Synthesis of fluoren-9-ones via palladium-catalyzed cyclocarbonylation of o-halobiaryls.

Article abstract of DOI:10.1021/ol006585j

The synthesis of various substituted fluoren-9-ones has been accomplished by a novel palladium-catalyzed cyclocarbonylation of o-halobiaryls. The cyclocarbonylation of 4'-substituted-2-iodobiphenyls produces very high yields of 2-substituted fluoren-9-ones bearing either electron-donating or electron-withdrawing substituents. 3'-Substituted 2-iodobiphenyls afford in excellent yields with good regioselectivity 3-substituted fluoren-9-ones. This chemistry has been successfully extended to polycyclic and heterocyclic fluorenones.

Full text of DOI:10.1021/ol006585j

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3675-3677
Synthesis of Fluoren-9-ones via
Palladium-Catalyzed Cyclocarbonylation
of o-Halobiaryls
Marino A. Campo and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received September 12, 2000
ABSTRACT
The synthesis of various substituted fluoren-9-ones has been accomplished by a novel palladium-catalyzed cyclocarbonylation of o-halobiaryls.
The cyclocarbonylation of 4′-substituted-2-iodobiphenyls produces very high yields of 2-substituted fluoren-9-ones bearing either electron-
donating or electron-withdrawing substituents. 3′-Substituted 2-iodobiphenyls afford in excellent yields with good regioselectivity 3-substituted
fluoren-9-ones. This chemistry has been successfully extended to polycyclic and heterocyclic fluorenones.
Fluorenones are an interesting class of compounds because
of their important biomedical applications.1 The most useful
syntheses of fluoren-9-ones include Friedel-Crafts closures
of biarylcarboxylic acids and derivatives,2 intramolecular [4
+ 2] cycloaddition reactions of conjugated enynes,3 oxidation
of fluorenes,4 and remote metalation of 2-biphenylcarboxa-
mides or 2-biphenyloxazolines.5 Fluoren-9-ones have been
recently synthesized by the palladium-catalyzed cyclization
of o-iodobenzophenones.6 We wish to report at this time a
novel palladium-catalyzed cyclocarbonylation of o-halobi-
aryls which offers a highly efficient, direct route to the
fluoren-9-one skeleton, as well as other related cyclic
aromatic ketones (eq 1).
bonylation reaction. All the optimization reactions were
carried out using commercially available 2-iodobiphenyl
under 1 atm of carbon monoxide and DMF as the solvent.
The yield of fluoren-9-one (2) was strongly dependent on
the nature of the palladium ligands. The presence of chelating
ligands, such as 1,10-phenanthroline and bis(diphenylphos-
phino)ethane, drastically reduced the yield of fluoren-9-one.
Similarly, electron-deficient phosphine ligands, such as tri-
(p-chlorophenyl)phosphine and tri(p-fluorophenyl)phosphine,
gave lower yields than triphenylphosphine. On the other
hand, the bulky, electron-rich ligand tricyclohexyl-
phosphine was by far the most effective ligand. We have
also explored the effect on the reaction yield of other
variables, such as the temperature, the palladium catalyst,
and the use of various bases. The optimum reaction condi-
tions thus far developed employ 1 atm of carbon monoxide,
1 equiv of the aryl halide (0.25 mmol), 5 mol % of
commercially available Pd(PCy3)2, and 2 equiv of anhydrous
cesium pivalate in DMF (6 mL) at 110 °C for 7 h; this
procedure provided a yield of 100%. Replacing the unusual
Our initial studies focused on developing an optimum set
of reaction conditions for the palladium-catalyzed cyclocar-
(1) (a) Han, Y.; Bisello, A.; Nakamoto, C.; Rosenblatt, M.; Chorev, M.
J. Pept. Res. 2000, 55, 230. (b) Greenlee, M. L.; Laub, J. B.; Rouen, G. P.;
DiNinno, F.; Hammond, M. L.; Huber, J. L.; Sundelof, J. G.; Hammond,
G. G. Biorg. Med. Chem. Lett. 1999, 9, 3225. (c) 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.
(3) (a) Danheiser, R. L.; Gould, A. E.; Pradilla, R. F.; Helgason, A. L.
J. Org. Chem. 1994, 59, 5514.
(4) (a) Hashemi, M.; Beni, Y. J. Chem. Res., Synop. 1999, 434. (b)
Nikalje, M.; Sudalai, A. Tetrahedron 1999, 55, 5903.
(5) (a) Ciske, F.; Jones, W. D., Jr. Synthesis 1998, 1195. (b) Wang, W.;
Snieckus, V. J. Org. Chem. 1992, 57, 424.
(2) (a) Olah, G. A.; Mathew, T.; Farnia, M.; Prakash, S. Synlett 1999,
1067. (b) Yu, Z.; Velasco, D. Tetrahedron Lett. 1999, 40, 3229.
(6) (a) Qabaja, G.; Jones, G. B. Tetrahedron Lett. 2000, 41, 5317.
10.1021/ol006585j CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Table 1. Synthesis of Fluorenones by the Pd-Catalyzed Cyclocarbonylation of o-Halobiarylsa
a All reactions were carried out under the previously specified optimal conditions. b The product ratio was determined by 1H NMR spectroscopic analysis.
cesium pivalate base with cesium carbonate or sodium acetate
was detrimental to the reaction, with the yield dropping from
100% to 82% and 92%, respectively.
By employing this protocol, 2-bromo- and 2-iodobiphenyl
afford fluoren-9-one (2) in a quantitative yield (Table 1,
entries 1 and 2). However, biphenyl-2-yl trifluoromethane-
sulfonate failed to afford the desired product under the
standard reaction conditions.
The utility of this reaction for the synthesis of 2-substituted
fluoren-9-ones was assessed by studying the cyclocarbony-
lation of readily prepared7 4′-substituted 2-iodobiphenyls
(entries 2-5). As indicated, the reaction works well, tolerat-
ing both electron-donating and electron-withdrawing sub-
stituents.
We have also addressed the question of regiochemistry in
the cyclocarbonylation of 3′-substituted 2-iodobiphenyls7
(entries 6 and 7). The cyclocarbonylation of the electron-
rich 2-iodo-3′-methylbiphenyl (10) and the electron-poor
3-(2-iodophenyl)benzaldehyde (13) afforded similar 9:1
regiochemical mixtures in excellent yields. In both cases the
predominant isomer arises from ring closure distal to the
substituent. These experimental results seem to indicate that
there is only a weak electronic effect during the cyclization
process and that a more important steric effect favors the
less hindered isomers 11 and 14.
This cyclocarbonylation does not appear to be significantly
affected by the presence of substituents ortho to the halo
group. For example, the palladium-catalyzed reaction of
2-iodo-3-methoxybiphenyl8 (16) produced 1-methoxyfluoren-
9-one (17) in 99% yield (entry 8).
(7) These starting materials were prepared using the procedure of Hart,
H.; Harada, K.; Du, C. J. F. J. Org. Chem. 1985, 50, 3104.
3676
Org. Lett., Vol. 2, No. 23, 2000

Interestingly, this palladium-catalyzed transformation is
not limited to biphenyl systems. As illustrated by entries
9-12, we have been able to apply this chemistry to
polycyclic and heterocyclic systems. Thus, treatment of
9-iodo-10-phenylphenanthrene9 (18) with carbon monoxide
under our standard reaction conditions produced indeno[1,2-
l]phenanthren-13-one10 (19) in 98% yield. Similarly, 2-bromo-
1-phenylnaphthalene11 (20) produced a 96% yield of benzo-
[c]flouren-7-one12 (21)(entry10).Furthermore,cyclocarbonyla-
tion of the heterocycle 4-iodo-3-phenylisoquinoline13 (22)
yields 11-oxoindeno[1,2-c]isoquinoline14 (23) in 95% yield
(entry 11). Finally, the metal-catalyzed transformation of
3-iodo-2-phenylbenzothiophene15 (24) produced a 67% yield
of 10-oxo-10H-benz[b]indeno[1,2-d]thiophene16 (25) (entry
12).
possibilities for the cyclization of intermediate A, either
insertion into an aromatic carbon hydrogen bond (path 1) or
electrophilic aromatic substitution (path 2). After elimination
of a molecule of HI, both of the reaction pathways converge
again to intermediate B, which subsequently undergoes
reductive elimination of the ketone with simultaneous
regeneration of the Pd(0) catalyst. Unfortunately, the ex-
perimental results do not provide conclusive evidence
favoring either one of these mechanistic paths.
This novel palladium-catalyzed reaction provides a short,
straightforward route to a variety of substituted fluoren-9-
ones under mild reaction conditions and short reaction times.
Our success in extending this reaction to other biaryl systems
indicates its potential for the synthesis of a wide variety of
aromatic ketones
The fact that the cyclocarbonylative ring closure occurs
equally well onto both electron-rich and electron-deficient
aryl systems with no apparent change in the yields (compare
entries 2-5 in Table 1) raises an interesting mechanistic
question. Scheme 1 provides a possible mechanism for this
process. The first step involves oxidative addition of the aryl
halide to Pd(0), followed by CO insertion to produce the
acylpalladium intermediate A. There are two mechanistic
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this research and Kawaken
Fine Chemicals Co., Ltd. for donation of the palladium
catalysts.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds in Table
1. This material is free of charge via the Internet at
http://pubs.acs.org.
OL006585J
Scheme 1
(8) This starting material was prepared using the procedure of Huisgen,
R.; Rist, H. Justus Liebigs Ann. Chem. 1955, 594, 137.
(9) This aromatic iodide was prepared from 9-phenyl-10-(trimethysilyl)-
phenanthrene (Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org.
Chem. 1997, 62, 7536) by the iodination procedure of Miller, R. B.;
McGarvey, G. Synth. Commun. 1978, 8, 291.
(10) (a) Sprinzak, Y. J. Am. Chem. Soc. 1958, 80, 5449. (b) Horspool,
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Intermed. 1991, 15, 271.
(11) Wittig, G.; Hellwinkel, D. Chem. Ber. 1964, 97, 769.
(12) (a) Fu, J.; Zhao, B.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991,
56, 1683. (b) Harvey, R. G.; Abu-shqara, E.; Yang, C. J. Org. Chem. 1992,
57, 6313.
(13) This aryl iodide was prepared by the procedure of Larock, R. C.;
Hunter, J.; Roesch, K.; Huang, Q., work in progress.
(14) (a) Wawzonec, S.; Stowell, J. K.; Karll, R. E. J. Org. Chem. 1966,
31, 1004. (b) Dusemund, J.; Kroeger, E. Arch. Pharm. 1987, 320, 617.
(15) This starting material was prepared using the procedure of Larock,
R. C.; Harrison, L. W. J. Am. Chem. Soc. 1984, 106, 4218.
(16) Sauter, F.; Dzerovicz, A. Monatsh. Chem. 1969, 100, 913.
Org. Lett., Vol. 2, No. 23, 2000
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