Friedel-Crafts-type cyclization of 2,2-difluorovinyl ketones via α-fluorocarbocations and its application in domino cyclizations

Article abstract of DOI:10.1021/ol060912r

2,2-Difluorovinyl ketones bearing an aryl group undergo Friedel-Crafts-type cyclization via carbocations stabilized by α-fluorines on treatment with a trimethylsilylating agent [Me₃SiOTf or Me₃SlB(OTf) ₄]. The reaction aff

Full text of DOI:10.1021/ol060912r

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3167-3170
Friedel
2,2-Difluorovinyl Ketones via
-Fluorocarbocations and Its
−Crafts-Type Cyclization of
r
Application in Domino Cyclizations
Junji Ichikawa,*,† Mikio Kaneko,‡ Misaki Yokota,† Masaaki Itonaga,‡ and
Takaharu Yokoyama‡
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and Department of Applied Chemistry,
Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
junji@chem.s.u-tokyo.ac.jp
Received April 14, 2006
ABSTRACT
2,2-Difluorovinyl ketones bearing an aryl group undergo Friedel
with a trimethylsilylating agent [Me3SiOTf or Me3SiB(OTf)4]. The reaction affords 4-fluorinated 3-acyl-1,2-dihydronaphthalenes, which are
successfully subjected to a substitution cyclodehydration process or a Nazarov-type cyclization to construct fused polycyclic systems.
−Crafts-type cyclization via carbocations stabilized by r-fluorines on treatment
−
Fluorine has a stabilizing effect on R-carbocations through
donation of its unshared electron pair to the vacant p-orbital
of the R-carbon, despite its electron-withdrawing inductive
effect.1 Since the former mesomeric effect is operative for
R-sp2 carbon, carbocations are stabilized by R-fluorine. The
R-carbocation-stabilizing effect is well exemplified in bio-
mimetic polyene cyclization,2 where fluoroalkene moieties
served as terminators. In contrast, cyclizations initiated by
R-fluorocarbocations are quite rare.3 We have reported one
of these examples, the fluorine-directed Nazarov-type cy-
clization of 2,2-difluorovinyl vinyl ketones, where the initial
carbocation is stabilized by the fluorines (Scheme 1).4
Scheme 1
† The University of Tokyo.
‡ Kyushu Institute of Technology.
(1) Smart, B. E. In Organofluorine Chemistry, Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum
Press: New York, 1994.
The results of the Nazarov-type cyclization implied that
treatment of a 2,2-difluorovinylcarbonyl functionality with
(2) (a) Johnson, W. S.; Daub, G. W.; Lyle, T. A.; Niwa, M. J. Am. Chem.
Soc. 1980, 102, 7800. (b) Johnson, W. S.; Lyle, T. A.; Daub, G. W. J. Org.
Chem. 1982, 47, 161. (c) Fish, P. V.; Johnson, W. S.; Jones, G. S.; Tham,
F. S.; Kullnig, R. K. J. Org. Chem. 1994, 59, 6150 and references therein.
(3) (a) Morikawa, T.; Kumadaki, I.; Shiro, M. Chem. Pharm. Bull. 1985,
33, 5144. (b) Kendrick, D. A.; Kolb, M. J. Fluorine Chem. 1989, 45, 273.
For a related paper, see: (c) Saito, A.; Okada, M.; Nakamura, Y.; Kitagawa,
O.; Horikawa, H.; Taguchi, T. J. Fluorine Chem. 2003, 123, 75.
10.1021/ol060912r CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/21/2006

a Lewis acid, such as trimethylsilyl trifluoromethanesulfonate
(TMSOTf), effectively generated difluoroallylic cations,
which were reactive enough to induce electrocyclization.
These results prompted us to investigate the reaction of these
cations with an intramolecular aryl group instead of a vinyl
group. Herein, we report the Friedel-Crafts-type cyclization
of 2,2-difluorovinyl ketones bearing an aryl group.5
2,2-Difluorovinyl ketones 1 bearing an aryl group were
designed as the Friedel-Crafts substrates to trap the gener-
ated cations with an intramolecular aryl moiety, leading to
4-fluorinated 3-acyl-1,2-dihydronaphthalenes 2. 2,2-Difluo-
rovinyl ketones 1 were readily synthesized by our method
in a one-pot operation, starting from commercially available
2,2,2-trifluoroethyl p-toluenesulfonate, acid chlorides, and
trialkylboranes, prepared by hydroboration of styrene deriva-
tives.6
due to its high ionizing power and low nucleophilicity.7
Among the Lewis acids tested, including TMSOTf, TMSB-
(OTf)4,8 BF3‚OEt2, AlEt3, and TiCl4, the silylating reagents
were especially effective for this cyclization, affording 2a
in high yield (Table 1, entries 3 and 4). The stronger
silylating agent, TMSB(OTf)4, drove the cyclization to
completion without HFIP. Moreover, the cyclization was also
promoted by a protic acid, CF3SO3H, to afford 2a in 77%
yield (Table 1, entry 8).9
The reaction of several other substrates 1 was examined
under conditions similar to those used in entry 3 (TMSOTf
in CH2Cl2-HFIP) and entry 4 [TMSB(OTf)4 in CH2Cl2] in
Table 1. The corresponding dihydronaphthalenes 2 bearing
several substituents were obtained in high to excellent yield,
as summarized in Table 2.
We attempted the generation of the R-fluorocarbocation
from 2,2-difluorovinyl ketone 1a (R1 ) Me, R2 ) R3 ) R4
) H, R5 ) Ph), which was expected to yield acyldihy-
dronaphthalene 2a via Friedel-Crafts-type alkylation ac-
companied by the loss of a fluoride ion. When 1a was treated
with 1.0 equiv of TMSOTf in dichloromethane, the cyclized
product 2a was obtained, albeit in low yield (Table 1, entry
Table 2. Synthesis of 4-Fluoro-1,2-dihydronaphthalenes 2 via
Friedel-Crafts-Type Cyclization of 1
Table 1. Effect of Lewis Acids (LA) and Solvents on the
Friedel-Crafts-Type Cyclization of 1a
entry R1
R2
R3
R4
R5
Ph
CH3 Ph
time/min
2
yielda/%
1
2
3
4
5
6
H
H
H
H
H
H
H
H
H
20
15
25
5
15
10
2b 89
2c 71 (80)
2a 84 (91)
2d 86
2e 70 (93)
2f
CH3
CH3 -(CH)4-
CH3
-(CH2)3-
H
H
H
H
Ph
Ph
c-Hex
Ph
H
H
H
84 (92)
a Numbers in parentheses indicate yields of 2 in the reaction conducted
with TMSB(OTf)4 in CH2Cl2.
An intermolecular version of the Friedel-Crafts-type
vinylation of arenes was examined using 2,2-difluorovinyl
ketone 3. The expected reaction of 3 proceeded with
m-dimethoxybenzene, which resulted in the replacement of
one or two vinylic fluorines by aryl groups under acidic
conditions to give 4 and 5 (Scheme 2).5,10 The intermolecular
entry
LA (equiv)
solvent
CH2Cl2
HFIP
CH2Cl2-HFIP (1:1)
time/min yield/%
1
2
3
4
5
6a
7
8
TMSOTf (1)
TMSOTf (1)
TMSOTf (1)
TMSB(OTf)4 (1) CH2Cl2
BF3‚OEt2 (2)
AlEt3 (3)
110
60
30
70
84
91
54
31
58
77
25
10
HFIP
HFIP
HFIP
CH2Cl2-HFIP (1:1)
40
180
110
20
TiCl4 (1)
CF3SO3H (1)
Scheme 2
a The reaction was conducted at rt.
1). The addition of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP)
as a cosolvent dramatically accelerated the cyclizaion to give
2a in 84% yield, along with a trace amount of an HFIP
substitution product of 1a (Table 1, entry 3).4 This result
indicates that HFIP is a superior solvent for cationic reactions
(4) (a) Ichikawa, J.; Miyazaki, S.; Fujiwara, M.; Minami, T. J. Org.
Chem. 1995, 60, 2320. See also: (b) Ichikawa, J.; Jyono, H.; Kudo, T.;
Fujiwara, M.; Yokota, M. Synthesis 2005, 39.
reaction of 3 did not proceed with anisol, which is more
reactive than alkylbenzenes, indicating that substrates 1 were
3168
Org. Lett., Vol. 8, No. 15, 2006

highly activated toward the Friedel-Crafts-type reaction by
the intramolecular aryl groups.
To confirm the effect of fluorine on the reactivity, we
studied the reaction of the corresponding monofluorinated
and fluorine-free substrates (Scheme 3). While all of the
For example, 2a was treated with both hydrazines and
amidines as bifunctional nucleophiles to construct hetero-
cycles via consecutive addition-elimination and cyclode-
hydration processes (Scheme 4).12 The reactions afforded
Scheme 4
Scheme 3
a For 8a and 8b: RNHNH2 (2.0 equiv), benzene, reflux or rt.
For 8c: PhNHNH2 (2.0 equiv), n-BuLi (2.0 equiv), THF, rt.
b Pyrazole 8a existed in a tautomeric mixture. c Regioisomer ratio
determined by GC analysis. d The precise regiochemistry of 8c
was established by X-ray crystallography.
substrates underwent the Friedel-Crafts-type cyclization, the
conditions required for completion of the reaction were
different: The monofluorinated substrate 6 needed a reaction
time 10 times longer than 1a. The fluorine-free substrate 7
gave no cyclized products until being heated under reflux.
These results clearly show that the vinylic fluorine acts as
an activating group, presumably due to its stabilizing effect
on the R-carbocations.11
Acyldihydronaphthalenes 2 thus obtained are a versatile
class of compounds because of their 2-fluorovinylcarbonyl
functionality, which readily reacts with nucleophiles to
provide a variety of polysubstituted naphthalene derivatives.10
pyrazole- or pyrimidine-fused ring systems, 4,5-dihydroben-
zo[g]indazoles 813 or 5,6-dihydrobenzo[h]quinazolines 9,14
in excellent yield with extremely high regioselectivity in the
pyrazole formation.
Furthermore, we attempted to use the two vinylic fluorines
in domino cyclization by combining the Friedel-Crafts-type
cyclization with the Nazarov-type cyclization depicted in
Scheme 1. When 2,2-difluorovinyl ketones 1 bearing both
a vinyl and an aryl group were exposed to TMSOTf in
HFIP, the Friedel-Crafts-type and the Nazarov-type cy-
clizations proceeded sequentially via intermediary 2-fluo-
rovinyl ketones 2.15 The reaction provided fused polycyclic
systems 10 and/or 11 bearing the steroid skeleton16 in good
yield with high diastereoselectivity in a one-pot operation
(Table 3).
(5) For recent reports on Friedel-Crafts-type reactions with conjugated
enones and enals, see: (a) Imachi, S.; Onaka, M. Chem. Lett. 2005, 34,
708 and references therein. (b) Palomo, C.; Oiarbide, M.; Kardak, B. G.;
Garc´ıa, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (c) Evans,
D. A.; Fandrick, K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942 and
references therein. (d) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L.
AdV. Synth. Catal. 2003, 345, 1247. For a Friedel-Crafts-type cyclization
of a conjugated enal, see: (e) Rettig, M.; Sigrist, A.; Re´tey, J. HelV. Chim.
Acta 2000, 83, 2246.
(6) Ichikawa, J. J. Fluorine Chem. 2000, 105, 257.
(7) For recent reports on the cationic reactions conducted in HFIP, see
ref 4b and references therein.
(8) Davis, A. P.; Muir, J. E.; Plunkett, S. J. Tetrahedron Lett. 1996, 37,
9401.
(9) Recently, we reported that CF3SO3H was less effective and that a
stronger acid such as Magic Acid (FSO3H‚SbF5) was needed to activate
simple 1,1-difluoro-1-alkenes without a carbonyl group toward Friedel-
Crafts cyclization.4b These results show that a carbonyl substituent assists
the formation of R-fluorocarbocation.
(10) Sequential substitution of the two fluorines in 2,2-difluorovinyl
ketones has been achieved under basic conditions with combinations of
C-, O-, S-, and N-nucleophiles; (a) Ichikawa, J.; Fujiwara, M.; Miyazaki,
S.; Ikemoto, M.; Okauchi, T.; Minami, T. Org. Lett. 2001, 3, 2345 and
references therein. (b) Ichikawa, J.; Kobayashi, M.; Yokota, N.; Noda, Y.;
Minami, T. Tetrahedron 1994, 50, 11637. (c) Xiao, L.; Kitazume, T. J.
Fluorine Chem. 1997, 86, 99. (d) Huang, X.; He, P.; Shi, G. J. Org. Chem.
2000, 65, 627.
Compound 10c was obtained as a single diastereomer,
which indicates that torquoselectivity in the conrotatory
(11) The rate of these Friedel-Crafts-type reactions seems to be
controlled by the generation of carbocations from the alkenes. For reviews
on the alkylation mechanisms, see: Roberts, R. M.; Khalaf, A. A. Friedel-
Crafts alkylation chemistry: a century of discoVery; Marcel Dekker: New
York, 1984; Chapter 3 and references therein.
(12) Ichikawa, J.; Kobayashi, M.; Noda, Y.; Yokota, N.; Amano, K.;
Minami, T. J. Org. Chem. 1996, 61, 2763.
(13) For recent reports on 4,5-dihydrobenzo[g]indazole derivatives,
see: (a) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org.
Chem. 2005, 70, 10030. (b) Murineddu, G.; Ruiu, S.; Mussinu, J.-M.; Loriga,
G.; Grella, G. E.; Carai, M. A. M.; Lazzari, P.; Pani, L.; Pinna, G. A. Bioorg.
Med. Chem. 2005, 13, 3309.
(14) 5,6-Dihydrobenzo[h]quinazoline derivatives are potent protein kinase
inhibiors. Rapecki, S.; Allen, R. J. Pharmacol. Exp. Ther. 2002, 303, 1325
and references therein.
(15) On treatment with 1.0 equiv of TMSOTf at rt for 5 min, 1 [R6 )
H, R7, R8 ) -(CH2)3-] afforded the corresponding 1-fluoro-3,4-dihydro-
phenanthrene 2 in 76% yield as a single cyclized product via the Friedel-
Crafts-type cyclization.
Org. Lett., Vol. 8, No. 15, 2006
3169

In summary, we have accomplished a fluorine-accelerated
Friedel-Crafts-type cyclization of 2,2-difluorovinyl ketones
bearing an aryl group. The reaction readily proceeded via
R-fluorocarbocations, generated by silylation of the carbonyl
oxygen in the substrates, leading to vinylation of the aromatic
ring. Domino cyclizations combined with the substitution-
cyclodehydration process or the Nazarov-type cyclization
allowed the construction of fused polycyclic systems. Thus,
the fluorine substituent has proven to be useful in electro-
philic reactions, due to its R-cation-stabilizing effect and
leaving group ability.
Table 3. Domino Reaction of the Friedel-Crafts-Type and the
Nazarov-Type Cyclizations
Acknowledgment. We thank Dr. T. Okauchi (Kyushu
Institute of Technology) and Dr. N. Kanoh (the University
of Tokyo) for the X-ray crystal structure analysis. We
gratefully acknowledge Central Glass Co., Ltd., for financial
support and the generous gift of HFIP. This work was also
supported by a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science.
entry
R6
R7
R8
time/h
product
yield/%
67
61
60a
25 (15:1)b
69 (11:1)d
1
2
3
4
5c
H
CH3
H
H
H
n-Pr
CH3
-(CH2)3-
H
H
H
2
10a
10b
10c
11a
11b
2.5
2.5
3
Note Added after ASAP Publication. Yield and substituent
data were missing in Scheme 4 in the version published
ASAP June 21, 2006; the corrected version was published
ASAP June 23, 2006.
H
H
H
3
a Single diastereomer. The precise stereochemistry of 10c was established
by X-ray crystallography of its hydrogenated product, obtained by selective
reduction of the trisubstituted double bond in 10c (H2, 5 mol % of PtO2 in
1% AcOH/AcOEt). b Diastereomer ratio determined by 13C NMR measure-
ment (peak heights). c B(OMe)3 (1.1 equiv) was added. d Diastereomer ratio
Supporting Information Available: Spectroscopic data
and experimental details. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
determined by H NMR measurement.
OL060912R
(16) Steroids are an important class of compounds, because of their
bioactivities and medicinal actions. For recent reports on the synthesis of
steroids, see: Ma, S.; Lu, P.; Lu, L.; Hou, H.; Wei, J.; He, Q.; Gu, Z.;
Jiang, X.; Jin, X. Angew. Chem., Int. Ed. 2005, 44, 5275 and references
therein.
(17) For recent reviews of the Nazarov cyclization, see: (a) Pellissier,
H. Tetrahedron 2005, 61, 6479. (b) Frontier, A. J.; Collison, C. Tetrahedron
2005, 61, 7577. (c) Tius, M. A. Eur. J. Org. Chem. 2005, 2193. (d) Harmata,
M. Chemtracts: Org. Chem. 2004, 17, 416.
Nazarov-type cyclization was strictly controlled by the
benzylic methyl group (Table 3, entry 3).17 While the domino
cyclization of substrate 1 (R6 ) R7 ) R8 ) H) was
accompanied by attack of water leading to 11a as well as
deprotonation, B(OMe)3 successfully trapped the intermedi-
ary cation to give 11b selectively (Table 3, entry 5).
3170
Org. Lett., Vol. 8, No. 15, 2006