 12.6; IR (film) 3198, 2950, 2873, 1800, 1715, 1630, 1498,
1460, 1290, 1159, 1066, 1004 cm−1; HRMS (ES) m/z = 400.1944
calcd for C22H30NO4Si [M − H]−, found 400.1935; CSP HPLC
(Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) = 19.5 min,
tR(2) = 22.9 min.
(R)-5′-Bromo-5-methyl-4-(triisopropylsilyl)-2H-spiro[furan-3,3′-
indoline]-2,2′-dione (9z). Following the general procedure using
10 mol % H2O and C6H5Cl:C6H5CH3 (1:1) at 40 °C, compound 9z
was obtained as a white solid in 82% yield: mp 180−181 °C;
[α]23D +70.66 (c 0.15, 92% ee, CH2Cl2); 1H NMR (500 MHz, CDCl3)
δ 8.80 (bs, 1H), 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.20 (d, J = 2.0 Hz,
1H), 6.81 (d, J = 8.0 Hz, 1H), 2.28 (s, 3H), 1.03 (d, J = 6.0 Hz, 9H),
1.00 (qq, J = 6.0, 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 9H); 13C NMR
(125 MHz, CDCl3) δ 173.7, 173.5 163.7, 140.9, 133.1, 129.8, 128.2,
115.8, 112.3, 108.9, 66.5, 19.1, 18.9, 16.7, 12.5; IR (film) 3252, 2950,
2873, 1800, 1722, 1622, 1475, 1383, 1228, 1166 cm−1; HRMS (ES)
m/z = 448.0944 calcd for C21H27BrNO3Si [M − H]−, found 448.0936;
CSP HPLC (Chiralpak IA, 1 mL/min, 95:5 hexanes:i-PrOH): tR(1) =
8.1 min, tR(2) = 21.7 min.
Protodesilation of 8n To Form 8c. To a solution of 8n (10 mg,
0.029 mmol) in CH2Cl2 was added a solution of TBAF in THF (0.073
mmol). The reaction mixture was stirred for 24 h at room temperature
and quenched with saturated aqueous NH4Cl. The aqueous layer was
extracted with diethyl ether, and the combined organic extracts were
dried (MgSO4), filtered, and concentrated. The residue was purified by
flash column chromatography (20% ethyl acetate/hexane) to afford 8c
as a white solid in 100% yield.
Ethyl 3-(1-(tert-Butyldimethylsilyl)-2-oxopropyl)-7-methyl-2-ox-
oindoline-3-carboxylate (10). To a flask of 8o (35 mg, 0.1 mmol)
and (CF3CO2)2Hg (40 mg, 0.1 mmol) were added AcOH (0.5 mL)
and H2O (0.3 mL). The reaction solution was stirred at room temp-
erature. After 45 min, the mixture was cooled to 0 °C, diluted with ethyl
acetate, and quenched with saturated aqueous Na2S2O3. The mixture
was stirred for 30 min at room temperature. The aqueous layer
was extracted with EtOAc, and the combined organic extracts were
washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, and
concentrated. The residue was purified by flash column chromatog-
raphy (40% ethyl acetate/hexane) to afford 10 as a white solid in 72%
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data including 1H and 13C NMR spectra.
X-ray crystallographic information for select compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
■
1
yield: H NMR (300 MHz, CDCl3) δ 9.24 (bs, 1H), 7.09 (d, J = 7.5
Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.94 (dd, J = 7.5, 7.8 Hz, 1H), 4.12
(qd, J = 10.5, 7.0 Hz, 1H), 4.10 (qd, J = 10.5, 7.0 Hz, 1H), 3.58 (s, 1H),
2.37 (s, 3H), 2.29 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H), 0.82 (s, 9H), 0.06
(s, 3H), −0.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 207.7, 177.4,
170.2, 140.0, 131.1, 128.5, 122.8, 121.7, 119.7, 62.7, 60.8, 49.7, 31.3,
27.2, 18.2, 16.5, 14.0, −5.0, −5.5; IR (film) 3213, 2966, 2866, 1737,
1715, 1661, 1468, 1259, 1213, 1027 cm−1; HRMS (ES) m/z =
390.2101 calcd for C21H33NO4Si [MH]+, found 390.2109.
Ethyl 3-(2-((tert-Butyldimethylsilyl)oxy)prop-1-en-1-yl)-7-methyl-
2-oxoindoline-3-carboxylate (12). To a flask of 10 (10 mg, 0.026
mmol) in toluene (1 mL) was added 4 Å MS (30 mg). The mixture
was stirred for 12 h at 45 °C and filtered through a plug of Celite. The
solution was concentrated in vacuo to afford 12 as a white solid in 93%
yield: [α]23D +176.57 (c 0.175, 89% ee, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 8.50 (bs, 1H), 7.07 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 8.0 Hz,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NSF (CHE-0616885
and CHE-0911713) and NIH (RO1GM87605). Partial
instrumentation support was provided by the NIH for MS
(1S10RR023444) and NMR (1S10RR022442) and by the NSF
for an X-ray diffractometer (CHE-0840438). The assistance of
Dr. Patrick Carroll in obtaining the crystal structures is
gratefully acknowledged. T.C. thanks the Vietnam Education
Foundation for a graduate scholarship.
11053
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
132, 15534−15536. (b) Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.;
Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 5064−5067. (c) Ding,
M.; Zhou, F.; Liu, Y. L.; Wang, C. H.; Zhao, X. L.; Zhou, J. Chem. Sci.
2011, 2, 2035−2039. (d) Wang, Y.; Liu, L.; Zhang, T.; Zhong, N. J.;
Wang, D.; Chen, Y. J. J. Org. Chem. 2012, 77, 4143−4147.
(13) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6477−6487. (b) Ashimori, A.; Bachand, B.;
Govek, S.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
6488−6499.
REFERENCES
■
(1) (a) Xu, Y. K.; Yang, S. P.; Liao, S. G.; Zhang, H.; Lin, L. P.; Ding,
J.; Yue, J. M. J. Nat. Prod. 2006, 69, 1347−1350. (b) Mugishima, T.;
Tsuda, M.; Kasai, Y.; Ishiyama, H.; Fukushi, E.; Kawabata, J.;
Watanabe, M.; Akao, K.; Kobayashi, J. J. Org. Chem. 2005, 70,
9430−9435. (c) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.;
Steyn, P. S. J. Chem. Soc., Perkin Trans. 1 1979, 1751−1761. (d) Lin,
H.; Danishefsky, S. Angew. Chem., Int. Ed. 2003, 42, 36−51.
(e) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748−8758. (f) Polonsky, J.; Merrien, M. A.; Prange, T.; Pascard, C.;
Moreau, S. J. Chem. Soc., Chem. Commun. 1980, 601−602. (g) Prange,
T.; Billion, M. A.; Vuilhorgne, M.; Pascard, C.; Polonsky, J.; Moreau, S.
Tetrahedron Lett. 1981, 22, 1977−1980. (h) Cui, C. B.; Kakeya, H.;
Osada, H. J. Antibiot. 1996, 49, 832−835.
(14) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921−
3924.
(15) (a) Trost, B. M.; Frederiksen, M. U. Angew. Chem., Int. Ed.
2005, 44, 308−310. (b) Trost, B. M.; Brennan, M. K. Org. Lett. 2006,
8, 2027−2030. (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129,
14548−14549.
(16) For general reviews: (a) Lutz, R. P. Chem. Rev. 1984, 84, 205−
247. (b) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry
1996, 7, 1847−1882. (c) Castro, A. M. M. Chem. Rev. 2004, 104,
2939−3002.
(2) (a) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590−
4591. (b) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2,
675−678. (c) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6500−6503.
(3) Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa,
A. Chem. Commun. 2006, 420−422.
(17) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
Int. Ed. 2001, 40, 4700−4703. (b) Abraham, L.; Koerner, M.; Schwab,
P.; Hiersemann, M. Adv. Synth. Catal. 2004, 346, 1281−1294 including
references therein. (c) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 9228−9229. (d) Uyeda, C.; Jacobsen, E. N. J. Am. Chem.
(4) (a) Mitchell, M. O.; Le Quesne, P. W. Tetrahedron Lett. 1990, 31,
2681−2684. (b) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto,
M. Tetrahedron Lett. 2003, 44, 1591−1593.
(5) Wang, H. J.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat.
Prod. 1998, 61, 804−807.
Soc. 2011, 133, 5062−5075. (e) Uyeda, C.; Rotheli, A. R.; Jacobsen, E.
̈
N. Angew. Chem., Int. Ed. 2010, 49, 9753−9756. Kaeobamrung, J.;
Mahatthananchai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010,
132, 8810−8812. (f) Geherty, M. E.; Dura, R. D.; Nelson, S. G. J. Am.
Chem. Soc. 2010, 132, 11875−11877.
(6) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.; Ohta, T.;
Williams, R. M.; Tsukamoto, S. Angew. Chem., Int. Ed. 2007, 46, 2254−
2256.
(7) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y.; Gao,
W.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish, D. A.;
Deschamps, J. R.; Wang, S. J. Am. Chem. Soc. 2005, 127, 10130−
10131.
(8) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Wang, S. J. Med. Chem. 2006, 49, 3432−3435.
(9) Franz, A. K.; Dreyfuss, P. D.; Schreiber, S. L. J. Am. Chem. Soc.
2007, 129, 1020−1021.
(10) Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.;
Cohen, J.; Huselton, C.; Illenberger, A.; Kern, J. C.; Hudak, V. A.;
Marella, M. A.; Melenski, E. G.; McComas, C. C.; Mugford, C. A.;
Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker, R.
C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861−1873.
(11) For reviews: (a) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org.
Biomol. Chem. 2012, 10, 5165−518. (b) Trost, B. M.; Brennan, M. K.
Synthesis 2009, 3003−3025. (c) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209−2219. Selected asymmetric reactions to access
spiroindoles: (d) Kato, S.; Yoshino, T.; Shibasaki, M.; Kanai, M.;
Matsunaga, S. Angew. Chem., Int. Ed. 2012, 51, 7007−7010.
(e) Mitsunuma, H.; Shibasaki, M.; Kanai, M.; Matsunaga, S. Angew.
Chem., Int. Ed. 2012, 51, 5217−5221. (f) Sun, W. S.; Zhu, G. M.; Wu,
C. Y.; Hong, L.; Wang, R. Chem.-Eur. J. 2012, 18, 6737−6741. (g) Jia,
Z. J.; Jiang, H.; Li, J. L.; Gschwend, B.; Li, Q. Z.; Yin, X. A.; Grouleff,
J.; Chen, Y. C.; Jorgensen, K. A. J. Am. Chem. Soc. 2011, 133, 5053−
5061. (h) Tan, B.; Candeias, N. R.; Barbas, C. F. J. Am. Chem. Soc.
2011, 133, 4672−4675. (i) Jiang, X. X.; Cao, Y. M.; Wang, Y. Q.; Liu,
L. P.; Shen, F. F.; Wang, R. J. Am. Chem. Soc. 2010, 132, 15328−
15333. (j) Wei, Q.; Gong, L. Z. Org. Lett. 2010, 12, 1008−1011.
(k) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.-Eur. J.
2010, 16, 2852−2856. (l) Chen, X. H.; Wei, Q.; Luo, S. W.; Xiao, H.;
Gong, L. Z. J. Am. Chem. Soc. 2009, 131, 13819−13825.
(m) Bencivenni, G.; Wu, L. Y.; Mazzanti, A.; Giannichi, B.;
Pesciaioli, F.; Song, M. P.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2009, 48, 7200−7203. (n) Bui, T.; Syed, S.; Barbas, C. F., III. J.
Am. Chem. Soc. 2009, 131, 8758−8759. (o) Overman, L. E.; Rosen, M.
D. Angew. Chem., Int. Ed. 2000, 39, 4596−4599. (p) Sebahar, P. R.;
Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666−5667.
(12) For review: Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010,
352, 1381−1407. Selected asymmetric reactions to access quaternary
oxindoles: (a) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2010,
(18) (a) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130,
16162−16163. (b) Cao, T.; Deitch, J.; Linton, E. C.; Kozlowski, M. C.
Angew. Chem., Int. Ed. 2012, 51, 2448−2451.
(19) Booker-Milburn, K. I.; Fedouloff, M.; Paknoham, S. J.; Strachan,
J. B.; Melville, J. L.; Voyle, M. Tetrahedron Lett. 2000, 41, 4657−4661.
(20) Burrows, C. J.; Carpenter, B. K. J. Am. Chem. Soc. 1981, 103,
6984−6986.
(21) Tsogoeva, S. B.; Durner, G.; Bolte, M.; Gobel, M. W. Eur. J. Org.
̈
̈
Chem. 2003, 1661−1664. Annamalai, V. R.; Linton, E. C.; Kozlowski,
M. C. Org. Lett. 2008, 11, 621−624.
(22) To achieve reproducible results, the [Cu(S,S)-box]Cl2 complex
was premade on a larger scale (100−200 mg) to ensure an accurate
ratio of copper to ligand (0.92:1.0). The copper chloride complex was
then treated with AgOTf, AgBF4, or AgSbF6, to exchange the
counterion on the copper.
(23) In addition, all glassware was base-washed to ensure there was
no trace acid to catalyze the rearrangement.
(24) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006, 106,
3561−3651.
(25) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.;
̂
Genet, J.-P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43,
320−325.
(26) Evans, D. A.; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller,
S. J. Angew. Chem., Int. Ed. 1995, 34, 798−800.
̈
(27) Balta, B.; Cem Ozturk, C.; Aviyente, V.; Vincent, M. A.; Hillier,
̈
I. A. J. Org. Chem. 2008, 73, 4800−4809.
(28) Examples of palladium as a Lewis acid: Strukul, G. Top. Catal.
2002, 19, 33−42.
(29) (a) Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem.
Soc. 2007, 129, 5031−5044. (b) Kiyama, K.; Mikami, K. Tetrahedron
Lett. 2004, 45, 7217−7120. (c) Kang, J.; Yew, K. H.; Kim, T. H.; Choi,
D. H. Tetrahedron Lett. 2002, 43, 9509−9512. (d) Mikami, K.;
Takahashi, K.; Sugiura, M.; Yanagisawa, M.; Nakai, T. Synlett 1995,
447−448. (e) Nakai, T. Tetrahedron Lett. 1987, 28, 5879−5882.
(f) Van der Baan, J. L.; Bickelhaupt, F. Tetrahedron Lett. 1986, 27,
6267−6270.
(30) (a) Nishimura, T.; Makino, H.; Nagaosa, M.; Hayashi, T. J. Am.
Chem. Soc. 2010, 132, 12865−12867. (b) Ogasawara, M.; Okada, A.;
Subbarayan, V.; Sorgel, S.; Takahashi, T. Org. Lett. 2010, 12, 5736−5739.
(c) Nemoto, T.; Kanematsu, M.; Tamura, S.; Hamada, Y. Adv. Synth.
11054
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055

The Journal of Organic Chemistry
Article
Catal. 2009, 351, 1773−1778. (d) Imada, Y.; Nishida, M.; Kutsuwa, K.;
Murahashi, S.-I.; Naota, T. Org. Lett. 2005, 7, 5837−5839. (e) Ogasawara,
M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123,
2089−2090.
(31) (a) Tejedor, D.; Mendez-Abt, G.; Cotos, L.; Garcia-Tellado, F.
Chem. Soc. Rev. 2013, Advance article DOI: 10.1039/C2CS35311C.
(b) Ohno, H.; Nagaoka, Y.; Tomioka, K. Modern Allene Chemistry;
Wiley-VCH: New York, 2008; pp 141−181. (c) Sherry, B. D.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 15978−15979. (d) Lo, V. K.-Y.; Liu,
Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529−1532.
(32) Krause, N.; Hoffmann-Roder, A. Modern Allene Chemistry;
̈
Wiley-VCH: New York, 2008; pp 997−1040.
(33) Diastereoselective versions have been reported: (a) Mulder, J.
A.; Hsung, R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. Org. Lett.
2002, 4, 1383−1386. (b) Frederick, M. O.; Hsung, R. P.; Lambeth, R.
H.; Mulder, J. A.; Tracey, M. R. Org. Lett. 2003, 5, 2663−2666.
(c) Kurtz, K. C. M.; Frederick, M. O.; Lambeth, R. H.; Mulder, J. A.;
Tracey, M. R.; Hsung, R. P. Tetrahedron 2006, 62, 3928−3938.
(d) Tang, Y.; Shen, L. C.; Dellaria, B. J.; Hsung, R. P. Tetrahedron Lett.
2008, 49, 6404−6409.
(34) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. Org. Lett.
2010, 12, 2314−2317.
(35) For related Au(III) reactions with achiral catalysts, see ref 31c.
(36) Tratrat, C.; Giorgi-Renault, S.; Husson, H.-P. J. Org. Chem.
2000, 65, 6773−6776.
(37) (a) Wierschke, S. G.; Chandrasekhar, J.; Jorgensen, W. L. J. Am.
Chem. Soc. 1985, 107, 1496−1500. (b) Hosomi, A. Acc. Chem. Res.
1988, 21, 200. (c) Fleming, I.; Dunogues, J.; Smithers, R. In Organic
Reactions; Kende, A. S., Ed.; Wiley: New York, 1989; Vol. 37, pp 57−
575. (d) Epstein, O. L.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 16480−
16481.
(38) (a) Schelper, M.; de Meijere, A. Eur. J. Org. Chem. 2005, 582−
592. (b) Brossat, M.; Heck, M. P.; Mioskowski, C. J. Org. Chem. 2007,
72, 5938−5941. (c) Mukherjee, S.; Kontokosta, D.; Patil, A.; Rallapalli,
S.; Lee, D. J. Org. Chem. 2009, 74, 9206−9209. (d) Kwong, F. Y.; Lee,
H. W.; Qiu, L.; Lam, W. H.; Li, Y.-M.; Kwong, H. L.; Chan, A. S. C.
Adv. Synth. Catal. 2005, 347, 1750−1754.
(39) Islam, M. S.; Brennan, C.; Wang, Q. W.; Hossain, M. M. J. Org.
Chem. 2006, 71, 4675−4677.
(40) Lee, S. J.; Anderson, T. M.; Burke, M. D. Angew. Chem., Int. Ed.
2010, 49, 8860−8863.
11055
dx.doi.org/10.1021/jo302039n | J. Org. Chem. 2012, 77, 11034−11055