Synthesis of 3,3-Disubstituted 2-Oxindoles by Deacylative Alkylation of 3-Acetyl-2-oxindoles

Article abstract of DOI:10.1055/s-0036-1590880

An innovative and efficient monoalkylation and nonsymmetrical 3,3-dialkylation of oxindoles has been achieved. First, the monoalkylation of 3-acetyl-2-oxindoles can be performed in good yields under mild reaction conditions using alkyl halides and benzylt

Full text of DOI:10.1055/s-0036-1590880

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
A. Ortega-Martínez et al.
Paper
Synthesis
Synthesis of 3,3-Disubstituted 2-Oxindoles by Deacylative Alkylation
of 3-Acetyl-2-oxindoles
Aitor Ortega-Martíneza,b
Cynthia Molinaa,b
Cristina Moreno-Cabrerizoa,b
José M. Sansano*a,b
Carmen Nájera*a
a Departamento de Química Orgánica and Centro de
Innovación en Química Avanzada (ORFEO-CINQA),
Facultad de Ciencias, Universidad de Alicante,
03080-Alicante, Spain
jmsansano@ua.es
cnajera@ua.es
b Instituto de Síntesis Orgánica, Facultad de Ciencias,
Universidad de Alicante, 03080-Alicante, Spain
Received: 09.06.2017
Accepted after revision: 22.07.2017
Published online: 22.08.2017
groups.9 Detrifluoroacetylative reactions have been studied
for the generation of fluoroenolates10 and applied to the
synthesis of 3-fluoro-2-oxindole enolates for subsequent
Mannich reactions.11
DOI: 10.1055/s-0036-1590880; Art ID: ss-2017-t0386-op
Abstract An innovative and efficient monoalkylation and nonsymmet-
rical 3,3-dialkylation of oxindoles has been achieved. First, the monoal-
kylation of 3-acetyl-2-oxindoles can be performed in good yields under
mild reaction conditions using alkyl halides and benzyltrimethylammo-
nium hydroxide (Triton B) as base at room temperature. This methodol-
ogy is applied to construct the synthetically challenging compound 1,3-
dimethyl-2-oxindole. Subsequent deacylative alkylation (DaA) of the al-
kylated 3-acetyl-2-oxindoles with alkyl halides takes place efficiently us-
ing LiOEt or by conjugate addition with electron-deficient alkenes in the
presence of Triton B at room temperature under argon, affording the
corresponding unsymmetrically 3,3-disubstituted 2-oxindoles. This
simple methodology has been applied to the synthesis of precursors of
horsfiline, esermethole, physostigmine, and phenserine alkaloids.
R2
R3
R2
R3
X
(a)
(b)
R2
O
O
O
N
N
N
R1
R4
R4
R4
R1
R1
(c)
(e)
CO2R2
Oallyl
(d)
(X = H, Hal)
R2
R2
CO2R3
CO2allyl
O
O
N
R1
N
R4
N
R1
R4
R4
R1
Scheme 1 Retrosynthetic analysis for the synthesis of 3,3-disubstitut-
ed 2-oxindoles
Key words deacylation, alkylation, 2-oxindoles, Michael addition,
Triton B
However, direct and selective successive alkylation of 2-
oxindoles with different electrophiles is not an easy syn-
thetic strategy because the first monoalkylation step is dif-
ficult to control and requires strong bases for the genera-
tion of the corresponding enolate. We envisaged that DaA
could be an excellent strategy for the synthesis of 3,3-di-
alkylated 2-oxindoles. In this work, we describe a base-
mediated monoalkylation of 3-acetyl-2-oxindoles followed
by a DaA as a simple process for the synthesis of 3,3-di-
alkylated oxindoles (Scheme 2).
Monoacylated N-methyloxindole 2a was prepared from
the corresponding 2-oxindole 1a, which is commercially
available, by reaction with acetic anhydride in the presence
of 4-(N,N-dimethylamino)pyridine (DMAP) at 140 °C for
5 h.12 Due to the concomitant acylation at the C3 carbon
and at the oxygen atom, the reaction mixture was treated
with KOH in MeOH followed by concentrated aqueous HCl
In the last years, the family of 3,3-disubstituted 2-oxin-
doles has attracted attention because this unit is present in
many natural products and synthetic drugs.1 Two main syn-
thetic strategies have been developed for the synthesis of
these compounds based on: (a) intramolecular coupling re-
actions such as Heck reactions,2 arylations of o-halogenat-
ed3 and unsubstituted4 anilides, and (b) alkylation of 3-sub-
stituted 2-oxindoles5 (Scheme 1). Recently, (c) Pd-catalyzed
decarboxylative allylation and benzylation reactions,6 (d)
the Meerwein–Eschenmoser–Claisen rearrangement,7 and
(e) Pd-catalyzed deacylative allylation8 have also been em-
ployed for the generation of a quaternary stereocenter at
the 3-position of 2-oxindoles.
The deacylative alkylation (DaA) reaction employs the
acetyl group as protecting, activating, and leaving group for
the alkylation of enolates and has been performed mainly
under Pd-catalyzed conditions for the introduction of allyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
A. Ortega-Martínez et al.
Paper
Synthesis
O
O
O
A
Me
OH
Me
Me
B
A
Me
O
base
B+
base
A+
Me
O
Triton B
O
O
THF, r.t., 5 min
N
N
R1
N
R1
N
N
R2
R2
R2
R1
Me
Me
3aa
4aa
A+ and B+ are different electrophilic species
Scheme 5 Synthesis of 1,3-dimethyl-2-oxindole 4aa
Scheme 2 Our proposal for the synthesis of 3,3-disubstituted 2-oxin-
doles
temperature, the corresponding allylated product 3ab was
obtained in 84% yield (Table 1, entry 2). These reaction con-
ditions were employed for the alkylation of 2 with different
alkyl halides to give the desired products 3 in good yield
(Table 1). Under these reaction conditions the alkylation
took place regioselectively at the 3-position of the oxindole.
Only in the case of n-pentyl bromide the reaction needed to
be carried out under reflux (entry 6). In the case of methyl
bromoacetate, the methyl ester was used to avoid transes-
terification with MeOH (entry 7). Compounds 3 were sensi-
tive to deacylation during the purification by flash chroma-
tography, affording the monoalkylated 2-oxindoles 4 in less
than 10% (entries 2–7).
to afford compound 2a in 88% yield (Scheme 3). For the syn-
thesis of oxindoles 2b and 2c, 5-methoxyisatin was trans-
formed into the corresponding 2-oxindoles 1b13 and 1c14,15
according to reported procedures. Further acylation of 1b
and 1c gave 2b and 2c in 68% and 24% overall yield, respec-
tively.
O
Me
X
X
1. Ac2O, DMAP, 140 °C
OH
O
N
R1
N
R1
2. KOH, MeOH
3. HCl
1
2a: R1 = Me, X = H (88%)
2b: R1 = Me, X = OMe (68%)
2c: R1 = Bn, X = OMe (24%)
Table 1 Monoalkylation of 3-Acetyl-2-oxindoles 2a
O
O
R2
Scheme 3 Synthesis of 3-acetyl-2-oxindoles 2
Me
OH
Me
O
X
X
Triton B
+ R2Hal
THF, r.t., o/n
N
N
When these reaction conditions were assayed with un-
substituted N-methyl-2-oxindole (1a) and allyl bromide,
the formation of a mixture of monoallylated 4ab and di-
allylated 5ab oxindole in 17% and 51% yield, respectively,
was observed (Scheme 4). Upon increasing the amount of
base and allyl bromide to 2 equiv, only diallylated com-
pound 5ab was formed quantitatively.
R1
R1
2
3
Entry
2
X
R1
R2Hal
3
Yield
(%)b
1
2
2ac
2a
H
Me
MeI
3aa
3ab
88
84d
Br
Br
H
H
Me
Me
Br
3
4
2a
2a
3ac
3ad
54e
68e
Triton B (1 equiv)
O
O
+
H
Me
CH2=CHCH2Br
(1.1 equiv)
N
N
Me
Me
5ab (51%)
O
5
6
7
8
9
2a
H
H
H
Me
Me
Me
Me
Bn
PhCH2Br
3ae
3af
84f
50h,d
69i
85
4ab (17%)
N
2ag
2a
n-C5H11Br
MeO2CCH2Br
MeI
Triton B (2 equiv)
Me
5ab (99%)
1a
CH2=CHCH2Br
(2 equiv)
3ag
3ba
3ca
2bj
2ck
OMe
OMe
Scheme 4 Allylation of N-methyl-2-oxindole 1a
MeI
92
a The reaction was performed on a 1.2 mmol scale at r.t. overnight in a
2/R2Hal molar ratio of 1:1.
However, when compound 3aa was treated with Triton
B it was possible to prepare 3-monomethylated oxindole
4aa in 67% yield (Scheme 5), which is an important starting
compound for the synthesis of alkaloids (see below). There-
fore, this methodology can be applied to the selective syn-
thesis of 3-monoalkylated oxindoles 4.
The alkylation of 2 was initially performed with LiOEt as
base and allyl bromide, affording the allylated product 3ab
in less than 5% yield. However, when Triton B (40wt% in
MeOH) was used as base in tetrahydrofuran (THF), at room
b Isolated yield after flash chromatography.
c MeI (2 equiv) was used on a 7.2 mmol scale.
d 6% deacylated compound was also obtained.
e 4% deacylated compound was also obtained.
f 5% deacylated compound was also obtained and the reaction was scaled up
to 1.8 mmol.
g 0.3 mmol scale.
h Under reflux.
i 10% deacylated compound was also obtained.
j 4.6 mmol scale.
k 0.6 mmol scale.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
A. Ortega-Martínez et al.
Paper
Synthesis
Table 2 (continued)
For the deacylative alkylation (DaA) of 3, several basic
conditions were tested, the best results were obtained with
a 1 M solution of lithium ethoxide in anhydrous THF at
room temperature under argon was used, which avoided
the formation of deacylated compounds 4. Under these re-
action conditions, the preparation of 3,3-dialkylated com-
pounds 6 could be successfully performed (Table 2). In the
case of the allylation of compound 3ae using Triton B in-
stead of LiOEt, a lower yield was obtained for product 6afb
(Table 2, compare entries 7 and 8). This reaction took place
by attack of the base to the acetyl group, forming the corre-
sponding lithium enolate, which underwent regioselective
alkylation at the 3-position.
Compounds 6bab and 6cab, derived from N-methyl-
and N-benzyl-5-methoxy-2-oxindoles 1b and 1c, respec-
tively, are precursors of the racemic natural alkaloid horsfil-
ine 716 and also of esermethole 8a,17 which is an intermedi-
ate for the synthesis of acetylcholinesterase inhibitors
physostigmine 8b and phenserine 8c18 (Figure 1). Deriva-
tives 6bai and 6cai are also precursors of esermethole 8a
and physostigmine 8b through a shorter synthetic pathway
than 6bab or 6cab.19
Entry 3
R3Hal
Product
6
Yield
(%)b
Me
CO2Et
O
6
3aa
EtO2CCl
6aaj
65
N
N
Me
Ph
O
7
8
9
3ae
3ae
3ba
CH2=CHCH2Br
CH2=CHCH2Br
CH2=CHCH2Br
6aeb
6aeb
6bab
67
Me
58d
75
Me
MeO
MeO
O
N
Me
Me
CN
93e
70
O
O
10
11
12
3ba
3ca
3ca
NCCH2Br
6bai
6cab
6cai
N
Me
Me
Me
Table 2 DaA of 3-Acetyl-2-oxindoles 3 with Alkyl Halidesa
MeO
MeO
CH2=CHCH2Br
NCCH2Br
N
O
R2
R3
R2
Me
O
Bn
X
X
LiOEt (1 equiv)
THF, r.t., 17 h
+ R3Hal
O
CN
O
N
N
R1
R1
74
3
6
N
Bn
Entry 3
R3Hal
Product
6
Yield
a The reaction was performed on a 0.15 mmol scale at r.t. overnight in a
3/R3Hal molar ratio of 1:1.
(%)b
b Isolated yield after flash chromatography.
c Cinnamyl bromide (1.5 equiv) was used.
d With Triton B as base (1 equiv).
Me
Me
Me
O
O
1
3aa
3aa
3aa
3aa
3aa
CH2=CHCH2Br
6aab
6aad
6aae
6aah
6aai
72
e 2 mmol scale.
N
Me
Conjugate addition of 3aa to electrophilic alkenes was
also studied using DaA. In this case, Triton B was a better
base than LiOEt, giving, in THF at room temperature under
argon, 9 in good yields (Table 3). Only in the absence of oxy-
gen was not the formation of 3-hydroxy-3-methyl-2-oxin-
dole observed (less than 5%). Acrylic systems gave the cor-
responding products in high yields. In the case of phenyl vi-
nyl sulfone, a lower yield (51%) was observed with
Br
2
3
4
5
69
87
75c
88
N
Me
Ph
O
O
PhCH2Br
N
Me
Me
Me
Ph
Me
Me
N
X
Ph
Br
N
MeO
Me
N
H
N
O
Me
Me
8a: X = OMe
N
H
CN
7
8b: X = OCONHMe
8c: X = OCONHPh
O
NCCH2Br
N
Figure 1 Natural alkaloids whose synthetic intermediates can be ac-
Me
cessed by using this methodology
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
A. Ortega-Martínez et al.
Paper
Synthesis
formation of 13% of O-alkylated product (entry 5). However,
the more electrophilic 1,1-disulfone, gave product 9af ex-
clusively in 83% yield (entry 6). When chalcone was used as
electrophile, a 1:0.7 mixture of diastereoisomers was ob-
tained (entry 8).
Table 3 DaA of 3-Acetyl-2-oxindoles 3 with Electrophilic Alkenesa
O
EWG
Me
Me
Me
O
Triton B
+
O
EWG
THF, r.t., o/n
N
N
It can be concluded that the acetylation of 2-oxindoles
allows their monoalkylation under mild conditions using
Triton B as base. By subsequent deacetylation it is possible
to prepare the corresponding 3-alkylated 2-oxindoles. The
3-substituted 3-acetyl-2-oxindoles can undergo deacylative
alkylation with alkyl halides in the presence of LiOEt or
with electrophilic alkenes by means of Triton B, affording
the corresponding 3,3-disubstituted 2-oxindoles under
very mild reaction conditions. This methodology is suitable
for the preparation of unsymmetrical 3,3-disubstituted ox-
indoles, which cannot be easily prepared by other strate-
gies.
Me
Me
3aa
9
Entry Alkenes
Product
9
Yield
(%)b
CO2tBu
Me
O
O
O
1
2
3
CH2=CHCO2tBu
CH2=CHCN
9aa
9ab
9ac
90
N
Me
CN
Me
Me
89
86
86
51c
83
85
N
Me
CONMe2
Melting points were determined with a Marienfeld melting-point me-
ter (MPM-H2) apparatus and are uncorrected. For flash chromatogra-
CH2=CHCONMe2
1
phy, silica gel 60 (40–60 μm) was employed. H NMR (300, 400 MHz
N
or 500 MHz) and 13C NMR (75, 101 or 126 MHz) spectra were record-
ed with Bruker AV300, Bruker AV400, and Bruker ADVANCE DRX500,
respectively, with CDCl3 as solvent and TMS as internal standard for
1H NMR spectra, and the chloroform signal for 13C NMR spectra;
chemical shifts are given in ppm. Low-resolution electron impact
(GC-EI) mass spectra were obtained at 70 eV with an Agilent 6890N
Network GC system and an Agilent 5973Network Mass Selective De-
tector. High-resolution mass spectra (GC-EI) were recorded with a
QTOF Agilent 7200 instrument for the exact mass and Agilent 7890B
for the GC. Analytical TLC was performed using ALUGRAM® Xtra SIL
G/UV254 silica gel plates, and the spots were detected under UV light
(λ=254 nm).
Me
COMe
Me
Me
Me
Me
4
5
6
7
CH2=CHCOMe
CH2=CHSO2Ph
CH2=C(SO2Ph)2
CH2=CHP(O)(OEt)2
9ad
9ae
9af
O
O
O
O
N
Me
SO2Ph
N
Me
SO2Ph
SO2Ph
Synthesis of 1-(2-Hydroxy-1-methyl-1H-indol-3-yl)ethanone (2a)
To a round-bottom flask containing a solution of N-methyl-2-oxin-
dole (4.85 g, 33 mmol) in acetic anhydride (36 mL, 381 mmol), DMAP
(118 mg, 0.96 mmol) was added. The mixture was heated at 140 °C
for 5 h. The mixture was evaporated under reduced pressure, the
crude residue was dissolved in MeOH (80 mL) and a solution of KOH
(18 g, 321 mmol) in MeOH (120 mL) at 0 °C was added. The solution
was stirred at r.t. for 22 h then cooled in an ice-bath at 0 °C and 12 M
aqueous HCl was added until pH 3. At this point, H2O (140 mL) was
added and the solution was extracted with EtOAc (3 × 140 mL). The
organic phases were dried over MgSO4, filtered, and concentrated.
The residue was purified by flash chromatography (hexane/EtOAc) to
give pure 2a.
N
Me
P(O)(OEt)2
9ag
N
Me
Ph
COPh
Me
Ph
8
9ah
97d
COPh
O
Yield: 5.5 g (88%); purple solid; mp 109–110 °C (hexane/EtOAc) (Lit.12
110–111 °C).
N
Me
a The reaction was performed on a 0.15 mmol scale at r.t. overnight in a
1:1.4 molar ratio.
The spectral data are consistent with reported data.12
b Isolated yield after flash chromatography.
c The O-alkylated product (13%) was also obtained using phenyl vinyl sul-
fone (1 equiv).
Synthesis of 1-(2-Hydroxy-1-methyl-5-methoxy-1H-indol-3-
yl)ethanone (2b)
d A 1:0.7 mixture of diastereomers was formed.
A round-bottom flask containing a solution of 5-methoxyisatin (3.54
g, 20 mmol) in anhydrous DMF (40 mL) was cooled to 0 °C, then sodi-
um hydride (606 mg, 24 mmol) was added in one portion and the
mixture was stirred for 5 min. Iodomethane was added (1.84 mL, 30
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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A. Ortega-Martínez et al.
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Synthesis
mmol) and the mixture was stirred at 0 °C for 30 min. The mixture
was poured in saturated aqueous NH4Cl (20 mL) and extracted with
dichloromethane (3 × 40 mL). The organic phase was washed with
H2O (3 × 15 mL) and brine (20 mL), dried over MgSO4, and evaporated
under vacuum. The dark-red solid was dissolved in hydrazine mono-
hydrate (12 mL, 247 mmol) and heated at 130 °C for 3 h. After cooling
the solution to r.t., H2O (50 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 50 mL). The organic phase was washed with
saturated aqueous NaHCO3 (50 mL), brine (50 mL), and dried over
MgSO4, filtered and concentrated.13 To the resulting residue, acetic
anhydride (22.5 mL, 238 mmol) was added. Then, DMAP (73.3 mg,
0.6 mmol) was added and the mixture was heated at reflux (140 °C)
for 5 h and then evaporated under reduced pressure. The residue was
dissolved in MeOH (50 mL), then a solution of KOH (11 g, 196 mmol)
in MeOH (70 mL) at 0 °C was added. The solution was stirred at r.t. for
22 h and then cooled in an ice-bath at 0 °C. A solution of 12 M aque-
ous HCl was added until pH 3. The organic solvent was evaporated
and the residue was extracted with EtOAc (3 × 100 mL), washed with
H2O (100 mL), dried over MgSO4, filtered and concentrated. The resi-
due was purified by flash chromatography (hexane/EtOAc) to give
pure 2b.
Monoalkylation of 3-Acetyl-2-oxindoles 2; General Procedure
To a solution of 3-acetyl-2-oxindole 2 (227 mg, 1.2 mmol) and alkyl
halide (1.2 mmol) in THF (7 mL) was added benzyltrimethylammoni-
um hydroxide (Triton B) in MeOH (40wt%, 0.545 mL, 1.2 mmol). The
reaction was stirred at r.t. overnight, H2O (20 mL) was added, the mix-
ture was extracted with EtOAc (3 × 20 mL) and the combined organic
layers were evaporated and dried over MgSO4. After evaporation of
the solvents the residue was purified by flash chromatography
(EtOAc/hexane) to afford the corresponding product 3 (see, Table 1).
Compounds 3aa (1.36 g, 88%),22 3ae (341 mg, 84%),22 3ba (899 mg,
85%),23 and 3ca (171 mg, 92%),22 are known.
3-Acetyl-3-allyl-1-methylindolin-2-one (3ab)
Yield: 192 mg (84%); pale-yellow oil.
1H NMR (300 MHz): δ = 7.36 (td, J = 7.7, 1.4 Hz, 1 H), 7.18 (dd, J = 7.4,
1.0 Hz, 1 H), 7.10 (td, J = 7.5, 1.0 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 5.30
(dddd, J = 16.8, 10.0, 7.8, 6.7 Hz, 1 H), 5.00 (m, 1 H), 4.88 (m, 1 H), 3.28
(s, 3 H), 2.91 (m, 2 H), 1.99 (s, 3 H).
13C NMR (101 MHz): δ = 200.7, 174.5, 144.3, 131.5, 129.3, 127.0,
124.2, 123.3, 119.5, 108.6, 66.4, 37.5, 26.6.
Overall yield: 2.97 g (68%); purple solid; mp 83–84 °C (hexane/EtOAc)
(Lit.20 83 °C).
The spectral data are consistent with reported data.20
LRMS (EI): m/z = 229 (9) [M]+, 188 (13), 187 (100), 186 (22), 172 (12),
160 (22), 158 (14), 144 (10), 143 (10).
HRMS (EI): m/z calcd. for C14H15NO2: 229.1103; found: 229.1107.
Synthesis of 1-(1-Benzyl-2-hydroxy-5-methoxy-1H-indol-3-
yl)ethanone (2c)
(E)-3-Acetyl-3-(3,7-dimethylocta-2,6-dien-1-yl)-1-methylindolin-
2-one (3ac)
A mixture of 5-methoxyisatin (2.84 g, 16 mmol) and K2CO3 (5.53 g, 40
mmol) was dissolved in anhydrous DMF (12 mL) under Ar. Benzyl
bromide (5.71 mL, 48 mmol) was added dropwise and the mixture
was stirred at r.t. for 19 h. The mixture was extracted with dichloro-
methane (3 × 20 mL) and the organic phase was washed with H2O (20
mL) and brine (20 mL), dried with MgSO4, filtered, and concentrated
to obtain a red solid.14 The crude material was dissolved in DMSO (12
mL), hydrazine hydrate (1.81 mL, 32 mmol) was added dropwise and
the mixture was heated at 150 °C for 5 h. The mixture was cooled to
r.t., extracted with EtOAc (2 × 100 mL), and the organic phase was
washed with H2O (100 mL) and brine (50 mL), dried over MgSO4, fil-
tered, and concentrated. The residue was purified by flash chroma-
tography (hexane/EtOAc) to give pure 1-benzyl-5-methoxy-2-oxin-
dole (2.55 g, 63%) as a brown oil.15
Yield: 210 mg (54%); brown oil.
1H NMR (300 MHz): δ = 7.34 (td, J = 7.7, 1.3 Hz, 1 H), 7.19 (dd, J = 7.5,
1.2 Hz, 1 H), 7.07 (td, J = 7.5, 1.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 4.89
(m, 1 H), 4.73–4.60 (m, 1 H), 3.26 (s, 3 H), 2.89 (m, 2 H), 2.01 (s, 3 H),
1.80 (m, 4 H), 1.62 (s, 3 H), 1.51 (s, 3 H), 1.49 (s, 3 H).
13C NMR (101 MHz): δ = 201.4, 175.0, 144.3, 139.9, 131.4, 129.2,
127.6, 124.3, 124.1, 123.1, 116.7, 108.3, 66.6, 39.9, 32.2, 26.8, 26.8,
26.6, 25.8, 17.7, 16.5.
LRMS (EI): m/z = 325 (8) [M]+, 214 (14), 198 (12), 190 (15), 189 (100),
171 (10), 160 (36), 159 (35), 69 (24).
HRMS (EI): m/z calcd. for C21H27NO2: 325.2042; found: 325.2044.
3-Acetyl-1-methyl-3-(prop-2-yn-1-yl)indolin-2-one (3ad)
The above product was dissolved in acetic anhydride (11.5 mL, 121
mmol) and DMAP (37 mg, 0.3 mmol) was added. The mixture was
heated at reflux (140 °C) for 6 h and then cooled to r.t. and evaporated
under reduced pressure. The residue was dissolved in MeOH (40 mL)
cooled at 0 °C and then a solution of KOH (8.5 g, 151 mmol) in MeOH
(60 mL) was added. The solution was stirred at r.t. for 18 h then the
solution was cooled in an ice-bath at 0 °C and 12 M aqueous HCl was
added until pH 3. The organic solvent was evaporated under reduced
pressure, H2O (50 mL) was added and the mixture was extracted with
EtOAc (3 × 50 mL). The organic phase was dried over MgSO4, filtered,
and concentrated. The residue was purified by flash chromatography
(hexane/EtOAc) to give pure 2c.
Yield: 186 mg (68%); brown solid; mp 84–86 °C (hexane/EtOAc).
1H NMR (300 MHz): δ = 7.41 (td, J = 7.7, 1.3 Hz, 1 H), 7.24 (dd, J = 7.4,
0.9 Hz, 1 H), 7.13 (td, J = 7.5, 0.9 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 3.32
(s, 3 H), 3.13 (dd, J = 16.8, 2.7 Hz, 1 H), 2.93 (dd, J = 16.9, 2.6 Hz, 1 H),
1.97 (s, 3 H), 1.76 (t, J = 2.6 Hz, 1 H).
13C NMR (101 MHz): δ = 199.5, 173.6, 144.7, 129.8, 126.7, 124.0,
123.5, 108.7, 78.6, 70.5, 65.1, 26.8, 26.3, 23.0.
LRMS (EI): m/z = 227 (8) [M]+, 186 (13), 185 (100), 184 (60), 157 (12),
156 (14), 128 (13).
HRMS (EI): m/z calcd. for C14H13NO2: 225.0946; found: 227.0945.
Overall yield: 1.15 g (24%); brown solid; mp 145–146 °C (hexane/EtOAc)
(Lit.21 150–151 °C).
3-Acetyl-1-methyl-3-pentylindolin-2-one (3af)
Yield: 39 mg (50%); colorless oil.
The spectral data are consistent with reported data.
1H NMR (300 MHz): δ = 7.35 (td, J = 7.6, 1.5 Hz, 1 H), 7.22–7.04 (m,
2 H), 6.91 (d, J = 7.8 Hz, 1 H), 3.29 (s, 3 H), 2.27–2.04 (m, 2 H), 2.00 (s,
3 H), 1.23–1.14 (m, 5 H), 0.83–072 (m, 4 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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A. Ortega-Martínez et al.
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Synthesis
13C NMR (101 MHz): δ = 201.5, 175.3, 144.3, 129.1, 127.7, 124.0,
123.3, 108.5, 66.9, 33.4, 31.9, 26.6, 26.6, 23.4, 22.4, 14.0.
Deacylative Alkylation of 3-Acetyl-2-oxindoles 3 with Electrophil-
ic Alkenes; General Procedure
LRMS (EI): m/z = 259 (7) [M]+, 218 (10), 217 (64), 161 (12), 160 (100),
147 (10).
Oxindole 3aa (30.5 mg, 0.15 mmol) and electrophilic alkene (0.21
mmol) were dissolved in THF (1.5 mL). After three cycles of freezing-
pump-thaw and filling the flask with Ar, benzyltrimethylammonium
hydroxide (Triton B) in MeOH (40wt%, 0.068 mL, 0.15 mmol) was
added. The mixture was stirred overnight at r.t. and extractive work-
up was performed with EtOAc (3 × 10 mL) and H2O (10 mL). The or-
ganic phases were dried with MgSO4, filtered and concentrated, and
the resulting crude product was purified by flash chromatography
(EtOAc/hexane) to give 9.
HRMS (EI): m/z calcd. for C16H21NO2: 259.1572; found: 259.1576.
Methyl 2-(3-Acetyl-1-methyl-2-oxoindolin-3-yl)acetate (3ag)
Yield: 215 mg (69%); purple oil.
1H NMR (300 MHz): δ = 7.38 (td, J = 7.7, 1.3 Hz, 1 H), 7.20 (d, J =
7.3 Hz, 1 H), 7.08 (td, J = 7.5, 1.0 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 3.50
(s, 3 H), 3.34 (s, 3 H), 3.40–3.19 (m, 2 H), 1.93 (s, 3 H).
Compounds 9aa (39 mg, 90%),28, 9ab (29 mg, 89%),29 9ad (30 mg,
86%),29 and 9ae (50 mg, 51%)30 are known.
13C NMR (101 MHz): δ = 199.2, 174.3, 170.3, 145.0, 129.7, 126.9,
123.8, 123.3, 108.8, 63.5, 51.9, 37.2, 27.0, 25.7.
LRMS (EI): m/z = 261 (2) [M]+, 219 (50), 160 (31), 159 (100), 130 (21).
3-(1,3-Dimethyl-2-oxoindolin-3-yl)-N,N-dimethyl Propanamide
(9ac)
HRMS (EI): m/z calcd. for C14H15NO4: 261.1001; found: 261.1005.
Yield: 34 mg (86%); yellow oil.
1H NMR (300 MHz): δ = 7.31–7.20 (m, 2 H), 7.08 (td, J = 7.5, 0.9 Hz,
1 H), 6.86 (d, J = 7.8 Hz, 1 H), 3.23 (s, 3 H), 2.84 (s, 6 H), 2.29–2.04 (m,
3 H), 1.93–1.80 (m, 1 H), 1.39 (s, 3 H).
13C NMR (101 MHz): δ = 180.4, 172.4, 143.1, 133.4, 128.1, 123.0,
122.9, 108.0, 47.8, 33.3, 28.3, 26.3, 24.0.
LRMS (EI): m/z = 260 (56) [M]+, 216 (17), 188 (15), 174 (62), 162 (92),
161 (93), 160 (100), 159 (11), 146 (13), 144 (12), 130 (19), 117 (12),
100 (44), 72 (16), 55 (12).
Deacylative Alkylation of 3-Acetyl-2-oxindoles 3 with Alkyl Ha-
lides; General Procedure
Oxindole 3 (0.15 mmol) and alkyl halide (0.165 mmol) were dissolved
under an argon atmosphere in anhydrous THF (1.5 mL). A 1 M solu-
tion of LiOEt (0.15 mL, 0.15 mmol) was added dropwise and the reac-
tion mixture was stirred at r.t. overnight. After extractive work-up
and flash chromatography, pure 3,3-dialkylated 2-oxindole 6 was ob-
tained (see, Table 2).
Compounds 6aab (22 mg, 72%),24 6aae (33 mg, 87%),25 6aah (31 mg,
75%),25 6aai (27 mg, 88%),19 6aaj (23 mg, 65%),22 6aeb (28 mg, 67%),26
6bab (26 mg, 75%),26 6bai (429 mg, 93%),19 and 6cai (34 mg, 74%)27
are known.
HRMS (EI): m/z calcd. for C15H20N2O2: 260.1525; found: 260.1521.
3-[2,2-Bis(phenylsulfonyl)ethyl]-1,3-dimethylindolin-2-one (9af)
Yield: 58 mg (83%); pale-yellow solid; mp 171–173 °C (hexane/EtOAc).
1H NMR (300 MHz): δ = 8.01 (m, 2 H), 7.85–7.75 (m, 2 H), 7.75–7.43
(m, 6 H), 7.35 (td, J = 7.7, 1.3 Hz, 1 H), 7.30–7.20 (m, 1 H), 7.14 (td, J =
7.5, 1.0 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H), 4.85 (dd, J = 5.2, 3.4 Hz, 1 H),
3.20 (s, 3 H), 2.78 (dd, J = 16.4, 3.4 Hz, 1 H), 2.69 (dd, J = 16.4, 5.2 Hz,
1 H), 1.37 (s, 3 H).
13C NMR (101 MHz): δ = 179.0, 143.5, 138.6, 136.3, 134.8, 134.3,
132.3, 130.9, 129.4, 129.1, 129.0, 128.9, 123.3, 122.7, 108.8, 79.1, 46.0,
31.2, 26.5, 23.9.
3-Propargyl-1,3-dimethylindolin-2-one (6aad)
Yield: 21 mg (69%); yellow oil.
1H NMR (400 MHz): δ = 7.46–7.43 (m, 1 H), 7.30 (td, J = 7.7, 1.2 Hz,
1 H), 7.09 (td, J = 7.6, 1.0 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H), 3.23 (s, 3 H),
2.70 (dd, J = 16.5, 2.7 Hz, 1 H), 2.49 (dd, J = 16.6, 2.7 Hz, 1 H), 1.96 (t,
J = 2.7 Hz, 1 H), 1.46 (s, 3 H).
13C NMR (101 MHz): δ = 179.5, 143.1, 133.1, 128.3, 123.3, 122.7,
108.1, 79.8, 70.8, 46.7, 27.8, 26.4, 21.9.
LRMS (EI): m/z = 469 (30) [M]+, 161 (34), 160 (100), 158 (11), 130
(10), 77 (21).
LRMS (EI): m/z = 199 (28) [M]+, 161 (11), 160 (100), 132 (9), 130 (8),
117 (10).
HRMS (EI): m/z calcd. for C24H23NO5S2: 469.1018; found: 469.1016.
HRMS (EI): m/z calcd. for C13H13NO: 199.0997; found: 199.0996.
Diethyl [2-(1,3-Dimethyl-2-oxoindolin-3-yl)ethyl] Phosphonate
(9ag)
3-Allyl-1-benzyl-5-methoxy-3-methylindolin-2-one (6cab)
Yield: 32 mg (70%); pale-yellow solid; mp 74–76 °C (hexane/EtOAc).
Yield: 41 mg (85%); yellow wax.
1H NMR (300 MHz): δ = 7.33–7.20 (m, 5 H), 6.82 (d, J = 2.5 Hz, 1 H),
6.65 (dd, J = 8.5, 2.5 Hz, 1 H), 6.57 (d, J = 8.4 Hz, 1 H), 5.48 (dddd, J =
16.9, 10.0, 7.9, 6.7 Hz, 1 H), 5.08–4.93 (m, 3 H), 4.77 (d, J = 15.7 Hz,
1 H), 3.75 (s, 3 H), 2.62 (dd, J = 13.5, 7.9 Hz, 1 H), 2.54 (dd, J = 13.5,
6.7 Hz, 1 H), 1.42 (s, 3 H).
13C NMR (75 MHz): δ = 180.0, 156.0, 136.2, 135.8, 135.1, 132.8, 128.8,
127.6, 127.4, 119.0, 111.7, 110.8, 109.4, 55.9, 48.9, 43.8, 42.6, 23.4.
1H NMR (300 MHz): δ = 7.35–7.23 (m, 1 H), 7.23–7.14 (m, 1 H), 7.08
(td, J = 7.5, 1.0 Hz, 1 H), 6.85 (d, J = 7.8 Hz, 1 H), 4.13–3.93 (m, 4 H),
3.21 (s, 3 H), 2.16 (m, 1 H), 2.00 (m, 1 H), 1.38 (s, 3 H), 1.28 (m, 8 H).
13C NMR (101 MHz): δ = 179.7, 143.4, 132.8, 128.3, 122.9, 122.7,
108.3, 61.8 (dd, J = 10.4, 6.5 Hz), 48.4, 48.2, 31.0 (d, J = 3.8 Hz), 26.3,
23.3, 21.6, 20.2, 16.5 (t, J = 5.3 Hz).
LRMS (EI): m/z = 325 (38) [M]+, 281 (13), 207 (40), 188 (10), 174 (17),
165 (16), 161 (27), 160 (100), 144 (11), 138 (15), 132 (10), 130 (12),
109 (17).
LRMS (EI): m/z = 308 (13), 307 (58) [M]+, 267 (20), 266 (100), 91 (67).
HRMS (EI): m/z calcd. for C20H21NO2: 307.1572; found: 307.1570.
HRMS (EI): m/z calcd. for C16H24NO4P: 325.1443; found: 325.1443.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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A. Ortega-Martínez et al.
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Synthesis
1,3-Dimethyl-3-(3-oxo-1,3-diphenylpropyl)indolin-2-one (9ah,
major diasteroisomer)
(4) (a) Jia, Y.-X.; Kündig, E. P. Angew. Chem. Int. Ed. 2009, 48, 1636.
(b) Perry, A.; Taylor, R. J. K. Chem. Commun. 2009, 3249.
(c) Ghosh, S.; De, S.; Kakde, B. N.; Bhunia, S.; Adhikary, A.; Bisai,
A. Org. Lett. 2012, 14, 5864.
Yield: 54 mg (97%); colorless oil.
1H NMR (300 MHz): δ = 7.98–7.87 (m, 2 H), 7.52 (m, 1 H), 7.48–7.35
(m, 2 H), 7.17 (m, 2 H), 7.07–6.97 (m, 6 H), 6.59 (d, J = 7.7 Hz, 1 H),
3.97 (dd, J = 8.1, 5.8 Hz, 1 H), 3.69–3.63 (m, 2 H), 3.05 (s, 3 H), 1.43 (s,
3 H).
13C NMR (101 MHz): δ = 198.9, 179.9, 142.9, 139.5, 137.2, 133.3,
133.1, 129.0, 128.6, 128.3, 127.9, 127.5, 126.8, 123.8, 122.4, 107.8,
51.6, 48.1, 38.4, 26.0, 22.1.
(5) (a) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008,
10, 3583. (b) He, R.; Ding, C.; Maruoka, K. Angew. Chem. Int. Ed.
2009, 48, 4559. (c) Cheng, L.; Liu, L.; Jia, H.; Wang, D.; Chen, Y.-J.
J. Org. Chem. 2009, 74, 4650. (d) Wu, X.; Liu, Q.; Liu, Y.; Wang, Q.;
Zhang, Y.; Chen, J.; Cao, W.; Zhao, G. Adv. Synth. Catal. 2013, 355,
2701. (e) Wei, Y.; Wen, S.; Liu, Z.; Wu, X.; Zheng, B.; Ye, J. Org.
Lett. 2015, 17, 2732. (f) Mechler, M.; Peters, R. Angew. Chem. Int.
Ed. 2015, 54, 10303. (g) Müller, J. M.; Stark, C. B. W. Angew.
Chem. Int. Ed. 2016, 55, 4798. (h) Ohmatsu, K.; Kikoyama, M.;
Ooi, T. J. Am. Chem. Soc. 2011, 133, 1307. (i) Zhu, Q.; Lu, Y.
Angew. Chem. Int. Ed. 2010, 49, 7753. (j) Peng, J.; Huang, X.; Cui,
H.-L.; Chen, Y.-C. Org. Lett. 2010, 12, 4260. (k) Bui, T.; Syed, S.;
Barbas, C. F. III. J. Am. Chem. Soc. 2009, 131, 8758. (l) Jiang, K.;
Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun. 2009, 3955.
(m) Li, X.; Xi, Z.-G.; Luo, S.; Cheng, J.-P. Org. Biomol. Chem. 2010,
8, 77. (n) Wang, L.-L.; Peng, L.; Bai, J.-F.; Huang, Q.-C.; Xu, X.-Y.;
Wang, L.-X. Chem. Commun. 2010, 46, 8064. (o) Trost, B. M.;
Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132, 15534. (p) Trost, B.
M.; Frederiksen, M. U. Angew. Chem. Int. Ed. 2005, 44, 308.
(6) For a recent review, see: Weaver, J. D.; Recio, A. III.; Grenning, A.
J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846.
LRMS (EI): m/z = 369 (5) [M]+, 209 (17), 208 (16), 207 (25), 161 (69),
160 (13), 105 (100), 77 (27).
HRMS (EI): m/z calcd. for C25H23NO2: 369.1729; found: 369.1723.
Funding Information
We gratefully acknowledge financial support from the Spanish Minis-
terio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387 and
Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de
Economía y Competitividad (MINECO) (projects CTQ2013-43446-P
and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, In-
dustria y Competitividad, Agencia Estatal de Investigación (AEI) and
Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects
CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Va-
lenciana (PROMETEO2009/039 and PROMETEOII/ 2014/017) and the
University of Alicante. A.O.-M. thanks MINECO for a predoctoral fel-
(7) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162.
(8) Kumar, N.; Das, M. K.; Ghosh, S.; Bisai, A. Chem. Commun. 2017,
53, 2170.
(9) (a) Grenning, A. J.; Tunge, J. A. Angew. Chem. Int. Ed. 2011, 50,
1688. (b) Grenning, A. J.; Tunge, J. A. J. Am. Chem. Soc. 2011, 133,
14785.
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(10) For a review, see: Mei, H.; Xie, C.; Aceña, J. L.; Soloshonok, V. A.;
Röschenthaler, G.-V.; Han, J. Eur. J. Org. Chem. 2015, 6401.
(11) (a) Xie, C.; Zhang, L.; Sha, W.; Soloshonok, V. A.; Han, J.; Pan, Y.
Org. Lett. 2016, 18, 3270. (b) A very similar reaction principle
was employed but using harsher conditions, see: Reisch, J.;
Muller, M.; Labitzke, H. Arch. Pharm. 1984, 317, 639.
(12) Jha, M.; Chou, T.-Y.; Blunt, B. Tetrahedron Lett. 2011, 67, 982.
(13) Zhang, Q. B.; Jia, W. L.; Ban, Y. L.; Zheng, Y.; Liu, Q.; Wu, L. Z.
Chem. Eur. J. 2016, 22, 2595.
Supporting Information
1
Copies of H and 13C NMR spectra of new products.Supporting infor-
mation for this article is available online at https://doi.org/10.1055/s-
0036-1590880.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H