Silyl Cyanopalladate-Catalyzed Friedel-Crafts-Type Cyclization Affording 3-Aryloxindole Derivatives

Article abstract of DOI:10.1055/a-1373-7017

3-Aryloxindole derivatives were synthesized through a Friedel-Crafts-type cyclization. The reaction was catalyzed by a trimethylsilyl tricyanopalladate complex generated in situ from trimethylsilyl cyanide and Pd(OAc) ₂. Wide varieties of diethyl phosphates derived from N -arylmandelamides were converted almost quantitatively into oxindoles. When N, N -dibenzylamide was used instead of an anilide substrate, a benzo-fused δ-lactam was obtained. An oxindole product was subjected to substitution reactions to afford 3,3-diaryloxindoles with two different aryl groups.

Full text of DOI:10.1055/a-1373-7017

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, 935–939
letter
935
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H. Ece et al.
Letter
Synlett
Silyl Cyanopalladate-Catalyzed Friedel–Crafts-Type Cyclization
Affording 3-Aryloxindole Derivatives
Hamdiye Ecea
Yuji Tangea
Taiga Yurino*b
Takeshi Ohkuma*b
Ar2
(EtO)2P(O)O
Ar1
R
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
N
R
Ar2
0
0
0
0-0
0
0
2
-4
1
5
8
-
3
4
6
3
Friedel–Crafts-type
cyclization
O
Ar1
0
0
0
0
-
0
0
0
2
-
5
4
6
7
-3
1
6
9
O
(Me3Si)[Pd(CN)3]
a Graduate School of Chemical Sciences and Engineering,
Hokkaido University, Kita 8, Nishi 5, Sapporo, Hokkaido
060-0808, Japan
O
P
EtO
EtO
O
R
N
b Division of Applied Chemistry and Frontier Chemistry Center,
Faculty of Engineering, Hokkaido University, Kita 13, Nishi 8,
Sapporo, Hokkaido 060-8628, Japan
Ar1
Ar2
O
tyurino@eng.hokudai.ac.jp
ohkuma@eng.hokudai.ac.jp
The first successful catalytic method
up to 99% yield with 19 examples
gram-scale synthesis
Corresponding Authors
Received: 24.12.2020
Accepted after revision: 26.01.2021
Published online: 26.01.2021
amide and the ortho-carbon of an N-aryl ring. The first
strategy (Scheme 1a) involves an intramolecular C(sp2)–
C(sp3) cross-coupling reaction of an N-acyl-ortho-haloani-
lide catalyzed by a Pd complex and a base.6 The Pd(0) spe-
cies oxidatively cleaves the carbon–halogen bond with the
help of coordination by the amide group. The reversibly
formed amide–enolate binds to the Pd(II) instead of the ha-
lide. The lactam is obtained by reductive release of the
Pd(0) species. The second strategy (Scheme 1b), -arylation
through a radical-nucleophilic aromatic substitution (SRN1
reaction), is also a useful approach that uses N-acyl-ortho-
iodoanilides as substrates.7,8 In the presence of a stoichio-
metric or excess amount of an alkali-metal base, the result-
ing enolate transfers an electron to the aryl iodide by sin-
gle-electron transfer to forming a C–C linkage, with ho-
molysis of the C–I bond. When ortho-fluoroanilides are
employed as substrates, the electron-deficient aromatic
ring undergoes nucleophilic substitution by the amide–
enolate under similar basic conditions (SNAr reaction).9
Thirdly, in a Friedel–Crafts-type cyclization of -halo-N-
arylamides (Scheme 1c), the aromatic part reacts as a nuc-
leophile to form a C–C bond with release of the halide (SN1-
type reaction).10 More than an equimolar amount of silver
Lewis acid is required to obtain the product in high yield.
This cyclization method has the benefit that an ortho-
haloanilide moiety does not necessarily have to be present
in the substrate. Therefore, the development of a catalytic
version of this reaction would be highly desirable. The use
of the alcoholic derivatives instead of halide compounds as
substrates would be even more advantageous.
DOI: 10.1055/a-1373-7017; Art ID: st-2020-u0646-l
Abstract 3-Aryloxindole derivatives were synthesized through a Frie-
del–Crafts-type cyclization. The reaction was catalyzed by a trimethylsi-
lyl tricyanopalladate complex generated in situ from trimethylsilyl cya-
nide and Pd(OAc)2. Wide varieties of diethyl phosphates derived from N-
arylmandelamides were converted almost quantitatively into oxindoles.
When N,N-dibenzylamide was used instead of an anilide substrate, a
benzo-fused -lactam was obtained. An oxindole product was subject-
ed to substitution reactions to afford 3,3-diaryloxindoles with two dif-
ferent aryl groups.
Key words Lewis acid catalysis, Friedel–Crafts reaction, cyclization,
oxindoles, SN1 reaction
Oxindoles (1,3-dihydro-2H-indol-2-ones) are a class of
benzo-fused five-membered lactams that are found in sev-
eral biologically active compounds, including naturally oc-
curring alkaloids. Among these, 3-aryloxindole derivatives
are frequently used as pharmaceutical agents (Figure 1).1–4
To meet the demand for these therapeutic agents, numer-
ous studies have investigated efficient methods for their
synthesis.5
Et2N
O
H
nC5H11
N
H
N
N
N
H2N
O
O
O
O
O
O
F
OH
Cl
F3C
OMe
OH
Cl
O
HO
oxyphenisatine
BMS-204352
SM-130686
XEN907
Recently, we have focused on Lewis acid catalysis by si-
lyl cyanometallate complexes generated in situ. It is well-
known that transition-metal compounds interact strongly
with the C-terminus of the cyanide ion (CN–). Transition-
metal salts (MXn) react with an excess of trimethylsilyl cya-
nide (TMSCN), spontaneously affording the corresponding
Figure 1 Bioactive compounds containing a 3-aryloxindole moiety
Scheme 1 illustrates three typical cyclization strategies
for constructing 3-aryloxindole structures.6–10 All three in-
volve C–C bond formations between the -position of an
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 935–939
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

936
H. Ece et al.
Letter
Synlett
strate. Our previous studies on nucleophilic isocyanation
and Friedel–Crafts-type allylation11–13 suggested that dieth-
yl phosphate should be the leaving group of choice. The cy-
clization of 1a was completed in the presence of Pd(OAc)2 (2
mol%) and Me3SiCN (2 equiv) in MeNO2 at 80 °C within 20
hours to afford the 3-phenyloxindole 2a in almost quantita-
tive yield (Table 1, entry 1). MeCN and 1,2-dime-
thoxyethane (1,2-DME) were also suitable solvents for this
reaction (entries 2 and 3). The reaction rate significantly
slowed in 1,4-dioxane, a cyclic ether, and in less-polar tolu-
ene (entries 4 and 5). The highly polar and coordinative
DMF completely suppressed the reaction (entry 6). Addi-
tion of Pd(OAc)2 was indispensable for the reaction (entry
7). None of the desired product was obtained in the absence
of the catalyst under otherwise identical conditions. The re-
action in MeNO2 was completed at 60 °C in 10 hours, and
we therefore adopted these as our optimized conditions
(entry 8).14 When the reaction was conducted with 1.2
equivalents of Me3SiCN, the yield of 2a markedly decreased
(entry 9). These results suggested that maintaining a large
excess of Me3SiCN relative to the Pd catalyst throughout the
reaction is necessary to form a sufficient amount of the active
species, (Me3Si)[Pd(CN)3], in the reaction system. Me3SiOAc
did not work as an alternative to Pd(OAc)2 (entry 10). The
yield of the product was low with Me3SiCl, although this de-
rivative did act as a catalyst for the transformation (entry
11). These experiments indicated that the silyl Lewis acid
(a) α-Arylation of amide through a cross-coupling reaction
R
N
R
N
Br
Ar2
O
O
Pd catalyst, base
Ar1
Ar2
O
Ar1
R
(b) SRN1 and SNAr reaction of ortho-haloanilide derivatives
N
R
N
X
Ar2
tBuOK (excess)
Ar1
Ar2
X = I: SRN1 reaction
X = F: SNAr reaction
O
Ar1
(c) Friedel–Crafts-type cyclization by a stoichiometric amount of AgTFA
R
N
Br
R
N
Ar2
O
AgTFA (1.5 equiv)
Ar1
Ar2
CH2Cl2, –78 °C to rt
20 h
O
Ar1
Scheme 1 Previous strategies to afford 3-aryloxindole derivatives
thermodynamically stable metal cyanides M(CN)n, a small
proportion of which is further reversibly converted into the
silyl cyanometallate (Me3Si)[M(CN)n+1]. The silyl part of the
ate complex has a Lewis acid character and might be appli-
cable as a catalyst in several organic transformations. In-
deed, we have successfully demonstrated nucleophilic iso-
cyanations and Friedel–Crafts-type allylations catalyzed by
silyl cyanometallate complexes (M = Pd, Ag).11–13 Notably,
the Lewis acid character of these catalysts can be varied by
changing the transition-metal species. The reversible fea-
ture of the catalysts might provide appropriate control of
the intensity of their acidity. Here we report a trimethylsilyl
cyanopalladate (M = Pd, n = 2)-catalyzed intramolecular
Friedel–Crafts-type substitution, affording 3-aryloxindole
derivatives (Scheme 2). The benzylic diethyl phosphates,
which are readily derived from the corresponding alcohols,
are well suited for use in the catalytic system instead of the
corresponding halides.
Table 1 Optimization of the Reaction Conditions
Me
N
(EtO)2(O)PO
Me
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
O
solvent, temp, time
O
1a
2a
Entry
Solvent
Temp (°C)
Time (h)
Yielda (%)
1
2
MeNO2
MeCN
80
80
80
80
80
80
80
60
60
60
60
20
20
20
20
20
20
20
10
10
24
24
>99
85
R
N
3
1,2-DME
96
(EtO)2(O)PO
Ar1
R
N
Ar2
O
Me3SiCN (excess)
Pd(OAc)2 cat.
4
1,4-dioxane
toluene
DMF
32
Ar2
O
5
48
Ar1
6
0
O
P
(Me3Si)[Pd(CN)3]
7b
8
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
0
EtO
EtO
O
R
N
>99 (98)
intramolecular
Friedel–Crafts
benzylation
activation by
silyl cyanometallate
Ar1
Ar2
9c
10d
11e
47
0
O
Scheme 2 Silyl cyanopalladate-catalyzed Friedel–Crafts cyclization af-
fording 3-aryloxindole derivatives
11
a 1H NMR yield. The isolated yield is given in parenthesis.
b No Pd(OAc)2 was employed as a catalyst.
Our investigation commenced with the optimization of
the reaction conditions (Table 1). We selected the N-meth-
yl-N-phenylmandelamide derivative 1a as a model sub-
c Me3SiCN (1.2 equiv) was added in the reaction mixture.
d Me3SiOAc was used instead of Pd(OAc)2 without Me3SiCN.
e Me3SiCl was used instead of Pd(OAc)2 without Me3SiCN.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 935–939

937
H. Ece et al.
Letter
Synlett
potentially promotes the cyclization as an active species,
and the silyl cyanopalladate generated in situ is the most
suitable catalyst.
groups or an electron-withdrawing bromo group (2l–n). A
strongly electron-withdrawing CF3 substituent completely
suppressed the reaction (2o). This is probably because the
reaction proceeds through an SN1-type substitution, similar
to a Friedel–Crafts-type allylation catalyzed by the silyl cy-
anometallate.13 An ortho-methyl group, which produced
steric hindrance around the reactive site, did not affect the
catalysis (2p). The yields of oxindoles with meta-substitut-
ed phenyl rings, 2q and 2r, showed slight decreases. 2-
Naphthyl and 3-thienyl products 2s and 2t, respective, were
obtained in 99% yield under the optimized conditions.
With the optimized reaction conditions in hand, we in-
vestigated the scope and limitations of the intramolecular
Friedel–Crafts-type reaction (Scheme 3). In addition to the
methyl group, sterically hindered 2-propyl or tert-butyl
groups could be introduced onto the N atom without retar-
dation of the oxindole formation (2b and 2c). N-Allyl and N-
benzyl moieties remained intact in the presence of the Pd
compound, and the corresponding cyclized products 2d and
2e were obtained almost quantitatively. N,N-Diphenyl-
amide 1f was also successfully converted into the triaryl
product 2f. In contrast to cyclization methods that use or-
tho-haloanilide derivatives (Schemes 1a and 2b), substitu-
ents were readily introduced onto the aniline phenyl rings
in the present approach. Both the 4-methyl product 2g and
the 3,5-dimethyl product 2h were obtained in 99% yield. In-
troduction of an electron-donating methoxy group or an
electron-withdrawing chloro group at the C4 position had
little effect on the yield of the corresponding products 2i
and 2j. The transformation of mandelamide 1k derived
from 5-aminoindole afforded the indole-fused oxindoles 2k
and 2k′ as a 1:1 mixture of regioisomers in 99% yield.
During purification, the relatively unstable 2k′ partially de-
composed.
Me
N
(EtO)2(O)PO
Me
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
O
MeNO2, 60 °C, 10 h
Ar
O
Ar
1
2
Me
Me
Me
Me
Me
N
O
N
N
O
N
N
O
O
O
OMe
Br
CF3
2l: 98% (98%)
2m: 99% (99%) 2n: 99% (98%)
2o: 0%
Me
2p: 99% (99%)
Me
N
Me
N
Me
N
O
N
O
O
O
R
N
(EtO)2(O)PO
R
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
S
Ar
O
MeO
MeNO2, 60 °C, 10 h
Ar
Ph
O
1
2
2q: 93% (93%)
2r: 92% (92%)
2s: 99% (98%)
2t: 99% (98%)
Scheme 4 Scope and limitations of the mandelic acid substructure. 1H
NMR yields are reported; the isolated yield is given in parentheses.
Me
N
O
N
N
N
O
O
O
Ph
Ph
Ph
Ph
This catalytic strategy was well suited to a gram-scale
synthesis (Scheme 5). The transformation of 3.02 g of 1a
with 2 mol% of Pd(OAc)2 was completed in 10 hours, afford-
ing 2a quantitatively (1.78 g).
2a: >99% (98%)
2b: 99% (98%)
2c: >99% (97%)
2d: 98% (98%)
Bn
N
O
Ph
N
O
Me
N
Me
N
O
O
Me
N
Ph
Ph
Ph
Ph
(EtO)2(O)PO
Me
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
2e: 99% (99%)
2f: 98% (97%)
2g: 99% (99%)
2h: 99% (98%)
O
Me
N
Me
N
Me
N
Me
N
MeNO2, 60 °C, 10 h
O
O
O
O
O
1a
2a
1.78 g (7.97 mmol)
Me
N
Me
N
MeO
Cl
Ph
3.02 g (7.99 mmol)
Ph
Ph
Ph
2i: 99% (98%)
2j: 99% (98%)
2k/2k’: 99%, 1:1 (82%, 1:0.64)
Scheme 5 Gram-scale synthesis of oxindole 2a under the optimized
conditions
Scheme 3 Scope and limitations of N-alkylaniline substructures. 1H
NMR yield are reported; the isolated yields are given in parentheses.
When a diethyl phosphate derived from 2-hydroxypen-
tanamide 3, an aliphatic analogue, was exposed to the opti-
mized reaction conditions, no cyclized product 4 was ob-
served (Scheme 6). This indicated that, for the cyclization to
proceed, an -aryl structure in the substrate is required to
stabilize the benzylic -cationic intermediate.
We then screened a series of 3-aryl moieties in the oxin-
doles (Scheme 4). Substituents in the para-position were
expected to influence the reactivity at the benzylic posi-
tions. The cyclization occurred quantitatively with the sub-
strates containing electron-donating methyl or methoxy
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 935–939

938
H. Ece et al.
Letter
Synlett
rived from N-arylmandelamides was promoted with a cata-
lytic amount of Pd(OAc)2 (2 mol%) in the presence of two
equivalents of Me3SiCN. Trimethylsilyl cyanopalladate
(Me3Si)[Pd(CN)3] generated in situ might act as a Lewis acid
catalyst. The reversible character with Pd(CN)2 and
Me3SiCN permits appropriate control of the acidity. This
procedure was applicable to a gram-scale reaction. A wide
variety of N-arylmandelamide derivatives were trans-
formed into the corresponding 3-aryloxindoles nearly
quantitatively (19 examples). No cyclization product was
observed in the reaction of an aliphatic -hydroxyamide
derivative, probably because benzylic stabilization of the
cationic intermediate was necessary. A benzo-fused -lact-
am was also obtained quantitatively when N,N-dibenzyl-
mandelamide was employed as a substrate. The 3-pheny-
loxindole was susceptible to substitution reactions at the
C3 position, and two different 3,3-diaryloxindoles were ob-
tained in high yield. Investigations of the properties of silyl
cyanometallate catalysts are underway in our laboratory.
Me
N
(EtO)2(O)PO
Me
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
O
MeNO2, 60 °C, 24 h
Pr
O
3
4: 0% yield
Scheme 6 Attempted intramolecular Friedel–Crafts-type reaction of
an aliphatic -hydroxyamide derivative
This reaction was also successfully applied to the forma-
tion of a -lactam structure (Scheme 7). The dibenzylamide
substrate 5 was smoothly transformed into 1,4-dihydroiso-
quinoline-3(2H)-one 6 in 99% yield under the usual condi-
tions. Note that a -lactam formed in preference to a -lac-
tam when the benzylanilide 1e was employed as a substrate
(see Scheme 3). This might be caused by the strong nucleo-
philicity of the anilide moiety.
Bn
(EtO)2(O)PO
Bn
N
Me3SiCN (2 equiv)
Pd(OAc)2 (2 mol%)
N
O
MeNO2, 60 °C, 10 h
O
Ph
6: 99% (98%)
5
Funding Information
Scheme 7 Intramolecular Friedel–Crafts-type reaction affording a ben-
zo-fused six-membered lactam
This work was supported by Grants-in-Aid from the Japan Society for
the Promotion of Sciences (JSPS) (Nos. 19H02706 and 19K15548). T.Y.
also acknowledges support from the Feasibility Study Program of the
Frontier Chemistry Center, Faculty of Engineering, Hokkaido Univer-
We demonstrated the synthetic utility of the 3-arylox-
indoles 2 by transforming 2a into a 3,3-diaryloxindoles 7a
and 8a bearing two different aromatic substructures
(Scheme 8). Nucleophilic aromatic substitution was em-
ployed for introduction of an electron-deficient aromatic
ring: the reaction of 3-phenyloxindole 2a with 2,4-dini-
trochlorobenzene promoted by Cs2CO3 (1 equiv) gave the
diaryloxindole 7a in 92% isolated yield.15 A Pd-catalyzed
coupling reaction was effective for substitution with an
electron-rich aromatic moiety; with a catalytic amount of
Pd(OAc)2 and t-Bu3PHBF4 in the presence of Cs2CO3 (3.7
equiv), 2a coupled with 4-methoxy-1-bromobenzene to
give the diaryl product 8a in 99% isolated yield.15
sity.
J
a
p
a
n
S
oc
i
e
ty
f
orth
e
Pr
o
m
oti
o
n
o
f
S
c
i
e
nc
e
(1
9
H
0
2
7
0
6)J
a
pa
n
S
oc
i
e
t
yfor
t
hePro
m
oti
o
n
o
f
S
c
i
e
nc
e
(
1
9
K
1
5
5
4
8)
H
o
k
k
a
i
d
o
U
n
i
v
ersi
t
y(
F
e
as
i
b
i
l
i
ytStu
d
y
Program)
Acknowledgment
We thank the Instrumental Analysis Support Office of the Frontier
Chemistry Center for allowing us to conduct the NMR analyses.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1373-7017.
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
S
u
p
p
orti
n
gI
n
f
orm
a
ti
o
n
In conclusion, we successfully developed a Friedel–
Crafts-type cyclization that gave synthetically useful 3-aryl-
oxindole derivatives. The reaction of diethyl phosphates de-
References and Notes
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Cl
Me
N
(1 equiv)
Me
N
O2N
NO2
O
Cs2CO3 (1 equiv)
O
Ph
DMF, reflux, 16 h
NO2
Ph
2a
7a: 92% yield
O2N
Br
(1.1 equiv)
MeO
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Me
N
O
Pd(OAc)2 (6 mol%)
tBu3PHBF4 (12 mol%)
Cs2CO3 (3.7 equiv)
Me
N
O
Ph
toluene, reflux, 16 h
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Ph
2a
8a: 99% yield
MeO
Scheme 8 Transformations of 3-aryloxindole 2a
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 935–939

939
H. Ece et al.
Letter
Synlett
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(12) Yurino, T.; Tange, Y.; Tani, R.; Ohkuma, T. Org. Chem. Front. 2020,
7, 1308.
(13) Yurino, T.; Ece, H.; Ohkuma, T. Asian J. Org. Chem. 2020, 9, 557.
(14) 1-Methyl-3-phenyl-1,3-dihydro-2H-indol-2-one (2a): Typical
Procedure
nyl)amino]-2-oxo-1-phenylethyl phosphate (1a: 130 mg, 0.35
mmol). Pd(OAc)2 (1.6 mg, 7.0 mol) was added, and the flask
was subjected to three evacuation–argon replacement cycles.
MeNO2 (2.0 mL) was added, and the solution was stirred for 15
min at 60 °C. TMSCN (71 mg, 0.72 mmol) was then added, and
the mixture was stirred at 60 °C for 10 h until the reaction was
complete [TLC, hexane–EtOAc (4:1)]. The reaction was
quenched with sat. aq NaHCO3, and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The collected organic layers
were washed with brine, dried (Na2SO4), filtered, and concen-
trated in vacuo. The yield of the product (>99%) was determined
from the 1H NMR spectrum of the crude product, with pyrazine
as an internal standard. The product was isolated by preparative
TLC (hexane–EtOAc, 4:1) as a white solid; yield: 76 mg (0.34
mmol, 98%); mp 126–132 °C.
1H NMR (400 MHz, CDCl3):  = 7.36–7.28 (m, 4 H, Ar-H), 7.22–
7.16 (m, 3 H, Ar-H), 7.07 (t, J = 7.6 Hz, 1 H, Ar-H), 6.91 (d, J = 7.6
Hz, 1 H, Ar-H), 4.62 (s, 1 H, CH), 3.26 (s, 3 H, NCH3). 13C NMR
(100 MHz, CDCl3):  = 176.0, 144.4, 136.6, 128.83, 128.79, 128.4
(two overlapping peaks), 127.5, 125.0, 122.7, 108.1, 52.0, 26.4.
(15) Mai, C.-K.; Sammons, M. F.; Sammakia, T. Org. Lett. 2010, 12,
2306.
A 20 mL Schlenk flask was charged with diethyl 2-[methyl(phe-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, 935–939