Catalytic double stereoinduction in asymmetric allylic alkylation of oxindoles

Article abstract of DOI:10.1002/chem.200902770

A highly regio-, diastereo-, and enantioselective allylic alkylation reaction of 3-monosubstituted oxindoles catalyzed by molybdenum is described. The reaction is affected by the electronic and steric variations of the nucleophile. The use of appropriate N-protecting group is particularly important for achieving high regio- and diastereoselectivity. Products from this reaction, containing vicinal quaternary-tertiary stereogenic centers, are valuable synthetic intermediates and should find utility in alkaloid synthesis.

Full text of DOI:10.1002/chem.200902770

DOI: 10.1002/chem.200902770
Catalytic Double Stereoinduction in Asymmetric Allylic Alkylation of
Oxindoles
Barry M. Trost* and Yong Zhang[a]
Abstract: A highly regio-, diastereo-, and enantioselective allylic alkylation reac-
tion of 3-monosubstituted oxindoles catalyzed by molybdenum is described. The
reaction is affected by the electronic and steric variations of the nucleophile. The
use of appropriate N-protecting group is particularly important for achieving high
regio- and diastereoselectivity. Products from this reaction, containing vicinal qua-
ternary-tertiary stereogenic centers, are valuable synthetic intermediates and
should find utility in alkaloid synthesis.
Keywords: alkylation · asymmetric
catalysis · molybdenum · oxindoles ·
quaternary center
Introduction
been very challenging owing to the lack of understanding of
the origin of the selectivity.
Asymmetric allylic alkylations (AAA) hold much promise
for simplifying asymmetric total syntheses and thus new de-
velopments represent an important goal.[1] One such illustra-
tion, is the evolution of the decarboxylation asymmetric al-
lylic alkylation (DAAA), which allows for the previously
difficult asymmetric alkylations of ketone enolates to be
more general.[2] Furthermore, development of systems em-
ploying Ir,[3] Cu,[4] and Mo[5] as asymmetric catalysts has sig-
nificantly expanded the scope of the nucleophile and elec-
trophile. Despite all these advancements, very few allylic al-
kylation reactions allow the simultaneous stereocontrol at
both the nucleophile and the allylic electrophile, especially
when a quaternary center is also created in the process. De-
velopment of such a reaction is highly desirable, as few
methods exist for the asymmetric construction of vicinal
quaternary or quaternary-tertiary stereogenic centers that
are abundantly present in biologically important mole-
cules.[6] We have reported that asymmetric alkylation of
azlactones[5b] and oxalactims[5c] in the presence of a chiral
molybdenum catalyst proceeded with excellent stereoselec-
tivity at both the nucleophile and electrophile. However, the
extension of this technology into other nucleophiles has
The present study concerns the use of oxindoles as nucle-
ophiles in the molybdenum reaction. The 3,3’-disubstituted
oxindoles are important targets for asymmetric synthesis be-
cause of their significance in biological applications.[7]
A
number of naturally occurring oxindole alkaloids that exhib-
it interesting medicinal properties contain chiral quaternary
centers at the 3 position of the oxindole. Since Julian first
demonstrated that the pyrrolidinoindoline core of physostig-
mine can be prepared by a reductive ring closure of a 3,3’-
disubstituted oxindole in 1935,[8] many synthetic efforts to-
wards the oxindole and pyrrolidinoindoline natural products
have incorporated oxindoles into their synthetic strategies.[9]
However, the asymmetric entry into this important structur-
al motif has been primarily achieved by resolution or diaste-
reoselective methods using chiral auxiliaries or existing chir-
ality. Only very recently have a few enantioselective meth-
ods for the synthesis of chiral 3,3’-disubstituted oxindoles
been reported.[10]
The recent success of Mo-catalyzed AAA reactions with
azlactones and oxalactims prompted us to investigate wheth-
er structurally similar oxindole nucleophiles would also per-
form well in such reactions. The enolates of azlactones, oxa-
lactims, and oxindoles are all stabilized by aromatic reso-
nance and are therefore more stable than the enolates of
the corresponding lactams and lactones. The cyclic nature of
these structures not only provides structural rigidity, but
also alleviates some of the steric difficulties when alkylating.
The use of mono-substituted oxindoles as nucleophiles
should be more difficult, however, as it involves formation
of a quaternary center as opposed to tertiary carbon centers
[a] Dr. B. M. Trost, Y. Zhang
Department of Chemistry, Stanford University
Stanford, CA 94305 (USA)
Fax : (+1)650-725-0002
E-mail: bmtrost@stanford.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902770.
296
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Chem. Eur. J. 2010, 16, 296 – 303

FULL PAPER
in azlactones and oxalactims, owing to the fact that one of
the substituents is a heteroatom in those latter cases. The
following discussion details the development of a Mo-cata-
lyzed regio-, diastereo- and enantioselective allylic alkyla-
tion reaction with 3-monosubstituted oxindoles as nucleo-
philes and our discovery that the high selectivity in the mo-
lybdenum reaction can be attained through simple and ra-
tional modification of the structure of the nucleophile.
Results and Discussion
Scope of the reaction with 3-aryloxindole as the nucleophile:
Given that the steric and electronic properties of the nucleo-
phile can significantly impact the reactivity and selectivity of
enolate alkylation reactions, we began our study by looking
at two sterically and electronically distinct oxindoles
(Table 1). Encouragingly, both 3-methyl (1a) and 3-phenyl-
With the optimized conditions in hand, we next looked to
examine the scope of the reaction with regard to the nucleo-
phile (Table 2). The steric size of the N-protecting group
does not seem to be important as methoxymethyl (2a) and
benzyl (2b) gave essentially identical results as methyl. The
methoxymethyl and benzyl group are valuable as they can
be easily removed to afford unprotected oxindoles.[11] We fo-
cused our studies on N-methyl compounds, however, as ox-
indoles bearing methoxymethyl and benzyl groups gave
more complicated proton NMR for the precise determina-
tion of regio- and diastereoselectivity, and are more difficult
to separate on chiral HPLC for the determination of ee.
Given that 3-phenyloxindole gave much better selectivity
than the more nucleophilic 3-methyoxindole (entries 1 and
2, Table 1), we hypothesized that the selectivity of the reac-
tion is inversely related to the nucleophilicity of the oxin-
doles. If this hypothesis is correct, oxindoles bearing elec-
tron-rich 3-aryl substituents, which are more nucleophilic,
should show diminished selectivity in the Mo reaction, com-
pared to the electron-neutral 1b. On the other hand, elec-
tron-deficient 3-aryloxindoles should provide enhanced se-
lectivity. Surprisingly, although the selectivity of the reaction
changed significantly as we systematically modified the elec-
tronics of the 3-aryl substituents on the oxindoles, the trend
is not as we had predicted. The regio-, and diastereoselectiv-
ity of the reaction decreased as more electron-withdrawing
para-substituents were placed on the phenyl ring (2g–2i).
Electron-donating groups such as dimethylamino (2e) and
methoxy (2 f) group, however, had little effects on the selec-
tivity. In all cases, the ee and yield of the reaction showed
little sensitivity to the electronic variations.
Steric demand of the nucleophile can have a significant
effect on the regioselectivity of the Mo-catalyzed allylic al-
kylation reaction.[12] In general, small nucleophiles are more
selective toward bond formation at the more hindered inter-
nal position of the p allyl, compared to the more bulky
ones. Thus, at the outset, we expected that the more com-
pact five-membered heterocycle-substituted oxindoles would
give better regioselectivity, favoring the branched product,
while oxindoles bearing bulky aryl groups would be less
branch selective. In contrast to this expectation, the bulky 2-
tolyl (2k) and 1-naphthyl (2l) substituted oxindoles gave ex-
cellent selectivity for the branched products, whereas the
smaller thienyl (2q), thiazoyl (2o), and indolyl (2p) substi-
Table 1. Screening of reaction conditions.
Entry
R
Ligand Base
(2a) L1 LiOtBu
T [8C] b/l[a]
d.r.[a] ee [%]
1
2
3
4
5
6
7
8
Me
G
RT
RT
2:1 1.2:1
4:1 8:1
–
95
–
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(2b)
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
KOtBu
NaOtBu
NaOtBu
NaOtBu
RT 2.5:1 5.5:1
RT 2.5:1
RT 4:1
RT 1.2:1
5:1
7:1
3:1
4:1
5:1
9:1
9:1
–
–
–
–
–
94
92
92
–
RT
RT
RT
0
5:1
10:1
16:1
16:1
16:1
9
10
11
60
[a] The branch/linear ratio (b:l) and the diastereoselectivity of the
branched product (d.r.) were determined by 1H NMR integration of the
crude reaction mixture
oxindole (1b) reacted to afford the alkylated products
smoothly at room temperature (entries 1 and 2). However,
the more stabilized 3-phenyloxindole (1b) gave much better
selectivity. Further optimizations of ligand, base and reac-
tion temperature revealed that among the ligands screened,
the standard and most easily available bispicolinamide
ligand L1 is the best ligand for the reaction with 1b (en-
tries 2–7); the selectivity of the reaction is not sensitive to
temperature from 0– 608C (entries 9–11); and the use of Na
base provided the best regio-, and diastereoselectivity, al-
though the ee is slightly lower than the reaction using Li or
K base (entry 8). Thus, the use of ligand L1 (15%mol),
[MoACHTUNGTRENNUNG(C7H8)(CO)3] (10%mol), and NaOtBu (1.1 equiv) in
THF at room temperature or 608C (entry 11) became our
standard conditions for the alkylation of 3-aryloxindoles.
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297

B. M. Trost and Y. Zhang
Table 2. Scope of the 3-aryloxindoles.
New mechanistic proposal: The puzzling trend observed
in the above electronic and steric studies prompted us to ad-
dress the question of what is the origin of stereocontrol in
the molybdenum reaction. Previous mechanistic studies
have revealed that the molybdenum reaction is an inner-
sphere process for which the selectivity determining step is
the reductive elimination from a p-allylmolybdenum eno-
late.[13] To evaluate why different nucleophiles behave differ-
ently in the molybdenum reaction, we need to better under-
stand the reductive elimination step.
We were aware of studies of reductive elimination involv-
ing Pd enolate complexes and that different bonding modes
of Pd enolate can affect the reactivity and selectivity of the
reductive elimination. Specifically, Culkin and Hartwig[14,15]
have shown that depending on the particular electronic and
steric circumstances, a C-bound or an O-bound Pd enolate
isomer may predominate; the C-bound and O-bound iso-
mers react differently; and that the stability and reactivity
of the enolates are not controlled by the pKa of the carbonyl
compounds.
We consider that the Mo AAA reaction may also involve
both or either O-bound and C-bound Mo enolate com-
plexes, both of which have been structurally characterized.
For example, p-allylmolybdenum complex 4 is an O-bound
enolate,[16] but CpMo complex 5 is C-bound (Scheme 1). In-
terestingly,
a high-valent molybdenum complex 6 also
adopts a C-bound structure as a result of favorable chelation
with an a-N atom.[17]
Scheme 1. Molybdenum enolate.
A reaction mechanism involving divergent reaction modes
of O-bound and C-bound Mo enolate complexes can ration-
alize the results from our studies with oxindoles as well as
other nucleophiles (Scheme 2). First of all, aromatic stabili-
zation favors O-bound enolate and a favorable “Claisen-
like” transition state allows the more substituted allyl termi-
nus to bond to the sp2 carbon of the O-enolate to form the
branched product (path A). The generally better regioselec-
tivity observed in the reaction of azlactone than that of ox-
indole can be ascribed to stronger aromatic stabilization in
the case of azlactone. Tuning the electronic and steric prop-
erties of the oxindole nucleophile, however, should influence
the equilibrium ratios of the two enolate isomers and which
isomer reacts to give the products. Sterically, a larger aryl
group should disfavor the crowded C-bound enolate and
favor the O-bound enolate structure, which leads to the nor-
mally preferred branched product. On the other hand, the
tuted oxindoles gave exclusively linear products. Further-
more, installing extra steric bulk on these heterocycles re-
versed the regioselectivity to give branched products with
excellent selectivity (2s, 2t, and 2u). Notably, the bulkier
oxindoles also gave better diastereoselectivity (2l vs. 2m, 2k
vs. 2b).
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Stereoinduction in the Alkylation of Oxindoles
FULL PAPER
the Mo enolate isomers to equilibrate. Indeed, the use of a
bis-methoxy ligand L2 improved the regioselectivity of the
reactions with substrate 2i and 2s significantly (Table 4).[18]
Table 4. Ligand effects on the regioselectivity.
Entry
Ar group
Ligand
b/l
7:1
18:1
2.5:1
16:1
d.r.
ee [%]
Scheme 2. O-bound vs. C-bound Mo enolate.
1
2
3
4
4-cyano-phenyl (2l)
4-cyano-phenyl (2l)
2,4-dimethyl-5-thiazoyl
2,4-dimethyl-5-thiazoylAHCTNUGTRENNNUG
L1
L2
L1
L2
4.5:1
4:1
19:1
19:1
89
92
92
93
G
more compact five-membered heterocycle substituted oxin-
doles should accommodate the C-bound enolate more readi-
ly. The steric crowding of a direct reductive elimination to a
quaternary sp3 center only allows bonding to the less hin-
dered primary allyl terminus in this case (path B). Electroni-
cally, electron-withdrawing 3-aryl substituents should stabi-
lize both enolate complexes and slow down their inter-con-
version. Hence, we see the regioselectivity of the reaction
deteriorates as more electron-withdrawing groups were in-
troduced.
Scope of the electrophile: The Mo-catalyzed AAA reaction
works well with a diverse array of 3-monosubstituted linear
allylic electrophiles, giving good to excellent regio-, diaster-
eo-, and enantioselectivity (Table 5). Further, an alkyl sub-
stituted allylating agent also gave good selectivity (entry 6).
Table 5. Scope of the allylic electrophile.[a]
Attempts to isolate and characterize the molybdenum
enolate complex by preforming the p-allylmolybdenum and
then adding the oxindole nucleophile at low temperature
were not successful. Even at À788C, we could not spectro-
scopically detect the presence of any Mo-enolate intermedi-
ate and only observed the formation of the alkylated prod-
uct. Interestingly, the regio- and diastereoselectivity of the
reaction at À788C is much lower than that at room tempera-
ture (Table 3), which we attributed to a slower interconver-
Entry
R group
Yield [%]
b/l[b]
d.r.[b]
ee [%][c]
1
2
3
4
5
6
3,4-Cl2-C6H3
4-OTBS-C6H4
2-furyl
2-thiophenyl
2-NHBocC6H4
2-(E)-butene
87
90
92
88
89
84
6:1
19:1
12:1
13:1
19:1
6:1
5.5:1
8:1
6:1
8:1
19:1
6:1
89
89
91
90
93
91
Table 3. Temperature effect on selectivity.
[a] The reaction was performed with 0.1 mmol of oxindole 1b and
0.12 mmol of cinnamyl carbonate. [b] The branch/linear ratio (b/l) and
the diastereoselectivity of the branched product (d.r.) was determined by
1H NMR integration of the crude reaction mixture. [c] The ee% was de-
termined by chiral HPLC.
Entry
T [8C]
Yield [%]
b/l
d.r.
ee [%]
1
2
RT
À78
89
40
10:1
1:1
8:1
2:1
92
91
The use of racemic branched allylic electrophiles in the
AAA reaction is desirable, as the corresponding allylic alco-
hol is easily prepared by addition of vinyl Grignard to an al-
dehyde. However, to prepare enantiopure product from rac-
emic starting material requires either a kinetic resolution,
for which half of the starting material is lost by default, or a
dynamic kinetic-asymmetric transformation (DYKAT), for
which equilibration of either the starting material or a reac-
tion intermediate allows the reaction to proceed to comple-
tion (Scheme 3).[19] Equilibration of the p-allylmolybdenum
complex is known to be sufficiently fast at low concentration
of nucleophile to provide synthetically useful DYKAT (k1 @
sion of the Mo-enolate isomers at low temperature that, in
turn, lead to unselective reaction via the C-bound molybde-
num enolate. This result prompted us to examine whether
promoting the equilibration between the enolate isomers
would move the reaction toward a Curtin–Hammett type sit-
uation and favor reductive elimination via the less hindered
O-bound enolate to give the branched product. We reasoned
that the use of a more electron-rich ligand should slow
down reductive elimination and thus allowing more time for
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299

B. M. Trost and Y. Zhang
low (entry 3). Gratifyingly, oxindoles that contain chelating
N-carbamoyl groups all gave greatly improved regioselectiv-
ity favoring the branched product. Furthermore, the diaste-
reoselectivity was found to correlate inversely with the
steric size of the N-carbamoyl group (entries 4–6), and the
smallest N-methoxycarbonyl (N-Moc) oxindole provided the
best diastereoselectivity of 7:1. This correlation between the
steric size of the N-substituent and the diastereoselectivity
of the reaction supports the proposed formation of a bis-
chelating molybdenum enolate intermediate that brought
the substituent on the nitrogen closer to the chiral catalyst.
As discussed earlier (Table 2), the reaction with N-alkyl-3-
aryloxindole, for which only mono-chelation is possible,
showed no sensitivity to the steric size of the substituent on
the nitrogen. The Moc group is labile under the reaction
conditions, and the deprotected amide can act as a catalyst
poison.[21] Subsequent optimization revealed that the use of
O,N-bis(trimethylsilyl)acetamide (BSA) as the stoichiomet-
ric base was compatible with the Moc group and afforded
Scheme 3. Dynamic kinetic resolution of branched allylic electrophiles.
k4).[20] In light of the ligand effect on the regioselectivity of
the reaction discussed above, we were intrigued by the pos-
sibility that an electron-rich ligand could promote
DYKAT process without modifying the concentration of the
nucleophile. Electron-rich ligand stabilizes the h1-allylmetal
complex thus facilitating equilibration of p-allylmolybde-
num complex. In addition, the rate of nucleophilic attack
and reductive elimination should both be slower with elec-
tron-rich ligand. The beneficia-
a
ry effect of the electron-rich
Table 6. Mo reaction with branched electrophiles.[a]
ligand was demonstrated by
comparing L1 and L2 in reac-
tions with several branched al-
lylic carbonate (Table 6). In all
cases, much improved selectiv-
ity, especially enantioselectivi-
ty, was observed with the more
electron-rich ligand L2.
Entry
R group
Ligand
Yield [%]
b/l[b]
d.r.[b]
ee [%][c]
Product
1
2
3
4
5
6
Ph
Ph
L1
L2
L1
L2
L1
L2
88
85
90
87
89
89
10:1
15:1
6:1
8:1
12:1
15:1
6:1
9:1
5:1
6:1
6.5:1
8:1
82
93
80
89
81
89
2b
2b
7a
7a
7b
7b
Optimization of 3-alkyloxin-
doles as nucleophiles: We have
discussed earlier that the reac-
tion with the synthetically very
3,4-L2C6H3
3,4-L2C6H3
4-OTBSC6H4
4-OTBSC6H4
[a] The reaction was performed with 0.1 mmol of oxindole 1b and 0.12 mmol of allylic carbonate. [b] The
branch/linear ratio (b/l) and the diastereoselectivity of the branched product (d.r.) was determined by
1H NMR integration of the crude reaction mixture. [c] The ee% was determined by chiral HPLC.
useful
1,3-dialkyloxindoles
produced a mixture of prod-
ucts with poor selectivity
(entry 1, Table 1). On the basis
of the assumption that promot-
ing a reaction pathway pro-
ceeding through an O-bound
molybdenum enolate should
improve the selectivity, we ex-
amined the effect of chelating
groups on the nitrogen of the
3-alkyloxindoles with the ex-
pectation that the formation of
a bis-chelated enolate may dis-
favor the formation of C-
bound enolate (Table 7). We
were encouraged that the use
of a 2-pyridyl group on the ni-
trogen improved the regiose-
lectivity of the reaction to a re-
spectable level, although the
d.r. of the reaction remains
Table 7. Screening of chelating groups.
Entry
R group
Base (equivalents)
Yield [%]
92
b/l
2:1
d.r.
ee [%]
1
Me (8a)
NaOtBu (1)
1.2:1
92
2
3
4
5
OAc
2-pyridyl (8c)
CO2tBu (8d)
G
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (1)
NaOtBu (0.1) BSA (1.2)
NaOtBu (0.1) BSA (1.2)
no reaction
14:1
12:1
15:1
15:1
89
85
86
60
88
83
1:1
3:1
5:1
7:1
7:1
7:1
nd[b]
98
99
98
98
CO2Et
6
CO2Me
CO2Me
CO2Me
7
15:1
15:1
8[a]
98
[a] performed with 2.5% [MoACTHNUTRGNE(UNG C7H8)(CO)3] and 3.75% L1. [b] nd=not determined.
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Chem. Eur. J. 2010, 16, 296 – 303

Stereoinduction in the Alkylation of Oxindoles
FULL PAPER
consistent conversion with only 2.5% catalyst loading
(entry 8).
Having identified the key parameters of the catalytic
system, the scope of the molybdenum reaction was next ex-
Table 8. Scope of the 3-alkyloxindoles.
Scheme 4. Model for stereoselectivity and X-ray structure of 9g.
stereoselectivity is consistent with our analysis that the reac-
tion proceeds through a bis-chelating O-bound molybdenum
enolate intermediate, as shown in Scheme 4. Path A is fa-
vored as it avoids the steric interaction between the 3-alkyl
group and the ligand. Reductive elimination from intermedi-
ate A via a “Claisen-like” transition state provides the
branched product. However, as the size of the carbamoyl
group increases, the steric congestion between the N-carba-
moyl group and the ligand disfavors path A and leads to de-
terioration of the diastereoselectivity. The proposed transi-
tion state is in agreement with the stereochemical outcome
of the reaction that was established by X-ray crystallograph-
ic analysis of compound 9g.
Conclusions
In conclusion, we have developed a molybdenum-catalyzed
allylic-alkylation reaction with oxindoles containing either
an aryl or an alkyl substituent the 3 position of the oxindole
that proceeds with high regio-, diastereo-, and enantioselec-
tivity. The products of the reaction are highly useful inter-
mediates for the preparation of oxindole and indoline natu-
ral products containing adjacent quaternary-tertiary stereo-
centers that are difficult to access by means of other meth-
ods. In the case of 3-aryloxindoles, the selectivity of the re-
action is sensitive towards the steric and electronic variation
of the aryl group. However, the use of an electron-rich
ligand can improve the regioselectivity. In the case of 3-alkyl-
oxinoles, the ability to influence regio- and diastereoselectiv-
ity of the molybdenum reaction through chelation control is
a significant finding. Furthermore, a predictive model in-
volving the intermediacy of C vs. O enolates has been devel-
oped and should have broad applicability with other classes
of nucleophiles. In particular, we are in the process of iden-
plored, in which a variety of 3-alkyloxindoles were efficient-
ly and selectively alkylated (Table 8). Substitution on the ox-
indole aromatic ring does not affect the reaction (9l–9n).
Functional groups such as allyl (9i), TBS ether (9j) and
ester groups (9k) at the 3 positions of the oxindoles are tol-
erated. Notably, increasing the size of the 3-alkyl group in-
creased the diastereoselectivity significantly, while maintain-
ing excellent levels of regio- and enantioselectivity (9g vs.
9h vs. 9 L). The largest N-isopropyl substituted oxindoles
(9l–9n), which are difficult substrates in several other asym-
metric oxindole syntheses, gave the branched product as es-
sentially a single enantiomer.[22] For the convenience of han-
dling and purification, the N-Moc group was removed in
situ with 1 equiv of NaOH in methanol upon completion of
the alkylation reaction.
The observation that the combination of a small N-carba-
moyl group and a large 3-alkyl group provided the best dia-
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301

B. M. Trost and Y. Zhang
the addition of cinnamyl tert-butyl carbonate (0.24 mmol) via syringe.
The resulting solution was stirred at 608C under Ar for 6 h until TLC in-
dicates complete consumption of the starting oxindole. The reaction mix-
ture was then cooled to 08C, and a solution of NaOH (0.25 mL, 1m in
MeOH) was added dropwise. The resulting solution was stirred for
30 min and the reaction was then quenched with H2O (10 mL). The mix-
ture was then extracted with EtOAc (3ꢁ10 mL), dried over sodium sul-
fate, concentrated, and purified through silica gel (15% EtOAc-pentane)
to give 9g as a clear oil (50 mg, 93% yield, 98% ee, 15:1 b/l, 7:1 d.r.).
Chiral HPLC, OD-column, flow rate 1.0 mL/min, 97:3 heptane/iPrOH, tA
(minor)=13.346 min, tB (major)=15.047 min. IR (film) n˜ =: 3210, 3081,
tifying other nucleophiles that are capable of chelation con-
trol with the molybdenum catalyst.
Experimental Section
All reactions were carried out in oven-dried flasks or pyrex test tubes
under a positive pressure of argon. Anhydrous solvents were obtained
from elution through alumina column, except for THF, which was dis-
tilled from Na-benzophenone ketyl. All reagents were purchased com-
mercially and used without further purification unless stated otherwise.
TLC was performed on precoated glass plates (Merck), flash chromatog-
raphy with silica gel 60, 230–400 mesh. Enantiomeric excesses were deter-
mined by using HPLC on Tsp Spectra series P100/UV100 apparatus with
a chiral stationary phase (see details where applies). Melting points (un-
corrected) were determined in open capillary tubes by using a Thomas-
Hoover apparatus. 1H NMR (0 ppm as internal standard) and 13C NMR
(77 ppm as internal standard) spectra were recorded by using a Varian
Mercury 400 (400 MHz for 1H NMR) and by using a Unity Inova 500
(500 MHz for 1H NMR). IR spectra (cmÀ1) were obtained by using a
Perkin–Elmer FT-IR Paragon 500 spectrometer, either using neat sample
on NaCl pad (for oils and liquids), or preparing a KBr pellet.
3061, , 3030, 2975, 2887, 1707, 1619, 1471, 1452, 1334, 1230, 1202, 1123,
1
994, 917, 753, 726, 701 cmÀ1; H NMR (500 MHz, CDCl3): d=8.50
C
7.25–7.14 (m,6H), 7.04–6.97ACTHNUGRTENUNG(m, 2H), 6.84(d, J=7.5, 1H), 6.19–6.07 (m,
1H), 5.21 (dm, J=17, 1H), 5.08 (dm, J=10, 1H), 3.73(d, J=10, 1H),
1.38 ppm (s, 3H); 13C NMR (125 MHz, CDCl3) d=182.3, 140.5, 139.3,
135.7, 132.5, 129.2, 127.8, 126.8, 124.6, 121.8, 117.9, 109.5, 57.0, 52.5,
22.2 ppm; HRMS (M+H): m/z: calcd for C18H18NO: 264.1388; found:
264.1379.
Acknowledgements
General procedure for Mo catalyzed AAA reactions with 3-aryloxindoles
We thank the National Institutes of Health (NIH-13598) for their gener-
ous support of our program. Y.Z. thanks Amgen for a graduate fellow-
ship.
1-methyl-3-phenyl-3-(1-phenylallyl)indolin-2-one (2b): To an oven-dried
test tube equipped with a magnetic stir bar was added ligand L1 (4.8 mg,
0.015 mmol) and [MoACHTUNGTRENNUNG(C7H8)(CO)3] (2.7 mg, 0.01 mmol). The test tube
was sealed with a rubber septum and THF (freshly distilled and degassed,
0.3 mL) was added via syringe. The test tube was then placed in a pre-
heated oil bath at 608C for 5 min until the solution turns deep purple.
The reaction was then allowed to cool to RT. A second oven-dried test
tube containing 0.1 mmol of the oxindole was transferred to the dry box
and to it sodium tert-butoxide (0.11 mmol, 11 mg) was added. The test
tube was sealed, taken out of the dry box, and to it was added degassed
THF (0.7 mL) at room temperature. The resulting solution was stirred
for 5 min before the solution of the active catalyst solution (0.3 mL) was
added via cannula, followed by the addition of cinnamyl tert-butyl car-
bonate (0.12 mmol) via syringe. The reaction was then stirred at 608C
under Ar for 2 h at which point TLC indicated complete consumption of
the starting oxindole. The reaction was then concentrated and column
purification (10% EtOAc-pentane) afforded the desired product as a
mixture of regio- and diastereomers. (31 mg, 92%, 16:1 b/l, 9:1 d.r., 92%
ee) Chiral HPLC, AD-column, flow rate 0.7 mL/min, 90:10 heptane/
iPrOH, tA (minor)=8.387 min, tB (major)=9.556 min. IR (film) n˜ =3058,
2926, 1708, 1610, 1493, 1470, 1373, 1349, 1255, 1131, 1089, 1025, 923, 757,
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689 cmÀ1 1H NMR (500 MHz, CDCl3) major diastereomer: d=7.61–7.58
;
(m, 2H), 7.34–7.27 (m, 2H), 7.26–7.21 (m, 2H), 7.08–6.98 (m, 5H), 6.89–
6.87 (m, 2H), 6.69(d, J=7.5, 1H), 6.06 (ddd, J=9.5, 10, 17, 1H), 5.18
(dm, J=17, 1H), 5.08 (dd, J=1.5, 10, 1H), 4.48(d, J=9.5, 1H), 3.09 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3) major diastereomer: d=177.1,
143.5, 139.0, 138.0, 135.8, 129.5, 129.3, 128.2, 128.1, 128.0, 127.3, 127.2,
126.7, 126.4, 121.7, 118.5, 107.9, 60.7, 57.2, 26.1 ppm; HRMS (EI): m/z:
calcd for C24H21NO: 339.1623; found: 339.1629.
General procedure for Mo catalyzed AAA reactions with 3-alkyloxin-
doles
3-methyl-3-(1-phenylallyl)indolin-2-one
equipped with magnetic stir bar was added Ligand L1 (4.8 mg,
0.015 mmol) and [Mo(C7H8)(CO)3] (2.7 mg, 0.01 mmol). The test tube
ACHTUNGTNER(NUNG 9g): To an oven-dried test tube
a
ACHTUNGTRENNUNG
was sealed with a rubber septum and THF (freshly distilled and degassed,
0.3 mL) was added via syringe. The test tube was then placed in a pre-
heated oil bath at 608C for 5 min until the solution turns deep purple.
The test tube was then taken out of the oil bath and let cool to RT. A
second test tube containing oxindole 8g (40 mg, 0.2 mmol) was dissolved
in 1 mL dry THF and cooled to 08C. A freshly prepared solution of
sodium tert-butoxide (4 mg, 0.02 mmol) in 0.3 mL THF was added drop-
wise. The resulting solution was warmed to RT and BSA (0.24 mmol) was
added via syringe. The resulting solution stirred for 5 min before the solu-
tion of the active catalyst solution was added via cannula, followed by
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302
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Chem. Eur. J. 2010, 16, 296 – 303

Stereoinduction in the Alkylation of Oxindoles
FULL PAPER
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Received: October 7, 2009
Published online: December 9, 2009
Chem. Eur. J. 2010, 16, 296 – 303
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