Palladium-catalyzed one-pot Suzuki coupling followed by arylpalladium addition to aldehyde: A convenient route to fluoren-9-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.08.062

Various fluoren-9-one derivatives were prepared efficiently by a one-pot reaction involving sequential Suzuki coupling of 2-bromophenyl boronic acid with 2-bromocarboxaldehyde followed by intramolecular arylpalladium addition to aldehyde.

Full text of DOI:10.1016/j.tetlet.2010.08.062

Tetrahedron Letters 51 (2010) 5604–5608
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed one-pot Suzuki coupling followed by arylpalladium
addition to aldehyde: a convenient route to fluoren-9-one derivatives
⇑
Sunanda Paul, Shubhankar Samanta, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various fluoren-9-one derivatives were prepared efficiently by a one-pot reaction involving sequential
Suzuki coupling of 2-bromophenyl boronic acid with 2-bromocarboxaldehyde followed by intramolecu-
lar arylpalladium addition to aldehyde.
Received 3 June 2010
Revised 17 August 2010
Accepted 18 August 2010
Available online 21 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluoren-9-one
Suzuki coupling
2-Bromophenyl boronic acid
Palladium catalyst
2-Bromocarboxaldehyde
The importance of fluoren-9-one, found in many biologically ac-
tive products, has been emphasized in organic chemistry. It con-
sists of essential structural backbone of various pharmaceuticals.1
Also number of natural products have been found containing fluo-
ren-9-one as the core structure. Examples of such natural products
include dengibsin, dengibsinin, dendroflorin, and kinobscurinone
showing a range of biological activities.2 Utility of fluoren-9-one
derivatives as photosensitizers in organic photoconductor devices
and their electrical and optical properties are also important.3
Therefore methodologies for the preparation of fluoren-9-one moi-
ety have attracted much attention from both academia and
industry.
Several methods for the preparation of fluoren-9-ones have
been developed among which the useful syntheses include Fri-
edel–Crafts ring closure of biarylcarboxylic acid and its deriva-
tives,4 remote aromatic metalation,5 oxidation of fluorenes,6
intramolecular Diels–Alder reaction of conjugated enyne or diaryl-
acetylene systems,7 ring contraction,8 etc.
Over the past decades Pd-catalyzed cross-coupling reactions
have become powerful tools for C–C bond formation to synthesize
a wide variety of organic compounds ranging from small molecules
to macromolecules. There are some synthetic protocols available
involving Pd-catalyzed coupling reactions leading to fluoren-9-
one moiety such as Pd-catalyzed cyclization of o-iodobenzophe-
none,9 cyclocarbonylation of o-halobiaryls,10 arylation followed
by oxidative Heck cyclization of aromatic aldoxime ether11 have
been reported. Larock and co-workers have synthesized fluoren-
9-one starting from 2-haloarenecarboxaldehyde via Pd-catalyzed
annulation of arynes.12 Our continued efforts in palladium-cata-
lyzed cyclization reactions on substrates derived from b-bromovi-
nyl aldehydes to develop the carbocycles and heterocycles13 have
driven us to develop a facile and efficient Pd-catalyzed synthesis
of functionalized fluoren-9-one derivatives starting from various
2-bromocarboxaldehydes along with 2-bromophenyl boronic acid
with two distinct sequential steps, Suzuki coupling followed by
arylpalladium addition to aldehyde, in one-pot.
We initially focused on the reaction between commercially
available 2-bromobenzaldehyde (1a) and 2-bromophenyl boronic
acid (2) for the preparation of fluoren-9-one (4a). Toward this we
carried out Suzuki coupling14 between 1a and 2 in presence of
Pd(PPh3)4 as catalyst, Et3N as base in DMF at 90 °C for 2 h where
the 20-bromobiphenyl-2-carbaldehyde (3) was obtained as the only
isolable product in good yield. It was expected to undergo the
intramolecular arylpalladation12,15 to aldehyde on subjecting to
Pd(0)-catalytic condition to construct the fluoren-9-one (4a). Thus
when this intermediate 3 was heated at somewhat higher temper-
ature (120 °C) in presence of Pd(OAc)2 as catalyst, Na2CO3 as base,
PPh3 as ligand in DMF for 13–14 h, it gave fluoren-9-one (4a)
accordingly (Scheme 1). We then envisioned that these two steps
can be carried out sequentially using one catalytic system in one-
pot without isolating the intermediate.
With this idea in mind, we carried out a survey of Pd-catalysts,
bases, solvents, and temperature to get the optimal condition for
the preparation of fluoren-9-one in one-pot (summarized in
Table 1). Initiallywe performed the reaction in presence of Pd(PPh3)4
⇑
Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.062

S. Paul et al. / Tetrahedron Letters 51 (2010) 5604–5608
5605
O
CHO
Br
CHO
Br
Pd(PPh3)4
Pd(OAc)2, PPh3
Br
+
Et3N, DMF
90-95 oC, 2h
82%
Na2CO3, DMF
(HO)2B
120 oC, 15 h, 75%
2
4a
1a
3
Pd(0)
Scheme 1. Synthesis of fluoren-9-one.
Table 1
Optimization studiesa
O
(HO)2B
catalyst, base
ligand, solvent
Br
+
+
Br
CHO
Br
CHO
4a
1a
2
3
Entry
Catalyst
Ligand
Base
Solvent
Temp (°C)
Yield%c
3
4a
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
—
—
—
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
—
Et3N
DMF
DMF
DMA
DMF
DMF
DMF
DMF
Tolueneb
DMF
DMF
120
120
130
100
120
120
120
110
120
120
79
78
73
67
10
10
—
50
50
<5
Tr
Tr
NaOAc
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
NaOAc
NaOAc
Et3N
<10
15
65
68
80
20
30
75
10
NaOAc
a
Reagents and conditions: o-bromobenzaldehyde (1 mmol), 2-bromophenyl boronic acid (1.2 mmol), catalyst (10 mol %), base (4 mmol),
ligand (0.5 mmol), and solvent (6 mL) at the indicated temperature for 15–16 h under N2.
b
Reaction was run in a two-necked round-bottomed flask with a reflux condenser.
Yields refer to the isolated yield after purification. Tr = traces.
c
as catalyst, Et3N as the base in dry DMF under N2 at 120 °C for 16 h
where the intermediate 20-bromobiphenyl-2-carbaldehyde (3) was
obtained in 79% yield accompanied by the traces amount of desired
fluoren-9-one (4a) (Table 1, entry 1). Changing the bases and sol-
vents with Pd(PPh3)4 did not effect this transformation appreciably
(entries 2, 3). On carrying out the reaction in presence Pd(OAc)2,
PPh3, Na2CO3 in DMF at 120 °C, 4a was formed in 65% yield at
120 °C (entry 5). Using NaOAc as a base improved the yield of 4a
to 80% (entry 7). However using toluene as a solvent gave poor yield
(20%) (entry 8). Therefore after a thorough screening with different
combination of catalyst, base, solvent, and temperature, the ‘opti-
mal’ condition was found when the substrates 1a (1 mmol) and 2
(1.2 mmol) were heated in presence of Pd(OAc)2 (10 mol %), PPh3
(0.5 mmol), NaOAc (4 mmol) in DMF (6 mL) at 120 °C for 15–16 h
under N2.16 Performing the reaction with Pd(OAc)2 less than
10 mol % under the same reaction condition leads to decrease in
yield of fluoren-9-one. With 5 mol % Pd(OAc)2 only 30% fluoren-9-
one (4a) along with 43% intermediate (3) was isolated. However in
none of the cases the biphenyl formed due to oxidative homocou-
pling product from boronic acid was found.
With the optimum reaction condition we successfully extended
our methodology to other substituted 2-bromocarboxaldehydes
(1a–1l). Among them o-bromonaphthalenecarboxaldehydes
(1e–1l) were synthesized from their corresponding tetralone
CHO
CHO
O
Br
Br
PBr3, DMF
DDQ
CHCl3, 25 oC
12 h
Benzene, reflux,
12 h
R
R
R
(1e-1g)
R = H, OMe
Br
R'
O
Br
CHO
CHO
PBr3, DMF
DDQ
CHCl3, 25 o
12 h
C
Benzene, reflux,
12 h
"R
"R
"R
R'
R'
R' = H, Me
R" = H, OMe
(1h-1l)
Scheme 2. Preparation of o-bromonaphthalenecarboxaldehydes.

5606
S. Paul et al. / Tetrahedron Letters 51 (2010) 5604–5608
Table 2
Synthesis of fluoren-9-one derivativesa
O
Br
+
(HO)2B
Br
Pd(OAc)2, NaOAc
PPh3, DMF, 120-130 oC,
16-28 h
CHO
(4a-4l)
2
(1a-1l)
Entry
1
Substrate
CHO
Product
Yield%b
80
O
Br
1a
4a
CHO
Br
O
2
3
4
79
86
76
Me
1b
Me
F
4b
O
F
CHO
Br
1c
4c
MeO
CHO
Br
O
MeO
1d
4d
O
CHO
Br
5
6
67
68
4e
1e
MeO
O
MeO
MeO
CHO
Br
4f
1f
OMe
O
CHO
7
66
4g
Br
1g
CHO
O
Br
8
9
53c
1h
4h
CHO
Br
O
MeO
53c
MeO
1i
1j
4i
CHO
Br
O
10
52c
MeO
4j
MeO

S. Paul et al. / Tetrahedron Letters 51 (2010) 5604–5608
5607
Table 2 (continued)
Entry
Substrate
Product
Yield%b
CHO
Br
O
11
51c
4k
1k
OMe
Me
OMe
CHO
Br
O
Me
12
54c
1l
4l
a
Reagent and conditions: All the reactions were carried out under the following conditions unless otherwise specified: 2-
bromocarboxaldehyde (1 mmol), 2-bromophenyl boronic acid (1.2 mmol), Pd(OAc)2 (10 mol %), PPh3 (0.5 mmol), NaOAc
(4 mmol), DMF (6 mL), at 120 °C for 15–16 h.
b
Yields refer to the isolated yield after purification.
These reactions were run at 130 °C and needed 28 h to reach completion.
c
derivatives in an excellent yield using Vilsmeier–Haack type reac-
tion17 followed by aromatization with 2,3-dichloro-5,6-dic-
yanobenzoquinone (DDQ) (Scheme 2).
experimental condition stated in Table 1, entry 2 (Scheme 4) where
we isolated 2-(2-bromophenyl)-cyclohex-1-enecarbaldehyde (5)
which confirmed that the dehydrogenation occurred during the
cyclization step. With 5, 7, and 8-membered cyclic b-bromovinylal-
dehydes, after Suzuki coupling the formed intermediate underwent
a complete decomposition under this reaction condition.
In conclusion we have successfully developed a simple and
effective one-pot synthesis of fluoren-9-one derivatives which in-
volves the Suzuki coupling of 2-bromophenyl boronic acid with
various 2-bromocarboxaldehydes followed by arylpalladium addi-
tion to aldehyde. To our knowledge this method is the first report
for the synthesis of fluoren-9-one using one-pot Suzuki coupling
followed by arylpalladation to aldehyde. It provides an efficient
synthesis of various fluoren-9-one and condensed fluoren-9-one
derivatives in moderate to good yield from the readily available
starting materials.
Several fluoren-9-one derivatives (4a–4l) were successfully pre-
pared from the reaction of various 2-bromoarenecarboxaldehydes
(1a–1l) with 2-bromophenyl boronic acid (2) under optimized
reaction condition (Table 2). With the substituted o-bromobenzal-
dehydes (1a–1d) and 2-bromonaphthalen-1-carboxaldehydes (1e–
1g), fluoren-9-one derivatives were isolated in moderate to good
yield. However the 1-bromonaphthalen-2-carboxaldehydes (1h–
1l) gave comparatively lower yield which may be due to the loca-
tion of bromine at the sterically hindered 1-position of naphtha-
lene and for this reason they required rather higher temperature
(130 °C) and prolonged reaction time (28 h) for the completion of
reaction.
A number of cyclic b-bromovinyl aldehydes (prepared from
Vilsmeier–Haack17 type reaction from their cyclic-keto derivatives)
were also subjected to the similar reaction condition where only 2-
bromocyclohex-1-enecarbaldehyde derivatives (1m–1n) gave flu-
oren-9-ones (4a, 4m) instead of 1,2,3,4-tetrahydro-fluoren-9-ones
which underwent Pd(0)-catalyzed dehydrogenation in the reaction
medium (Scheme 3).
Acknowledgments
We thank DST, New Delhi for the financial support. S.P. and S.S.
thanks CSIR, New Delhi for senior research fellowship.
In order to investigate the step at which dehydrogenation oc-
curred, we carried out the reaction of 2-bromocyclohex-1-enecarb-
aldehyde (1m) with 2-bromophenyl boronic acid (2) using the
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.062.
O
Pd(OAc)2, PPh3,
'"R
CHO
Br
Br
References and notes
'"R
+
NaOAc, DMF, 120 o
16 h
C
1. (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) Bischoff, G.; Gromann, U.; Lindau, S.; Skolziger, R.; Witkowski, W.; Bohley,
C.; Naumann, S.; Sagi, J.; Meister, W. V.; Hoffmann, S. J. Biomol. Struct. Dyn.
2000, 18, 199; (d) 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; (e) 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;
(f) Jones, W. D.; Ciske, F. L.; Dinerstein, R. J.; Diekema, K. A. U.S. Patent
6004,959, 1999.
(HO)2B
1m R"' = H
1n R"' = Me
2
4a R"' = H
4m R"' = Me
Scheme 3. Synthesis of fluoren-9-one derivatives from 2-bromocyclohex-1-enecar-
baldehydes.
2. (a) Talapatra, S. K.; Bose, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1985, 41,
2765; (b) Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 2553; (c) Wu, X. Y.;
Qin, G. W.; Fan, D. J.; Xu, R. S. Phytochemistry 1994, 36, 477; (d) Fan, C.; Wang,
W.; Wang, Y.; Qin, G.; Zhao, W. Phytochemistry 2001, 57, 1255.
3. (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.
4. (a) Olah, G. A.; Mathew, T.; Farnia, M.; Prakash, S. Synlett 1999, 1067; (b) Yu, Z.;
Velasko, D. Tetrahedron Lett. 1999, 40, 3229; (c) Gruber, J.; Li, R. W. C.; Aguiar, L.
H. J. M. C.; Benvenho, A. R. V.; Lessmann, R.; Huemmelgen, I. A. J. Mater. Chem.
2005, 15, 517; (d) Reim, S.; Lau, M.; Langer, P. Tetrahedron Lett. 2006, 47, 6903.
Br
(HO)2B
Pd(PPh3)4, NaOAc
DMF, 120 oC, 15h
+
Br
CHO
CHO
Br
1m
2
5
Scheme 4. Isolation of intermediate 2-(2-bromophenyl)-cyclohex-1-enecarbalde-
hyde.

5608
S. Paul et al. / Tetrahedron Letters 51 (2010) 5604–5608
5. (a) Fu, J. M.; Zhao, B. P.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991, 56, 1683;
(b) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
6. (a) Hashemi, M.; Beni, Y. J. Chem. Res., Synop. 1999, 434; (b) Nikalje, M.; Sudalai,
A. Tetrahedron 1999, 55, 5903; (c) Dhakshinamoorthy, A.; Alvaro, M.; Garcia, H.
J. Catal. 2009, 267, 1.
15. (a) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4089;
(b) Meegalla, S. K.; Taylor, N. J.; Rodrigo, R. J. Org. Chem. 1992, 57, 2422.
16. General procedure for the one-pot Pd-catalyzed synthesis of fluoren-9-ones: The 2-
bromocarboxaldehyde (1 mmol), 2-bromophenyl boronic acid (1.2 mmol), dry
NaOAc (4 mmol), and PPh3 (0.5 mmol) were placed in a two-necked round-
bottomed flask, flushed with N2 and DMF (6 mL) was added to it. After
degasification, Pd(OAc)2 (10 mol %) catalyst was added and the mixture was
heated at 120–130 °C for 16–28 h. The mixture was allowed to cool, diluted
with water, and extracted with ethyl acetate (3 ꢀ 15 mL). The solvent was
evaporated in vacuo after drying over Na2SO4 to give the crude product which
was purified by silica gel (60–120 mesh) column chromatography using
petroleum ether/ethyl acetate (50:1) as the eluent.
7. (a) Danheiser, R. L.; Gould, A. E.; Pradilla, R. F.; Helgason, A. L. J. Org. Chem. 1994,
´
´
´
´
59, 5514; (b) Rodrıguez, D.; Martınez-Esperon, M. F.; Navarro-Vazquez, A.;
´
´
Castedo, L.; Domınguez, D.; Saa, C. J. Org. Chem. 2004, 69, 3842.
8. (a) Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 2556; (b) Ferreira, S.
B.; Kaiser, C. R.; Ferreira, V. F. Synlett 2008, 2625.
9. Qabaja, G.; Jones, G. B. Tetrahedron Lett. 2000, 41, 5317.
10. Campo, M. A.; Larock, R. C. Org. Lett. 2000, 2, 3675.
11. (a) Sun, C. L.; Liu, N.; Li, B. J.; Yu, D. G.; Wang, Y.; Shi, Z. J. Org. Lett. 2010, 12,
184; (b) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. H. Angew. Chem.,
Int. Ed. 2008, 47, 9462.
12. (a) Zhang, X.; Larock, C. R. Org. Lett. 2005, 7, 3973; (b) Waldo, J. P.; Zhang, X.;
Shi, F.; Larock, C. R. J. Org. Chem. 2008, 73, 6679.
13. (a) Mal, S. K.; Ray, D.; Ray, J. K. Tetrahedron Lett. 2004, 45, 277; (b) Ray, D.; Mal,
S. K.; Ray, J. K. Synlett 2005, 2135; (c) Ray, D.; Paul, S.; Brahma, S.; Ray, J. K.
Tetrahedron Lett. 2007, 48, 8005; (d) Ray, D.; Ray, J. K. Org. Lett. 2007, 9, 1617;
(e) Jana, R.; Samanta, S.; Ray, J. K. Tetrahedron Lett. 2008, 49, 851; (f) Jana, R.;
Chatterjee, I.; Samanta, S.; Ray, J. K. Org. Lett. 2008, 10, 4795; (g) Nandi, S.; Ray,
J. K. Tetrahedron Lett. 2009, 50, 6993; (h) Paul, S.; Jana, R.; Ray, J. K. Synlett 2010,
2010, 1463.
Spectral data of representative compounds: 2-fluoro-fluoren-9-one (4c):18 From
2-bromo-5-fluoro-benzaldehyde (1c) (0.1 g, 0.49 mmol) and 2-bromophenyl
boronic acid (2) (0.12 g, 0.59 mmol) with Pd(OAc)2 (10 mol %), NaOAc
(1.9 mmol) and PPh3 (0.25 mmol) in DMF (5 mL) at 120 °C for 15 h, product
4c was obtained as yellow solid in 86% yield (0.083 g); mp 113–115 °C (lit. mp
117 °C); IR (KBr): 1718, 1601, 1458, 1268 cmꢁ1 1H NMR (CDCl3, 200 MHz) d
;
7.13 (1H, dt, J = 2.4, 8.2), 7.23–7.24 (1H, m), 7.27–7.33 (1H, m), 7.42–7.46 (3H,
m), 7.62 (1H, d. J = 7.2). 13C NMR (100 MHz, CDCl3) d 111.8 (d, J = 24), 120.0,
120.8 (d, J = 23), 121.5 (d, J = 8), 124.5, 128.7, 134.3, 134.9, 136.3 (d, J = 7),
140..1, 143.8, 163.5 (d, J = 248), 192.4. Elemental analysis: found: C, 78.62; H,
3.65. C13H7FO requires C, 78.78; H, 3.56. HRMS (ESI, 70 eV): m/z = 199.0554
[M++H] (calcd mass for C13H8FO: 199.0559 [M++H]).
14. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437; (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
17. Coates, R. M.; Senter, P. D.; William, R. J. Org. Chem. 1982, 47, 3597.
18. Ernst, B.; Hellmut, H.; Dietrich, W. Ber. Dtsch. Chem. Ges. 1933, 66B, 46.