Efficient synthesis of fluoren-9-ones by the palladium-catalyzed annulation of arynes by 2-haloarenecarboxaldehydes

Article abstract of DOI:10.1021/jo8009215

(Chemical Equation Presented) Fluoren-9-ones and derivatives are readily prepared in good yields by the annulation of in situ generated arynes by 2-haloarenecarboxaldehydes in the presence of a palladium catalyst.

Full text of DOI:10.1021/jo8009215

Efficient Synthesis of Fluoren-9-ones by the Palladium-Catalyzed
Annulation of Arynes by 2-Haloarenecarboxaldehydes
Jesse P. Waldo, Xiaoxia Zhang, Feng Shi, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
ReceiVed April 29, 2008
Fluoren-9-ones and derivatives are readily prepared in good yields by the annulation of in situ generated
arynes by 2-haloarenecarboxaldehydes in the presence of a palladium catalyst.
Introduction
Recent groundbreaking work in the area of metal-catalyzed
transformations of arynes, including the palladium-catalyzed
cyclotrimerization of benzynes to form triphenylenes,1 has
provided novel new ways to rapidly construct fused aromatic
polycycles. The metal-catalyzed cocyclization of arynes with
alkynes has also been investigated.2 In addition, metal-catalyzed
carbonylative cycloadditions of arynes3 and the cocyclotrimer-
ization of arynes with bicyclic alkenes4 and allenes5 have been
reported. More recently, our group and others have synthesized
fused polycyclic aromatics by palladium-catalyzed annulations
of arynes with aryl halides.6 We have also reported a palladium-
catalyzed, three-component, sequential intermolecular coupling
of aryl halides, alkynes, and arynes.7
The construction of heterocycles and carbocycles by the
palladium-catalyzed annulation of alkynes by functionally
substituted aryl halides has proven a powerful synthetic tool.8
Specifically, we have reported that 2-halobenzaldehydes can
react with internal alkynes in the presence of a palladium catalyst
to form substituted indenones in good yields.9Analogous to that
FIGURE 1.
work, we recently reported the synthesis of fluoren-9-ones by
the palladium-catalyzed annulation of in situ generated benzynes
by 2-haloarenecarboxaldehydes.10 This provides a convenient
synthesis of fluoren-9-ones, which are an important class of
carbocycle, because of their important role in pharmaceutical
applications,11 as photosensitizers,12 and their use as key
intermediates in organic synthesis.13 A number of fluoren-9-
one natural products, including dengibsin, dengibsinin, and
dendroflorin, have recently been reported to occur in the Asiatic
orchid Dendrobium gibsonii Lindley (Figure 1.).14 We now
report the full details of our work on the palladium-catalyzed
annulation of arynes by 2-haloarenecarboxaldehydes.
(8) For reviews, see: (a) Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
(b) Larock, R. C. Palladium-Catalyzed Annulation. In PerspectiVes in Organo-
palladium 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.
(9) Larock, R. C.; Doty, M. J.; Cacchi, S. J. Org. Chem. 1993, 58, 4579.
(10) Zhang, X.; Larock, R. C. Org. Lett. 2005, 7, 3973.
(11) (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.
(12) (a) Atsumi, T.; Murata, J.; Kamiyanagi, I.; Fujisawa, S.; Ueha, T. Arch.
Oral Biol. 1998, 43, 73. (b) Li, Y.-C.; Huang, F.-M.; Lee, S.-S.; Lin, R.-H.;
Chou, M.-Y.; Chang, Y.-C. J. Biomed. Mater. Res., Part B 2008, 84B, 58.
(13) (a) Koyama, H.; Kamikawa, T. Tetrahedron Lett. 1997, 38, 3973. (b)
Carney, J. R. J. Org. Chem. 1997, 62, 320.
(1) (a) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. 1998, 37, 2659. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L.
Org. Lett. 1999, 1, 1555. (c) Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E.; Castedo,
L. Org. Lett. 2000, 2, 1629.
(2) (a) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Am. Chem. Soc. 1999,
121, 5827. (b) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Synlett 2000, 1061.
(c) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org. Chem. 2000, 65, 6944.
(d) Pen˜a, D.; Pe´rez, D.; Guitia´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, 69,
8445.
(5) Hsieh, J.-C.; Rayabarapu, D. K.; Cheng, C.-H. Chem. Commun. 2004,
532.
(6) (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 15716.
(b) Jayanth, T. T.; Cheng, C.-H. Chem. Commun. 2006, 894. (c) Liu, Z.; Larock,
R. C. J. Org. Chem. 2007, 72, 223.
(7) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007, 119, 2587.
10.1021/jo8009215 CCC: $40.75
Published on Web 08/07/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6679–6685 6679

Waldo et al.
SCHEME 1
SCHEME 2
Results and Discussion
The synthesis of 10-iodophenanthrene-9-carbaldehyde (30)
was achieved by the iodocyclization of 3-(biphen-2-yl)prop-2-
yn-1-ol, followed by oxidation with MnO2 (eq 2).16
In our earlier study, it was found that the “optimal” conditions
for our palladium-catalyzed annulation of arynes by 2-haloare-
necarboxaldehydes involves stirring 0.3 mmol of the 2-iodo-
benzaldehyde (1), 1.5 mmol of the benzyne precursor 2-(trim-
ethylsilyl)phenyl triflate (2a), 1.5 mmol of CsF, 5 mol % of
Pd(dba)2, and 5 mol % of P(o-tolyl)3 ligand in 4 mL of 1:1
MeCN/toluene at 110 °C for 12 h. This affords the desired
fluoren-9-one (3) in a 75% yield (eq 1).
With a number of new o-iodoarenecarboxaldehydes in hand,
we examined the scope of the fluoren-9-one synthesis (Table
1). When 2-iodobenzaldehyde (1) and 2-bromobenzaldehyde (4)
were allowed to react with 2-(trimethylsilyl)phenyl trifluo-
romethanesulfonate (2a) under our optimized conditions, fluo-
ren-9-one (3) was isolated in good yields, although a 2-fold
increase in reaction time was required for the reaction of 4 to
reach completion (Table 1, compare entries 1 and 2). 5-Bromo-
2-iodobenzaldehyde (5) reacted selectively to afford the desired
2-bromofluoren-9-one (6) in good yield (Table 1, entry 3).
6-Fluoro-2-iodobenzaldehyde (7) reacted cleanly to provide
1-fluorofluoren-9-one (8) in an 82% yield (Table 1, entry 4).
The slight increase in the yield of 8 compared to the parent
system may be due to the electron-withdrawing nature of the
fluorine atom on the aromatic ring, which presumably facilitates
the oxidative addition of Pd(0) to the carbon-iodine bond of
7. In addition, the fluorine atom may increase the electrophilicity
of the aldehyde moiety, promoting the final cyclization step (see
the later mechanistic discussion). On the contrary, the reaction
of 2-iodo-4,5-methylenedioxybenzaldehyde (9) with triflate 2a
provided only a 50% yield of the desired fluoren-9-one 10 (Table
1, entry 5). This marked decrease in yield, as compared to the
parent system, may be due to the electron-rich aromatic ring.
Both 2-iodo-5,6-methylenedioxybenzaldehyde (11) and 2-bromo-
5,6-methylenedioxybenzaldehyde (13) provided the correspond-
ing fluoren-9-one 12. However, the aryl bromide gave a
significantly reduced yield (Table 1, compare entries 6 and 7).
The higher yield of 12 from 11, as opposed to that of 10 from
9, might be explained by the electron-withdrawing inductive
effect of the oxygen atoms of 11 being greater due to their
To determine the scope and limitations of this chemistry, a
number of new o-haloarenecarboxaldehydes were required.
However, many of the necessary starting materials were not
readily accessible from commercial sources. The synthesis of
o-iodonaphthalenecarboxaldehyde starting materials was achieved
by employing a useful variant of some of our previously
reported15 iodocyclization chemistry using appropriate benzylic-
substituted propargylic diols, followed by oxidation of the
resulting naphthalen-1-ylmethanols by MnO2 (Scheme 1). The
requisite diols are easily prepared by the reaction of the lithium
acetylide dianion of propargyl alcohol with the corresponding
2-arylacetaldehyde or 2-arylacetone in THF at 0 °C, followed
by quenching with a saturated solution of aqueous NH4Cl.
In addition to the o-halonaphthalenecarboxaldehydes de-
scribed above, we prepared 6-iodobenzothiophene-7-carboxal-
dehyde (28) by an analogous route starting from 2-(thiophen-
3-yl)acetaldehyde (Scheme 2). The iodocyclization of the
thiophene-containing diol occurred selectively at the 2-position
of the thiophene. The major side product appeared to arise by
simple dehydration to an enynol product that did not cyclize.
(14) (a) Talapatra, S. K.; Bose, S.; Mallik, A. K.; Talapatra, B. Tetrahedron
1985, 41, 2765. (b) Fan, C.; Wang, W.; Wang, Y.; Qin, G.; Zhao, W.
Phytochemistry 2001, 57, 1255. (c) Wu, X. Y.; Qin, G. W.; Fan, D. J.; Xu,
R. S. Phytochemistry 1994, 36, 477.
(15) We have reported the synthesis of naphthalenes by the electrophilic
cyclization of benzylic-substituted propargylic alcohols; see: Zhang, X.; Sarkar,
S.; Larock, R. C. J. Org. Chem. 2006, 71, 236.
(16) For the synthesis of iodine-containing fused polycyclic aromatics by
the electrophilic cyclization of 2-(1-alkynyl)biaryls, see: (a) Yao, T.; Campo,
M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677. (b) Yao, T.; Campo, M. A.;
Larock, R. C. J. Org. Chem. 2005, 70, 3511.
6680 J. Org. Chem. Vol. 73, No. 17, 2008

Efficient Synthesis of Fluoren-9-ones
TABLE 1. Synthesis of Fluoren-9-ones by the Palladium-Catalyzed Annulation of Arynes by o-Haloarenecarboxaldehydesa
J. Org. Chem. Vol. 73, No. 17, 2008 6681

Waldo et al.
TABLE 1. Continued
a Unless otherwise specified, all reactions were carried out using 0.3 mmol of the aldehyde, 1.5 mmol of the aryne precursor, 1.5 mmol of CsF, 5 mol
% of Pd(dba)2, and 5 mol % of P(o-tol)3 in 4 mL of 1:1 CH3CN/toluene at 110 °C for 12 h. b Isolated yield after column chromatography on silica gel.
c The reaction required 24 h to reach completion and the yield was determined by GC-MS. d The yield was determined by 1H NMR spectroscopy.
e The yield of the other isomer was 7% according to gas chromatographic analysis.
proximity to the aldehyde group, thus making the aldehyde more
electrophilic (Table 1, compare entries 5 and 6). When 2-iodo-
4,5-dimethoxybenzaldehde (14) was reacted with triflate 2, the
desired fluoren-9-one 15 was obtained in a 53% yield (Table 1,
entry 8). This result is in line with the reaction of triflate 2a
with aldehyde 9. 2-Iodo-3,4,5-trimethoxybenzaldehyde (16)
provided 2,3,4-trimethoxyfluoren-9-one (17) in only a modest
yield of 41% (Table 1, entry 9). The decrease in yield, compared
6682 J. Org. Chem. Vol. 73, No. 17, 2008

Efficient Synthesis of Fluoren-9-ones
with other aryl ethers, is presumably due to a steric effect of
the MeO group ortho to the iodine atom. Steric congestion
around the carbon-iodine bond may hinder oxidative addition
of palladium to the C-I bond.
In addition to benzaldehyde substrates, the annulation reaction
has also been applied to 2-iodonaphthalene-1-carboxaldehydes.
The annulation of triflate 2a by 1-iodonaphthalene-2-carboxal-
dehyde (18) provided fluorenone derivative 19 in a 48% yield
(Table 1, entry 10). A marked increase in the yield of fluorenone
was observed when 2-iodonaphthalene-1-carboxaldehyde (20)
was allowed to react with triflate 2a (Table 1, compare entries
10 and 11). The increase in yield of 21, compared to regioisomer
19, is apparently due to decreased steric crowding around the
carbon-iodine bond, resulting in a more facile oxidative
addition of the palladium moiety. Reactions of 2-iodo-4-
methylnaphthalene-1-carboxaldehyde (22) and 2-iodo-4-phe-
nylnaphthalene-1-carboxaldehyde (24) with triflate 2a proceeded
smoothly and provided the corresponding fluorenones 23 and
25, respectively, in good yields (Table 1, entries 12 and 13).
2-Iodo-3,7-dimethylnaphthalene-1-carboxaldehyde (26) afforded
the desired compound 27 (Table1, entry 14). However, the yield
suffered, presumably due to steric hindrance in the vicinity of
the carbon-iodine bond of 26. 6-Iodobenzothiophene-7-car-
boxaldehyde (28) gave the corresponding thiophene-containing
fluorenone 29 in a 52% yield (Table 1, entry 15). When
phenanthrene 30 was allowed to react with triflate 2a, the desired
fluoren-9-one derivative 31 was obtained in a 61% yield (Table
1, entry 16). Naphthalene 32 was employed to see if this
methodology could be extended to 6-membered rings, but
unfortunately, triphenylene was observed as the major product
of this reaction, along with the reduced starting material
naphthalene-1-carboxaldehyde (Table 1, entry 17). A double
annulation was attempted by using diiododialdehyde 33. Un-
fortunately, the latter reaction provided a complex reaction
mixture, and none of the desired product was observed (Table
1, entry 18). A similar result was obtained when the reaction
was performed using 0.3 mmol of diiododialdehyde 33, 3.0
mmol of 2-(trimethylsilyl)phenyl triflate (2a), 3.0 mmol of CsF,
10 mol % of Pd(dba)2, and 10 mol % of P(o-tolyl)3 ligand in 8
mL of 1:1 CH3CN/toluene.
FIGURE 2.
regioisomer 36 over the other regioisomer can be attributed to
coordination of the methoxy group to the palladium in the
biarylpalladium intermediate 37 (Figure 2.).18 This regiochem-
istry also places the palladium on the inductively more
thermodynamically stable carbanionic carbon. Intermediate 37
is also the product one would expect from the aryl moiety of
the initial ArPdX adding to the most sterically accessible carbon
of the aryne. As observed in the carbopalladation of alkynes,8
Pd presumably prefers to add to the more hindered end of the
aryne, which is ortho to the methoxy group.
In addition to benzyne precursors, we have also examined
the effect of naphthyne2c precursor 2e on the annulation process.
We were pleased to find that one major regioisomer was formed
in a 50% yield from the reaction of naphthyne precursor 2e
with aldehyde 1 (Table 1, entry 23). This result is in agreement
with the suggestion that the aryl moiety of the initial ArPdX
adds to the more sterically exposed carbon of the aryne and
that Pd prefers to add to the more hindered C1 of naphthyne.
In addition to the substrates illustrated in Table 1, we have
also attempted to employ substituted 2-haloacrylaldehydes in
this palladium-catalyzed annulation reaction to synthesize
indenones.9 Unfortunately, reactions with 2-iodocyclohex-1-
enecarboxaldehyde and (Z)-3-iodo-3-phenylacrylaldehyde pro-
duced complex mixtures, and only poor yields of indenones were
achieved. Also, our attempts employing pyridine substrates, such
as 2-bromopyridine-3-carboxaldehyde, 4-bromopyridine-3-car-
boxaldehyde, and 2-fluoro-4-iodopyridine-3-carboxaldehyde, as
starting materials did not lead to any formation of the desired
fluoren-9-ones. This result is not surprising, since pyridine itself
is known to react with benzynes to give novel polymers with
o-phenylene and 2,3-dihydropyridine units in the main chain.19
Based on previously reported palladium-catalyzed annulations
of alkynes,8 particularly the synthesis of indenones by the
palladium-catalyzed coupling of internal alkynes with 2-ha-
loarenecarboxaldehydes,9 we propose that this fluorenone
synthesis proceeds through one or more of several possible
pathways shown in Scheme 3. One possible pathway proceeds
by the oxidative cyclization of Pd(0) with aryne A generated
from the silyl triflate to form palladacycle B (path a).20 Oxidative
addition of 1 to this palladacycle forms Pd(IV) intermediate C.
Reductive elimination gives rise to arylpalladium(II) intermedi-
ate E. However, we cannot rule out the possibility that Pd(0)
inserts directly into the C-I bond of 1 to form intermediate D,
which then undergoes carbopalladation of the aryne A to give
rise to intermediate E (path b). This pathway has been suggested
by experiments in our earlier work on the synthesis of fused
polycyclic aromatics by the palladium-catalyzed annulation of
In addition to the above reactions, which examined only the
use of the benzyne precursor triflate 2a as an annulation partner,
other aryne precursors have been examined in our methodology.
4,5-Dimethoxybenzyne precursor 2b was examined under our
annulation conditions and gave the expected 2,3-dimethoxy-
fluoren-9-one (15), although the yield was poor (Table 1, entry
19). The low yield in this latter reaction may be attributed to
the slower rate of generation of 4,5-dimethoxybenzyne from
2b, compared with the generation of benzyne from 2a, as has
been suggested by earlier work in our group.6a,c However, when
dimethylbenzyne precursor 2c was allowed to react with
2-iodobenzaldehydes 1 and 7 under our optimized conditions,
it provided the corresponding fluoren-9-one products 34 and
35, respectively, in good yields (Table 1, entries 20 and 21).
The reaction of 3-methoxybenzyne, generated from triflate 2d,
exibited good regioselectivity (Table 1, entry 22). The reaction
gave rise to both isomeric methoxyfluoren-9-ones in ap-
proximately a 9:1 ratio as determined by gas chromatographic
analysis. 1-Methoxyfluoren-9-one (36) was the major product
(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. 1997, 70, 3117.
(19) Ihara, E.; Kurokawa, A.; Koda, T.; Muraki, T.; Itoh, T.; Inoue, K.
Macromolecules 2005, 38, 2167.
(20) (a) Matsubara, T. Organometallics 2003, 22, 4297. (b) Yoshida, H.;
Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 5052. (c)
Retbøll, M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M. A.; Wenger,
E. J. Am. Chem. Soc. 2002, 124, 8348.
1
as determined by comparison of its H and 13C NMR spectra
with those of the known compound.17 The preference for
(17) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
J. Org. Chem. Vol. 73, No. 17, 2008 6683

Waldo et al.
SCHEME 3
SCHEME 4
arynes by aryl halides.6a,c Arylpalladium intermediate E can then
add the carbon-palladium bond across the aldehyde to produce
a palladium(II) alkoxide F,21 which can undergo ꢀ-hydride
elimination to produce the fluorenone product (path d). Alter-
natively, intermediate E can undergo oxidative addition of the
aldehyde C-H bond to form palladium(IV) intermediate G,22
followed by elimination of HI, and regeneration of the Pd(0)
catalyst by further reductive elimination to the fluoren-9-one
(path c). A similar mechanism involving oxidative addition of
the aldehyde to an organopalladium(II) intermediate has been
proposed for the palladium-catalyzed reactions of o-bromoben-
zaldehyde with methyl acrylate.23 However, there does not
appear to be any particular precedent favoring any of these
pathways.
acetylenic fluoren-9-one 39 and 2-(3,4,5-trimethoxyphenyl)fluo-
ren-9-one (38) in high yields.
Conclusions
In summary, we have developed a novel synthesis of fluoren-
9-ones, which involves the palladium-catalyzed annulation
reaction of arynes by 2-haloarenecarboxaldehydes. This method
provides an efficient synthesis of substituted fluoren-9-ones from
readily available starting materials. In addition, this methodology
provides a route to fluoren-9-ones that avoids the use of harsh
oxidizing agents and strong mineral acids.26 Our process has
been shown to be tolerant of benzaldehydes containing multiple
halogens. The resulting halogenated 2-bromofluoren-9-one may
be further elaborated by palladium-catalyzed processes, such
as Sonogashira and Suzuki-Miyaura cross-coupling reactions.
Furthermore, this methodology has been extended to naphthalene
derivatives of fluoren-9-ones and has also been shown to work
in the presence of a heterocycle.
In order to demonstrate the utility of 2-bromofluoren-9-one
(6) generated by our methodology, we have elaborated the
carbon-bromine bond by palladium-catalyzed, microwave-
assisted Sonogashira24 and Suzuki-Miyaura25 cross-coupling
reactions (Scheme 4). These reactions proceeded cleanly to give
(21) (a) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999,
40, 4089. (b) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc.
1999, 121, 3545.
(22) Wei, L.; Wei, L.; Pan, W.; Wu, M. Synlett 2004, 1497.
(23) Meegalla, S. K.; Taylor, N. J.; Rodrigo, R. J. Org. Chem. 1992, 57,
2422.
(24) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J. Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chter 5, pp
203-229. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467. (c) Erdelyi, M.; Gogoll, A. J. Org. Chem. 2001, 66, 4165.
(25) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki, A.
J. Organomet. Chem. 1999, 576, 147, and references therein.
Experimental Section
General Procedure for the Synthesis of Alkynediols. Propargyl
alcohol (16.6 mmol, 930 mg, 0.98 mL) was dissolved in THF (100
mL) and cooled to 0 °C. Under an atmosphere of argon, n-BuLi
(2.5 M in hexanes, 33.2 mmol, 13.3 mL) was added slowly and
(26) (a) Greenlee, M. L.; DiNinno, F. P.; Cama, L. D.; Heck, J. V. (Merck
and Co., Inc., USA). U.S. Patent 5,034,384, 1991. (b) Yu, Z.; Velasco, D.
Tetrahedron Lett. 1999, 40, 3229.
6684 J. Org. Chem. Vol. 73, No. 17, 2008

Efficient Synthesis of Fluoren-9-ones
the resulting solution allowed to stir at 0 °C for 1 h. A solution of
the appropriate arylacetaldehyde or arylacetone (8.3 mmol) in THF
(10 mL) was added slowly, and the solution was allowed to warm
to room temperature over a period of 12 h. The solution was
quenched with a satd aq NH4Cl solution and extracted with EtOAc
(3 × 20 mL). The organic layers were combined, dried (MgSO4),
and concentrated under reduced pressure. The crude products were
isolated by flash column chromatography on silica gel (2:1 hexanes/
EtOAc).
5-Phenylpent-2-yne-1,4-diol. The indicated compound was
isolated as a pale yellow oil: 1H NMR (CDCl3, 400 MHz) δ
2.94-2.95 (d, J ) 6.6 Hz, 2H), 3.66 (br s, 2H), 4.16 (s, 2H),
4.52-4.55 (t, J ) 6.5 Hz, 1H), 7.21-7.30 (m, 5H); 13C NMR
(CDCl3) δ 44.0, 50.7, 63.2, 84.0, 86.1, 127.0, 128.5, 129.8, 136.8;
HRMS calcd for C11H12O2 176.0837, found 176.0840.
General Procedure for the Electrophilic Cyclization of
Alkynediols by ICl, Followed by Oxidation with MnO2. A 1.2
mmol portion of the alkynediol, 2 equiv of NaHCO3, and 8 mL
of CH3CN were placed in a vial and stirred for 1 min at room
temperature. Two equivalents of ICl in 2 mL of CH3CN was
added dropwise to the vial. The reaction mixture was stirred at
room temperature for 10 min. The reaction mixture was then
diluted with 25 mL of EtOAc and washed with 20 mL of satd
aq Na2S2O3. The organic layer was separated, and the aqueous
layer was extracted with another 25 mL of EtOAc. The combined
organic layers were dried over MgSO4 and filtered. The solvent
was evaporated under reduced pressure and the crude residue
was filtered through a plug of silica gel rinsed with 25% EtOAc
in hexanes. The solvent was evaporated under reduced pressure
and the residue was dissolved in CHCl3 (50 mL). The solution
was cooled to 0 °C and MnO2 (6.0 equiv based on the alkynediol)
was added. The solution was warmed to room temperature and
stirred for 18 h. The suspension was filtered through a plug of
celite and the solvent evaporated under reduced pressure. The
residue was purified by flash column chromatography on silica
gel using a gradient solvent system (40:1 hexanes/EtOAc to 9:1
hexanes/EtOAc).
was evaporated under reduced pressure, and the crude residue
was filtered through a plug of silica gel and rinsed with 25%
EtOAc in hexanes. The solvent was evaporated under reduced
pressure, and the residue was dissolved in CHCl3 (50 mL). The
solution was cooled to 0 °C, and MnO2 (6.0 equiv) was added.
The solution was warmed to room temperature and stirred for
18 h. The suspension was filtered through a plug of Celite and
the solvent evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel using a gradient
solvent system (40:1 hexanes/EtOAc to 9:1 hexanes/EtOAc) to
afford 243 mg (76%) of the product as a yellow oil that solidified
1
upon standing: mp 80-82 °C; H NMR (CDCl3, 400 MHz) δ
7.34-7.41 (m, 5H) 7.43-7.47 (m, 2H) 7.50-7.54 (dt, J ) 1.5,
7.5 Hz, 1H), 9.26 (s, 1H); 13C NMR (CDCl3) δ 106.5, 127.8,
128.1, 128.6, 128.8, 128.9, 130.7, 130.8, 139.6, 140.2, 150.4,
185.9; HRMS calcd for C15H9IO 331.9698, found 331.9700.
General Procedure for the Palladium-Catalyzed Synthesis
of Fluoren-9-ones. The 2-iodoarenecarboxaldehyde (0.30 mmol),
the 2-(trimethylsilyl)aryl triflate (1.50 mmol), CsF (1.50 mmol),
Pd(dba)2 (0.015 mmol), P(o-tolyl)3 (0.015 mmol), 2 mL of toluene,
and 2 mL of MeCN were placed in a 4 dram vial, and the vial was
sealed. The reaction mixture was stirred first at room temperature
for 1 min and then heated to 110 °C for 12 h. The mixture was
allowed to cool to room temperature (CAUTION: OPENING THE
VIAL AT HIGH TEMPERATURE CAN BE DANGEROUS!),
diluted with diethyl ether, washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The product was
isolated by flash chromatography on silica gel using hexanes/EtOAc
as the eluent.
1-Fluoro-9H-fluoren-9-one (8). The indicated compound was
1
obtained as a yellow solid in an 82% yield: mp 117-119 °C; H
NMR (CDCl3, 300 MHz) δ 6.89-6.95 (t, J ) 8.4 Hz, 1H),
7.29-7.35 (m, 2H), 7.43-7.53 (m, 3H), 7.65-7.67 (d, J ) 7.5
Hz, 1H); 13C NMR (CDCl3) δ 116.61, 116.65, 117.59, 117.87,
120.12, 120.29, 120.88, 124.69, 129.90, 134.19, 134.86, 137.23,
137.34, 143.59, 143.63, 146.56, 146.61, 157.79, 161.29, 190.36
(extra peaks due to F splitting); HRMS calcd for C13H7FO 198.0481,
found 198.0485.
2-Iodonaphthalene-1-carboxaldehyde (20). The indicated com-
1
pound was isolated as a yellow solid: mp 77-79 °C; H NMR
Acknowledgment. We gratefully acknowledge the National
Institute of General Medical Sciences (R01 GM070620 and R01
GM079593), the National Institutes of Health Kansas University
Center of Excellence for Chemical Methodologies and Library
Development (P50 GM069663), and the National Science Founda-
tion for partial support of this research and Johnson Matthey, Inc.
and Kawaken Fine Chemicals Co., Ltd. for donations of palladium
catalysts. We also thank Mr. Donald Rogness at Iowa State
University for preparation of the naphthyne precursor.
(CDCl3, 400 MHz) δ 7.55-7.59 (dt, J ) 1.1, 7.5 Hz, 1H),
7.62-7.67 (m, 2H), 7.80-7.82 (d, J ) 8.1 Hz, 1H), 7.94-7.96 (d,
J ) 8.7 Hz, 1H), 9.01-9.03 (d, J ) 8.7 Hz, 1H), 10.39 (s, 1H);
13C NMR (CDCl3) δ 105.6, 124.2, 127.5, 128.5, 129.4, 130.6, 131.7,
133.8, 135.1, 137.1, 199.0; HRMS calcd for C11H7IO 281.9542,
found 281.9546.
Procedure for the Cyclization of 3-(Biphenyl-2-yl)prop-2-yn-1-
ol by ICl and Oxidation by MnO2 To Form 10-Iodophenanthrene-
9-carbaldehyde (30). To a solution of 3-(biphenyl-2-yl)prop-2-yn-
1-ol (0.96 mmol) in CH2Cl2 (10 mL) under N2 was added ICl (1.2
equiv) in CH2Cl2 (2 mL) at -78 °C. The reaction mixture was
stirred at -78 °C for 0.5 h. The reaction mixture was then diluted
with 25 mL of EtOAc and washed with 20 mL of satd aq
Na2S2O3. The organic layer was separated, and the aqueous layer
was extracted with another 25 mL of EtOAc. The combined
organic layers were dried over MgSO4 and filtered. The solvent
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.
JO8009215
J. Org. Chem. Vol. 73, No. 17, 2008 6685