A R T I C L E S
Zhao et al.
Scheme 3. Plausible Palladium Migration Mechanism (Route A)
(Table 1, entry 1). After 12 h reaction, the crude imine product
obtained was hydrolyzed by aqueous HCl in acetone to afford
a 95% yield of the desired fluoren-9-one 2a after flash
chromatography. It appears that the “optimal” palladium migra-
tion conditions, which have been successfully employed in a
number of previously reported palladium migration reactions,
work well in this fluoren-9-one synthesis.
We next investigated the scope and limitations of this process,
as shown in Table 1. The effect of substituents on the arene
which would bear the imidoyl palladium moiety was first
examined. A 5-methoxy-substituted imine 1b was prepared and
allowed to react in the usual fashion, and a 90% yield of the
fluoren-9-one 2b was obtained (entry 2). However, imine 1c
bearing a methyl group on the 4 position of the arene only
affords a 56% yield of the desired product 2c (entry 3). In this
case, the electron density on the imidoyl group is presumably
increased by the para-methyl group, which apparently retards
imidoyl C-H activation. The 5-fluoro-substituted imine 1d
affords an 80% yield of the fluoren-9-one product 2d (entry 4).
imidoyl palladium complexes have generally been obtained by
the oxidative addition of imidoyl halides to Pd(0) species.9
We then investigated the effect of substituents on the arene,
which undergoes the cyclization reaction. Surprisingly, almost
quantitative yields of fluoren-9-ones have been obtained for both
electron-rich and electron-poor functionally substituted sub-
strates, which raises some question as to whether the intramo-
lecular arylation step proceeds via electrophilic aromatic
substitution as usually assumed (entries 5-8). These results also
suggest that the palladium migration could be the rate-
determining step in this overall transformation. The only
exception to the high yields was the reaction employing the
substrate 1i with a 2-chloro group, where only a 65% yield of
the fluoren-9-one 2j was obtained, possibly due to competing
oxidative addition of the aryl chloride or perhaps hindered
reaction of the aromatic ring or simply reduction in the number
of ortho positions available for reaction (entry 9). Imines 1j
and 1k afforded 95 and 92% yields of the expected fluoren-9-
ones, respectively (entries 10 and 11). Once again, neither
electron-donating nor electron-withdrawing groups on the ring
undergoing substitution seem to have a significant effect on the
yield. When the naphthalene substrate 1l was prepared and
allowed to react under our usual reaction conditions, arylation
took place in both the 3 and 1 positions of the naphthalene in
a 91% overall yield, with the less hindered product 2k
predominant (9:1) (entry 12). The furan-containing ring present
in imine 1m facilitates electrophilic aromatic substitution, and
within 2 h, the reaction was complete (entry 13). However,
because the resulting 8H-indeno[2,1-b]furan-6-one was not
stable under our hydrolysis conditions, we were only able to
isolate a 50% yield of the ketone. Omitting the hydrolysis step,
the corresponding imine 2m was obtained in an 82% yield.
Results and Discussion
Synthesis of Fluoren-9-ones via Aryl to Imidoyl Palladium
Migration. Fluoren-9-ones are the core structures of many
biologically interesting and pharmaceutically important com-
pounds.10 The most useful syntheses of fluoren-9-ones include
Friedel-Crafts ring closures of biarylcarboxylic acids,11 in-
tramolecular [4 + 2] cycloaddition reactions of conjugated
enynes,12 the oxidation of fluorenes,13 the remote metalation of
2-biphenylcarboxamides or 2-biphenyloxazolines,14 and the
palladium-catalyzed cyclocarbonylation of o-halobiaryls.15 Those
methods generally suffer from the use of strong acids, strong
bases, toxic CO gas, or harsh reaction conditions. Recently, the
first intramolecular arene acylation reaction by aryl-substituted
aldehydes has been reported to cyclize biphenyl-2-carbaldehydes
to fluoren-9-ones, but the reaction efficiency is only moderate
and only a few fluoren-9-ones have been prepared this way.16
Our previous work indicated that the aryl-3,4 or alkyl
palladium5 intermediates generated by palladium migration
processes can be readily trapped by intramolecular arylation to
afford a variety of polycyclic structures. Therefore, we envi-
sioned that an imidoyl palladium intermediate generated from
an aryl to imidoyl palladium migration process might also
undergo facile intramolecular arylation to afford biologically
interesting fluoren-9-one derivatives. To examine this possibility,
we first treated imine 1a (0.25 mmol) with 5 mol % of Pd-
(OAc)2, 5 mol % of bis(diphenylphosphino)methane (dppm),
and 2 equiv of CsO2CCMe3 (CsPiv) in DMF (4 mL) at 100 °C
(9) (a) Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 5344 and
references therein. (b) Owen, G. R.; Ramon, V.; Andres, J. P; Williams,
D. J. Organometallics 2003, 22, 4511.
Mechanistic Studies of the Fluoren-9-one Synthesis. After
we investigated the reaction scope and limitations, we examined
the reaction mechanism of this fascinating process. In fact, it
appears that this reaction proceeds through a rather unusual
mechanism. Presumably, Pd(0) first undergoes oxidative addi-
tion to the aryl iodide 1a to generate intermediate A. The
palladium moiety may then undergo further oxidative addition
of the imidoyl C-H bond to afford a palladacycle(IV) inter-
mediate B, which can undergo reductive elimination to form
palladacycle(II) C or the imidoyl palladium intermediate D.
Alternatively, palladacycle(II) C may be directly generated from
(10) (a) Greenlee, M. L.; Laub, J. B.; Rouen, G. P.; DiNinno, F.; Hammond,
M. L.; Huber, J. L.; Sundelof, J. G.; Hammond, G. G. Bioorg. Med. Chem.
Lett. 1999, 9, 3225. (b) Perry, P. J.; Read, M. A.; Davies, R. T.; Gowan,
S. M.; Reszka, A. P.; Wood, A. A.; Kelland, L. R.; Neidle, S. J. Med.
Chem. 1999, 42, 2679. (c) Tierney, M. T.; Grinstaff, M. W. J. Org. Chem.
2000, 65, 5355.
(11) (a) Olah, G. A.; Mathew, T.; Farnia, M.; Prakash, S. Synlett 1999, 1067.
(b) Yu, Z.; Velasco, D. Tetrahedron Lett. 1999, 40, 3229.
(12) Danheiser, R. L.; Gould, A. E.; Pradilla, R. F.; Helgason, A. L. J. Org.
Chem. 1994, 59, 5514.
(13) Nikalje, M.; Sudalai, A. Tetrahedron 1999, 55, 5903.
(14) (a) Ciske, F.; Jones, W. D., Jr. Synthesis 1998, 1195. (b) Wang, W.;
Snieckus, V. J. Org. Chem. 1992, 57, 424.
(15) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
(16) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem.,
Int. Ed. 2006, 45, 3140.
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5290 J. AM. CHEM. SOC. VOL. 129, NO. 16, 2007