Novel Methodology for the Efficient Synthesis of 3-Aryloxindoles: [1,2]-Phospha-Brook Rearrangement-Palladium-Catalyzed Cross-Coupling Sequence

Article abstract of DOI:10.1055/s-0035-1561859

A novel methodology for the efficient synthesis of 3-aryloxindoles from isatin derivatives was developed. The methodology involves the formation of an oxindole having a phosphate moiety at the C-3 position via the [1,2]-phospha-Brook rearrangement under Bronsted base catalysis followed by palladium-catalyzed cross-coupling with aryl boron reagents. The one-pot synthesis of 3-aryloxindoles from isatin derivatives is also described.

Full text of DOI:10.1055/s-0035-1561859

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
A. Kondoh et al.
Letter
Synlett
Novel Methodology for the Efficient Synthesis of 3-Aryloxindoles:
[1,2]-Phospha-Brook Rearrangement–Palladium-Catalyzed Cross-
Coupling Sequence
Azusa Kondoha
Akira Takeib
Masahiro Terada*a,b
O
O
O
Ar
B
O
O
OP(OPh)2
Ar
O
HP(OPh)2
cat. i-Pr2NEt
K
leaving
group
cat. Pd/XPhos
O
O
O
R
R
R
a Research and Analytical Center for Giant Molecules,
Graduate School of Science, Tohoku University,
Aoba-ku, Sendai 980-8578, Japan
N
N
N
[1,2]-phospha-
Brook
cross-coupling
14 examples
up to 82%
Bn
Bn
Bn
up to 94%
mterada@m.tohoku.ac.jp
b Department of Chemistry, Graduate School of
Science, Tohoku University, Aoba-ku, Sendai
980-8578, Japan
Received: 07.03.2016
Accepted after revision: 30.03.2016
Published online: 07.04.2016
methodology involves arylation of isatin derivatives using
arylating agents, such as aryl lithium and aryl Grignard re-
agents, followed by dehydration (Scheme 1, a).7 An alterna-
tive methodology is C-3 selective arylation of C-3 unsubsti-
tuted oxindoles, which are accessible by the reduction of
the corresponding isatin derivatives, catalyzed by transi-
tion-metal complexes, such as a palladium and a nickel
complex (Scheme 1, b).8 Although both methodologies are
highly reliable, they require the use of reactive arylating
agents and/or harsh reductive conditions, so that there re-
mains the issue of functional-group tolerance. Recently, the
arylation of 3-diazooxindoles has also been reported
(Scheme 1, c).9 While the reaction proceeds under mild re-
action conditions, the introducible aryl group is rather lim-
ited. Therefore, a new methodology that allows the efficient
synthesis of 3-aryloxindoles from isatin derivatives under
mild reaction conditions would be highly valuable.
In this context, we envisioned a new methodology
based on the two-step sequence strategy shown in Scheme
1 (d). The first step of our designed methodology is the di-
rect conversion of a keto moiety at the C-3 position of isatin
derivatives into a phosphate moiety via the [1,2]-phospha-
Brook rearrangement.10,11 Treatment of isatin derivatives 1
with a secondary phosphite in the presence of a catalytic
amount of Brønsted base would result in the addition of
phosphite to a keto moiety followed by the migration of the
dialkoxyphosphoryl moiety from carbon to oxygen, that is,
the [1,2]-phospha-Brook rearrangement, to provide corre-
sponding phosphate 2. This transformation of ketones is
known to take place under mild reaction conditions, espe-
cially in the case of α-keto carbonyl compounds including
isatin derivatives. The second step is the introduction of an
aryl group by palladium-catalyzed cross-coupling reaction
with aryl boron reagents utilizing the phosphate moiety of
2 as a leaving group. Although the coupling reaction of ox-
indole derivatives having a leaving group at the C-3 posi-
DOI: 10.1055/s-0035-1561859; Art ID: st-2016-u0165-l
Abstract A novel methodology for the efficient synthesis of 3-arylox-
indoles from isatin derivatives was developed. The methodology in-
volves the formation of an oxindole having a phosphate moiety at the
C-3 position via the [1,2]-phospha-Brook rearrangement under Brønst-
ed base catalysis followed by palladium-catalyzed cross-coupling with
aryl boron reagents. The one-pot synthesis of 3-aryloxindoles from isat-
in derivatives is also described.
Key words oxindole derivatives, phospha-Brook rearrangement,
Brønsted base catalysis, cross-coupling, palladium catalyst
Oxindole derivatives with C-3 functionalities are com-
mon motifs in biologically active natural products and
pharmaceuticals.1 3-Aryloxindoles are particularly import-
ant because they not only belong to one of the privileged
subclasses but also serve as valuable building blocks in or-
ganic synthesis. For instance, these compounds are widely
employed as substrates in various catalytic asymmetric re-
actions to provide 3,3-disubstituted oxindoles possessing
quaternary stereogenic centers.2 Many methodologies for
the synthesis of 3-aryloxindoles have been developed over
the past decades. They can be divided into two types of ap-
proaches. The first is the intramolecular cyclizations of α-
aryl acetanilide derivatives, including acid-promoted Frie-
del–Crafts cyclization,3 base-promoted cyclization,4 or pho-
toinduced cyclization.5 Palladium-catalyzed intramolecular
α-arylation of amides, developed in recent years, is also cat-
egorized as this approach.6 The reaction efficiently provides
3-aryloxindoles; however, this approach requires multistep
syntheses of each precursor for the cyclization, which is not
suitable for divergent syntheses. The second approach,
which is more commonly utilized, is based on transforma-
tions starting from isatin derivatives. The most general
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
A. Kondoh et al.
Letter
Synlett
phospha-Brook rearrangement under Brønsted base cataly-
sis. N-Benzyl-protected isatin 1a was chosen as the initial
substrate, and the reaction with diphenyl phosphite was at-
tempted. As a result, the reaction reached completion with-
in 10 minutes by using N,N-diisopropylethylamine as a cat-
alyst and corresponding oxindole 2a having a phosphate
moiety at the C-3 position was obtained in high yield
(Scheme 2).13 These conditions were applicable to a wide
range of isatin derivatives having different protective
groups, including MOM, PMB, and Boc groups, and a variety
of substituents on the benzene ring to afford the corre-
sponding oxindole derivatives in good to high yields except
for isatin 1n having a methoxy group at the C-6 position.
The reaction with diethyl phosphite instead of diphenyl
phosphite did not proceed under the reaction conditions
with N,N-diisopropylethylamine as a catalyst. In this case,
DBU was found to be a suitable catalyst and corresponding
product 2q was quantitatively obtained (Equation 1).
a–c) conventional methodologies
HO
Ar
O
R
R
a)
Ar-M
dehydration
N
M = Li, MgX
PG
O
Ar
Ar-X
b)
reduction
cat. M
O
O
O
O
R
R
N
M = Pd, Ni
N
N
PG
PG
PG
c)
1
4
N2
Ar-H, TfOH
or
(ArBO)3, base
diazotization
R
N
PG
O
d) new methodology (this work)
O
OP(OR)2
O
Ar
HP(OR)2
Ar-B
3
cat. base
cat. Pd
O
R
O
O
R
R
N
N
N
PG
cross-
coupling
PG
[1,2]-phospha-
Brook
PG
1
2
4
Scheme 1 Synthetic methodologies for 3-aryloxindoles from isatin de-
rivatives
O
O
OP(OEt)2
O
HP(OEt)
2 (1.1 equiv)
base (10 mol%)
O
O
N
tion has never been studied, we expected that the cross-
coupling would be possible because the phosphate moiety
is located at the benzylic position as well as at the position
α to an amide group.12 Herein, we report a new synthesis of
3-aryloxindoles from isatin derivatives using the [1,2]-
phospha-Brook rearrangement–cross-coupling sequence
strategy. We also describe the one-pot synthesis of 3-ary-
loxindoles from isatin derivatives.
toluene, r.t., 10 min
N
Bn
2q
base:
Bn
1a
i-Pr2NEt <1%
DBU 99%
Equation 1 The reaction of 1a with diethyl phosphite
Next, the investigation of the cross-coupling reaction of
oxindole derivatives thus synthesized with aryl boron re-
agents was undertaken. Initially, the reaction of 2a and phe-
nyl boronic acid (3a) was examined by treatment with a
catalytic amount of Pd2(dba)3 and various types of ligands
in the presence of 2.0 equivalents of K2CO3 in toluene at
60 °C for seven hours (Table 1, entries 1–7). As a result,
XPhos was found to be a prominent ligand for this transfor-
mation, and the desired product was obtained in moderate
yield along with the formation of 5a as a byproduct (Table 1,
entry 5). Other phosphine ligands and the NHC ligand did
not provide the desired product 4aa except for SPhos (albeit
only in 3% yield), and 5a was obtained as a major product in
many cases.14 Screening of the solvent revealed that, in ad-
dition to toluene, ethereal solvents, such as THF and methyl
tert-butyl ether (MTBE), could be used, and 4aa was ob-
tained in moderate yields (Table 1, entries 8 and 9). Further-
more, addition of H2O to toluene or MTBE as a co-solvent
improved the yield (Table 1, entries 10 and 12). At this
stage, other aryl boron reagents were tested (Table 1, en-
tries 13–16). While phenyl boronic acid pinacol ester (3b)
and potassium phenyltrifluoroborate (3d) provided 4aa
only in low yield (Table 1, entries 13 and 15), phenyl boron-
ic acid neopentyl glycol ester (3c) afforded the product in
comparable yield to that of phenyl boronic acid (3a, Table 1,
entry 14). In addition, the reaction with phenyl cyclic-triol-
borate potassium salt 3e15 proceeded without using K2CO3
to provide the product in moderate yield (Table 1, entry 16).
The investigation began by exploring the conditions for
the direct conversion of a keto moiety at the C-3 position of
the isatin derivatives into a phosphate moiety via the [1,2]-
O
O
OP(OPh)2
O
HP(OPh)2
(1.1 equiv)
i-Pr2NEt (10 mol%)
O
R
O
R
N
toluene, r.t., 10 min
N
PG
PG
1
2
O
O
PG = Bn
(2a) 94%
Me (2b) 91%
MOM (2c) 91%
PMB (2d) 89%
i-Pr (2e) 92%a
Boc (2f) 42%b
OP(OPh)2
OP(OPh)2
O
O
N
N
R
PG
Bn
R = MeO(2n) <1%
CF3 (2o) 85%
R = Me (2g) 92%
MeO (2h) 72%
O
O
OMe
OP(OPh)2
OP(OPh)2
F
Cl
Br
(2i)
(2j)
91%
91%
R
MeO
O
O
(2k) 85%
92%
NO2 (2m) 60%
N
N
CF3 (2l)
(2p) 90%
Bn
Bn
Scheme 2 Synthesis of oxindole derivatives having a phosphate moi-
ety at the C-3 position via the [1,2]-phospha-Brook rearrangement un-
der Brønsted base catalysis. Yields are isolated yields. a Reaction was
carried out for 40 min. b Reaction was carried out for 1 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
A. Kondoh et al.
Letter
Synlett
Further optimization of the reaction conditions was con-
ducted by using 3e as the arylating agent (Table 1, entries
17 and 18). Finally, the yield was improved to 80% by per-
forming the reaction in a 2:1 mixture of toluene and H2O
using NaHCO3 as an additive (Table 1, entry 18).16,17
ined (Scheme 3). Aryl boron reagents having substituents at
the para position, such as methoxy, fluoro, or chloro
groups, provided the corresponding products 4af, 4ag, and
4ah, respectively, in moderate to good yields. The meta-
tolyl boron reagent 3i also underwent the reaction without
any problem, and 4ai was obtained in good yield. In con-
trast, ortho-tolyl boron reagent 3j only provided the re-
duced product 5a in 69% yield. 2-Naphthyl boron reagent
3k and 5-indolyl boron reagent 3l were applicable to this
reaction to afford the corresponding products 4ak and 4al,
respectively, in good yields. Heteroaryl boron reagents, such
as 2-pyridyl and 2-thienyl boron reagents, were also tried;
however, the corresponding products were not obtained,
and the reduced product 5a and the remaining 2a were ob-
served in the crude reaction mixture.
Table 1 Screening of Reaction Conditions for Cross-Coupling Reaction
of Oxindole Derivatives 2 and Aryl Boron Reagents 3
O
Pd2(dba)3 (2.5 mol%)
ligand (5.0–10 mol%)
K2CO3 (2.0 equiv)
OP(OPh)2
Ph
+
Ph-B
3
O
O
O
+
solvent, 60 °C, 7 h
N
N
N
Bn
Bn
Bn
(1.5 equiv)
2a
4aa
5a
O
O
O
O
O
O
BF3K
B
B
B
B(OH)2
B =
O
K
3a
3b
3c
3d
3e
O
Ar
Pd2(dba)3 (2.5 mol%)
XPhos (10 mol%)
NaHCO3 (2.0 equiv)
OP(OPh)2
O
O
Entry
3
Ligand (mol%) Solvent
Yield of 4aa Yield of 5a
O
Ar
B
O
+
(%)a
(%)a
N
O
3
toluene/H2O (2:1)
60 °C, 7 h
N
K
Bn
Bn
2a
4
1
2
3a
Ph3P (10)
PCy3 (10)
Pt-Bu3 (10)
SPhos (10)
XPhos (10)
dppf (5)
toluene
<1
53
32
<1
29
36
64
5
(1.5 equiv)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3e
toluene
toluene
toluene
toluene
toluene
<1
<1
3
3
4
MeO
F
Cl
4af
80%
4ag
73%
4ai
81%
4aj
<1%
4ah
59%
5
41
<1
<1
59
35
56
34
62
28
52
25
52
73
(80)
(5a 17%)
(5a 21%)
(5a 19%)
(5a 69%)
(5a 17%)
6
4ak
4al
7
IMes·HCl (10) toluene
79%
70%
(5a 21%)
(5a 30%)
8
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
XPhos (10)
THF
21
36
29
16
21
11
25
10
26
16
17
N
Me
9
MTBE
Scheme 3 Scope of aryl cyclic-triolborate potassium salts 3. Yields are
based on 1H NMR analysis of the crude reaction mixture by using
1,1,2,2-tetrabromoethane as the internal standard.
10
11
12
13
14
15
16b
17b
toluene–H2O (2:1)
THF–H2O (2:1)
MTBE–H2O (2:1)
MTBE–H2O (2:1)
MTBE–H2O (2:1)
MTBE–H2O (2:1)
MTBE–H2O (2:1)
toluene–H2O (2:1)
toluene–H2O (2:1)
Next, the scope of oxindole derivatives 2 was examined
(Scheme 4). The substrates having an electron-donating
group at the C-5 position, such as a methyl or methoxy
group, underwent the reaction smoothly to provide the
corresponding products 4ge and 4he in good yields. In re-
gard to a halogen moiety at the C-5 position, fluoro and
chloro groups were compatible under the reaction condi-
tions, and the coupling products 4ie and 4je, respectively,
were obtained in moderate yields, although a bromo group
was not tolerated. In contrast, introducing a strong elec-
tron-withdrawing group to the C-5 or C-6 position, such as
a trifluoromethyl or nitro group, detrimentally affected the
reaction. The reaction with the substrates 2l and 2o having
a trifluoromethyl group at the C-5 and C-6 positions, re-
spectively, provided the corresponding products 4le and
4oe in modest yields. The reaction of the substrate having a
nitro group at the C-5 position did not provide the desired
product 4me. In these cases, very poor mass balance was
observed, indicating that decomposition of electron-defi-
cient 2 might occur under the reaction conditions. The re-
18b,c 3e
PCy2
PCy2
N
N
MeO
OMe
i-Pr
i-Pr
Cl
IMes·HCl
SPhos
XPhos
i-Pr
a Yields are based on 1H NMR analysis of the crude reaction mixture by using
1,1,2,2-tetrabromoethane as the internal standard. Isolated yield is given in
parentheses.
b Reaction was conducted without K2CO3.
c Reaction was conducted with 2.0 equivalents of NaHCO3 as an additive.
With the optimum conditions in hand, the scope of ox-
indole derivatives 2 and aryl boron reagents 3 was investi-
gated. First, the scope of aryl boron reagents 3 was exam-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
A. Kondoh et al.
Letter
Synlett
action of the substrate having two methoxy groups at the
C-4 and C-5 positions provided the product 4pe in low yield
along with a significant amount of reduced product 5p.
O
O
Ph
B
O
3e
(1.5 equiv)
K
O
Pd2(dba)3 (2.5 mol%)
XPhos (10 mol%)
NaHCO3 (2.0 equiv)
O
Ph
O
HP(OPh)2
i-Pr2NEt (10 mol%)
(1.1 equiv)
Ph
OP(OPh)2
O
O
Pd2(dba)3 (2.5 mol%)
XPhos (10 mol%)
O
toluene/H2O (2:1)
60 °C, 7 h
toluene, r.t., 10 min
O
N
N
O
R
Ph
O +
B
4aa
68%
R
Bn
Bn
N
1a
O
N
toluene/H2O (2:1)
60 °C, 7 h
K
Bn
Bn
(5a 17%)
3e
(1.5 equiv)
2
4
Scheme 5 One-pot synthesis of 3-aryloxindole 4aa from isatin deriva-
tive 1a
Ph
Ph
Ph
Ph
Me
MeO
O
F
Cl
O
O
O
N
N
N
N
Bn
Bn
Bn
Bn
dole having a phosphate moiety at the C-3 position via the
[1,2]-phospha-Brook rearrangement under Brønsted base
catalysis and the subsequent palladium-catalyzed cross-
coupling reaction with aryl boron reagents. The benefit of
the newly developed methodology was proven by conduct-
ing the one-pot synthesis of 3-aryloxindole derivatives
from isatin derivatives. Further application of the method-
ology, that is, the combination of the [1,2]-phospha-Brook
rearrangement under Brønsted base catalysis and a trans-
formation of the resulting phosphate under transition-met-
al catalysis, is in progress.
4ge
82%
4he
75%
4ie
75%
4je
43%
(5g 13%)
(5h 17%)
(5i 17%)
(5j 26%)
OMe
Ph
Ph
Ph
Ph
F3C
O2N
O
MeO
O
O
O
N
N
N
N
F3C
Bn
Bn
Bn
Bn
4le
33%
4me
<1%
4oe
17%
4pe
26%
(5l 23%)
(5m 20%)
(5o 34%)
(5p 39%)
Scheme 4 Scope of 3-oxindoles 2.18 Yields are based on 1H NMR analy-
sis of the crude reaction mixture by using 1,1,2,2-tetrabromoethane as
the internal standard.
Acknowledgment
The reaction with 2q having a diethoxyphosphoryloxy
group at the C-3 position instead of a diphenoxyphosphor-
yloxy group was also tested under the optimum reaction
conditions (Equation 2). The reaction with this substrate
also proceeded; however, the yield of 4aa was slightly low-
er than that obtained with 2a, and the amount of byproduct
5a was increased.
This work was partially supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformations by
Organocatalysts’ from the Ministry of Education, Culture, Sports, Sci-
ence and Technology (MEXT), Japan, and a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science (JSPS).
Supporting Information
O
Ph
Pd2(dba)3 (2.5 mol%)
XPhos (10 mol%)
NaHCO3 (2.0 equiv)
OP(OEt)2
Supporting information for this article is available online at
O
O
http://dx.doi.org/10.1055/s-0035-1561859.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
O
Ph
B
O
+
N
O
toluene/H2O (2/1)
60 °C, 7 h
N
K
Bn
Bn
3e
(1.5 equiv)
4aa
71%
2q
References and Notes
(5a 24%)
(1) For selected reviews, see: (a) Trost, B. M.; Brennan, M. K. Synthe-
sis 2009, 3003. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem.
Int. Ed. 2007, 46, 8748. (c) Steven, A.; Overman, L. E. Angew.
Chem. Int. Ed. 2007, 46, 5488. (d) Higuchi, K.; Kawasaki, T. Nat.
Prod. Rep. 2007, 24, 843. (e) Marti, C.; Carreira, E. M. Eur. J. Org.
Chem. 2003, 2209. (f) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org.
Chem. 2011, 6821. (g) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381.
(2) For selected recent examples, see: (a) Wang, Z.; Kang, T.; Yao,
Q.; Ji, J.; Liu, X.; Lin, L.; Feng, X. Chem. Eur. J. 2015, 21, 7709.
(b) Naganawa, Y.; Aoyama, T.; Nishiyama, H. Org. Biomol. Chem.
2015, 13, 11499. (c) Badiola, E.; Fiser, B.; Gómez-Bengoa, E.;
Mielgo, A.; Olaizola, I.; Urruzuno, I.; García, J. M.; Odriozola, J.
M.; Razkin, J.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2014,
136, 17869. (d) Shirakawa, S.; Koga, K.; Tokuda, T.; Yamamoto,
K.; Maruoka, K. Angew. Chem. Int. Ed. 2014, 53, 6220. (e) Zhu, X.-
L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y.; Tan, B. Org. Lett.
2014, 16, 2192. (f) Deng, Q.-H.; Bleith, T.; Wadepohl, H.; Gade, L.
Equation 2 Reaction of oxindole 2q with 3e
Finally, the one-pot synthesis of 3-aryloxindoles from
isatin derivatives was attempted (Scheme 5). Isatin deriva-
tive 1a and diphenyl phosphite were treated with a catalyt-
ic amount of i-Pr2NEt in toluene for 10 minutes. A stock
solution of the mixture of Pd2(dba)3 and XPhos, additional
toluene, NaHCO3, 3e, and H2O were added sequentially, and
the resulting mixture was stirred for seven hours at 60 °C.19
The desired 3-aryloxindole 4aa was successfully obtained
in good yield. This result demonstrated the benefit of the
newly developed methodology.
In conclusion, a novel methodology for the efficient syn-
thesis of 3-aryloxindoles from isatin derivatives was devel-
oped. The methodology involves the formation of an oxin-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
A. Kondoh et al.
Letter
Synlett
H. J. Am. Chem. Soc. 2013, 135, 5356. (g) Trost, B. M.; Masters, J.
T.; Burns, A. C. Angew. Chem. Int. Ed. 2013, 52, 2260. (h) Zhong,
F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew.
Chem. Int. Ed. 2013, 52, 943. (i) Wang, C.; Yang, X.; Enders, D.
Chem. Eur. J. 2012, 18, 4832.
(8.7 mL) was added i-Pr2NEt (75 μL, 0.43 mmol). The resulting
mixture was stirred at room temperature for 10 min. The reac-
tion was quenched with sat. aq NH4Cl, and the product was
extracted with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated. The residue was
purified by column chromatography (hexane–EtOAc, 2:1) to
provide 2a (1.9 g, 4.1 mmol, 94%) as a colorless oil.
(3) Bruce, J. M.; Sutcliffe, F. K. J. Chem. Soc. 1957, 4789.
(4) Fleming, I.; Loreto, M. A.; Wallace, I. H. M.; Michael, J. P. J. Chem.
Soc., Perkin Trans. 1 1986, 349.
Compound 2a: 1H NMR (600 MHz, CDCl3): δ = 1.08 (t, J = 7.2 Hz,
3 H), 3.63–3.95 (m, 2 H), 7.24–7.27 (m, 5 H), 7.28–7.31 (m, 1 H),
7.36–7.40 (m, 2 H), 7.52 (dd, J = 8.4, 1.2 Hz, 1 H), 7.54 (ddd,
J = 7.2, 7.2, 1.2 Hz, 1 H), 7.59–7.62 (m, 1 H), 7.66 (ddd, J = 7.2,
7.2, 1.2 Hz, 1 H), 7.94 (dd, J = 7.8, 0.60 Hz, 1 H). 13C NMR (150
MHz, CDCl3): δ = 13.7, 62.0, 88.1, 93.6, 122.9, 123.2, 128.0,
128.16 (2 C), 128.23, 128.3, 130.0, 130.6, 131.2, 131.4, 132.2,
132.5, 134.7, 141.4, 141.7, 163.0, 188.5. 31P NMR (243 MHz,
CDCl3): δ = –10.8. IR (ATR): 3061, 2984, 1748, 1731, 1691, 1597,
1496, 1442, 1197, 1020 cm–1. ESI-HRMS: m/z calcd for C24H18O3
[M + Na]+: 377.1148; found: 377.1148.
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(16) Typical Procedure for the Synthesis of 3-Aryloxindoles 4
The reaction of 2a and 3e is representative (Table 1, entry 18).
Pd2(dba)3 (6.8 mg, 7.5 μmol) and XPhos (14 mg, 30 μmol) were
dissolved in toluene (0.60 mL), and the solution was stirred for
15 min. Compound 2a (0.14 g, 0.30 mmol) in toluene (2.4 mL),
NaHCO3 (50 mg, 0.60 mmol), 3e (0.11 g, 0.45 mmol), and H2O
(1.5 mL) were sequentially added, and the resulting mixture
was then warmed to 60 °C. After stirred for 7 h, the reaction was
quenched with sat. aq NH4Cl, and the product was extracted
with EtOAc. The combined organic layer was dried over Na2SO4
and evaporated. The crude mixture was purified by column
chromatography (hexane–EtOAc, 4:1) to afford 4aa (72 mg, 0.24
mmol, 80%) as a white solid.
Compound 4aa: 1H NMR (400 MHz, CDCl3): δ = 4.74 (s, 1 H),
4.90 (d, J = 15.6 Hz, 1 H), 5.00 (d, J = 15.6 Hz, 1 H), 6.79 (d, J = 7.8
Hz, 1 H), 7.02 (dd, J = 7.2, 7.2 Hz, 1 H), 7.14–7.18 (m, 1 H), 7.18–
7.24 (m, 3 H), 7.24–7.37 (m, 8 H). 13C NMR (100 MHz, CDCl3):
δ = 43.9, 52.0, 109.2, 122.7, 125.1, 127.3, 127.59, 127.62, 128.3,
128.4, 128.8, 128.89, 128.92, 135.9, 136.7, 143.6, 176.1.
(17) The exploratory investigation for reaction conditions are sum-
marized in the Supporting Information.
(18) With these substrates 2, the reaction without NaHCO3 provided
almost the same or slightly better yields than those obtained
with NaHCO3.
(19) Procedure for the One-Pot Synthesis of 3-Aryloxindoles
To a solution of 1a (50 mg, 0.21 mmol) and diphenyl phosphite
(45 μL, 0.23 mmol) in toluene (0.42 mL) was added i-Pr2NEt (3.6
μL, 21 μmol). The resulting mixture was then stirred at room
temperature for 10 min. A stock solution of Pd2(dba)3 (4.8 mg,
5.3 μmol) and XPhos (10 mg, 21 μmol) in toluene (0.42 mL),
toluene (3.4 mL), NaHCO3 (35 mg, 0.42 mmol), 3e (77 mg, 0.31
(13) Typical Procedure for the Synthesis of Oxindole Derivatives 2
Synthesis of 2a is representative. To a solution of 1a (1.0 g, 4.3
mmol) and diphenyl phosphite (0.92 mL, 4.8 mmol) in toluene
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
A. Kondoh et al.
Letter
Synlett
mmol), and H2O (2.1 mL) were added sequentially, and the
resulting mixture was then warmed to 60 °C. After stirred for 7
h, the reaction was quenched with sat. aq NH4Cl, and the
product was extracted with EtOAc. The combined organic layer
was dried over Na2SO4 and evaporated. The residue was purified
by column chromatography (hexane–EtOAc, 4:1) to provide 4aa
(43 mg, 0.14 mmol, 68%) as a white solid.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F