Efficient helicene synthesis: Friedel-crafts-type cyclization of 1,1-difluoro-1-alkenes

Article abstract of DOI:10.1002/anie.200801396

(Chemical Equation Presented) The unique properties of fluorine substituents, leaving groups that also stabilize an a carbocation, are exploited in a high-yielding synthesis of substituted [4]- to [6]helicenes in three or four steps from commercially available compounds: Two fused benzene rings are constructed in the title reaction of readily prepared 1,1-difluoro-1-alkenes containing two aryl groups followed by dehydrogenation (see scheme).

Full text of DOI:10.1002/anie.200801396

Communications
DOI: 10.1002/anie.200801396
Helical Compounds
Efficient Helicene Synthesis: Friedel–Crafts-type Cyclization of
1,1-Difluoro-1-alkenes**
Junji Ichikawa,* Misaki Yokota, Takao Kudo, and Satoshi Umezaki
Helicenes are nonplanar ortho-fused aromatic compounds
with helical chirality.[1] Their extraordinary optical and
electronic properties have been of interest for a long time.[2]
During the last decade,studies have been carried out toward
their application in asymmetric synthesis,[3] molecular recog-
nition,[4] and materials science,for example,as liquid crystals,
sensors,and dyes. [5]
Helicenes have been synthesized by the classical oxidative
photocyclization of stilbene derivatives.[6] Although useful,
this reaction is not suitable for large-scale production because
of the high-dilution conditions. Quite recently,new methods
for helicene synthesis amenable to scale-up have been
Scheme 1. Friedel–Crafts-type cyclization of 1,1-difluoro-1-alkenes.
developed on the basis of the construction of a benzene ring
by the Diels–Alder reaction,[7] radical cyclization,[8] meta-
[10]
thesis,[9] or C H arylation as a key step.[11] In contrast to
these reactions,the [2 +2+2] cycloisomerization of triynes[12]
can be used to construct three rings in a single step. The
formation of multiple benzene rings in such a way has great
potential for the construction of higher-order helicene
skeletons.
tion of
a
starting difluoroalkene with magic acid
ꢀ
(FSO3H·SbF5). Magic acid then promoted the elimination of
HF from the corresponding cyclized intermediate to give the
a-fluorocarbocation B,which underwent hydrolysis of the
ꢀ
C F bond to afford a final cyclic-ketone product.
These results prompted us to investigate the use of the
Friedel–Crafts-type cyclization in a domino reaction by
trapping the carbocation B with another aryl group. We
expected to be able to construct fused tetracyclic structures in
a one-pot operation by such a domino Friedel–Crafts-type
cyclization of difluoroalkenes containing an aryl group in
both branches of the difluorovinylidene unit to provide facile
access to helicene precursors. A subsequent dehydrogenation
step would give the target helicenes. The key feature of this
method is the construction of two fused benzene rings from a
difluoroalkene. Herein,we report a short,efficient route to
helicenes that utilizes the characteristics of fluorine substitu-
ents.
A fluorine substituent has an a-carbocation-stabilizing
effect due to the donation of its unshared electron pair to the
vacant p orbital of the a carbon atom. At the same time,its
high electronegativity makes it a potential leaving group as a
fluoride ion (Fꢀ). By exploiting these two unique properties,
we recently developed an electrophilic cyclization of
1,1-difluoro-1-alkenes:
a
Friedel–Crafts-type alkylation
(Scheme 1).[13] This Friedel–Crafts-type cyclization occurred
via an a,a-difluorocarbocation A generated by the protona-
[*] Prof. J. Ichikawa
Department of Chemistry
Graduate School of Pure and Applied Sciences
University of Tsukuba, Tsukuba, Ibaraki 305-8571 (Japan)
Fax: (+81)29-853-4237
E-mail: junji@chem.tsukuba.ac.jp
Homepage: http://www.chem.tsukuba.ac.jp/junji/
The starting materials were designed as 1,1-difluoro-1-
alkenes bearing two aryl groups,each of which was linked to
the vinylic carbon atom by a two-methylene-unit tether. The
symmetrical 1,1-difluoroalkenes 1b and 1k were synthesized
readily by our previously reported method in a one-pot
operation from commercially available 2,2,2-trifluoroethyl
4-methylbenzenesulfonate (CF3CH2OTs) and trialkyl bor-
anes prepared by the hydroboration of vinyl arenes
(Scheme 2).[14] Other 1,1-difluoroalkenes, including nonsym-
metrical 1,1-difluoroalkenes, were prepared by an SN2’
reaction[15] of aryl methyl anions with the trifluoromethyl-
substituted vinyl compound 2,which was obtained readily
from ethyl trifluoroacetate by a Grignard reaction[16] followed
by a Wittig reaction (Scheme 3).[17] Compound 2 can also be
prepared by the alkylation with benzyl bromide of
2-(trifluoromethyl)allylsilane,[18] derived from CF3CO2Et.
1,1-Difluoroalkenes 1 were subjected to reaction condi-
tions similar to those used for the synthesis of cyclic
M. Yokota, S. Umezaki
Department of Chemistry, Graduate School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
T. Kudo
Department of Applied Chemistry
Kyushu Institute of Technology
Sensui-cho, Tobata, Kitakyushu 804-8550 (Japan)
[**] We thank Dr. N. Kanoh (The University of Tokyo) for X-ray crystal-
structure analysis. We acknowledge a generous gift of (CF3)2CHOH
from Central Glass Co. This research was supported by a Grant-in-
Aid for Scientific Research from the Japan Society for the Promotion
of Science.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801396.
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Table 1: Domino Friedel–Crafts-type cyclization of 1 and dehydroge-
nation.[a]
Entry
Precursor
Yield [%]
3
4
1
2
1a
1b
87
80
Scheme 2. Preparation of symmetrical 1,1-difluoro-1-alkenes 1:
a) nBuLi (2.1 equiv), THF, ꢀ788C, 0.5 h; b) BR3 (1.1 equiv), ꢀ788C,
3
82[b]
0.5 h; c) MeONa (3.1 equiv), room temperature, 3 h (for 1b); room
temperature, 2 h, then reflux, 1 h (for 1k); d) Br2 (3.0 equiv), ꢀ788C,
1 h, then room temperature, 1 h.
85
3
4
5
6
7
R=o-Me
R=m-Me
R=p-Me
R=o-OMe
1c
1d
1e
1 f
1g
84
89
80
27
59
81
80
96[b]
80
R=m-OMe
82
8
1h
92
82
[a] For the reaction conditions, see Scheme 4. [b] The dehydrogenation
was conducted with Pd on carbon.
Scheme 3. Preparation of nonsymmetrical 1,1-difluoro-1-alkenes 1:
=
a) Ph(CH2)2MgBr (0.9 equiv), Et2O, ꢀ788C!RT, 1 h; b) Ph3P CH2
(1 equiv), Et2O, ꢀ788C!RT, 1.5 h; c) RC6H4CH2Li (1 equiv), Me2N-
(CH2)2NMe2 (1 equiv), THF, ꢀ788C, 1 h, then room temperature, 1 h;
d) ref. [18]; e) PhCH2Br (1.1 equiv), CsF (1.1 equiv), HCONMe2, 608C,
7 h.
entries 6 and 7). Subsequent dehydrogenation of the cyclized
products 3 was carried out successfully by using trityl
tetrafluoroborate or palladium on carbon to give [4]helicenes
4 in high yields (Table 1).
ketones.[13] The treatment of 1a with magic acid (2.5 equiv) in
1,1,1,3,3,3-hexafluoropropan-2-ol induced the expected
domino Friedel–Crafts-type cyclization to afford readily the
fused tetracyclic compound 3a in 87% yield (Scheme 4 and
To elucidate the effect of fluorine substituents on the
domino Friedel–Crafts-type cyclization,we exposed the
dichloroalkene counterpart of 1a and a carboxylic acid
derivative,2-(2-phenylethyl)-4-phenylbutanoic acid,to
magic acid under similar conditions. Whereas the reaction
of 1a gave 3a in 87% yield,the dichloroalkene was converted
into 3a in only 3% yield,even upon heating at reflux.
2-(2-Phenylethyl)-4-phenylbutanoic acid underwent a single
cyclization to give the ketone 2-(2-phenylethyl)-3,4-dihydro-
2H-naphthalen-1-one in 84% yield without the formation of
3a. These results demonstrate the advantage of fluorine
substituents in the construction of polycyclic systems.
The domino-cyclization–dehydrogenation sequence was
extended to the synthesis of [5] and [6]helicenes from
difluoroalkene precursors 1 containing naphthalene rings.
As we had observed previously that naphthyl-substituted
difluoroalkenes underwent the Friedel–Crafts-type cycliza-
tion regioselectively at the 1-position of the ring because of
electronic effects,[13] we anticipated that the domino cycliza-
tion–dehydrogenation of the naphthalene derivative 1i would
lead to the corresponding [5]helicene. However, 1i under-
went cyclization exclusively at the 3-position of the naphtha-
lene ring to give 5,6,7,8-tetrahydronaphtho[1,2-a]anthracene
(3i) in 62% yield [Eq. (1)]. Thus,the regiochemistry of the
reaction is controlled by steric effects rather than by
electronic effects in the construction of sterically hindered
polycyclic systems.
Table 1,entry 1). Similarly,difluoroalkenes
1b–1e and 1h
underwent the domino cyclization to afford the correspond-
ing fused ring systems containing methyl groups or a tolyl or
methylnaphthyl group in good to excellent yields (Table 1,
entries 2–5 and 8).[19] The domino cyclization proceeded even
in the case of 1 f and 1g with a methoxyphenyl group,despite
the fact that protonation of the methoxy oxygen atom
decreased the nucleophilicity of the aromatic ring (Table 1,
Scheme 4. Reaction conditions for the domino Friedel–Crafts-type
cyclization of 1 and dehydrogenation.
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(437 mg,1.38 mmol) in (CF 3)2CHOH (4 mL) at 08C under argon.
The resulting mixture was stirred for 1 h at 08C then warmed to room
temperature and stirred for 1 h at room temperature. Phosphate
buffer (pH 7) was then added to quench the reaction,and the mixture
was extracted with CH2Cl2 three times. The combined extracts were
washed with brine and dried over Na2SO4. The solvent was removed
under reduced pressure,and the residue was purified by column
chromatography on silica gel (hexane) to give 3a (111 mg,87%) as a
colorless solid.
Dehydrogenation of 3a: Triphenylmethylium tetrafluoroborate
(370 mg,1.12 mmol) and 3a (76 mg,0.33 mmol) were dissolved in 1,2-
dichloroethane (4 mL),and the resulting mixture was heated at reflux
for 3 h under argon. The solvent was removed under reduced
pressure,and the residue was purified by thin-layer chromatography
on silica gel (hexane/AcOEt,10:1) to give 4a
We therefore introduced a methyl group to protect the
3-position of the naphthalene ring. Upon the treatment of 1j
with magic acid (2.5 equiv),the desired pentacyclic com-
pound 3j was obtained in 78% yield. The dehydrogenation of
3j provided the [5]helicene 4j in 80% yield (Scheme 5).[20] We
(60 mg,80%) as a colorless solid.
Received: March 24,2008
Published online: May 28,2008
Keywords: alkenes · carbocations ·
.
cyclization · fluorinated substituents ·
helicenes
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solution in (CF3)2CHOH (2 mL) to a solution of FSO3H·SbF5
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