Synthesis of 9-alkylidene-9H-fluorenes by a novel palladium-catalyzed rearrangement

Article abstract of DOI:10.1021/ol000220h

(matrix presented) In the presence of a palladium catalyst and NaOAc, aryl iodides react with 1-aryl-1-alkynes to afford 9-alkylidene-9H-fluorenes in good yields. This process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) rearrangement of the resulting vinylic palladium intermediate to an arylpalladium species, and (4) aryl-aryl coupling with simultaneous regeneration of the Pd(0) catalyst.

Full text of DOI:10.1021/ol000220h

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3329-3332
Synthesis of 9-Alkylidene-9H-fluorenes
by a Novel Palladium-Catalyzed
Rearrangement
Qingping Tian and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received August 4, 2000
ABSTRACT
In the presence of a palladium catalyst and NaOAc, aryl iodides react with 1-aryl-1-alkynes to afford 9-alkylidene-9H-fluorenes in good yields.
This process appears to involve (1) oxidative addition of the aryl iodide to Pd(0), (2) alkyne insertion, (3) rearrangement of the resulting vinylic
palladium intermediate to an arylpalladium species, and (4) aryl−aryl coupling with simultaneous regeneration of the Pd(0) catalyst.
Palladium-catalyzed processes have proven remarkably use-
ful in organic synthesis.1 Oftentimes, only minor variations
in reaction conditions have a profound effect on the outcome
of the overall process. For example, seemingly minor
modifications in the reagents employed in the reaction of
iodobenzene and diphenylacetylene have been reported to
produce in good yields as the sole product 1,2,3,4-tetraphen-
ylnaphthalene (1),2 9,10-diphenylphenanthrene (2),3 or tri-
phenylethylene (3) (eq 1).4 We have recently observed
mmol, 10 mol %), NaOAc (0.50 mmol), and n-Bu4NCl (0.25
mmol) in 5 mL of DMF for 12 h at 100 °C, we have been
able to isolate 9-benzylidene-9H-fluorene in 62% yield (eq
2). While we5 and others6 have recently reported a number
of simple annulation processes of internal alkynes, where
the annulation takes place by simple addition across the
acetylene triple bond, this unusual reaction is quite novel.
another unusual reaction of iodobenzene, diphenylacetylene,
and a palladium catalyst that results from only minor
variations in the reaction conditions previously reported. By
heating iodobenzene (0.25 mmol), diphenylacetylene (0.25
mmol), Pd(OAc)2 (0.0125 mmol, 5 mol %), PPh3 (0.0250
A careful examination of the effect of the reaction
conditions on the yield of fluorene has been carried out. The
best yields of fluorene 4 are obtained by employing only 1
equiv of alkyne. The addition of catalytic amounts of PPh3
and an equivalent of some chloride source (n-Bu4NCl is
(1) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: New
York, 1996.
(2) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organometallics
1987, 6, 1941.
(3) (a) Dyker, G. J. Org. Chem. 1993, 58, 234. (b) Dyker, G.; Kellner,
A. Tetrahedron Lett. 1994, 35, 7633.
10.1021/ol000220h CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/27/2000

slightly better than LiCl) improves the yield somewhat.
Larger amounts of these reagents proved detrimental to the
yield.
In the Z isomer 11a, the phenyl ring present on the vinylic
carbon C-10 can exhibit an anisotropic effect7 on the ring
which bears the CO2Et group. This interaction may shield
the protons on that ring, and as a result, the chemical shift
of proton H-4 on that ring should appear at a higher field.
No such anisotropic interaction can exist in the E isomer
11b, and the signal for H-4 should appear at a lower field.
Therefore, the configuration of 11a and 11b is tentatively
assigned as Z and E, respectively.
Heteroaromatic iodides have also been examined in the
reaction. The reaction of 3-iodopyridine afforded a good yield
of a mixture of regio- and stereoisomers (entry 9). All of
these isomers are known compounds, and the structural
assignments are thus based on the literature.8
Like much of our previous palladium chemistry, the choice
of base is critical to the reaction. In the absence of any base,
no fluorene is observed. Using 1 equiv of n-Bu4NCl and 10
mol % of PPh3, bases other than NaOAc have been observed
to give much lower yields of the fluorene 4 and 9,10-
diphenylphenanthrene (2) as a side product. For example,
using K2CO3 afforded a 71% yield of the phenanthrene 2
and only 8% of the fluorene 4. These reaction conditions
are virtually the same as those employed by Dyker previously
to produce 9,10-diphenylphenanthrene, except that he used
n-Bu4NBr rather than n-Bu4NCl.3 The base Na2CO3 produced
30% of phenanthrene 2 and 20% of fluorene 4, while KOAc
afforded 12% phenanthrene 2 and 42% fluorene 4. The base
NaOAc produced a 62% yield of the desired fluorene 4 and
none of the phenanthrene 2. This investigation led to the
following standard reaction procedure: 1 equiv of aryl halide
(0.25 mmol), 1 equiv of alkyne (0.25 mmol), 5 mol % of
Pd(OAc)2, 10 mol % of PPh3, 2 equiv of NaOAc, and 1 equiv
of n-Bu4NCl in DMF at 100 °C.
As one can see from Table 1, in most cases the E isomers
are the sole or predominant products in the reaction. Previous
literature has shown that these types of fluorene compounds
undergo interconversions when heated to 140 °C in Decalin.8a
Therefore, we suspect that the formation of isomers is due
to isomerization of the initially formed E isomer, which is
expected to be produced in the reaction. This has been proven
by the following experiments. We were able to separate the
Z and E isomers (11a and 11b) from the reaction of ethyl
4-iodobenzoate and diphenylacetylene by preparative TLC
(entry 8). When submitted to the standard palladium reaction
conditions, both isomers 11a and 11b gave the same 40:60
mixture of 11a and 11b, which was exactly the same ratio
as that obtained from the original reaction of ethyl 4-iodo-
benzoate and diphenylacetylene. However, without Pd(OAc)2
present, simple heating of the E isomer 11b for the same
period of time in DMF generated a 12:88 mixture of isomers
11a and 11b, indicating that Pd(OAc)2 or perhaps Pd(0) plays
an important role in the isomerization process.
On the basis of the structure of the products from this
reaction (Table 1) and our present understanding of orga-
nopalladium chemistry, especially the active role of Pd(IV)
as an intermediate in organopalladium chemistry,9 we
propose the following mechanism for this reaction (Scheme
1). The oxidative addition of Pd(0) to iodobenzene produces
the arylpalladium intermediate 13, which rapidly inserts the
alkyne to produce the vinylic palladium species 14. This in
turn undergoes oxidative addition to the neighboring aryl
C-H bond to generate Pd(IV) intermediate 15, which
isomerizes to the new stereoisomeric Pd(IV) intermediate
16 differing from 15 only in its stereochemistry about
palladium. Reductive elimination of 16 leads to Pd(II)
intermediate 17, which undergoes single bond rotation and
oxidative addition to the neighboring phenyl ring to afford
Pd(IV) intermediate 18. Two consecutive reductive elimina-
tions finally afford the product and HI and regenerate the
With this standard procedure in hand, we explored the
scope and limitations of the reaction by first examining other
alkynes. As shown in Table 1, the alkynes that have been
successful in this reaction have an aryl group and another
sterically hindered group, such as an aryl, tert-butyl, or
similar group (entries 1-3). 1-Phenylpropyne gives a messy
reaction with little or no fluorene evident. The structural
features required of the alkyne can be easily rationalized by
examining the mechanism proposed for this process (see
Scheme 1).
Various substituted aryl iodides generally work as well
as iodobenzene (entries 4-8). The aromatic ring may contain
either electron-donating or electron-withdrawing groups.
Most aryl iodides bearing a substituent in the ortho position,
such as 2-iodobenzotrifluoride (entry 4) and 1-tert-butyl-2-
iodobenzene (entry 5), afforded the expected E isomers
cleanly. However, other substrates, such as 2-iodotoluene
(entry 6), produced mixtures of Z and E isomers. Aryl iodides
bearing functional groups in the para position have also
afforded mixtures of Z and E isomers (entries 7 and 8).
The structural assignment of the Z and E isomers is based
on 1D and 2D NMR spectroscopy. For example, the 2D
NOESY spectra of 8 (entry 5) clearly show a cross-peak
between the protons of the tert-butyl group and the vinylic
proton H-10. This confirms that 8 exists in the E configu-
ration. In some cases, 1D 1H NMR spectra provide sufficient
information to assign the stereochemistry. For example, the
1H NMR spectra of compounds 11a and 11b (entry 8) exhibit
doublets for proton H-4 at 8.37 and 8.39 ppm, respectively.
(7) Gu¨nther, H. NMR Spectroscopy, 2nd ed.; John Wiley & Sons: New
York, 1995; pp 85-93.
(4) Cacchi, S.; Felici, M.; Pietroni, B. Tetrahedron Lett. 1984, 25, 3137.
(5) (a) Larock, R. C. Palladium-Catalyzed Annulation. J. Organomet.
Chem. 1999, 576, 111. (b) Larock, R. C. Palladium-Catalyzed Annulation.
In PerspectiVes in Organopalladium Chemistry for the XXI Century; Tsuji,
J., Ed.; Elsevier Press: Lausanne, Switzerland, 1999; 317 pages. (c) Larock,
R. C. Palladium-Catalyzed Annulation. Pure Appl. Chem. 1999, 71, 1435.
(6) (a) Schore, N. E. Chem. ReV. 1988, 88, 1081. (b) Pfeffer, M. Recl.
TraV. Chim. Pays-Bas 1990, 109, 567.
(8) (a) Prostakov, N. S.; Moiz, S. S.; Soldatenkov, A. T.; Zvolinskii, V.
P.; Cherenkova, G. I. Khim. Geterotsikl. Soedin. 1971, 1398. (b) Prostakov,
N. S.; Varlamov, A. V.; Anismov, B. N.; Mikhailova, N. M.; Vasil’ev, G.
A.; Zakharov, P. I.; Galiullin, M. A. Khim. Geterotsikl. Soedin. 1978, 1234.
(9) (a) Canty, A. J. Acc. Chem. Res. 1992, 25, 83, and references therein.
(b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl.
1997, 36, 119. (c) Catellani, M.; Chiusoli, G. P.; Costa, M. Pure Appl.
Chem. 1990, 62, 623.
3330
Org. Lett., Vol. 2, No. 21, 2000

Table 1. Palladium-Catalyzed Cross-Coupling of Aryl Halides and 1-Aryl-1-alkynesa
a Reaction conditions: 5 mol % of Pd(OAc)2, 10 mol % of PPh3, 1 equiv of aryl iodide, 1 equiv of alkyne, 2 equiv of NaOAc, and 1 equiv of n-Bu4NCl
in DMF at 100 °C.
Pd(0) catalyst. Alternatively, intermediate 17 may undergo
electrophilic aromatic substitution to produce species 19
directly, thus avoiding the Pd(IV) intermediate 18. To our
knowledge, the novel migration of vinylic palladium(II)
intermediate (14) to an arylpalladium(II) species (17) has
not been observed previously, although Dyker has suggested
the formation of intermediate Pd(II) palladiacycles similar
to 15 and 16 without the HI.10 Dyker’s intermediates are
suggested to arise from vinylic halides by oxidative addition
of Pd(0), but they undergo further oxidative addition of a
Org. Lett., Vol. 2, No. 21, 2000
3331

Scheme 1
second molecule of vinylic halide to eventually give com-
catalyzed rearrangement.
plicated dimeric products.
It appears that phenanthrene 2 is formed in the presence
of K2CO3 by either cyclization of 14 to a palladiacycle like
15 or 16, but without the HI present, or reductive elimination
of HI from intermediates 15 or 16 to produce the same
palladiacycle, which in turn undergoes oxidative addition by
another molecule of iodobenzene, eventually leading to
phenanthrene 2.
In conclusion, the Pd-catalyzed coupling of aryl iodides
and 1-aryl-1-alkynes provides an efficient synthetic route to
9-alkylidene-9H-fluorenes. This unusual process is believed
to involve an unprecedented intramolecular migration of a
vinylic palladium intermediate to an arylpalladium species.
On the basis of the proposed mechanism, the synthesis of a
9-alkylidene-9H-fluorene has also been achieved from a
vinylic iodide. We are presently studying the scope of this
novel palladium migration chemistry and will report on that
chemistry shortly.
From the proposed mechanism, it is obvious that the
alkyne must have an aryl group on one end of the triple bond
and a sterically bulky group on the other end of the alkyne
to get the alkyne insertion regiochemistry necessary to
eventually form the fluorene product. Previous alkyne
annulation work has clearly shown that the regiochemistry
of alkyne insertion into an arylpalladium bond is dominated
by steric effects.5,6
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research, Kawaken Fine Chemicals Co., Ltd. for donation
of the palladium acetate, and Merck and Co., Inc. for an
Academic Development Award in Chemistry.
Vinylic palladium intermediate 14 is a proposed interme-
diate in the overall process. Since this intermediate should
be easily generated by the oxidative addition of Pd(0) to the
corresponding vinylic iodide, one might expect to observe
the formation of fluorene 4 from 1,2,2-triphenyl-1-iodo-
ethylene under our reaction conditions. Indeed, the expected
product 4 was obtained from the reaction in 70% yield (eq
3). Thus, 9-alkylidene-9H-fluorenes can also be readily
prepared from vinylic iodides by this novel palladium-
Supporting Information Available: The standard pal-
ladium-catalyzed cross-coupling procedure, characterization
1
of all fluorenes prepared, and H and 13C NMR spectra for
all fluorene products in Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) (a) Dyker, G.; Nerenz, F.; Siemsen, P.; Bubenitschek, P.; Jones, P.
G. Chem. Ber. 1996, 129, 1265. (b) Dyker, G.; Siemsen, P.; Sostman, S.;
Wiegand, A.; Dix, I.; Jones, P. G. Chem. Ber./Recl. 1997, 130, 261.
OL000220H
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