Palladium-catalyzed annulation of arynes by 2-halobenzaldehydes: Synthesis of fluoren-9-ones

Article abstract of DOI:10.1021/ol0514597

(Chemical Equation Presented) Arynes, generated in situ from 2-(trimethylsilyl)aryl triflates and CsF, undergo annulation by o-haloarenecarboxaldehydes in the presence of a Pd catalyst, providing a useful new method for the synthesis of fluoren-9-ones in good yields.

Full text of DOI:10.1021/ol0514597

ORGANIC
LETTERS
2
005
Vol. 7, No. 18
973-3976
Palladium-Catalyzed Annulation of
Arynes by 2-Halobenzaldehydes:
Synthesis of Fluoren-9-ones
3
Xiaoxia Zhang and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received June 22, 2005
ABSTRACT
Arynes, generated in situ from 2-(trimethylsilyl)aryl triflates and CsF, undergo annulation by o-haloarenecarboxaldehydes in the presence of
a Pd catalyst, providing a useful new method for the synthesis of fluoren-9-ones in good yields.
The transition-metal-catalyzed transformations of arynes have
recently received considerable attention. Pioneering work in
The palladium-catalyzed annulation of alkynes by func-
tionally substituted aryl halides has proven to be a very
efficient method for the construction of a wide variety of
1
this area involved the cyclotrimerization of arynes and the
2
10
cocyclization of arynes with alkynes. More recently, metal-
heterocycles and carbocycles. However, similar carbopal-
3
catalyzed carbonylative cycloadditions of arynes and the
ladation reactions of arynes are unprecedented to the best
4
11
cocyclotrimerization of arynes with bicyclic alkenes and
of our knowledge. Our continuing interest in palladium-
5
allenes have been reported. Great progress has also been
catalyzed annulation reactions prompted us to explore such
possibilities. Herein, we report the first example of the
palladium-catalyzed annulation of arynes by o-halobenzal-
made in the addition of element-element σ-bonds to arynes,
6
7
8
including Si-Si, C-Sn, and Sn-Sn bonds. There are also
a few examples of the addition of π-allylpalladium com-
pounds to arynes.9
1
2
dehydes. This provides a convenient synthesis of fluoren-
-ones, which are of considerable interest because of their
9
1
3
important biomedical applications and their use as key
synthetic intermediates.
(1) (a) Pe n˜ a, D.; Escudero, S.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. Angew.
1
4
Chem., Int. Ed. 1998, 37, 2659. (b) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo,
L. Org. Lett. 1999, 1, 1555. (c) Pe n˜ a, D.; Cobas, A.; P e´ rez, D.; Guiti a´ n, E.;
Castedo, L. Org. Lett. 2000, 2, 1629.
(
2) (a) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. J. Am. Chem. Soc.
(9) (a) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 729. (b) Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto,
Y. J. Am. Chem. Soc. 2000, 123, 7280. (c) Jeganmohan, M.; Cheng, C.-H.
Org. Lett. 2004, 6, 2821. (d) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-
H. Org. Lett. 2005, 7, 2921.
(10) For reviews, see: (a) Larock, R. C. 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; pp 111-124. (c) Larock, R. C. Pure
Appl. Chem. 1999, 71, 1435.
1
2
2
999, 121, 5827. (b) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. Synlett
000, 1061. (c) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. J. Org. Chem.
000, 65, 6944. (d) Pe n˜ a, D.; P e´ rez, D.; Guiti a´ n, E.; Castedo, L. Eur. J.
Org. Chem. 2003, 1238. (e) Sato, Y.; Tamura, T.; Mori, M. Angew. Chem.,
Int. Ed. 2004, 43, 2436.
(
3) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J.
Am. Chem. Soc. 2001, 123, 12686.
4) Jayanth, T. T.; Jeganmohan, M.; Cheng, C.-H. J. Org. Chem. 2004,
9, 8445.
(
6
(
32.
5) Hsieh, J.-C.; Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2004,
(11) Our own group has reported the synthesis of carbazoles and
dibenzofurans by the cross-coupling of o-iodoanilines and o-iodophenols
with arynes, followed by palladium-catalyzed cyclization. However, this
process does not involve the carbopalladation of arynes. See: Liu, Z.;
Larock, R. C. Org. Lett. 2004, 6, 3739.
(12) For the palladium-catalyzed annulation of internal alkynes by
o-halobenzaldehydes, see: Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org.
Chem. 1993, 58, 4579.
5
(
6) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am.
Chem. Soc. 2003, 125, 6638.
7) Yoshida, H.; Honda, Y.; Shirakawa, E.; Hiyama, T. Chem. Commun.
001, 1880.
8) Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem., Int.
Ed. 2004, 43, 5052.
(
2
(
1
0.1021/ol0514597 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/04/2005

Table 1. Synthesis of Fluoren-9-ones by the Palladium-Catalyzed Annulation of Silylaryl Triflates by o-Haloarenecarboxaldehydesa
a
All reactions were run under the following conditions unless otherwise specified: 0.30 mmol of o-halobenzaldehyde, 5 equiv of silylaryl triflate, 5 equiv
b
of CsF, 5% of Pd(dba)2, and 5% of P(o-tolyl)3 in 4 mL of 1:1 MeCN/toluene were heated at 110 °C for 12 h. This reaction needed 24 h to reach completion,
and the yield was determined by GC-MS. Yield of the other isomer was 7% according to gas chromatographic analysis.
c
The high reactivity15 and short lifetime of benzyne and
other arynes suggest that their use as a component of a
catalytic reaction might be difficult. Therefore, our prelimi-
nary efforts focused on the optimization of reaction condi-
tions for the reaction of 2-iodobenzaldehyde (1) with silylaryl
triflate 2, which we have observed to afford fluoren-9-one
3
5% P(o-tolyl) as the catalyst in 4 mL of MeCN at 70 °C.
The desired product 3 was obtained in a 36% yield. The
yield was improved to 51% when using 2 mL of toluene
and 2 mL of MeCN as the solvent. Other solvents such as
THF, DMF, and toluene alone all gave poor yields (0-24%).
The choice of base was also crucial for the success of the
(3) (eq 1).
3
reaction. Replacement of CsF with KF or utilizing NEt or
(
13) (a) Tierney, M. T.; Grinstaff, M. W. J. Org. Chem. 2000, 65, 5355.
(
b) Han, Y.; Bisello, A.; Nakamoto, C.; Rosenblatt, M.; Chorev, M. J. Pept.
Res. 2000, 55, 230. (c) 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. (d) 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. (e) Jones, W. D.; Ciske, F. L.; Dinerstein,
R. J.; Diekema, K. A. U.S. Patent 6,004, 959, 1999.
Compound 1 (0.30 mmol) was initially treated with 3 equiv
of silylaryl triflate 2 plus 3 equiv of CsF, a combination
(14) (a) Koyama, H.; Kamikawa, T. Tetrahedron Lett. 1997, 38, 3973.
b) Carney, J. R. J. Org. Chem. 1997, 62, 320.
(
(15) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.
16
known to generate benzyne, along with 5% Pd(OAc)
2
and
(16) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
3974
Org. Lett., Vol. 7, No. 18, 2005

Cs
2
CO
3
as a base together with CsF greatly decreased the
group to Pd.3,18 Intermediate 19 is also the product one would
expect from the more anionic aryl moiety of ArPdX adding
to the more remote carbon of the aryne. In addition, as
observed in the carbopalladation of alkynes, Pd may prefer
to add to the more hindered end of the aryne, which is ortho
to the methoxy group.
yield. Using pyridine, none of the desired product was
generated at all. Control experiments revealed that in the
absence of the palladium catalyst or the CsF, no fluorenone
10
3
was obtained. Variation of the Pd catalyst and ligands had
a minimal effect. For example, 5% Pd(dba) with 5% P(o-
tolyl) improved the yield to 59%. Similar yields (50-57%)
were obtained using Pd(dba) plus dppf or 2-(dicyclohexyl-
2
3
2
phosphino)biphenyl. The ligand dppe provided only a 38%
yield of 3. The yield was dramatically improved to 75% when
5
1
equiv of silylaryl triflate 2 and 5 equiv CsF were used at
10 °C. Therefore, the following reaction conditions were
chosen as our “optimal” conditions: 0.30 mmol of aryl
halide, 5 equiv of the silylaryl triflate, 5 equiv of CsF, 5%
On the basis of the known chemistry of organopalladium
compounds and alkynes, the following mechanism is pro-
posed (Scheme 1; ligands are omitted for simplicity). First,
Pd(dba)
10 °C for 12 h.
This palladium-catalyzed annulation reaction was success-
2 3
, 5% P(o-tolyl) in 4 mL of 1:1 toluene/MeCN at
1
fully extended to other o-haloarenecarboxaldehydes and
substituted arynes (Table 1). When o-bromobenzaldehyde
was employed as the aryl halide, a yield comparable to that
of o-iodobenzaldehyde was obtained, although a much longer
reaction time was required (compare entries 1 and 2, Table
Scheme 1
1). The addition of a fluorine substituent on the aromatic
ring of the aldehyde improved the yield to 82% (entry 3).
This could be because the electron-withdrawing fluorine
facilitates oxidative addition of the aryl iodide to the
palladium and at the same time increases the electrophilicity
of the carbonyl group (see the later mechanistic discussion).
On the other hand, the reaction of 2-iodo-4,5-methylene-
dioxybenzaldehyde (7) with triflate 2 generated fluorene-9-
one derivative 8 in only a 56% yield (entry 4). One might
be tempted to attribute this to the electron-rich nature of the
aromatic ring. The corresponding 2-bromobenzaldehyde
afforded an even lower yield. However, electron-rich 2-iodo-
5
,6-methylenedioxybenzaldehyde (9) reacts smoothly with
triflate 2 to provide the desired product 10 in a 72% yield
entry 5). Even annulation with the corresponding aryl
bromide 11 proceeded without problems in a moderate yield
entry 6). The reaction was also successfully applied to
naphthaldehyde 12 (entry 7). The slightly lower yield here
might be due to the fact that the iodide is located on the
sterically hindered 1 position of the naphthalene, thereby
slowing the oxidation-addition to Pd and/or hindering aryne
annulation.
(
the aryne generated from the triflate coordinates with Pd(0),
affording palladacycle A. Oxidative addition of the aryl
iodide to A generates arylpalladium(IV) complex B. Reduc-
tive elimination affords a new arylpalladium intermediate
(
19
C. Intermediate C can add to the carbonyl group and
subsequently undergo â-hydride elimination (path a), or the
20
aldehyde C-H bond may oxidatively add to the palladium
In addition to 2, other substituted aryne precursors have
also been successfully exploited in this process. Thus, triflate
4 with two methyl groups on the phenyl ring furnished
products 15 and 16 in 71 and 73% yields, respectively
entries 8 and 9). Reaction with 3-methoxybenzyne (from
to produce an organopalladium(IV) intermediate E, which
subsequently undergoes rapid reductive elimination to pro-
vide the desired product and regenerate the Pd(0) catalyst
(path b). The exact pathway is unclear.
The involvement of an aryne in this catalytic reaction is
strongly supported by the results of the reaction between 1
and 20, which affords a 71% yield of a mixture of two
regioisomeric products 21 and 22 in a nearly 1:1 ratio as
1
(
triflate 17) showed good regioselectivity, affording the two
possible isomeric fluoren-9-ones in a 9:1 ratio as determined
by GC-MS analysis. Compound 18 is the major product as
1
13
determined by comparison of its H and C NMR spectra
with those of the known compound.17 Fluoren-9-one 18 is
apparently formed by preferential formation of intermediate
(18) (a) Takeuchi, R.; Yasue, H. J. Org. Chem. 1993, 58, 5386. (b)
Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn.
1
1
997, 70, 3117.
1
9, which may be favored due to coordination of the methoxy
(19) (a) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett.
999, 40, 4089. (b) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am.
Chem. Soc. 1999, 121, 3545.
(20) Wei, L.; Wei, L.; Pan, W.; Wu, M. Synlett 2004, 1497.
(17) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
Org. Lett., Vol. 7, No. 18, 2005
3975

1
determined by GC-MS and H NMR spectroscopic analysis
(
of substituted fluoren-9-ones from readily available starting
materials. Extension of this method to the synthesis of other
biological interesting heterocycles and carbocycles and the
exploration of similar protocols with other functionally
substituted haloarenes and arynes are underway.
Scheme 2). This observation indicates that the aryl group
Scheme 2
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, and the National Institute of
General Medical Sciences (GM 070620) for partial support
of this research and Kawaken Fine Chemicals Co., Ltd., and
Johnson Matthey, Inc., for donating the palladium acetate.
of the starting aryl halide adds about equally to the two
carbons originally attached to the silyl and OTf groups, in
agreement with the formation of an aryne from 20 prior to
reaction with the aldehyde 1.
In conclusion, we have developed a new palladium-
catalyzed annulation reaction of arynes by 2-haloarenecar-
boxaldehydes. This method provides an efficient synthesis
Supporting Information Available: General experimen-
tal procedures and spectral data for all of the starting
materials and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0514597
3976
Org. Lett., Vol. 7, No. 18, 2005