Synthesis of 9-fluorenylidenes and 9,10-phenanthrenes through palladium-catalyzed aryne annulation by o-halostyrenes and o-halo allylic benzenes

Article abstract of DOI:10.1021/jo9017827

(Chemical Equation Presented) A number of functionally substituted 9-fluorenylidenes and 9,10-phenanthrenes have been synthesized from substituted o-halostyrenes and o-halo allylic benzenes respectively in good yields by the palladium-catalyzed annulation

Full text of DOI:10.1021/jo9017827

pubs.acs.org/joc
Synthesis of 9-Fluorenylidenes and 9,10-Phenanthrenes through
Palladium-Catalyzed Aryne Annulation by o-Halostyrenes and
o-Halo Allylic Benzenes
Shilpa A. Worlikar and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received August 19, 2009
A number of functionally substituted 9-fluorenylidenes and 9,10-phenanthrenes have been synthe-
sized from substituted o-halostyrenes and o-halo allylic benzenes respectively in good yields by the
palladium-catalyzed annulation of arynes. The methodology tolerates a variety of functional groups,
including cyano, ester, aldehyde, and ketone groups, occurs under relatively mild reaction condi-
tions, and involves the generation of two new carbon-carbon bonds, thus providing these important
carbocyclic ring systems in a single synthetic step.
Introduction
dimethoxy-7,8-methylenedioxyphenanthrene and 2,7-dihy-
droxy-1-methyl-5-vinylphenanthrene exhibit cytotoxicity.7
Since 9-fluorenylidene and phenanthrene derivatives are
biologically and pharmaceutical important, the synthesis of
these vital classes of compounds is of paramount impor-
tance. 9-Fluorenylidenes are mainly synthesized from 9H-
fluoren-9-one derivatives using a Wittig reaction8 or from
9H-fluorene derivatives.9 Several methods have been re-
ported for the synthesis of phenanthrene derivatives, and
some of these approaches have significant disadvantages,
including the use of toxic chemicals, harsh reaction condi-
tions, or multistep reaction sequences.10 The synthesis of
phenanthrenes by the cocyclization of arynes and alkynes is
also known,11 but in most cases these reactions are not
regioselective.
Derivatives of 9-fluorenylidenes and phenanthrenes are
known to possess significant biological activity. Many der-
matological and photostable cosmetic compositions1 use the
9-fluorenylidene derivative Lumefantrine. Paranylene, a
9-fluorenylidene derivative, is used in dispersible formula-
tions of anti-inflammatory agents.2 Thus, derivatives of 9-
fluorenylidenes are significant in the cosmetic and pharma-
ceutical fields. The thermochromic properties of 3-fluoren-9-
ylidene-20-hydroxy-3-phenylpropiophenone are known,3
and 2,4,7-trinitro-9-fluorenylmethacrylate (TNFMN) has
been used to study the donor-acceptor interactions of
poly(FIMA)s with different tacticities.4 The phenan-
threne derivative 3,7-dihydroxy-2,4,8-trimethoxyphenan-
threne is known for its anti-inflammatory properties,5 while
the derivative aristolochic acid exhibits tumor-inhibitory
properties.6 The phenanthrene derivatives 3-hydroxy-2,4-
(7) (a) Kovacs, A.; Forgo, P.; Zupko, I.; Rethy, B.; Falkay, G.; Szabo, P.;
Hohmann, J. Phytochemistry 2007, 68, 687. (b) Dellagreca, M.; Fiorentinob,
A.; Isidorib, M.; Lavorgna, M.; Monaco, P.; Previtera, L.; Zarrelli, A.
Phytochemistry 2002, 60, 633.
(8) (a) Trippett, S.; Walker, D. M. J. Chem. Soc. 1961, 2130.
(b) Kendurkar, P. S.; Tewari, R. S. Ind. J. Chem., Sect. B 1977, 15B, 290.
(c) Bestmann, H. J.; Schlosser, W. Synthesis 1979, 201. (d) Wittig, G.;
Schoch-Gruebler, U. J. Liebigs Ann. Chem. 1978, 2, 362. (e) Abdel-Malek,
H. A. Egypt. J. Chem. 2005, 48, 129.
(1) Mueller, S.; Herzog, B.; Quass, K. Photostable cosmetic or der-
matological compositions containing sunscreens. PCT Int. Appl. WO
2006034968, 2006.
(2) Britten, N. J.; Burns, J. W.; Hallberg, J. W.; Waldron, N. A.; Watts, J.
L. Dispersible formulations of an anti-inflammatory agent. PCT Int. Appl.
WO 2004082588, 2004.
(3) Schoenberg, A.; Singer, E. Ber. 1961, 94, 248.
(4) Ishizawa, H.; Nakano, T.; Yade, T.; Tsuji, M.; Nakagawa, O.;
Yamaguchi, T. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 4656.
(5) Bordat, P.; Tarroux, R.; Charveron, M.; David, B. Phenanthrene
derivatives, their synthesis, anti-inflammatory activity, and use in treating
inflammatory skin diseases. Fr. Demande WO 2006089881, 2006.
(6) Kupchan, S. M.; Wormser, H. C. J. Org. Chem. 1965, 30, 3792.
(9) (a) Ye, J.; Ge, J.; Chen, X.; Zhao, Z.; Lu, P. Tetrahedron 2007, 63,
11040. (b) Cadierno, V.; Diez, J.; Garcia-Garrido, S. E.; Gimeno, J.; Nebra,
N. Adv. Synth. Catal. 2006, 348, 2125. (c) Hudgens, D. P.; Taylor, C.; Batts,
T. W.; Patel, M. K.; Brown, M. L. Bioorg. Med. Chem. 2006, 14, 8366.
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9132 J. Org. Chem. 2009, 74, 9132–9139
Published on Web 11/10/2009
DOI: 10.1021/jo9017827
r
2009 American Chemical Society

Worlikar and Larock
JOCArticle
In synthetic organic chemistry, transition-metal-catalyzed
annulation reactions have played a particularly valuable role
of late.12 For instance, a variety of carbocycles and hetero-
cycles have been synthesized by the Pd-catalyzed annulation
of alkynes by substituted aryl and vinylic halides.13 How-
ever, the major difficulty in applying these reactions to
arynes is the high reactivity of arynes14 compared to alkynes,
and the harsh reaction conditions often needed to generate
arynes in situ, which also severely limits the functional group
compatibility of the chemistry. Arynes often undergo Pd-
catalyzed cyclotrimerization15 to form polycyclic aromatic
hydrocarbons as a result of their high reactivity. A very
mild method of aryne generation from silylaryl triflate 2a in
the presence of CsF16 has been used in our research labora-
tories and reported in the literature for a variety of Pd-
catalyzed annulation reactions,17 cycloaddition reactions,18
electrophilic and nucleophilic reactions,19 and insertion
reactions.20
also been reported in the literature.22 We recently reported
the palladium-catalyzed aryne insertion and subsequent
cyclization of o-halostyrenes to give 9-fluorenylidenes.23
We report herein full details of our work on the synthesis of
9-fluorenylidenes and extensions of our methodology to
obtain phenanthrenes from o-halo allylic benzenes by pal-
ladium-catalyzed aryne insertion and subsequent cycliza-
tion.
Results and Discussion
The focus of our early studies on this project was the
palladium-catalyzed aryne annulation of substituted o-
halostyrenes to give substituted 9-fluorenylidenes in good
yields. (E)-3-(2-Iodophenyl)acrylonitrile (1a) was used as a
model system for optimization of the reaction conditions,
and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate
(2a) was used as the aryne precursor. Early in this work,
the reaction was run with 0.3 mmol of 1a, 2.0 equiv of 2a,
5 mol % Pd(dba)2, 5 mol % P(o-tolyl)3, and 3 equiv of CsF
as the base in 5 mL of 1:9 acetonitrile/toluene at 110 °C in a
sealed vial to obtain a 28% isolated yield of the desired
2-(9H-fluoren-9-ylidene)acetonitrile (3a) (eq 1; Table 1,
entry 1).
We have previously reported palladium-catalyzed alkyne
annulations using ethyl (E)-4-(2-iodophenyl)-2-butenoate
to obtain naphthalenes,21 and the palladium-catalyzed
alkyne annulation of methyl 3-(2-iodophenyl)acrylate has
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Previously in our laboratories, we have found that the
polarity of the acetonitrile/toluene solvent system greatly
affects the yields of the aryne products under our experi-
mental conditions, as it controls the rate of aryne forma-
tion. An increase in the polarity of the solvent system only
slightly increased the yield of the desired product 3a
(entries 2-5). When the reaction was run in pure acetoni-
trile, the yield dropped to 25% (entry 6) with a simulta-
neous increase in the amount of the triphenylene side
product resulting from palladium-catalyzed cyclotrimeri-
zation of the benzyne. None of the desired product was
obtained when pure toluene was used as the solvent for the
reaction, and both the starting o-halostyrene 1a and the
benzyne precursor 2a remained unreacted under those
conditions (entry 7). We believe that this is due to the low
solubility of the fluoride source in toluene, which hinders
formation of the benzyne. With 1:1 acetonitrile/toluene as
the optimized solvent system for the reaction, we tried to
improve the yield of the desired product 3a by increasing
the amount of the Pd(dba)2 catalyst to 10 mol % and the
P(o-tolyl)3 ligand to 10 mol %. There was only a slight
increase in the yield of the desired product 3a to 39% (entry
8). An increase in the P(o-tolyl)3 ligand to 20 mol % further
increased the yield to 49% (entry 9). While maintaining a
1:2 ratio of the Pd(dba)2 to the P(o-tolyl)3 but further
increasing the amount of the catalyst and the ligand, no
significant increase in the yield was observed (entry 10).
The reaction in the absence of P(o-tolyl)3 did not yield the
desired product 3a (entry 11).
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J. Org. Chem. Vol. 74, No. 23, 2009 9133

Worlikar and Larock
JOCArticle
TABLE 1. Optimization of Palladium-Catalyzed Benzyne Insertion
into (E)-3-(2-Iodophenyl)acrylonitrile Using Various Solvents and Li-
gands (eq 1)a
TABLE 2. Optimization of the Palladium-Catalyzed Benzyne Insertion
into (E)-3-(2-Iodophenyl)acrylonitrile with dppm as the Ligand (eq 1)a
Pd(dba)2 dppm
entry (mol %) (mol %)
precursor
(equiv) (equiv) (h) (°C)
CsF time temp % yieldb
3a
solvent
(CH3CN/
mol %
entry Pd(dba)2
%
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
5
20
20
20
20
20
20
20
5
10
10
10
40
20
2.0
2.0
2.0
1.5
1.2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
3
3
3
3
2
5
3
3
3
3
3
3
24
85
52c
68c
92
phosphine ligand (mol %)
PhCH3) yieldb
24 100
24 120
24 110
24 110
24 110
24 110
24 110
24 110
24 110
24 110
24 110
12 110
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
P(o-tolyl)3 (5)
1:9
1:7
1:5
1:3
1:1
1:0
0:1
1:1
1:1
1:1
1:1
1:1
28c
36c
35c
35c
37c
25c
0c
P(o-tolyl)3 (5)
P(o-tolyl)3 (5)
P(o-tolyl)3 (5)
P(o-tolyl)3 (5)
P(o-tolyl)3 (5)
P(o-tolyl)3 (5)
91
69c
78
86
49c
62c
69c
42
9
5
10 P(o-tolyl)3 (10)
10 P(o-tolyl)3 (20)
15 P(o-tolyl)3 (30)
20
10 tris(2,4,6-trimethoxyphenyl)-
phosphine (20)
39c
49c
48c
0c
10
11
12
13
10
20
10
10
9
10
11
12
76
71c,d
40c
aRepresentative procedure: (E)-3-(2-iodophenyl)acrylonitrile (0.3
mmol), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, Pd(dba)2,
dppm, CsF, and solvent (5 mL) were placed in a 4 dram vial. The vial
was sealed with a screw cap. The reaction was then stirred at the desired
temperature for the indicated time. bIsolated yields. cSome starting
material 1a was left. dGC yields.
13
14
10 tris(2,6-dimethoxyphenyl)-
phosphine (20)
10 tri(2-methoxyphenyl)phosphine
(20)
10 tri(2-furyl)phosphine (20)
1:1
1:1
75
84
15
16
17
18
1:1
1:1
1:1
1:1
30
25c
10 [(CH3)3P AgI]4 (20)
3
<5c,d
32
ligand did not improve the yield of the reaction (entry 19),
affording only a 35% yield of 3a. The phosphine ligands
dppp and dppf gave extremely poor yields (entries 20 and
21), but to our surprise dppm improved the yield to 91%
(entry 22).
10 tri(tert-butyl)phosphine (20)
10 2-(di-tert-butylphosphino)biphenyl
(20)
19
20
21
22
10 4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene (Xantphos) (20)
10 1,3-bis(diphenylphosphino)-
propane (dppp) (20)
1:1
1:1
1:1
1:1
35
<5c,d
<5d
91
With dppm as the apparent ligand of choice, the reaction
has been carried out at a lower temperature. At 85 °C, the
desired product 3a was obtained in a lower 52% yield (Table
2, entry 1), and the reaction did not go to completion. When
the reaction was run at 100 °C, the yield increased to 68%
(entry 2), while a further increase in the temperature to
120 °C did not have much effect on the yield of the product
(compare Table 1, entry 22 and Table 2, entry 3). Reducing
the amount of the benzyne precursor to 1.5 equiv did not
affect the yield of the desired product 3a (entry 4), but a
further reduction of 2a to 1.2 equiv decreased the yield of 3a
to 69% (entry 5). Either a decrease or an increase in the
amount of the base CsF gave reduced yields of 78% and
86%, respectively (compare entries 4, 6, and 7). This varia-
tion in yields probably reflects a variation in the rate
of benzyne formation from the 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate.
After optimization of the reaction conditions with respect
to the solvent system, the phosphine ligand, the temperature,
the amount of the aryne precursor and the base, we also
studied if the reaction can be carried out at a lower catalyst
loading with different palladium catalyst to phosphine
ligand ratios. When the reaction was run with only 5 mol
% of the Pd(dba)2 catalyst and 5 mol % of the dppm ligand,
the yield decreased to 49% (entry 8). An increase in the
amount of the dppm ligand to 10 mol % increased the yield
to 62% (entry 9), indicating that a ratio of Pd(dba)2 to the
dppm ligand of 1:2 works better than the ratio of 1:1, even at
a lower catalyst loading. To double check this finding, the
reaction was carried out with 10 mol % of Pd(dba)2 and
10 mol % of the dppm ligand, which afforded only a 69%
yield of the desired product 3a (compare entries 4 and 10). A
higher Pd(dba)2 to dppm ligand ratio or a further excess of
the dppm ligand decreased the yields of 3a to 42% and 76%
respectively (entries 11 and 12). A reduced reaction time
gave a lower yield of 71% (entry 13). Thus, our optimized
10 1,10-bis(diphenylphosphino)-
ferrocene (dppf) (20)
10 1,1-bis(diphenylphosphino)-
methane (dppm) (20)
aRepresentative procedure: (E)-3-(2-iodophenyl)acrylonitrile (0.3
mmol), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2.0 equiv),
Pd(dba)2, ligand, CsF (3 equiv), and solvent (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. bIsolated yields. cSome starting material 1a was
left. dGC yields.
Noting the importance of the ligand in the reaction,
various ligands have been screened with the aim of increas-
ing the yield of the 9-fluorenylidene 3a. Electron-rich
tris(2,4,6-trimethoxyphenyl)phosphine gave a reduced
yield of 40% (entry 12), while tris(2,6-dimethoxyphenyl)-
phosphine increased the yield to 75% (entry 13).
Relatively unhindered tri(2-methoxyphenyl)phosphine
improved the yield still further to 84% (entry 14). Along
with steric factors, the electronic nature of the phosphine
ligand seems to have an effect on the overall yield of the
desired product 3a (compare entries 12-14). To further
study the effect on the yield of the desired product, in the
presence of an oxygen moiety in the phosphine ligand
(compare entries 9 and 14), the reaction was carried out
with tri(2-furyl)phosphine as the ligand, which gave a poor
30% yield of 3a (entry 15). The ligand trimethylphosphine
obtained from [(CH3)3P AgI]4 gave a poor 25% yield of
3
the desired product 3a (entry 16). The bulkier phos-
phine ligand tri(tert-butyl)phosphine gave an extremely
poor yield (<5%), while 2-(di-tert-butylphosphino)-
biphenyl gave only a 32% yield of the fluorenylidene
(entries 17 and 18). We have also screened biden-
tate ligands with a view toward improving the yield of
the desired 9-fluorenylidene 3a. The bidentate Xantphos
9134 J. Org. Chem. Vol. 74, No. 23, 2009

Worlikar and Larock
JOCArticle
SCHEME 1
(entry 7). Previously aryl triflates have proved to work well in
oxidative palladium insertion chemistry. Thus, we carried
out a reaction with 2-(3-oxo-3-phenylpropenyl)phenyl tri-
fluoromethanesulfonate, but none of the desired product
was obtained. When a stronger electron-withdrawing nitro
group was placed on the o-halostyrene, the reaction also
failed to give the desired product 3f (entry 8). Instead, we got
a polymeric residue in the reaction flask. We believe 2-(2-
nitrovinyl)iodobenzene (1h) undergoes polymerization un-
der our reaction conditions. We therefore carried out the
reaction at a lower temperature but again failed to get the
desired product 3f. Also, when an electron-donating methyl
group was placed on the double bond of the o-halostyrene, as
in 1-iodo-2-(1-propenyl)benzene, the reaction with
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a)
failed to give the desired fluorenylidene under our reaction
conditions. When electron-donating methoxy groups were
placed on the o-halostyrene, we obtained an extremely poor
yield (<5%), presumably because oxidative addition of
palladium is unfavorable in such electron-rich aryl halides
(compare entries 5 and 9). On the other hand, the electron-
rich substrate 1j with a carbon-iodine bond, instead of a
carbon-bromine bond, gave the desired product in a 73%
yield (entry 10). The fluorine-containing o-halostyrene 1k
reacted with 2a to give a 46% yield of the fluorenylidene
(entry 11). However, the reaction was slow and did not go to
completion even at the higher temperature of 140 °C. The
structure of the major product has not been rigorously
established but is assumed to be the less hindered E-isomer.
Five percent of a minor isomer has also been observed.
We have also studied the scope of the reaction using
various aryne precursors. The model system 1a on reaction
with the aryne precursor 2b gave the desired compounds 3k
and 3l as a 11:1 mixture of inseparable isomers in an 82%
overall yield (entry 12). It is unclear as to which stereoisomer
is the major product. The aryne precursor 2c with two
electron-rich methoxy groups gave a slightly lower yield of
78% when allowed to react with the model system 1a; a 4:1
ratio of stereoisomers was obtained (entry 13). Again, the
stereochemistry of the major isomer is unknown. The slightly
lower yield may be due to the slower rate of aryne formation
from precursor 2c, as observed previously by us.
SCHEME 2
conditions for the palladium-catalyzed aryne annulation are
0.3 mmol of 1a, 1.5 equiv of 2a, 10 mol % of Pd(dba)2,
20 mol % of dppm, 3 equiv of CsF in 5 mL of 1:1 acetonitrile/
toluene at 110 °C in a sealed vial for 24 h.
Using our best reaction conditions for the aryne annula-
tion, we further examined the scope of this reaction on
various substrates. Aryl halide 1k was prepared by standard
Wittig chemistry (Scheme 1), using commercially available
aldehyde 4a. The aryl halide 1t was prepared by con-
densation of o-iodobenzaldehyde with diethyl malonate
(Scheme 2). Aryl halides 1a, 1h, and 1r were obtained from
commercial sources, and 1b,24 1c,24 1d,25 1e,26 1f,23 1g,27 1i,23
1j,23 1l,28 1m,28 1n,21 1o,28 1p,28 1q,29 and 1s30 were prepared
according to literature procedures. The benzyne precursor 2a
is commercially available, and the aryne precursors 2b,18
2c,18 2d,18 and 2e18 were prepared according to literature
procedures.
The model system 1a under our optimized conditions with
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (2a) as
the benzyne precursor gave an 91% isolated yield of the
desired product 3a (Table 3, entry 1). To study the more
facile oxidative addition of aryl iodides over aryl bromides,
the reaction was carried out using the corresponding aryl
bromide, (E)-3-(2-bromophenyl)acrylonitrile (1b). Com-
pound 3a was indeed obtained in a slightly lower 79% yield
(entry 2). The cis isomer (Z)-3-(2-bromophenyl)acrylonitrile
(1c) gave a slightly lower yield of 72% than the correspond-
ing trans isomer, (E) 3-(2-bromophenyl)acrylonitrile (1b)
(compare entries 2 and 3). With a methyl ester as the
electron-withdrawing group (EWG) on the double bond of
the o-halostyrene 1d, the yield dropped to 76% under our
optimized conditions (compare entries 1 and 4). Similar
results were obtained using the corresponding bromide-
containing ethyl ester (compare entries 2 and 5). With an
aldehyde as the EWG on the o-halostyrene 1f, a 76% yield of
the desired product 3d was obtained (entry 6), which is
comparable to that obtained with an ester group present
on the double bond of the o-halostyrene, but with a ketone
present in the o-halostyrene 1g, the yield dropped to 61%
When we carried out the palladium-catalyzed aryne an-
nulation using aryne precursor 2-(trimethylsilyl)phenyl tri-
fluoromethanesulfonate (2a) and o-halostyrene 1r, bearing a
trisubstituted double bond, under our optimized reaction
conditions, the reaction was messy and the desired product
3w was obtained in an extremely low (<5%) yield as
determined by GC analysis (Scheme 3). We have also tried
an analogous reaction with o-halostyrene 1s, where
the electron-withdrawing groups on the double bond of the
styrene were ester groups, instead of cyano groups. The
desired product 3x was again obtained in a very low
(<5%) yield as determined by GC analysis. A reaction with
the corresponding aryl iodide 1t only slightly improved the
yield to ∼5-10%, and the reaction was cleaner when com-
pared to that of aryl bromide 1s.
(24) Solodenko, W.; Kunz, U.; Jas, G.; Kirschning, A. Bioorg. Med.
Chem. Lett. 2002, 12, 1833.
(25) Grigg, R.; Inman, M.; Kilner, C.; Koppen, I.; Marchbank, J.; Selby,
P.; Sridharan, V. Tetrahedron 2007, 63, 6152.
ꢀ
ꢀ
(26) Metay, E.; Leonel, E.; Sulpice-Gaillet, C.; Nedelec, J. Y. Synthesis
ꢀ ꢀ
We have also been able to extend our methodology
to the synthesis of phenanthrene derivatives from the
corresponding o-halo allylic benzenes. Ethyl (E)-4-(2-
iodophenyl)but-2-enoate (1l) on reaction with 2a gave a
62% yield of the desired 9-phenanthrene 3o (entry 14).
2005, 1682.
(27) Davey, W.; Gwilt, J. R. J. Am. Chem. Soc. 1957, 79, 1015.
(28) Huang, Q.; Larock, R. C. Org. Lett. 2002, 4, 2505.
(29) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804.
(30) Ksander, G. M.; de Jesus, R.; Yuan, A.; Ghai, Y. R. D.; Trapani, A.;
McMartin, C.; Bohacek, R. J. Med. Chem. 1997, 40, 495.
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TABLE 3. Synthesis of 9-Fluorenylidenes and Phenanthrenes by Palladium-Catalyzed Aryne Annulation of o-Halostyrenes and o-Halo Allylic Benzenesa
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TABLE 3. Continued
aRepresentative procedure: aryl halide 1(a-r) (0.3 mmol), silylaryl triflate 2(a-e) (2.0 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. bGC
yields. cEight percent of a minor isomer is observed by GC analysis. dSome starting material 1k was left. The reaction did not go to completion even at 140
°C. eFive percent of a minor isomer is observed by GC analysis. fThe ratio was determined by H1 NMR spectroscopy.
Ethyl (E)-4-(2-bromophenyl)but-2-enoate (1m) gave
a
SCHEME 3
slightly lower yield of 49% of 3o, presumably as a result of
reasons mentioned previously. Ethyl (E)-4-(2-iodophenyl)-
but-2-enoate, when allowed to react with the electron-rich
aryne precursor 2c, gave a somewhat lower yield of 45% of
the desired phenanthrene 3p (compare entries 14 and 16).
The o-halo allylic benzene 1n gave a poor ∼20% yield of the
desired phenanthrene 3q, but the product could not be
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JOCArticle
SCHEME 4
purified (entry 17). An electron-withdrawing cyano group on
the o-halo allylic benzene 1o, instead of an ester group, gave a
slightly lower 58% yield of the desired phenanthrene 3r,
contrary to our observations with the analogous fluorenyli-
denes (compare entries 14 and 18, and entries 1 and 4). (Z)-
4-(2-Iodophenyl)-2-butenenitrile (1p) gave a 47% yield of the
desired phenanthrene, which was slightly less than the (E)-
isomer (compare entries 18 and 19). o-Halo allylic benzene
1o, when treated with the aryne precursors 2b and 2d, gave
52% and 50% yields, respectively, of the corresponding
phenanthrenes 3s and 3t (entries 20 and 21). Thus, the yield
of the reaction decreases when more electron-rich aryne
precursors are used. When inductively electron-withdrawing
fluorine atoms were placed on the aryne precursor 2e, none
of the desired product was obtained for reasons not known to
us. The o-halostyrene 1q gave the phenanthrene 3v in a 35%
yield. This product, however, could not be separated from
the corresponding triphenylene, which is the major side
product in all of these reactions.
On the basis of the known reactions of organopalladium
compounds with alkynes,13 we propose two possible me-
chanistic pathways, path a or path b, for these reactions
(Scheme 4). In path a, the aryne generated from the triflate in
the presence of the fluoride source coordinates with Pd(0),
affording palladacycle I.31 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 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 aryne32 to afford arylpalladium inter-
mediate 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 β-hydride elimination when
n = 0. When n = 1, the phenanthrene is obtained by further
isomerization of the resulting olefin. This isomerization may
be promoted by the base present in the reaction or by the
palladium hydride generated during the process. Similar
intramolecular palladium-catalyzed Heck reactions, followed
by olefin isomerization, have been reported by us during the
carbopalladation of alkynes to generate naphthalenes.21
Conclusions
A range of substituted fluorenylidenes and phenanthrenes
have been obtained using a one-step palladium-catalyzed
aryne insertion of o-halostyrenes and o-halo allylic benzenes,
respectively, from starting materials that are readily avail-
able or easily synthesized. The arynes are obtained in situ
under mild reaction conditions from the corresponding
2-(trimethylsilyl)aryl trifluoromethanesulfonates and CsF,
thus rendering the methodology tolerant of a variety of
functional groups, including cyano, ester, aldehyde, ketone,
and methoxy groups. This provides a handle for further
organic transformations. A fluorine moiety can also be
introduced into the products. This methodology provides a
very convenient and general approach to these two impor-
tant classes of aromatic hydrocarbons.
Experimental Section
3-(2-Fluoro-6-iodophenyl)acrylonitrile (1k). This compound
was prepared by the following procedure. To a solution of
(triphenylphosphoranylidene)acetonitrile (4.5 mmol) in 30 mL
of CH2Cl2 was added dropwise a solution of the 2-fluoro-6-
iodobenzaldehyde (3.0 mmol) in 6 mL of CH2Cl2 at 0 °C under an
inert argon atmosphere. The resulting mixture was stirred at 25
°C for 24 h and monitored by TLC. The solvent was then
evaporated under reduced pressure. The solid residue was dis-
solved in 15 mL of hexanes, and the mixture was stirred at 25 °C
for 30 min. The Ph3PO was filtered off, and the solvent was
removed under reduced pressure. The residue was purified by
flash chromatography on silica gel using hexanes/EtOAc as the
eluent to afford the desired product as a white solid: mp 82-83
°C; 1H NMR (400 MHz, CDCl3) δ 6.12 (d, J = 16.8 Hz, 1H),
(31) (a) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A.
Organometallics 2005, 24, 156. (b) Yoshida, H.; Tanino, K.; Ohshita, J.;
Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 5052.
(32) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. Org. Lett. 2007, 9,
5589.
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7.03-7.16 (m, 2H), 7.41 (d, J = 16.8 Hz, 1H), 7.75 (d, J = 7.7 Hz,
1H); 13C NMR (100 MHz, CDCl3) 101.64, 101.66, 104.0,
3104.2, 115.4, 116.8, 117.0, 117.8, 124.9, 125.0, 132.70, 132.79,
136.35, 136.39, 148.54, 148.57, 159.6, 162.1 (extra peaks due to
splitting by fluorine); HRMS m/z 272.94554 (calcd C9H5FIN,
272.94508).
General Procedure for the Palladium-Catalyzed Annulation of
Arynes by o-Halostyrenes and o-Halo Allylic Benzenes. To 0.3
mmol of the aryl halide were added the o-silylaryl triflate (1.5
equiv), Pd(dba)2 (10 mol %), dppm (20 mol %), and 1:1 CH3CN/
PhCH3 (5 mL). CsF (3.0 equiv) was then added, and the vial was
sealed with a screw cap. The reaction mixture was then stirred at
110 °C for 24 h. After the reaction was complete, the resulting
solution was washed with brine (25 mL) and extracted with
EtOAc (25 mL). The combined EtOAc fractions were dried over
Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel using hexanes/
EtOAc as the eluent to afford the desired product.
2-(9H-Fluoren-9-ylidene)acetonitrile (3a). This compound
was obtained as a yellow solid: mp 109-111 °C (lit.33
109-110 °C); 13C NMR (100 MHz, CDCl3) δ 88.6, 120.3,
120.4, 121.7, 125.5, 128.0, 128.5, 131.9, 132; HRMS m/z
203.07381 (calcd C15H9N, 203.07350). The 1H NMR spectrum
matches the literature data.33
Diethyl [(2-Iodophenyl)methylene]propanedioate (1t). This
compound was prepared by the following procedure. To a
solution of 2-iodobenzaldehyde (10 mmol), diethyl malonate
(10 mmol), and piperidine (1.5 mmol) in 60 mL of toluene was
added benzoic acid (1.0 mmol). The reaction mixture was
refluxed for 5 h using a Dean-Stark condenser for water
removal. The mixture was cooled to room temperature and
diluted with diethyl ether (100 mL) and EtOAc (100 mL). The
organic layer was separated and washed two times each with 2 N
HCl, satd aq NaHCO3, and brine. The organic layer was then
dried over MgSO4, and the solvent was evaporated under
reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel using hexanes/EtOAc as the eluent and
further subjected to distillation to remove traces of diethyl
malonate (bp 195-196 °C) at ∼200 °C to afford the desired
product as a brown oil: 1H NMR (400 MHz, CDCl3) δ 1.14 (t,
J = 7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 4.19 (q, J = 7.2 Hz,
2H), 4.33 (q, J = 7.0 Hz, 2H), 7.03-7.07 (m, 1H), 7.29-7.39 (m,
2H), 7.83 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.9, 14.2, 61.6, 61.8, 99.6, 128.2, 128.6, 128.9, 131.1,
137.4, 139.4, 145.9, 163.5, 165.4; IR (neat, cm-1) 3060, 2979,
1746, 1627, 1458, 1361; HRMS m/z 374.00220 (calcd
C14H15IO4, 374.00151).
Acknowledgment. We thank the National Institute of Gen-
eral Medical Sciences (GM070620), the National Institutes of
Health Kansas University Chemical Methodologies and Li-
brary 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 palladium catalysts.
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.
(33) Dibbiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.; Gokel, G.
W. J. Org. Chem. 1979, 44, 4640.
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