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Published on the web September 17, 2010
Stereoselective Synthesis of 3-(1-Cyanoalkylidene)oxindoles by Palladium-catalyzed
Cyclization Reaction of 2-(Alkynyl)aryl Isocyanates with Copper(I) Cyanide
Tomoya Miura, Takeharu Toyoshima, Osamu Kozawa, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(Received September 7, 2010; CL-100771; E-mail: murakami@sbchem.kyoto-u.ac.jp)
Table 1. Optimization of reaction conditionsa
A palladium-catalyzed cyclization reaction of 2-(alkynyl)-
aryl isocyanates with copper(I) cyanide provides an efficient
method for the stereoselective synthesis of (Z)-configured 3-(1-
cyanoalkylidene)oxindoles.
n-Bu
NC
n-Bu
CN
n-Bu
5 mol%
Pd/dppf
+
+ [M]−CN
O
O
100 °C
2 h
2
N
N
NCO
1a
(1.1 equiv)
H
H
(E)-3a
(Z)-3a
The 3-alkylideneoxindole (3-alkylideneindolin-2-one) skel-
eton is a prevalent structural motif found in a number of
biologically active compounds in therapeutic use such as
Semaxanib,1 Sunitinib,2 Tenidap,3 and Soulieotine.4 In addition,
3-alkylideneoxindoles have been widely employed as valuable
intermediates in the synthesis of indole alkaloids and drug
candidates.5,6 Thus, considerable efforts have been made on the
development of efficient methods for the construction of this
skeleton. Transition-metal-catalyzed cyclization reactions pres-
ent useful methods for the stereoselective synthesis of unsym-
metrically substituted 3-alkylideneoxindoles.7 For example, N-
methyl-N,3-diphenylpropiolamide reacted with aryl halides in
the presence of a palladium catalyst to give stereochemically
defined 3-(1-aryl-1-phenylmethylidene)oxindoles through a se-
quence of carbopalladation/C-H activation/intramolecular C-C
bond formation processes.7a Heteroatom-substituted 3-alkyli-
deneoxindoles were synthesized by palladium-catalyzed cy-
clization reactions of N-methyl-N,3-diphenylpropiolamide with
phthalimide7c or acetic acid.7d On the other hand, we have
recently reported the palladium-catalyzed cyclization reactions of
2-(alkynyl)aryl isocyanates8 with external nucleophiles such as
organoboronic acids,9a amides,9b alcohols, and thiols.9c These
reactions permit the stereoselective incorporation of various
kinds of substituents on the exocyclic double bond of the
resulting 3-alkylideneoxindoles. We next examined the possibil-
ity to incorporate a cyano nucleophile with good stereoselectivity
analogous to that observed with other nucleophiles. In this paper
are described the results of the palladium-catalyzed cyclization
reaction of 2-(alkynyl)aryl isocyanates with copper(I) cyanide.10
When 2-(1-hexynyl)phenyl isocyanate (1a, 1.0 equiv) was
treated with potassium cyanide (2a) (1.1 equiv) in the presence
of Pd2(dba)3¢CHCl3/dppf (5.0 mol % of Pd; dppf = 1,1¤-bis(di-
phenylphosphino)ferrocene) in DMF at 100 °C for 2 h, 3-(1-
cyanopentylidene)oxindole (3a) was produced in 11% NMR
yield (Z/E = 5:>95, Table 1, Entry 1). Although a cyano
nucleophile was introduced on the exocyclic double bond, the
observed stereochemistry was opposite to our expectation. The
screening of metal cyanides revealed that the use of copper(I)
cyanide considerably improved the yield and, in particular,
selectively produced the (Z)-isomer (Z/E = 94:6, Entry 5).
Furthermore, changing the solvent to 1,4-dioxane led to the
best result in terms of both yield and selectivity (84% yield,
Z/E = >95:5, Entry 6).11,12
Entry [M]-CN (2)
Solvent
DMF
Yield/%b
Z/Ec
1
2
3
4
5
6
KCN (2a)
K4Fe(CN)6 (2b) DMF
n-Bu3SnCN (2c) DMF
Zn(CN)2 (2d)
CuCN (2e)
CuCN (2e)
11
0
44
64
99
5:>95
®
89:11
33:67
94:6
DMF
DMF
1,4-dioxane 99 (84) >95:5
aReaction conditions: 1a (0.20 mmol), [M]-CN (0.22 mmol),
Pd2(dba)3¢CHCl3/dppf (5.0 mol % of Pd) in solvent (2 mL) at
100 °C for 2 h. b 1H NMR yield using CHCl2CHCl2 as an
internal standard, isolated yield in parenthesis. cThe ratio
1
determined by H NMR.
n-Bu
n-Bu
Pd(0)
Pd(II)
O
1a
Pd(0)
O
N
C
N
B
A
CN
Pd(II)
Cu(I)
n-Bu
n-Bu
CN
H2O
CuCN
Cu(I)
3a
−Pd(0)
O
O
N
N
C
D
Scheme 1. A proposed mechanism.
cyclization reaction of 2-(alkynyl)aryl isocyanates with organo-
boronic acids.9a Initially, substrate 1a binds to a palladium(0)
catalyst to generate the chelate complex A, which undergoes
oxidative cyclization to form the oxapalladacycle B. Subsequent
transmetalation of B with copper(I) cyanide produces the
palladium(II) cyanide C. Finally, reductive elimination affords
the intermediary copper alkoxide D and regenerates the starting
palladium(0) catalyst. Protonolysis of D occurs during aqueous
workup to give the (Z)-configured 3a in a stereoselective
manner.
A variety of 2-(alkynyl)aryl isocyanates are subjected to
the palladium-catalyzed reaction with copper(I) cyanide (2e)
(Table 2). The substrates 1b-1d possessing primary and secon-
dary alkyl groups at the alkyne terminus reacted well to afford
the corresponding 3-(1-cyanoalkylidene)oxindoles 3b-3d in
good yields with excellent selectivities (Z/E = >95:5, Entries
1-3). Even a bulky tert-butyl group permitted the reaction and
We propose the following mechanism shown in Scheme 1,
which is analogous to that we previously postulated for the
Chem. Lett. 2010, 39, 1132-1133
© 2010 The Chemical Society of Japan
Miura, Tomoya
