Transition-metal-catalyzed electrophilic activation of 1,1-difluoro-1- alkenes: Oxindole synthesis via intramolecular amination

Article abstract of DOI:10.1246/cl.2010.248

In the presence of a catalytic amount of palladium(II) chloride, β,β-difluorostyrenes bearing a sulfonamido group at the ortho position were treated with trimethylsilyl trifluoro-methanesulfonate to afford oxindoles in high yield. The reactions proceeded via 5-endo-trig cyclization, hydrolysis, and desulfonylation. This sequence allowed the transformation of difluorostyrenes into free oxindoles in a one-pot operation.

Full text of DOI:10.1246/cl.2010.248

doi:10.1246/cl.2010.248
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48
Published on the web February 6, 2010
Transition-metal-catalyzed Electrophilic Activation of 1,1-Difluoro-1-alkenes:
Oxindole Synthesis via Intramolecular Amination
Hiroyuki Tanabe and Junji Ichikawa*
Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba 305-8571
(
Received December 22, 2009; CL-091134; E-mail: junji@chem.tsukuba.ac.jp)
In the presence of a catalytic amount of palladium(II)
Table 1. Effects of transition-metal catalysts and Lewis acids
chloride, ¢,¢-difluorostyrenes bearing a sulfonamido group at
the ortho position were treated with trimethylsilyl trifluoro-
methanesulfonate to afford oxindoles in high yield. The
reactions proceeded via 5-endo-trig cyclization, hydrolysis,
and desulfonylation. This sequence allowed the transformation
of difluorostyrenes into free oxindoles in a one-pot operation.
O
O
MXn (10 mol%)
LA
TsHN
CF2
n-Bu
TsN
HN
H O
2
n-Bu +
n-Bu
(
CF ) CHOH
3 2
60 °C, 24 h
1a
2a
3a
Yield/%
a 3a
Entry
MXn
LA (equiv)
2
1
2
3
4
5
6
7
8
9
[Pd(MeCN)4](BF4)2
[Pd(MeCN) ](BF )
Pd(OAc)2
PdCl2(PPh3)2
PdCl2
®
BF3¢OEt2 (1.0)
0
0
22
34
<1
73
0
1
,1-Difluoro-1-alkenes possess electrophilic character be-
Me SiOTf (1.0)
10
15
<1
12
0
0
0
0
0
0
0
0
0
4
4 2
3
cause of the electron-withdrawing inductive effect of the two
fluorine atoms. Whereas they react with strong nucleophiles
such as alkyllithiums and Grignard reagents, the nucleophiles
that can be employed are restricted to reactive anionic species.
Because of the low electron density of their alkene moiety, a
Me3SiOTf (1.0)
1
Me3SiOTf (1.0)
Me3SiOTf (1.0)
Me3SiOTf (1.0)
®
PdCl2
PdCl2
NiCl2
PtCl2
Cu(OAc)2
Cu(OTf)2
AgSbF6
AuCl
0
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
86
<5
0
37
87
80
77
2
3
limited number of electrophiles, iodine, mercuric acetate, tin
4
5
tetrachloride, and Magic Acid (FSO3H¢SbF6), have been used
for the activation of difluoroalkenes, where a stoichiometric
amount of the reagent was required. Thus, their electrophilic
activation in a catalytic manner is highly desirable for the
transformation of 1,1-difluoro-1-alkenes.
1
0
1
1
1
2
13
14
Me SiOTf (2.0)
3
Me3SiOTf (2.0)
It is widely known that transition metals, especially late
transition metals, can be an electrophilic activator of alkenes
because of their strong interaction with ³ electrons. Concerning
6
were designed to undergo aminopalladation10 via alkene­metal
complexes, leading to indole derivatives. On treatment with
[Pd(MeCN)4](BF4)2 catalyst and BF3¢OEt2 under the previous
difluoroalkenes, there are reported alkene-coordinated metal
7
complexes, although they have not been utilized in the
8
transformation of difluoroalkenes. We took notice of such
transition-metal complexes and recently succeeded in the
electrophilic activation of 1,1-difluoro-1-alkenes using a cationic
palladium complex, [Pd(MeCN)4](BF4)2, which allowed
Friedel­Crafts-type cyclization with an intramolecular aryl
reaction conditions, difluorostyrene 1a gave no cyclized
products (Table 1, Entry 1). However, the use of Me3SiOTf as
a fluoride ion scavenger promoted the cyclization to give the
hydrolyzed products, oxindole with and without a tosyl group,
2a and 3a in 10% and 22% yield, respectively, instead of the
expected 2-fluoroindole 4a (Entry 2). Several palladium cata-
lysts were tested and PdCl2 provided the best total yield (85%)
of the cyclic products (Entry 5). Both the metal catalyst and
Me3SiOTf were essential for this reaction (Entries 6 and 7), and
the increased amount of Me3SiOTf (2 equiv) gave free oxindole
8
group.
Besides the palladium catalyst, BF3¢OEt2 promoted the
above reaction via ¢-fluorine elimination8 and capture of a
fluoride ion, which regenerated an active, cationic Pd(II) species
without any reoxidants. These results showed that a combination
,9
11,12
of (i) a transition metal (MX ) as activator of alkenes and (ii) a
3a in 86% yield as the sole product (Entry 8).
Because no
n
Lewis acid (LA) as scavenger of fluoride ions is important for
the catalytic substitution of the vinylic fluorines (Scheme 1).
Here, we report transition-metal-catalyzed activation of ¢,¢-
difluorostyrenes and intramolecular amination via replacement
of the fluorine atom.
alkenes were observed, ¢-hydrogen elimination did not occur
under the reaction conditions. Whereas other catalysts such as
NiCl and PtCl were not effective, Cu(OTf) , AgSbF , and
2
2
2
6
AuCl activated 1a to afford 3a in high yield (Entries 12­14).
Under the conditions of Entry 8, no reaction occurred using
Et2O, THF, MeCN, or DMF as solvent, which confirmed the
dramatic effect of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as a
solvent in the activation of difluoroalkenes with the transition
metal. HFIP, possessing high ionizing power with low nucleo-
philicity, would stabilize the cationic intermediate to promote
The starting materials, 1,1-difluoro-1-alkenes 1, bearing a p-
toluenesulfonamide group at the ortho position as a nucleophile,
NuH
LA
F
F
F
F
F
Nu
R
LA –[MXn-1]+ Nu
–[LA-F] –
F
MXn
F
5
MXn
the amination.
–
HX
MXn-1
R
R
R
R
R
R
Several difluorostyrenes 1b­1g bearing other substituents
were subjected to the catalytic conditions used above. The
results are summarized in Table 2. The activation method was
R
Scheme 1. Electrophilic activation of difluoroalkenes with catalyst.
Chem. Lett. 2010, 39, 248­249
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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49
Table 2. Synthesis of oxindoles 3 from difluorostyrenes 1
F
TsHN
TsHN
CF2
O
TsN
TsHN
CF2
R3
HN
R
+ SiF
R
PdCl2 (10 mol%)
Me3SiOTf (2.0 equiv) H2O
R3
R' 1
PdX2
R'
4
(
CF ) CHOH
R2
3 2
R2
HX + H O
SiX
2
F
R1
R1
R1
CF2
1
3
F
TsN
PdX2
Entry
R2
R3
Temp/°C
Time/h
Yield/%
O
R
R
PdX
HN
1
2
3
4
5
6
7
H
H
H
Cl
Me
H
H
H
H
H
H
n-Bu
H
60
60
60
60
60
60
rt
24
2
87 (3a)
90 (3b)
78 (3c)
71 (3d)
91 (3e)
79 (3f)
20 (3g)
R
R'
R' A
a
s-Bu
n-Bu
n-Bu
n-Bu
n-Bu
24
24
24
24
24
R'
3
HX
Me
H
Scheme 2. A plausible reaction mechanism for oxindole synthesis.
OMe
aDiastereomeric ratio = 1:1.
We are grateful to the Asahi Glass Foundation for financial
support and Central Glass Co., Ltd. for a generous gift of
1
,1,1,3,3,3-hexafluoropropan-2-ol (HFIP).
effective for difluorostyrenes 1b­1f (Entries 2­6). Monosubsti-
tuted difluoroalkene 1b exhibited higher reactivity and afforded
References and Notes
1
V. J. Lee, in Comprehensive Organic Synthesis, ed. by B. M. Trost,
Pergamon, Oxford, 1991, Vol. 4, p. 69.
T. Morikawa, I. Kumadaki, M. Shiro, Chem. Pharm. Bull. 1985, 33,
3b in 2 h. Difluorostyrenes 1d­1f bearing a chloro or a methyl
group gave the corresponding oxindoles 3d­3f in high yield,
whereas 1g bearing a methoxy group underwent demethylation
at 60 °C. The reaction carried out at room temperature, however,
provided 3g in 20% yield (Entry 7).
To establish the mechanism, we examined the reaction of an
NH2-bearing difluorostyrene, which gave no cyclized products.
This result suggests the detosylation occurred after the cycliza-
tion of 1. In addition, 2-fluoroindole 4a13 was treated with an
equimolar amount of trifluoromethanesulfonic acid (TfOH) in
HFIP at room temperature. Indole 4a was transformed into
oxindole 3a in 77% yield (eq 1), which supports the claim that
2
5144.
3
4
D. A. Kendrick, M. Kolb, J. Fluorine Chem. 1989, 45, 273.
A. Saito, M. Okada, Y. Nakamura, O. Kitagawa, H. Horikawa, T.
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references therein.
5
6
7
2-fluoroindoles 4 would be intermediates in the above oxindole
formation.
8
9
F
O
TsN
HN
TfOH (1.0)
H2O
10 T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem.
Rev. 2008, 108, 3795.
n-Bu
n-Bu
ð1Þ
(
CF ) CHOH
3
2
11 To a solution of 1a (73 mg, 0.20 mmol) in HFIP (2.0 mL) was added
rt, 30 min
TMSOTf (72 ¯L, 0.40 mmol) and PdCl2 (3.5 mg, 0.020 mmol) at
room temperature. After the reaction mixture was stirred for 24 h at
60 °C, the reaction was quenched with saturated aq NaHCO3 and the
aqueous layer was extracted twice with AcOEt. The combined
extracts were washed with brine and dried over Na2SO4. After
removal of the solvent, the residue was purified by preparative TLC
4
a
3a 77%
Considering the facts mentioned above, a plausible reaction
mechanism for the oxindole synthesis is outlined in Scheme 2.
A transition-metal catalyst would be coordinated by 1 to provide
alkylmetal intermediates A via 5-endo-trig cyclization. ¢-
Fluorine elimination should be preferentially promoted by
Me3SiOTf to regenerate the catalyst along with 4. Finally, the
hydrolysis and detosylation of 4 would occur to yield 3.
The oxindoles obtained above are common and important
components in natural products and biologically active mole-
(
SiO2, hexane:AcOEt = 5:1) to afford 3a (32 mg, 86%) as a colorless
oil.
12 (CF3)2CHOTs was isolated quantitatively along with 3a.
1
3 J. Ichikawa, Y. Wada, M. Fujiwara, K. Sakoda, Synthesis, 2002,
917.
1
1
4 For a recent review, see: C. V. Galliford, K. A. Scheidt, Angew.
Chem., Int. Ed. 2007, 46, 8748.
1
4
cules. Classical methods for the synthesis of oxindoles are
based on intramolecular condensation
15 a) A. H. Beckett, R. W. Daisley, J. Walker, Tetrahedron 1968, 24,
6093. b) W. Cabri, I. Candiani, M. Colombo, L. Franzoi, A.
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Hatanaka, J. J. Kodanko, M. Oestreich, L. E. Overmann, L. A.
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15a
or radical cycliza-
1
5b
tion.
Recently, palladium-catalyzed methods, such as the
Mizoroki­Heck reaction,1
5c­15e
15f
coupling reactions,
and
Buchwald­Hartwig-type amination1 have been developed,
5g
while a Wacker-type oxindole synthesis has not been reported
1
6
previously.
In conclusion, we have developed a transition-metal-
catalyzed method for the electrophilic activation of electron-
deficient 1,1-difluoro-1-alkenes, which successfully promoted
their Wacker-type cyclization with an intramolecular sulfon-
amide group.
2008, 14, 3527, and references therein.
1
6 For a Wacker-type indole synthesis, see: a) M. Gowan, A. S. Caillé,
C. K. Lau, Synlett 1997, 1312. b) T. Kondo, T. Okada, T. Mitsudo,
J. Am. Chem. Soc. 2002, 124, 186. c) S. R. Fix, J. L. Brice, S. S.
Stahl, Angew. Chem., Int. Ed. 2002, 41, 164.
Chem. Lett. 2010, 39, 248­249
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/