Activation of 1,1-difluoro-1-alkenes with a transition-metal complex: Palladium(II)-catalyzed friedel - crafts-type cyclization of 4,4-(difluorohomoallyl)arenes

Article abstract of DOI:10.1021/ol702279w

(Chemical Equation Presented) Cationic palladium(II) ([Pd(MeCN) ₄](BF₄)₂) provides the first transition-metal-catalyzed method for electrophilic activation of electron-deficient 1,1-difluoro-1-alkenes, which allows their Friedel-Crafts-type cyclization with an intramolecular aryl group via a Wacker-type process. By using BF₃·OEt₂, the cyclization was effected by a catalytic amount of the palladium without its reoxidation.

Full text of DOI:10.1021/ol702279w

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4639-4642
Activation of 1,1-Difluoro-1-alkenes with
a Transition-Metal Complex:
Palladium(II)-Catalyzed
Friedel)Crafts-Type Cyclization of
4,4-(Difluorohomoallyl)arenes
Misaki Yokota,† Daishi Fujita,† and Junji Ichikawa*,‡
Department of Chemistry, Graduate School of Pure and Applied Sciences,
UniVersity of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan, and Department of
Chemistry, Graduate School of Science, The UniVersity of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
junji@chem.tsukuba.ac.jp
Received September 18, 2007
ABSTRACT
Cationic palladium(II) ([Pd(MeCN)4](BF4)2) provides the first transition-metal-catalyzed method for electrophilic activation of electron-deficient
1,1-difluoro-1-alkenes, which allows their Friedel Crafts-type cyclization with an intramolecular aryl group via a Wacker-type process. By
using BF3 OEt2, the cyclization was effected by a catalytic amount of the palladium without its reoxidation.
−
‚
Unactivated alkenes generally react with a wide variety of
electrophiles, but not with nucleophiles. One of the best
solutions to the problem of poor reactivity toward nucleo-
philes is activation of alkenes with transition-metal com-
plexes, as exemplified by the Wacker reaction,1 where water
adds to an alkene-palladium(II) complex in a nucleophilic
manner. This strategy has now been expanded to a variety
of catalytic C-O,2 C-N,2a,3 and C-C4 bond formations
between alkenes and nucleophiles, which are widely applied
in the synthesis of complex natural products.5
In contrast to unactivated alkenes, 1,1-difluoro-1-alkenes
possess electrophilic character because of the electron-
withdrawing inductive effect of the two fluorine atoms.6
Whereas they react with strong nucleophiles such as alkyl-
lithiums, their reactivity is not great enough to react with
weak nucleophiles such as arenes and alkenes. Thus, elec-
trophilic activation of 1,1-difluoroalkenes is highly desirable,
while being more difficult compared with that of unactivated
alkenes, because of the low electron density of difluoroal-
kenes. A limited number of electrophiles, iodine,7 mercuric
acetate,8 tin tetrachloride,9 and Magic acid (FSO3H‚SbF5),10
† The University of Tokyo.
‡ University of Tsukuba.
(1) Tsuji, J. Palladium Reagents and Catalysits; Wiley: Chichester, 2003;
Chapter 3.
(2) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309. (b)
Reiter, M.; Turner, H.; Gouverneur, V. Chem. Eur. J. 2006, 12, 7190-
7203. (c) Komeyama, K.; Morimoto, T.; Nakayama, Y.; Takaki, K.
Tetrahedron Lett. 2007, 48, 3259-3261.
(3) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J.
Am. Chem. Soc. 2006, 128, 1828-1839 and references therein.
(4) (a) Liu, C.; Widenhoefer, R. A. Chem. Eur. J. 2006, 12, 2371-2382
and references therein. (b) Han, X.; Widenhoefer, R. A. Org. Lett. 2006, 8,
3801-3804 and references therein.
(5) For recent reports, see: (a) Tietze, L. F.; Stecker, F.; Zinngrebe, J.;
Sommer, K. M. Chem. Eur. J. 2006, 12, 8770-8776. (b) Liao, X.; Zhou,
H.; Yu, J.; Cook, J. M. J. Org. Chem. 2006, 71, 8884-8890.
(6) Smart, B. E. In Organofluorine Chemistry, Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum: New York, 1994; Chapter 3.
(7) Morikawa, T.; Kumadaki, I.; Shiro, M. Chem. Pharm. Bull. 1985,
33, 5144-5146.
(8) Kendrick, D. A.; Kolb, M. J. J. Fluorine Chem. 1989, 45, 273-276.
(9) Saito, A.; Okada, M.; Nakamura, Y.; Kitagawa, O.; Horikawa, H.;
Taguchi, T. J. Fluorine Chem. 2003, 123, 75-80.
10.1021/ol702279w CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/03/2007

have been employed for the activation of difluoroalkenes,
where a stoichiometric amount of the electrophile was
required. The development of a transition-metal catalyst for
the reaction of 1,1-difluoro-1-alkenes with weak nucleophiles
is therefore a significant challenge.
Table 1. Effect of Transition-Metal Complexes in Activation
of Difluoroalkene 1a
We intended to activate 1,1-difluoro-1-alkenes with a
transition-metal complex (MXn), which would promote the
reaction with a nucleophile, as shown in Scheme 1. The
entry
MXn (equiv)
conditions 2a (%) 3a (%) 4a (%)
1
AuCl3 (1.0)
AuCl3 (1.0)
AuCl(PPh3) (1.0) reflux, 3 h
RuCl3 (1.0)
PdCl2L2 (1.0)
PdL4(BF4)2 (1.0)
reflux, 6 h
reflux, 6 h
24
30
36
46
55
25
36
1
1
1
4
2
0
2
3
0
3
4
0
0
1
0
0
22
5
0
5
0
Scheme 1. Activation of 1,1-Difluoro-1-alkenes with a
2a
3b
4a
5c
6c
Transition-Metal Complex
reflux, 5 h
rt, 3 h
rt, 0.5 h
7c,d PdL4(BF4)2 (1.0)
8c
9c,e PdL4(BF4)2 (0.05) rt, 0.5 h
10c,e PdL4(BF4)2 (0.01) rt, 9 days
120 °C, 2 h
PdL4(BF4)2 (0.05) rt, 1 h
86
82
process would allow substitution by the accompanying
â-fluorine elimination,11 which might preserve the oxidation
state of the metal. Thus, this reaction was expected to proceed
with only a catalytic amount of metal complex without the
need for a reoxidizing reagent.12
a AgOTf (2.0 equiv) was added. b AgOTf (1.0 equiv) was added. c L )
MeCN. d [bmin][NTf2] was used as a solvent. e BF3‚OEt2 (1.0 equiv) was
added.
MeCONMe2. Ionic liquid, 1-butyl-3-methylimidazolium bis-
(trifluoromethanesulfonyl)imide ([bmin][NTf2]), was a rather
effective solvent, although it required a high temperature
(entry 7).
The cationic palladium-promoted cyclization yielded not
only cyclic ketones 2a and 3a but also fluoroarene 4a,
presumably via â-fluorine and â-hydrogen elimination from
cyclized intermediate A, respectively (Scheme 2). The former
The starting materials, 1,1-difluoro-1-alkenes 1 bearing an
aryl group as a nucleophile were designed to undergo
Friedel-Crafts-type cyclization via metal-alkene complexes,
leading to 4-fluorinated 1,2-dihydronaphthalene derivatives.
On treatment of difluoroalkene 1a with AuCl3 in THF, which
is often employed in alkene activation,13 no cyclized products
were obtained. However, the use of 1,1,1,3,3,3-hexafluoro-
propan-2-ol (HFIP)14 as a solvent with high ionizing power
promoted the cyclization to give the hydrolyzed products,
cyclic ketone 2a along with its regioisomer 3a, in 25% yield
instead of the expected 4-fluoro-1,2-dihydrophenanthrene 5a
(Table 1, entry 1). Addition of AgOTf to AuCl3 or AuCl-
(PPh3) was examined for the generation of cationic gold
complexes, which improved the yield of the cyclic ketones
(entries 2 and 3). These results suggest that highly electro-
philic transition-metal species can activate difluoroalkene 1a
in HFIP, and such a tendency was also observed for Ru(III)
(entry 4).15,16 In particular, a cationic palladium complex,
[Pd(MeCN)4](BF4)2,2b,3 showed a prominent activity to give
the cyclized compounds in a total yield of 49% at room
temperature within 0.5 h (entry 6). The dramatic effect of
HFIP as a solvent was confirmed again in the activation with
Pd(II), since no reaction occurred in Et2O, MeCN, or
Scheme 2. Catalytic Activation of Difluoroalkene 1a
process generated a palladium fluoride species, PdFL3(BF4),
which seemed to be less active. A palladium hydride species,
PdHL3(BF4), formed in the latter process, turned to Pd(0).
These facts prevented the catalytic turnover (Table 1, entry
8). Taking advantage of the high affinity of boron for
fluorine, we tried the use of BF3‚OEt2 with the palladium
complex to accelerate the â-fluorine elimination from A and
regenerate the active cationic species, PdL4(BF4)2, which
would make this process catalytic in palladium.
(10) Ichikawa, J.; Jyono, H.; Kudo, T.; Fujiwara, M.; Yokota, M.
Synthesis 2005, 39-46.
(11) (a) Ichikawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425-
4427 and references therein. (b) Zhao, H.; Ariafard, A.; Lin, Z. Organo-
metallics 2006, 25, 812-819.
(12) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156-
4157.
(13) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006,
45, 7896-7936.
(14) For recent reports on the cationic reactions conducted in HFIP,
see: ref 10 and references therein.
(15) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581-584
and references therein.
(16) No reaction occurred on treatment of 1a with RuCl3 (1 equiv) in
HFIP at reflux.
When 1a was treated with 0.05 equiv of [Pd(MeCN)4]-
(BF4)2 and 1 equiv of BF3‚OEt2 at room temperature, the
4640
Org. Lett., Vol. 9, No. 22, 2007

yield of cyclic ketone 2a was raised to 86% (Table 1, entry
9).17 Even 0.01 equiv of Pd promoted the cyclization, albeit
requiring a longer reaction time (entry 10).
When several difluoroalkenes 1 bearing other substituents
were subjected to the catalytic conditions obtained above,
the cyclization readily proceeded to afford the corresponding
cyclic ketones 2 in high yield, as shown in Table 2. This
cleophilic attack of the aryl group. There was, however, the
possibility of a Heck-type reaction via aromatic C-H bond
activation.20 To establish the mechanism, we examined the
cyclization via arylpalladium intermediate B, prepared by
oxidative addition of 6 to Pd(0). The reaction of 6 afforded
5-exo cyclization product 8 as well as 6-endo product 7
(Scheme 4), although no 5-exo products were obtained in
Scheme 4. Cyclization via Arylpalladium Intermediates
Table 2. Cyclization of Difluoroalkenes 1
entry R1
R2
R3
R4
R5
time (h)
2 (%)
1a
2
3
4
5
6
7
8
9e
-(CH)4-
H
H
H
Me
Me
Me
H
H
H
H
H
H
H
H
2
2
11
1
47
0.5
12
30
22
89 (2a + 3a)
89 (2b)
83 (2c)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
OMe
H
OH
CF3
H
79 (2d)
70 (2e + 2f)b
66 (2f + 2k)c
78 (2g + 2l)d
15 (2h)
the cyclization of 1b (Table 2, entry 2). These results show
that the palladium-catalyzed Friedel-Crafts-type cyclization
proceeds via a Wacker-type mechanism. In addition, the
cyclization of 1a occurred only in a solvent with high
ionizing power like HFIP, which also supports the theory
that the cyclization proceeds via the Wheland intermediates.
To elucidate the effect of fluorine on the Friedel-Crafts-
type cyclizations, we compared the reactions of 1a and the
corresponding monofluoroalkene (E/Z ) 5.5:1) under the
same conditions. Whereas 1a gave 2a in 86% yield, the
monofluoroalkene gave 1,2,3,4-tetrahydrophenanthrene (11%
yield), 1,2,3,4-tetrahydroanthracene (4% yield), and phenan-
threne (19% yield) along with a complex mixture, probably
due to polymerization of the double bond. Treatment of
dichloro- and dibromoalkenes 9 with a catalytic amount of
Pd(II) gave only a trace amount of cyclized products, and
even 1 equiv of Pd(II) did not work well (Scheme 5). These
OMe Me
H
H
H
Me
Me
H
n-C5H11
65 (2i)
a The reaction was conducted at 0 °C. b The regioisomer of 2e,
6-methoxy-4-methyl-3,4-dihydro-2H-naphthalen-1-one (2f),18 was also ob-
tained (2e/2f ) 76/24). c The regioisomer of 2f, 8-methoxy-4-methyl-3,4-
dihydro-2H-naphthalen-1-one (2k), was also obtained (2f/2k ) 79/21).d The
regioisomer of 2g, 6-hydroxy-4-methyl-3,4-dihydro-2H-naphthalen-1-one
(2l),17 was also obtained (2g/2l ) 65/35). e [Pd(MeCN)4](BF4)2 (0.1 equiv)
and BF3‚OEt2 (2.0 equiv) were used.
activating method was effective even for difluoroalkenes
1e-g bearing a methoxy or a hydroxy group, which were
unsuitable under strong acid conditions (entries 5-7). The
reaction of difluoroalkene 1j with a phenyl group tethered
by an o-phenylene linkage afforded 9-fluorophenanthrene 5j
in 54% yield, which confirms the generation of cyclic
fluoroalkenes 5 as intermediates (Scheme 3).19
Scheme 5. Cyclization of Dichloro- and Dibromoalkenes
Scheme 3. Cyclization of Difluoroalkene 1j
results indicate that using a cationic palladium together with
BF3‚OEt2 allows a specific activation of 1,1-difluoroalkenes.
The cyclization of fluoroalkenes 1 has been presumed to
proceed through a Wacker-type mechanism including nu-
(19) The cyclization of 1j was conducted in the dark to prevent
photochemical 6π-electrocyclization. Lapouyade, R.; Hanafi, N.; Marand,
J.-P. Angew. Chem., Int. Ed. 1982, 21, 766-767.
(17) The corresponding intermolecular Friedel-Crafts-type reaction
between 1,1-difluoro-6-phenylhex-1-ene and 1,3-dimethoxybenzene (10
equiv) in HFIP did not proceed under these reaction conditions, and neither
did the intramolecular reaction.
(18) Regioisomers 2f and 2l were probably obtained via spiro intermedi-
ates generated by ipso attack of the aromatic ring.
(20) For a review on functionalization of arenes via C-H bond activation,
see: Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633-
639.
(21) For a report on Pd(0)-catalyzed hydroalkoxylation of hexafluoro-
propene, see: Matsukawa, Y.; Mizukado, J.; Quan, H.; Tamura, M.; Sekiya,
A. Angew. Chem., Int. Ed. 2005, 44, 1128-1130.
Org. Lett., Vol. 9, No. 22, 2007
4641

In conclusion, we have developed the first transition-metal-
catalyzed method for the electrophilic activation of electron-
deficient 1,1-difluoro-1-alkenes,21 which successfully pro-
motes their Friedel-Crafts-type cyclization with an intra-
molecular aryl group via a Wacker-type process. By adding
BF3‚OEt2, the cyclization was effected by a catalytic amount
of cationic palladium without reoxidation.
by a Grant-in-Aid for Scientific Research from the Japan
Society for the Promotion of Science.
Supporting Information Available: Spectroscopic data
and experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We acknowledge a generous gift of
OL702279W
HFIP from Central Glass Co., Ltd. This work was supported
4642
Org. Lett., Vol. 9, No. 22, 2007