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)

TsHN

CF2
R

R'

cat. PdCl2
TMSOTf

FO

TsN
RHN

H2O

R

(CF3)2CHOH
R'R'

REPRINTED FROM

Vol.39 No.3

2010 p.248–249
CMLTAGMarch 5, 2010

The Chemical Society of Japan
Published on the web February 6, 2010; doi:10.1246/cl.2010.248

doi:10.1246/cl.2010.248
Published on the web February 6, 2010248

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)chloride, ¢,¢-diﬂuorostyrenes bearing a sulfonamido group at
the ortho position were treated with trimethylsilyl triﬂuoromethanesulfonate to aﬀord oxindoles in high yield. The
reactions proceeded via 5-endo-trig cyclization, hydrolysis,and desulfonylation. This sequence allowed the transformationof diﬂuorostyrenes into free oxindoles in a one-pot operation.

1,1-Diﬂuoro-1-alkenes possess electrophilic character because of the electron-withdrawing inductive eﬀect of the two
ﬂuorine atoms.1 Whereas they react with strong nucleophiles
such as alkyllithiums and Grignard reagents, the nucleophilesthat can be employed are restricted to reactive anionic species.
Because of the low electron density of their alkene moiety, alimited number of electrophiles, iodine,2 mercuric acetate,3 tin
tetrachloride,4 and Magic Acid (FSO3H¢SbF6),5 have been used
for the activation of diﬂuoroalkenes, where a stoichiometricamount of the reagent was required. Thus, their electrophilic
activation in a catalytic manner is highly desirable for thetransformation of 1,1-diﬂuoro-1-alkenes.
It is widely known that transition metals, especially latetransition metals, can be an electrophilic activator of alkenes
because of their strong interaction with ³ electrons.6 Concerning
diﬂuoroalkenes, there are reported alkene-coordinated metalcomplexes,7 although they have not been utilized in thetransformation of diﬂuoroalkenes. We took notice of suchtransition-metal complexes and recently succeeded in theelectrophilic 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 arylgroup.8
Besides the palladium catalyst, BF3¢OEt2 promoted theabove reaction via ¢-ﬂuorine elimination8,9 and capture of a
ﬂuoride ion, which regenerated an active, cationic Pd(II) species
without any reoxidants. These results showed that a combinationof (i) a transition metal (MXn) as activator of alkenes and (ii) a
Lewis acid (LA) as scavenger of ﬂuoride ions is important forthe catalytic substitution of the vinylic ﬂuorines (Scheme 1).
Here, we report transition-metal-catalyzed activation of ¢,¢diﬂuorostyrenes and intramolecular amination via replacementof the ﬂuorine atom.
The starting materials, 1,1-diﬂuoro-1-alkenes 1, bearing a ptoluenesulfonamide group at the ortho position as a nucleophile,FR

FRMXnFRNuHFLAMXn–HXR

NuR

FR+F LA –[MXn-1] Nu

MXn-1–[LA-F] –RFR

Scheme 1. Electrophilic activation of diﬂuoroalkenes with catalyst.

Chem. Lett. 2010, 39, 248­249

Table 1. Eﬀects of transition-metal catalysts and Lewis acids
TsHN

CF2MXn (10 mol%)
LA
H2 O

O
HN
n-Bu +n-Bu (CF3)2CHOH
60 °C, 24 h1aO

TsNn-Bu

2aEntryMXn1234567891011121314[Pd(MeCN)4](BF4)2[Pd(MeCN)4](BF4)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2
®
PdCl2
PdCl2
NiCl2
PtCl2
Cu(OAc)2
Cu(OTf)2
AgSbF6AuCl

LA (equiv)
BF3¢OEt2 (1.0)
Me3SiOTf (1.0)
Me3SiOTf (1.0)
Me3SiOTf (1.0)
Me3SiOTf (1.0)
Me3SiOTf (1.0)®
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)
Me3SiOTf (2.0)

3aYield/%
2a3a01015<11200000000002234<1730086<5037878077

were designed to undergo aminopalladation10 via alkene­metalcomplexes, leading to indole derivatives. On treatment with[Pd(MeCN)4](BF4)2 catalyst and BF3¢OEt2 under the previous
reaction conditions,8 diﬂuorostyrene 1a gave no cyclized
products (Table 1, Entry 1). However, the use of Me3SiOTf asa ﬂuoride ion scavenger promoted the cyclization to give thehydrolyzed products, oxindole with and without a tosyl group,
2a and 3a in 10% and 22% yield, respectively, instead of theexpected 2-ﬂuoroindole 4a (Entry 2). Several palladium catalysts were tested and PdCl2 provided the best total yield (85%)
of the cyclic products (Entry 5). Both the metal catalyst andMe3SiOTf were essential for this reaction (Entries 6 and 7), andthe increased amount of Me3SiOTf (2 equiv) gave free oxindole
3a in 86% yield as the sole product (Entry 8).11,12 Because noalkenes were observed, ¢-hydrogen elimination did not occur
under the reaction conditions. Whereas other catalysts such as
NiCl2 and PtCl2 were not eﬀective, Cu(OTf)2, AgSbF6, andAuCl 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 thedramatic eﬀect of 1,1,1,3,3,3-hexaﬂuoropropan-2-ol (HFIP) as asolvent in the activation of diﬂuoroalkenes with the transition
metal. HFIP, possessing high ionizing power with low nucleophilicity, would stabilize the cationic intermediate to promote
the amination.5
Several diﬂuorostyrenes 1b­1g bearing other substituentswere subjected to the catalytic conditions used above. Theresults are summarized in Table 2. The activation method was© 2010 The Chemical Society of Japanwww.csj.jp/journals/chem-lett/249
Table 2. Synthesis of oxindoles 3 from diﬂuorostyrenes 1FTsHN

CF2HN

PdCl2 (10 mol%)
Me3SiOTf (2.0 equiv) H2O

R3

R

R2

R1 1

R1

Entry

R1

R2

R3

Temp/°C

Time/hYield/%

12
3
4
567H
H
H
ClMeHOMeHHHHHMeHn-Bu
Hs-Bun-Bun-Bun-Bun-Bu

60
60
60
606060rt24224
2424
24
24

87 (3a)90 (3b)78 (3c)a71 (3d)91 (3e)79 (3f)
20 (3g)Diastereomeric ratio = 1:1.

aeﬀective for diﬂuorostyrenes 1b­1f (Entries 2­6). Monosubstituted diﬂuoroalkene 1b exhibited higher reactivity and aﬀorded
3b in 2 h. Diﬂuorostyrenes 1d­1f bearing a chloro or a methylgroup 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 cyclization of 1. In addition, 2-ﬂuoroindole 4a13 was treated with anequimolar amount of triﬂuoromethanesulfonic acid (TfOH) in
HFIP at room temperature. Indole 4a was transformed intooxindole 3a in 77% yield (eq 1), which supports the claim that
2-ﬂuoroindoles 4 would be intermediates in the above oxindoleformation.
FOTsNn-BuTfOH (1.0)

H2 O

HNn-Bu(CF3)2CHOH
rt, 30 min4að1Þ

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, thehydrolysis and detosylation of 4 would occur to yield 3.
The oxindoles obtained above are common and importantcomponents in natural products and biologically active molecules.14 Classical methods for the synthesis of oxindoles arebased on intramolecular condensation15a or radical cyclization.15b Recently, palladium-catalyzed methods, such as theMizoroki­Heck reaction,15c­15e coupling reactions,15f andBuchwald­Hartwig-type amination15g have been developed,
while a Wacker-type oxindole synthesis has not been reported
previously.16
In conclusion, we have developed a transition-metalcatalyzed method for the electrophilic activation of electrondeﬁcient 1,1-diﬂuoro-1-alkenes, which successfully promotedtheir Wacker-type cyclization with an intramolecular sulfonamide group.

Chem. Lett. 2010, 39, 248­249

RSi X

FTsNO

R' 1PdX2

HX + H2O

3CF2+ Si F

R3

R' 4(CF3)2CHOH

R2TsHN

TsN

O

TsHN

F

CF2
PdX2
R

R
PdX

HN
R
R' 3

R'R' A
HXScheme 2. A plausible reaction mechanism for oxindole synthesis.

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).
References and Notes
1 V. J. Lee, in Comprehensive Organic Synthesis, ed. by B. M. Trost,Pergamon, Oxford, 1991, Vol. 4, p. 69.
2 T. Morikawa, I. Kumadaki, M. Shiro, Chem. Pharm. Bull. 1985, 33,5144.
3 D. A. Kendrick, M. Kolb, J. Fluorine Chem. 1989, 45, 273.
4 A. Saito, M. Okada, Y. Nakamura, O. Kitagawa, H. Horikawa, T.
Taguchi, J. Fluorine Chem. 2003, 123, 75.
5 a) J. Ichikawa, H. Jyono, T. Kudo, M. Fujiwara, M. Yokota,Synthesis 2005, 39. b) J. Ichikawa, M. Yokota, T. Kudo, S. Umezaki,Angew. Chem., Int. Ed. 2008, 47, 4870.
6 For reviews, see: a) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew.
Chem., Int. Ed. 2004, 43, 3368. b) L. F. Tietze, H. Ila, H. P. Bell,Chem. Rev. 2004, 104, 3453. c) A. R. Chianese, S. J. Lee, M. R.
Gagné, Angew. Chem., Int. Ed. 2007, 46, 4042.
7 D. Ristic-Petrovic, D. J. Anderson, J. R. Torkelson, R. McDonald,M. Cowie, Organometallics 2003, 22, 4647, and references therein.
8 M. Yokota, D. Fujita, J. Ichikawa, Org. Lett. 2007, 9, 4639.
9 T. Miura, Y. Ito, M. Murakami, Chem. Lett. 2008, 37, 1006, andreferences therein.
10 T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M. Tada, Chem.
Rev. 2008, 108, 3795.
11 To a solution of 1a (73 mg, 0.20 mmol) in HFIP (2.0 mL) was added
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 theaqueous layer was extracted twice with AcOEt. The combined
extracts were washed with brine and dried over Na2SO4. Afterremoval of the solvent, the residue was puriﬁed by preparative TLC(SiO2, hexane:AcOEt = 5:1) to aﬀord 3a (32 mg, 86%) as a colorlessoil.
12 (CF3)2CHOTs was isolated quantitatively along with 3a.
13 J. Ichikawa, Y. Wada, M. Fujiwara, K. Sakoda, Synthesis, 2002,
1917.
14 For a recent review, see: C. V. Galliford, K. A. Scheidt, Angew.
Chem., Int. Ed. 2007, 46, 8748.
15 a) A. H. Beckett, R. W. Daisley, J. Walker, Tetrahedron 1968, 24,6093. b) W. Cabri, I. Candiani, M. Colombo, L. Franzoi, A.
Bedeschi, Tetrahedron Lett. 1995, 36, 949. c) A. B. Dounay, K.
Hatanaka, J. J. Kodanko, M. Oestreich, L. E. Overmann, L. A.
Pfeifer, M. M. Weiss, J. Am. Chem. Soc. 2003, 125, 6261. d) A.
Pinto, Y. Jia, L. Neuville, J. Zhu, Chem.®Eur. J. 2007, 13, 961. e) Y.
Yasui, H. Kamisaki, Y. Takemoto, Org. Lett. 2008, 10, 3303. f) Y.-X.
Jia, E. P. Kündig, Angew. Chem., Int. Ed. 2009, 48, 1636, andreferences therein. g) A. Correa, S. Elmore, C. Bolm, Chem.®Eur. J.
2008, 14, 3527, and references therein.
16 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.

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