One-Pot Tandem Diastereoselective and Enantioselective Synthesis of Functionalized Oxindole-Fused Spiropyrazolidine Frameworks

Article abstract of DOI:10.1002/chem.201403990

A highly efficient palladium(0)-catalyzed asymmetric [3+2] cycloaddition using 3-diazooxindoles serving as dipolarophiles affords functionalized pyrazolidine derivatives in an atom-economical way. In addition, by trapping the pyrazolidine derivatives with maleimides, the corresponding spiropyrazolidine oxindoles containing multiple stereogenic centers have been obtained in high yields along with moderate to good levels of diastereoselectivity and enantioselectivity under mild conditions. Thus, a novel three-component one-pot tandem reaction has been developed.

Full text of DOI:10.1002/chem.201403990

DOI: 10.1002/chem.201403990
Communication
&
Asymmetric Catalysis
One-Pot Tandem Diastereoselective and Enantioselective
Synthesis of Functionalized Oxindole-Fused Spiropyrazolidine
Frameworks
Liang-Yong Mei,[a] Xiang-Ying Tang,*[a, b] and Min Shi*[a, b]
in 1993, Kascheres and co-workers introduced a novel synthe-
Abstract: A highly efficient palladium(0)-catalyzed asym-
metric [3+2] cycloaddition using 3-diazooxindoles serving
as dipolarophiles affords functionalized pyrazolidine deriv-
atives in an atom-economical way. In addition, by trapping
the pyrazolidine derivatives with maleimides, the corre-
sponding spiropyrazolidine oxindoles containing multiple
stereogenic centers have been obtained in high yields
along with moderate to good levels of diastereoselectivity
and enantioselectivity under mild conditions. Thus,
a novel three-component one-pot tandem reaction has
been developed.
sis of 1,2,3-triazoles through the reactions of 3-diazooxindoles
with enaminones, in which 3-diazooxindoles were used as
a source for generating dipoles.[7] Later, Kanemasa et al.
showed the first successful examples of enantioselective [3+2]
cycloadditions of trimethylsilyldiazomethane with 3-(2-alkeno-
yl)-2-oxazolidinones by using (R,R)-DBFOX/Ph metal perchlorate
complexes as chiral Lewis acids.[8] Afterwards, several similar
[3+2] annulations of other diazo substrates, such as diazoal-
kanes or diazoacetates, with various olefins in the presence of
a base,[9] Lewis acid,[10] or in the absence of such an additive[11]
have been reported. Nevertheless, among these works, all
diazo compounds are restricted to acting as 1,3-dipoles that
react with a dipolarophile. In addition, owing to the CÀN and
NÀN multiple bonds, 3-diazooxindoles could also serve as po-
tential dipolarophiles for participation in annulations with an
additional 1,3-dipole; however, work related to this has not
been disclosed so far. Therefore, we attempted to apply 3-diaz-
The spirooxindole core is one of the most important structural
motifs and exists in a number of natural products and pharma-
cological compounds with diverse bioactivity properties.[1] It
has consequently captured great interest from syn-
thetic and medicinal chemists, and many elegant ap-
proaches for its synthesis have been developed.[2] As
a new kind of synthetic precursors for the construc-
tion of spirocyclic oxindoles, 3-diazooxindoles have
recently caught much attention. By reacting with
transition metals, 3-diazooxindoles can generate tran-
sient electrophilic carbenoids, which can undergo
a wide range of attractive reactions such as cyclopro-
panations,[3] XÀH insertions,[4] ylide formations,[5] and
the other reactions.[6] However, among these transfor-
mations, the release of nitrogen is inevitable, which
is not atom economical. To avoid this disadvantage,
Scheme 1. Palladium-catalyzed cycloaddition of vinyl cyclopropanes with 3-diazooxin-
doles. EWG=electron-withdrawing group.
new types of reactions should be employed in an
atom-economical way by retaining the nitrogen
atoms of 3-diazooxindoles. As a matter of fact, early
ooxindoles in the cycloaddition reactions, either by its interac-
tion with a dipolarophile as the 1,3-dipole, or with a 1,3-dipole
as the dipolarophile, thus providing an atom-economical and
facile way to prepare heterocyclic compounds containing an
NÀN bond.
[a] L.-Y. Mei, Dr. X.-Y. Tang, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
East China University of Science and Technology
Meilong Road No. 130, Shanghai, 200237 (China)
[b] Dr. X.-Y. Tang, Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Recently, vinyl cyclopropanes bearing electron-withdrawing
groups have emerged as useful intermediates for the synthesis
of various cyclic compounds.[12] By generating the 1,3-dipolar
compound in the presence of a Pd(0) catalyst and subsequent
trapping with diverse dipolarophiles,[13] vinyl cyclopropanes
can provide direct ways to a variety of substituted five-mem-
354 Fenglin Road, Shanghai 200032 (China)
E-mail: siocxiangying@mail.sioc.ac.cn
mshi@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403990.
Chem. Eur. J. 2014, 20, 13136 – 13142
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Communication
bered rings. On this aspect, we have previously reported on
the Pd(0)-catalyzed [3+2] cycloaddition of vinylcyclopropane
with b,g-unsaturated a-ketoesters to afford functionalized cy-
clopentanes;[13f] we have also reported on the diastereo- and
enantioselective construction of oxindole-fused spirotetrahy-
drofuran scaffolds through palladium-catalyzed [3+2] cycload-
dition of vinylcyclopropane and isatins in the presence of
chiral imidazoline–phosphine ligands.[13g] As part of our ongo-
ing investigations into these cycloadditions as well as our goal
to construct heterocyclic compounds containing an NÀN bond,
as we proposed above, we envisaged to transform 3-diazoox-
indoles through use of a Pd/chiral imidazoline–phosphine cata-
lytic system (Scheme 1). On one hand, spiropyridazine oxin-
doles could be obtained through a [3+3] cycloaddition when
3-diazooxindoles serve as a source of 1,3-dipoles as reported
(Scheme 1, reaction a); on the other hand, the pyrazolidine de-
rivatives could be obtained if 3-diazooxindoles act as the dipo-
larophiles in a [3+2] annulation reaction (Scheme 1, reac-
tion b).
Scheme 2. Initial results for the Pd-catalyzed asymmetric [3+2] cycloaddi-
tion.
ene at 08C provided the best outcomes, the results being sum-
marized in Table SI-3 in the Supporting Information.
Based on the above preliminary results, further optimizations
by screening the ligands when using dibenzhydryl 2-vinylcyclo-
propane-1,1-dicarboxylate (1b) and 1-benzyl-3-diazoindolin-2-
one (2a) as the model substrates in the presence of [Pd2(dba)3]
in toluene at 08C were carried out and the results are shown
in Table 1. First, the use of chiral imidazoline–phosphine ligand
We first examined the reaction between vinyl cyclopropanes
1a and 1b with 1-benzyl-3-diaz-
oindolin-2-one (2a) in the pres-
ence of chiral imidazoline–phos-
Table 1. Screening of ligands and Pd catalysts for asymmetric [3+2] cycloaddition.
phine ligand (aR,S,S)-L1 and
[Pd2(dba)3]
(dba=dibenzylide-
neacetone) in toluene at 08C, as
shown in Scheme 2. To our de-
light, the [3+2] cycloaddition
proceeded smoothly to afford
the pyrazolidine derivatives.
Using dimethyl 2-vinylcyclopro-
pane-1,1-dicarboxylate (1a) as
substrate
furnished
desired
product 3a in 40% yield with
57% ee, while the use of dibenz-
hydryl 2-vinylcyclopropane-1,1-
dicarboxylate (1b) as substrate
produced corresponding adduct
3b in 82% yield with 69% ee.
Then, screening of ligands L1–
L23 by using dimethyl 2-vinylcy-
clopropane-1,1-dicarboxylate
(1a) or dibenzhydryl 2-vinylcy-
clopropane-1,1-dicarboxylate
Entry[a]
Pd(0)
Ligand
Yield [%][b]
ee [%][c]
(1b) and 1-benzyl-3-diazoindo-
lin-2-one (2a) as model sub-
strates in toluene resulted in
1
2
3
4
5
6
7
8
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3·CHCl3]
[Pd2{3,5-(OMe)2-dba}3]
[Pd2(dba)3·CHCl3]
[Pd2(dba)3]
L9
95
95
61
trace
trace
trace
trace
98
81
L17
L19
L20
L21
L22
L23
L9
L9
L9
L9
45[e]
41[e]
n.d.
n.d.
n.d.
n.d.
85
chiral
imidazoline–phosphine
ligand (aR,S,S)-L9 being identi-
fied as the best ligands for this
reaction; the results of these ex-
periments are summarized in Ta-
bles SI-1 and SI-2 in the Support-
ing Information. Moreover, the
screening of solvents, tempera-
ture, and additives revealed that
conducting the reactions in tolu-
9
96
95
92
81
85
81
10[d]
11[d]
[a] The reaction was conducted with 1b (0.1 mmol) and 2a (0.15 mmol) in solvent (1.0 mL). [b] Yield of isolated
product. [c] The ee values were determined by HPLC by using a Chiralcel IB-3 column. [d] 30 mol% CHCl3 was
added. [e] The sense of enantioselectivity is opposite that found for L9.
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L9 yielded desired product 3b in 95% yield with 81% ee, while
chiral phosphine–oxazoline ligand L17 afforded product 3b in
95% yield with 45% ee in favor of the other enantiomer
(Table 1, entries 1 and 2). Next, we found that chiral BINAP
ligand L19 was also effective, though giving desired product
3b in lower yield and ee value (Table 1, entry 3). However,
other ligands such as L20–L23 with different chiral scaffolds
produced 3b in a trace amount (Table 1, entries 4–7). On the
basis of these experiments, we chose dibenzhydryl 2-vinylcy-
clopropane-1,1-dicarboxylate (1b) and 1-benzyl-3-diazoindolin-
2-one (2a) as substrates, toluene as the solvent, and L9 as the
ligand to screen the Pd(0) source. We found that replacing
[Pd2(dba)3] with [Pd2(dba)3·CHCl3] resulted in the formation of
3b in 98% yield with 85% ee (Table 1, entry 8). Nevertheless,
replacing [Pd2(dba)3] with [Pd2{3,5-(OMe)2-dba}3] did not lead
to better reaction outcomes (Table 1, entry 9). Considering that
the trace of CHCl3 in [Pd2(dba)3·CHCl3] may serve as an additive
in the reaction, a small amount of CHCl3 (30 mol%) was added
into the reaction mixtures so as to improve the reaction out-
come; unfortunately, no significant improvement was observed
(Table 1, entries 10 and 11). Therefore, the use of [Pd2-
(dba)3·CHCl3] as the Pd(0) source, L9 as the ligand, and toluene
as the solvent, is the optimized conditions for this reaction
(Table 1, entry 8).
tibacterial agents[1i] and natural products, such as ibophylli-
dine,[15] have scaffolds similar to those of spiropyrazolidine ox-
indoles 5, we were encouraged to further explore these two
sequential cycloadditions through the construction of oxin-
dole-fused spiropyrazolidine frameworks 5 owing to their po-
tential interesting biological activities (Scheme 3, equation b).
Therefore, we attempted to develop a one-pot tandem [3+2]
cycloaddition of vinylcyclopropanes 1, 3-diazooxindoles 2, and
maleimides 4 in the presence of [Pd2(dba)3·CHCl3] and chiral
imidazoline–phosphine ligand (aR,S,S)-L9. Because the prod-
uct’s enantioselectivity was determined in the first step of the
[3+2]-cycloaddition between vinylcyclopropane 1 and 3-diazo-
oxindole 2, no alteration of ee value would be observed for
the one-pot tandem process. As can be seen from Scheme 3,
the spiropyrazolidine oxindoles 5a and 5b were successfully
obtained in 54 and 75% yields, respectively, through the one-
pot tandem reaction process with no alteration of ee values as
expected compared with the stepwise process (Scheme 3,
equation c). It should be emphasized here that the imidazo-
line–phosphine ligand plays a significant role in the formation
of pyrazolidine derivatives 3 because much lower yields or ee
values of 3 were obtained in the presence of other phosphine
ligands.
Having established the opti-
mal reaction conditions, we next
turned our attention to the sub-
strate scope and transformation
of the products, the results
being shown in Scheme 3. Using
dimethyl
2-vinylcyclopropane-
1,1-dicarboxylate (1a) or dibenz-
hydryl 2-vinylcyclopropane-1,1-
dicarboxylate (1b) with 1-
benzyl-3-diazoindolin-2-one (2a)
as the substrates, desired pyra-
zolidine derivatives 3a and 3b
were obtained in good yields
with moderate to good ee values
(Scheme 3, equation a). Notably,
products 3 could be employed
as latent efficient 1,3-dipoles be-
cause they have a similar struc-
ture to that of azomethine
imines.[14] Thus, we used N-phe-
nylmaleimide (4a) as a dipolaro-
phile to react with 3 so as to re-
alize a later-stage [3+2] annula-
tion. Indeed, the reaction be-
tween
3 and 4a proceeded
smoothly in CH2Cl2 at room tem-
perature to deliver desired func-
tionalized spiropyrazolidine oxin-
doles 5 in quantitative yields
without alteration of ee values
(Scheme 3, equation b). More-
over, because some reported an- Scheme 3. Substrate scope for [3+2] cycloaddition and a trial one-pot tandem reaction.
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13138

Communication
Having determined the viability of three-component one-
pot tandem reaction, different substrates 1 were examined by
using 1-benzyl-3-diazoindolin-2-one (2a) and N-phenylmalei-
mide (4a) as the model substrates in the presence of [Pd2-
(dba)3·CHCl3] and ligand (aR,S,S)-L9 and the results are summar-
ized in Table SI–4 in the Supporting Information. No further re-
markable improvement on the reaction outcomes was ob-
served by screening a wide range of substrates 1 bearing dif-
ferent ester groups, such as substrates 1c–1k under the
standard reaction conditions. Thus, we used dibenzhydryl 2-vi-
nylcyclopropane-1,1-dicarboxylate (1b), 1-benzyl-3-diazoindo-
lin-2-one (2a), and N-phenylmaleimide (4a) as the substrates,
toluene as the solvent, and [Pd2(dba)3·CHCl3] as the catalyst in
the presence of ligand (aR,S,S)-L9 as the optimal reaction con-
ditions; an array of 3-diazooxindoles 2 and maleimides 4 were
evaluated and the results are shown in Table 2. At first, using
dibenzhydryl 2-vinylcyclopropane-1,1-dicarboxylate (1b) and 1-
benzyl-3-diazoindolin-2-one (2a) as the model substrate, we
examined a variety of maleimides 4b–4e bearing different N-
protecting groups (Table 2, entries 2–5). All these N-protecting
groups were tolerated in this reaction, affording structurally
varied spiropyrazolidine oxindoles 5ab–5ae in moderate yields
with moderate to good levels of diastereoselectivity and 85%
ee, while N-methylmaleimide (4c) gave the best performance.
Then, different 3-diazooxindoles 2 that exhibit diverse electron-
ic and steric effects were studied using dibenzhydryl 2-vinylcy-
clopropane-1,1-dicarboxylate (1b) and N-methylmaleimide (4c)
as the model substrate (Table 2, entries 6–21). Using 3-diazoox-
indoles bearing different types of N-protecting groups such as
2b, 2c, and 2d, the desired spirocyclic oxindoles 5bc, 5cc and
5dc were obtained in 72–85% yields with 8.1:1–11.5:1 levels of
diastereoselectivity and 77–80% ee (Table 2, entries 6–8). Sub-
sequently, the influence of substituents at different positions
of the aromatic rings of 3-diazooxindoles was explored. As can
be seen from Table 2, this protocol is amenable to a diverse
array of 3-diazooxindoles 2 with electronically different sub-
stituents at the C5, C6, or C7 positions, giving the correspond-
ing spiropyrazolidine oxindoles 5 fc–5qc in 52–84% yields
with 6.7:1–11.5:1 levels of diastereoselectivity and 61–90% ee
(Table 2, entries 10–21). The electronic nature of the substitu-
ents impacts on the enantioselectivity and reactivity. For exam-
ple, 3-diazooxindoles 2 f, 2j, 2k, 2o, and 2q with electron-do-
nating groups on the aromatic rings produced the correspond-
ing products 5 with 82–90% ee (Table 2, entries 10, 14, 15, 19,
and 21), while 2g, 2h, 2i, 2l, 2m, 2n, and 2p with electron-
withdrawing groups on the aromatic rings delivered the corre-
sponding products 5 with 61–80% ee (Table 2, entries 11–13,
16–18, and 20). However, when R2 is at the C4 position of 3-di-
azooxindoles, no reaction occurred perhaps owing to a steric
effect (Table 2, entry 9). To our delight, the levels of enantiose-
lectivity of spiropyrazolidine oxindoles 5 could be largely im-
proved by recrystallization from CH2Cl2/iPrOH/n-hexane
(Table 2, entries 1, 15, and 17–
19). Moreover, the configuration
of racemate 3a has been con-
Table 2. Substrate scope for the Pd/L9-catalyzed one-pot tandem reaction.
firmed by X-ray diffraction, and
the absolute configuration of
5oc has also been assigned by
X-ray diffraction as 3R, 3a’S, 7’S,
9a’S. Accordingly, the products
5a–5qc have the same 3R, 3a’S,
Entry[a]
R1
R2/R3
R4
Yield [%][b]
d.r.[c]
ee [%][d]
7’S, 9a’S absolute configuration
and the pyrazolidine derivatives
3a and 3b have the same S ab-
solute configuration at C7’ posi-
tion as that of 5oc. The ORTEP
drawing of 3a and 5oc and
their CIF data are shown in the
Supporting Information.[16]
1
2
3
4
5
6
7
8
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
CHPh2, 1b
H/Bn, 2a
H/Bn, 2a
H/Bn, 2a
H/Bn, 2a
H/Bn, 2a
H/Me, 2b
Ph, 4a
H, 4b
5b, 75
6.1:1
4.0:1
9.0:1
2.1:1
1.7:1
8.1:1
11.5:1
10.1:1
n. d.[e]
8.1:1
6.7:1
10.1:1
9.0:1
10.1:1
7.3:1
7.3:1
9.0:1
11.5:1
9.0:1
9.0:1
7.3:1
85 (93)[f]
85
85
85
85
80
80
77
–
87
80
68
64
82
84 (97)[f]
72
5ab, 72
5ac, 80
5ad, 60
5ae, 56
5bc, 81
5cc, 85
5dc, 72
5ec, 0
5 fc, 81
5gc, 76
5hc, 67
5ic, 70
5jc, 84
5kc, 78
5lc, 80
5mc, 78
5nc, 52
5oc, 81
5pc, 53
5qc, 73
Me, 4c
Bn, 4d
CHPh2, 4e
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
Me, 4c
H/MOM, 2c
H/Boc, 2d
4-Cl/Bn, 2e
5-Me/Bn, 2 f
5-F/Bn, 2g
5-I/Bn, 2h
5-NO2/Bn, 2i
6-Me/Bn, 2j
6-OMe/Bn, 2k
6-Cl/Bn, 2l
7-Br/Bn, 2m
7-CF3/Bn, 2n
5,7-Me2/Bn, 2o
5,7-Cl2/Bn, 2p
5-Cl, 7-Me/Bn, 2q
9
To illustrate the generality of
the Pd(0)/L9 catalytic system, di-
methyl acetylenedicarboxylate 6
was used as a dipolarophile to
trap the 1,3-dipole intermediate
formed in situ by the reaction of
1b and 2a, and the reaction was
examined under the standard re-
action conditions (Scheme 4).
Notably, desired functionalized
spiropyrazolidine oxindole 7 was
obtained in 75% yield, 3.2:1 d.r.,
and 85% ee in a single opera-
tion.
10
11
12
13
14
15
16
17
18
19
20
21
61 (90)[f]
65 (86)[f]
90 (97)[f]
63
84
[a] The reaction was conducted with 1 (0.1 mmol), 2 (0.15 mmol), and 4 (0.12 mmol) in toluene (1.0 mL).
[b] Yield of isolated major isomer. [c] The diastereomeric ratios were determined by H NMR spectroscopic anal-
ysis of the crude reaction mixture. [d] The ee values were determined by HPLC by using Daicel IB-3 and IF-3
columns. [e] Not detected. [f] After crystallization from CH2Cl2/iPrOH/n-hexane.
1
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Communication
(Scheme 6).[13a,d,f,g] Firstly, the key zwitterionic (p-allyl) palladi-
um intermediates 10 and 10’ were formed through initial nu-
cleophilic attack of palladium at the double bond of vinylcyclo-
propane 1b and interconvert through p–s–p equilibration.
Owing to the more significant steric repulsion between the
phenyl group on imidazoline–phosphine ligand L9 and the
malonate moiety in vinylcyclopropane 1b, intermediate 10 is
thermodynamically more favored. Then, the nucleophilic attack
of the malonate anion onto the NÀN triple bond in 3-diazoox-
indole 2a and the subsequent nucleophilic attack of another
nitrogen atom on the in situ generated (p-allyl) palladium
complex 10 gave the desired product 3b along with the re-
lease of the Pd catalyst. Finally, observed major diastereomer
5b was obtained through the [3+2] cycloaddition of 3b with
maleimide 4a through the Si face of 4a owing to the steric re-
pulsion of vinyl group on 3b.
In conclusion, we have disclosed the construction of func-
tionalized pyrazolidine derivatives by using 3-diazooxindoles as
dipolarophiles through a highly efficient palladium(0)-catalyzed
asymmetric [3+2] cycloaddition in an atom-economical way.
Furthermore, by trapping the pyrazolidine intermediates with
maleimides, the spiropyrazolidine oxindoles containing multi-
ple stereogenic centers have been obtained in high yields
along with moderate to good levels of diastereoselectivity and
enantioselectivity under mild reaction conditions. Thus, a novel
one-pot tandem reaction of vinylcyclopropanes, 3-diazooxin-
doles and maleimides in the presence of [Pd2(dba)3·CHCl3] and
chiral imidazoline–phosphine ligand (aR,S,S)-L9 has been devel-
oped. Imidazoline–phosphine ligand plays a crucial role to give
the corresponding products in good yields and ee values. Fur-
ther investigations on expanding the scope of this reaction to-
wards a wide range of other 1,3-dipoles as well as the applica-
tions of this protocol to natural product synthesis are in prog-
ress.
Scheme 4. Extension of the Pd/L9-catalyzed one-pot tandem reaction.
We have further explored the transformations of products 3
and 5 in order to illustrate their synthetic utility. As shown in
Scheme 5, product 3b could be easily converted into com-
pound 8 in 85% yield with 85% ee by a simple treatment with
NaBH4 in THF/MeOH (1:1) through a cascade reaction process;
Scheme 5. Transformations of products 3b and 5ac.
a
proposed mechanism has
been shown in Scheme SI-1 in
the Supporting Information. Fur-
thermore, the corresponding al-
cohol 9 could be obtained from
5ac in 52% yield with 85% ee
through hydroboration with BH3
in THF and subsequent treat-
ment with 1.0m aqueous solu-
tion of sodium hydroxide and
30% aqueous hydrogen perox-
ide solution. No significant
change could be observed in
the levels of enantioselectivity
during these transformations.
To explain the stereochemical
outcome of this Pd/L9-catalyzed
tandem reaction, we tentatively
proposed a plausible reaction
mechanism based on our experi-
mental results and previously re-
ported
mechanistic
studies Scheme 6. Proposed mechanism.
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Communication
M. Nethaji, J. Org. Chem. 2004, 69, 5631–5637; f) D. Xing, C.-C. Jing, X.-
F. Li, H. Qiu, W.-H. Hu, Org. Lett. 2013, 15, 3578–3581.
Acknowledgement
[6] a) S. Muthusamy, D. Azhagan, Tetrahedron Lett. 2011, 52, 6732–6735;
b) S. Muthusamy, K. Selvaraj, Tetrahedron Lett. 2013, 54, 6886–6888;
c) Y. Qian, C.-C. Jing, C.-W. Zhai, W.-H. Hu, Adv. Synth. Catal. 2012, 354,
301–307.
[7] R. Augusti, C. Kascheres, J. Org. Chem. 1993, 58, 7079–7083.
[8] S. Kanemasa, T. Kanai, J. Am. Chem. Soc. 2000, 122, 10710–10711.
[9] a) M. D. Carriꢁn, M. E. Camacho, J. Leon, G. Escames, V. Tapias, D. A. Cas-
troviejo, M. A. Gallo, A. Espinosa, Tetrahedron 2004, 60, 4051–4069;
b) R. Muruganantham, S. M. Mobin, I. N. N. Namboothiri, Org. Lett. 2007,
9, 1125–1128.
We are grateful for the financial support from Shanghai Munic-
ipal Committee of Science and Technology (11JC1402600), the
National Natural Science Foundation of China (20472096,
20872162, 20672127, 21372241, 21302203, 21361140350,
21121062, 20732008 and 20902019), the National Basic Re-
search Program of China (973)-2010CB833302, and the Funda-
mental Research Funds for the Central Universities.
[10] a) T. Kano, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2006, 128,
2174–2175; b) M. P. Sibi, L. M. Stanley, T. Soeta, Org. Lett. 2007, 9,
1553–1556; c) H. Suga, Y. Furihata, A. Sakamoto, K. Itoh, Y. Okumura, T.
Tsuchida, A. Kakehi, T. Baba, J. Org. Chem. 2011, 76, 7377–7387; d) S.
He, L. Chen, Y.-N. Niu, L.-Y. Wu, Y.-M. Liang, Tetrahedron Lett. 2009, 50,
2443–2445; e) X. Qi, J. M. Ready, Angew. Chem. 2007, 119, 3306–3308;
Angew. Chem. Int. Ed. 2007, 46, 3242–3244.
[11] a) M. Kissane, S. E. Lawrence, A. R. Maguire, Org. Biomol. Chem. 2010, 8,
2735–2748; b) Y. Hari, S. Tsuchida, R. Sone, T. Aoyama, Synthesis 2007,
21, 3371–3375; c) J.-W. Xie, Z. Wang, W.-J. Yang, L.-C. Kong, D.-C. Xu,
Org. Biomol. Chem. 2009, 7, 4352–4354; d) T. Hanamoto, Y. Hakoshima,
M. Egashira, Tetrahedron Lett. 2004, 45, 7573–7576.
[12] a) Z. Goldschmidt, B. Crammer, Chem. Soc. Rev. 1988, 17, 229–267; b) T.
Hudlicky, T. M. Kutchan, S. M. Naqvi, Org. React. 1985, 33, 247–335; c) K.
Burgess, J. Org. Chem. 1987, 52, 2046–2051; d) Y. Morizawa, K. Oshima,
H. Nozaki, Tetrahedron Lett. 1982, 23, 2871–2874; e) K. Hiroi, A. Yamada,
Tetrahedron: Asymmetry 2000, 11, 1835–1841; f) A. P. Dieskau, M. S.
Holzwarth, B. Plietker, J. Am. Chem. Soc. 2012, 134, 5048–5051;
g) A. F. G. Goldberg, N. R. O’Connor, R. A. Craig II, B. M. Stoltz, Org. Lett.
2012, 14, 5314–5317; h) D. C. Behenna, Y. Liu, T. Yurino, J. Kim, D. E.
White, S. C. Virgil, B. M. Stoltz, Nature Chem. 2012, 4, 130–133; i) C. M.
Reeves, C. Eidamshaus, J. Kim, B. M. Stoltz, Angew. Chem. 2013, 125,
6850–6853; Angew. Chem. Int. Ed. 2013, 52, 6718–6721.
[13] a) I. Shimizu, Y. Ohashi, J. Tsuji, Tetrahedron Lett. 1985, 26, 3825–3828;
b) I. Shimizu, Y. Ohashi, J. Tsuji, Chem. Lett. 1987, 6, 1157–1158; c) A. T.
Parsons, M. J. Campbell, J. S. Johnson, Org. Lett. 2008, 10, 2541–2544;
d) B. M. Trost, P. J. Morris, Angew. Chem. 2011, 123, 6291–6294; Angew.
Chem. Int. Ed. 2011, 50, 6167–6170; e) A. F. G. Goldberg, B. M. Stoltz,
Org. Lett. 2011, 13, 4474–4476; f) L.-Y. Mei, Y. Wei, Q. Xu, M. Shi, Organo-
metallics 2012, 31, 7591–7599; g) L.-Y. Mei, Y. Wei, Q. Xu, M. Shi, Orga-
nometallics 2013, 32, 3544–3556.
[14] a) R. Shintani, T. Hayashi, J. Am. Chem. Soc. 2006, 128, 6330–6331;
b) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 11654–
11655; c) X. Xu, Y. Qian, P. Y. Zavalij, M. P. Doyle, J. Am. Chem. Soc. 2013,
135, 1244–1247; d) A. Chan, K. A. Scheidt, J. Am. Chem. Soc. 2007, 129,
5334–5335; e) R. Na, C. Jing, Q. Xu, H. Jiang, X. Wu, J. Shi, J. Zhong, M.
Wang, D. Benitez, E. Tkatchouk, W. A. Goddard III, H. Guo, O. Kwon, J.
Am. Chem. Soc. 2011, 133, 13337–13348; f) R. Shintani, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 10778–10779; g) T. Imaizumi, Y. Yamashita, S. Ko-
bayashi, J. Am. Chem. Soc. 2012, 134, 20049–20052; h) M. Wang, Z.
Huang, J. Xu, Y. R. Chi, J. Am. Chem. Soc. 2014, 136, 1214–1217; i) T. Ha-
shimoto, M. Omote, K. Maruoka, Angew. Chem. 2011, 123, 3551–3554;
Angew. Chem. Int. Ed. 2011, 50, 3489–3492; j) M.-C. Tong, X. Chen, H.-Y.
Tao, C.-J. Wang, Angew. Chem. 2013, 125, 12603–12606; Angew. Chem.
Int. Ed. 2013, 52, 12377–12380; k) H. Guo, H. Liu, F. Zhu, R. Na, H. Jiang,
Y. Wu, L. Zhang, Z. Li, H. Yu, B. Wang, Y. Xiao, X.-P. Hu, M. Wang, Angew.
Chem. 2013, 125, 12873–12877; Angew. Chem. Int. Ed. 2013, 52, 12641–
12645; l) M. Keller, A. S. S. Sido, P. Pale, J. Sommer, Chem. Eur. J. 2009,
15, 2810–2817; m) N. Luo, Z. Zheng, Z.-K. Yu, Org. Lett. 2011, 13, 3384–
3387; n) X. Fang, J. Li, H.-Y. Tao, C.-J. Wang, Org. Lett. 2013, 15, 5554–
5557.
Keywords: ligands · oxindoles · palladium · pyrazolidines ·
tandem reactions
[1] a) J. Yang, X. Z. Wearing, P. W. Le Quesne, J. R. Deschamps, J. M. Cook, J.
Nat. Prod. 2008, 71, 1431–1440; b) P. R. Sebahar, R. M. Williams, J. Am.
Chem. Soc. 2000, 122, 5666–5667; c) T. Onishi, P. R. Sebahar, R. M. Wil-
liams, Org. Lett. 2003, 5, 3135–3137; d) S. Edmondson, S. J. Danishefsky,
L. Sepp-Lorenzino, N. Rosen, J. Am. Chem. Soc. 1999, 121, 2147–2155;
e) T. D. Bagul, G. Lakshmaiah, T. Kawabata, K. Fuji, Org. Lett. 2002, 4,
249–251; f) K. A. Miller, S. Tsukamoto, R. M. Williams, Nat. Chem. 2009,
1, 63–68; g) B. M. Trost, N. Cramer, H. Bernsmann, J. Am. Chem. Soc.
2007, 129, 3086–3087; h) K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang,
S. Qiu, S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Krajewski, P. P. Roller, S.
Wang, J. Med. Chem. 2006, 49, 3432–3435; i) C.-B. Cui, H. Kakeya, H. J.
Osada, Tetrahedron 1996, 52, 12651–12666; j) T. J. Greshock, A. W.
Grubbs, P. Jiao, D. T. Wicklow, J. B. Gloer, R. M. Williams, Angew. Chem.
2008, 120, 3629–3633; Angew. Chem. Int. Ed. 2008, 47, 3573–3577;
k) G. Laus, D. Brossner, K. Keplinger, Phytochemistry 1997, 45, 855–860;
l) A. Thangamani, Eur. J. Med. Chem. 2010, 45, 6120–6126.
[2] For recent reviews, see: a) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112,
6104–6155; b) K. Shen, X. Liu, L. Lin, X. Feng, Chem. Sci. 2012, 3, 327–
334; c) R. Rios, Chem. Soc. Rev. 2012, 41, 1060–1074; d) R. Dalpozzo, G.
Bartoli, G. Bencivenni, Chem. Soc. Rev. 2012, 41, 7247–7290; e) N. R.
Ball-Jones, J. J. Badillo, A. K. Franz, Org. Biomol. Chem. 2012, 10, 5165–
5181; f) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156–1171;
g) J. J. Badillo, N. V. Hanhan, A. K. Franz, Curr. Opin. Drug Di. Dev. 2010,
13, 758–776; h) F. Zhou, Y. L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352,
1381–1407; i) B. M. Trost, M. K. Brennan, Synthesis 2009, 3003–3025;
j) C. V. Galliford, K. A. Scheidt, Angew. Chem. 2007, 119, 8902–8912;
Angew. Chem. Int. Ed. 2007, 46, 8748–8758; k) H. Lin, S. J. Danishefsky,
Angew. Chem. 2003, 115, 38–53; Angew. Chem. Int. Ed. 2003, 42, 36–51;
l) R. M. Williams, R. J. Cox, Acc. Chem. Res. 2003, 36, 127–139; m) A. B.
Dounay, L. E. Overman, Chem. Rev. 2003, 103, 2945–2963; n) C. Marti,
E. M. Carreira, Eur. J. Org. Chem. 2003, 2209–2219.
[3] a) S. Muthusamy, D. Azhagan, B. Gnanaprakasam, E. Suresh, Tetrahedron
Lett. 2010, 51, 5662–5665; b) B. V. S. Reddy, T. Rajasekaran, G. Karthik,
T. P. Rao, Tetrahedron Lett. 2012, 53, 3416–3420; c) C. Meyers, E. M. Car-
reira, Angew. Chem. 2003, 115, 718–720; Angew. Chem. Int. Ed. 2003, 42,
694–696; d) D. D. Schwarzer, P. J. Gritsch, T. Gaich, Angew. Chem. 2012,
124, 11682–11684; Angew. Chem. Int. Ed. 2012, 51, 11514–11516; e) C.
Marti, E. M. Carreira, J. Am. Chem. Soc. 2005, 127, 11505–11515; f) Z.-Y.
Cao, X. Wang, C. Tan, X.-L. Zhao, J. Zhou, K. Ding, J. Am. Chem. Soc.
2013, 135, 8197–8200; g) Z.-Y. Cao, F. Zhou, Y.-H. Yu, J. Zhou, Org. Lett.
2012, 15, 42–45; h) S. A. Bonderoff, A. Padwa, Org. Lett. 2013, 15,
4114–4117; i) S. Muthusamy, C. Gunanathan, M. Nethaji, Synlett 2004,
639–642.
[4] a) S. Muthusamy, C. Gunanathan, S. A. Babu, E. Suresh, P. Dastidar,
Chem. Commun. 2002, 824–825; b) S. Muthusamy, T. Karikalan, C. Guna-
nathan, E. Suresh, Tetrahedron 2012, 68, 1595–1605; c) S. Muthusamy, P.
Srinivasan, Tetrahedron Lett. 2009, 50, 3794–3797; d) B. M. Trost, J. Xie,
J. D. Sieber, J. Am. Chem. Soc. 2011, 133, 20611–20622; e) S. Muthusa-
my, C. Gunanathan, Synlett 2003, 1783–1786.
[15] a) F. Khuong-Huu, M. Cesario, J. Guilhem, R. Goutarel, Tetrahedron 1976,
32, 2539–2543; b) C. Kan, H.-P. Husson, H. Jacquemin, S.-K. Kan, M. Lou-
nasmaa, Tetrahedron Lett. 1980, 21, 55–58; c) C. Kan, H.-P. Husson, S.-K.
Kan, M. Lounasmaa, Tetrahedron Lett. 1980, 21, 3363–3366; d) M. E.
Kuehne, T. H. Matsko, J. C. Bohnert, L. Motyka, D. O. Smith, J. Org. Chem.
1981, 46, 2002–2009; e) W. G. Bornmann, M. E. Kuehne, J. Org. Chem.
1992, 57, 1752–1760; f) M. E. Kuehne, U. K. Bandarage, A. Hammach, Y.-
[5] a) S. Muthusamy, R. Ramkamar, A. K. Mishra, Tetrahedron Lett. 2011, 52,
148–150; b) B. Alcaide, P. Almendros, C. Aragoncillo, R. Callejo, M. P.
Ruiz, M. R. Torres, Eur. J. Org. Chem. 2012, 2359–2366; c) L. Ren, X.-L.
Lian, L.-Z. Gong, Chem. Eur. J. 2013, 19, 3315–3318; d) X. Guo, W.-H. Hu,
Acc. Chem. Res. 2013, 46, 2427–2440; e) S. Muthusamy, C. Gunanathan,
Chem. Eur. J. 2014, 20, 13136 – 13142
www.chemeurj.org
13141
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
L. Li, T. Wang, J. Org. Chem. 1998, 63, 2172–2183; g) I. P. Andrews, O.
Kwon, Chem. Sci. 2012, 3, 2510–2514.
[16] a) H. D. Flack, Acta Crystallogr. Sect. A 1983, 39, 876–881; b) R. W. W.
Hooft, L. H. Straver, A. L. Spek, J. Appl. Crystallogr. 2008, 41, 96–103.
Received: June 16, 2014
Published online on August 28, 2014
Chem. Eur. J. 2014, 20, 13136 – 13142
www.chemeurj.org
13142
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim