Palladium-catalyzed synthesis of 9-fluorenylidenes through aryne annulation

Article abstract of DOI:10.1021/ol900554r

The palladium-catalyzed annulation of arynes by substituted o-halostyrenes produces substituted 9-fluorenylidenes in good yields. This methodology provides this important carbocyclic ring system in a single step, which involves the generation of two new c

Full text of DOI:10.1021/ol900554r

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2413-2416
Palladium-Catalyzed Synthesis of
9-Fluorenylidenes through Aryne
Annulation
Shilpa A. Worlikar and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received March 16, 2009
ABSTRACT
The palladium-catalyzed annulation of arynes by substituted o-halostyrenes produces substituted 9-fluorenylidenes in good yields. This
methodology provides this important carbocyclic ring system in a single step, which involves the generation of two new carbon-carbon
bonds, occurs under relatively mild reaction conditions, and tolerates a variety of functional groups, including cyano, ester, aldehyde, and
ketone groups.
9-Fluorenylidenes are key structural units found in many
compounds possessing biological activity. Derivatives of 9H-
fluoren-9-ylidenes, commonly known as 9-fluorenylidenes,
are pharmaceutically and cosmetically significant. The
9-fluorenylidene derivative paranylene is used in dispersible
formulations of anti-inflammatory agents,1 while the 9-fluo-
renylidene derivative lumefantrine is used in dermatological
and photostable cosmetic compositions.2 3-Fluoren-9-ylidene-
2′-hydroxy-3-phenylpropiophenone exhibits thermochromic
properties.3 2,4,7-Trinitro-9-fluorenylmethacrylate (TNFMN)
has been used to study the donor-acceptor interactions of
poly(FIMA)s with different tacticities.4
important. In the literature, 9-fluorenylidenes are mainly
synthesized, either from 9H-fluoren-9-one derivatives using
a Wittig reaction5 or from 9H-fluorene derivatives.6
Transition-metal-catalyzed annulation reactions are very
valuable from a synthetic point of view.7 The Pd-catalyzed
annulation of alkynes by substituted aryl and vinylic halides
has been employed for the synthesis of a variety of
carbocycles and heterocycles,8 and some of these reactions
have also been recently extended to arynes. The major
difficulty in employing arynes is the high reactivity of arynes9
compared to alkynes and the harsh reaction conditions often
needed to generate arynes in situ. A common problem
associated with the high reactivity of arynes is their Pd-
Due to the pharmaceutical and biological importance of
these compounds, the synthesis of 9-fluorenylidenes is
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10.1021/ol900554r CCC: $40.75
Published on Web 05/04/2009
 2009 American Chemical Society

catalyzed cyclotrimerization10 to form polycyclic aromatic
hydrocarbons. Also, the harsh reaction conditions often
required to obtain arynes severely limit the functional group
compatibility of the chemistry. It has been reported that the
silylaryl triflate 2a in the presence of CsF generates benzyne
under very mild reaction conditions.11 This method of aryne
generation has been used in our research laboratories and
reported in the literature for a variety of electrophilic and
nucleophilic reactions,12 Pd-catalyzed annulation reactions,13
cycloaddition reactions,14 and insertion reactions.15
The palladium-catalyzed alkyne annulation of methyl 3-(2-
iodophenyl)acrylate has been reported in the literature.16 To
the best of our knowledge, analogous palladium-catalyzed
aryne insertions and subsequent cyclization of o-halostyrenes
have not been reported previously. We report herein an
efficient approach to 9-fluorenylidenes, which proceeds in
good yields from starting materials that are readily available
or easy to synthesize, and involves a palladium-catalyzed
annulation of arynes.
“optimal” procedure involves heating 0.3 mmol of 1a, 1.5
equiv of 2a, 10 mol % of Pd(dba)2, 20 mol % of dppm, and
3.0 equiv of CsF in 5 mL of 1:1 acetonitrile/toluene at 110
°C in a sealed vial for 24 h.
After obtaining our best reaction conditions for the aryne
annulation, we examined the scope of this reaction on various
substrates. Aryl halides 1a and 1g were obtained from
commercial sources. Aryl halides 1e, 1h, and 1i were
prepared by standard Wittig chemistry (Scheme 1), using
Scheme 1. Starting Material Preparation
commercially available aldehydes 4a and 4b, while 4c was
prepared according to a literature procedure.17 Aryl halides
1b,18 1c,18 1d,19 and 1f20 were prepared according to
literature procedures. The benzyne precursor 2a is com-
mercially available, while the aryne precursor 2b14 has been
prepared according to a literature procedure.
(E)-3-(2-Iodophenyl)acrylonitrile (1a) was used as a model
system for optimization of the reaction conditions using
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) as the
aryne precursor. We optimized the reaction conditions with
respect to different ratios of the acetonitrile/toluene solvent
system; the phosphine ligands P(o-tolyl)3, tris(2,4,6-tri-
methoxyphenyl)phosphine, tris(2,6-dimethoxyphenyl)phos-
phine, tri(2-methoxyphenyl)phosphine, tri(2-furyl)phosphine,
[(CH3)3P·AgI]4, tri(tert-butyl)phosphine, 2-(di-tert-butylphos-
phino)biphenyl, xantphos, dppp, dppf, and dppm; the tem-
peratures (85, 100, 110, and 120 °C) at which the reaction
is run; the amount of the aryne precursor; the amount of
CsF; and various Pd(dba)2 catalyst loadings (5-20 mol %)
with different ratios of Pd(dba)2 catalyst to dppm ligand. Our
The reaction of aryl iodide 1a under our optimized
conditions with 2-(trimethylsilyl)phenyl trifluoromethane-
sulfonate (2a) as the benzyne precursor gave an 91% isolated
yield of the desired product 3a (Table 1, entry 1). Compound
3a was obtained in a slightly lower 79% yield, when the
reaction was carried out using the corresponding aryl
bromide, (E)-3-(2-bromophenyl)acrylonitrile (1b). The im-
proved yield from the aryl iodide is no doubt a direct result
of the more facile oxidative addition of aryl iodides over
aryl bromides. The cis isomer (Z)-3-(2-bromophenyl)acry-
lonitrile (1c) gave a slightly lower yield of 72% than the
corresponding trans isomer, (E) 3-(2-bromophenyl)acryloni-
trile (1b) (compare entries 2 and 3). With an ethyl ester as
the electron-withdrawing group (EWG) on the double bond
of the o-halostyrene 1d, the yield dropped to 75% under our
optimized conditions (compare entries 2 and 4). With an
aldehyde as the EWG on the o-halostyrene 1e, a 76% yield
of the desired product 3c was obtained (entry 5). The yield
is comparable to that obtained with an ester group present
on the double bond of the o-halostyrene. With a ketone
present in the o-halostyrene 1f, the yield dropped to 61%
(entry 6). When a stronger electron-withdrawing nitro group
was placed on the o-halostyrene, the reaction failed to give
the desired product 3e (entry 7). Instead, we observed the
formation of a polymeric residue. We believe 2-(2-nitrovi-
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2414
Org. Lett., Vol. 11, No. 11, 2009

Table 1. Synthesis of 9-Fluorenylidenes by the Palladium-Catalyzed Aryne Annulation of o-Halostyrenesa
a Representative procedure: o-halostyrene 1a-i (0.3 mmol), silylaryl triflate 2a,b (1.5 equiv), 10 mol % of Pd(dba)2, 20 mol % of dppm, CsF (3 equiv)
and 1:1 CH3CN/PhCH3 (5 mL) were placed in a 4 dram vial. The vial was sealed with a screw cap. The reaction was then stirred at 110 °C for 24 h. b GC
d
yields. c Eight percent of a minor isomer is observed by GC analysis. The ratio was determined by H NMR spectroscopy.
1
nyl)iodobenzene (1g) undergoes polymerization under our
reaction conditions.
We have also studied the scope of the reaction using a
different aryne precursor. The aryl iodide 1a upon reaction
with the aryne precursor 2b gave the desired compounds 3i
and 3j as a 1:11 mixture of inseparable isomers in an 82%
overall yield (entry 10). It is unclear as to which stereoisomer
is the major product. The o-halo allylic benzene, ethyl (E)-
4-(2-iodophenyl)but-2-enoate, on reaction with 2a gave a
modest 62% yield of the ethyl (phenanthren-9-yl)acetate
(Figure 1). The reactions to obtain the phenanthrene nucleus
are under further investigation.
When electron-donating methoxy groups were placed on
the aryl bromide 1h, we obtained an extremely poor yield
(<5%), presumably because oxidative addition to palladium
is unfavorable in such electron-rich aryl bromides (compare
entries 4 and 8). On the other hand, the electron-rich substrate
1i with a carbon-iodine, instead of a carbon-bromine bond,
gave the desired product in a 73% yield (entry 9). The
stereochemistry of the major product has not been rigorously
established, but is assumed to be the less hindered E-isomer.
Eight percent of a minor isomer has also been observed.
We propose the following possible mechanisms for these
reactions based on the known reactions of organopalladium
Org. Lett., Vol. 11, No. 11, 2009
2415

III. Alternatively, according to path b, Pd(0) might add
oxidatively to the aryl halide to afford the arylpalladium(II)
intermediate IV, which in turn might add to the aryne22 to
afford arylpalladium intermediate III. Regardless of how
intermediate III is generated, the palladium-carbon bond
in this intermediate can then add across the neighboring
carbon-carbon double bond to afford intermediate V, which
directly affords the fluorenylidene product by ꢀ-hydride
elimination.
Our investigation has shown that a range of fluorenylidenes
can be obtained from simple starting materials that are readily
available or easily synthesized, using a one step palladium-
catalyzed aryne insertion of o-halostyrenes. The arynes are
obtained in situ under mild reaction conditions from the
corresponding 2-(trimethylsilyl)aryl trifluoromethanesulfonates
and CsF. Our methodology is tolerant of a variety of
functional groups, including cyano, ester, aldehyde, ketone,
and methoxy groups, which can provide a handle for further
organic transformations. This methodology provides a very
convenient and general approach to this important class of
aromatic hydrocarbons.
Figure 1. Synthesis of ethyl (phenanthren-9-yl)acetate.
compounds with alkynes (Scheme 2).8 The reaction can
follow two pathways, path a or path b. In path a, the aryne
Scheme 2. Tentative Mechanisms
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM070620), the National Insti-
tutes of Health Kansas University Chemical Methodologies
and Library Development Center of Excellence (P50
GM069663), and the National Science Foundation for
support of this research, and Johnson Matthey, Inc., and
Kawaken Fine Chemicals Co., Ltd., for donations of pal-
ladium catalysts.
generated from the triflate in the presence of the fluoride
source coordinates with Pd(0), affording palladacycle I.21
Oxidative addition of the aryl halide to I might generate an
arylpalladium(IV) complex II. Upon reductive elimination,
complex II could afford a new arylpalladium intermediate
Supporting Information Available: General experimental
procedures and spectral data for all previously unreported
starting materials and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL900554R
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