Fluorenone synthesis by palladacycle-catalyzed sequential reactions of 2-bromobenzaldehydes with arylboronic acids

Article abstract of DOI:10.1021/ol200693d

Chemical equations presented. A new, anionic four-electron donor-based (type I) palladacycle-catalyzed sequential reaction of 2-bromobenzaldehydes with arylboronic acids based on the addition reaction, cyclization via C-H activation-oxidation sequence is described. Our study provided an efficient access to a variety of substituted fluorenones/indenofluorenediones from readily available arylboronic acids and 2-bromobenzaldehydes.

Full text of DOI:10.1021/ol200693d

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2452–2455
Fluorenone Synthesis by Palladacycle-
Catalyzed Sequential Reactions of
2-Bromobenzaldehydes with Arylboronic
Acids
Tao-Ping Liu, Yuan-Xi Liao, Chun-Hui Xing, and Qiao-Sheng Hu*
Department of Chemistry, College of Staten Island and the Graduate Center of the City
University of New York, Staten Island, New York 10314, United States
qiaosheng.hu@csi.cuny.edu
Received March 15, 2011
ABSTRACT
A new, anionic four-electron donor-based (type I) palladacycle-catalyzed sequential reaction of 2-bromobenzaldehydes with arylboronic acids
based on the addition reaction, cyclization via CÀH activationÀoxidation sequence is described. Our study provided an efficient access to a
variety of substituted fluorenones/indenofluorenediones from readily available arylboronic acids and 2-bromobenzaldehydes.
One-pot, multistep reactions such as sequential, tandem,
domino, or cascade reactions combine two or more bond-
forming reactions into one synthetic process and can lead
to rapid increase of molecular complexity with minimized
isolation/purification efforts.1,2 The development of new
one-pot, multistep reactions represents one of the most
active frontiers in synthetic organic chemistry. In our
laboratory, we were interested in exploring anionic four-
electron donor-based (type I) palladacycles, which consti-
tute a large family of readily available and air-stable cyclic
palladium(II) complexes (Figure 1),3,4 as catalysts for
addition reactions of arylboronic acids with carbonyl-
containing compounds.5À8 We have demonstrated that
type I palladacycles such as 1À3 (Figure 1) efficiently
catalyzed addition reactions of arylboronic acids with
carbonyl-containing compounds.6 Studies from other
groups as well as our group also showed that Type I
(5) For recent reviews on transition metal-catalyzed addition reac-
tions of organoborons with carbonyl-containing compounds, see: (a)
Miyaura, N. Synlett 2009, 2039–2050. (b) Gutnov, A. Eur. J. Org. Chem.
2008, 4547–4554. (c) Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 3364–
3366. (d) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844.
(e) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169–196 and
references cited therein.
(6) (a) Xing, C.-H.; Liao, Y.-X.; He, P.; Hu, Q.-S. Chem. Commun.
2010, 3010–3012. (b) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett.
2007, 9, 343–346. (c) He, P.; Lu, Y.; Hu, Q.-S. Tetrahedron Lett. 2007, 48,
5283–5288.
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Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006.
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6989.
(2) For recent reviews on sequential reactions, see: (a) Nicolaou,
K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993–3009. (b) Kirsch, S. F.
Synthesis 2008, 3183–3204. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
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(4) Most type I palladacycles are known to exist as bridged dimers
and to dissociate into monomeric forms during reactions. Type I
palladacycles in this paper were drawn in monomeric forms.
r
10.1021/ol200693d
Published on Web 04/11/2011
2011 American Chemical Society

us that type I palladacycles could function as two kinds of
palladium catalysts [Pd(II) and Pd(0) catalysts] under
different reaction temperature. We thus envisioned that a
new sequential reaction could be developed by taking
advantage of this double catalyst nature of type I pallada-
cycles: addition reactions of arylboronic acids with halo-
bearing aromatic aldehydes at lower temperature followed
by cyclization via CÀH activation10 at elevated tempera-
ture to form fluorenols (A), which could be further oxi-
dized to fluorenones (B) (Scheme 1).11 This new type of
sequential reaction could thus lead to rapid access to
substituted fluorenones, which are usefulstartingmaterials
for organic synthesis,12,13 from readily available 2-bromo-
benzaldehydes and arylboronic acids. In this communica-
tion, we reported our results on such a new sequential
reaction.
Figure 1. Type I palladacycles.
palladacycles could generate Pd(0) species upon treatment
with arylboronic acids at elevated temperature.3,9 Such
generated Pd(0) species could undergo oxidative addition
with aryl halides to form arylPd(II)X species,3 which could
undergo other transformations including cross-coupling
reactions via CÀH activation. These studies suggested to
(9) Also see: Bedford, R. B.; Hazelwood, S. L.; Limmert, M. E.;
Albisson, D. A.; Draper, S. M.; Scully, P. N.; Coles, S. J.; Hursthouse,
M. B. Chem.;Eur. J. 2003, 9, 3216–3227.
(10) For recent reviews for CÀH activation, see: (a) Chen, X.; Engle,
K. M.; Wang, D.-H.; Yu, J.-Q. Angew Chem., Int. Ed. 2009, 48, 5094–
5115. (b) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–
1101. (c) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731–
1770. (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633–639.
Scheme 1. Type I Palladacycles As Double Catalysts for a New
Sequential Reaction Based on the Addition Reaction, Cycliza-
tion via CÀH Activation, and Oxidation Sequence
(11) For recent examples of Pd(II)-catalyzed oxidation of alcohols,
see: (a) R., J.; Goddard, W. A., III J. Am. Chem. Soc. 2006, 128, 9651–
9660. (b) Schultz, M. J.; Adler, R. S.; Zierkiewicz, W.; Privalov, T.;
Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 8499–8507. (c) Steinhoff,
B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004, 126, 11268–
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B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726.
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mann, F.; Piehler, T.; Haase, D.; Saak, W.; Luetzen, A. Eur. J. Org.
Chem. 2005, 1991–2001. (c) Cheng, X.; Hou, G.-H.; Xie, J.-H.; Zhou, Q.-
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mond, G. G. Biorg. Med. Chem. Lett. 1999, 9, 3225–3230. (h) Perry, P. J.;
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Carney, J. R. J. Org. Chem. 1997, 62, 320–324.
(13) For recent examples of other tandem, domino, sequential, or
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Li, B.-J.; Yu, D.-G.; Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184–187.
(b) Zhao, Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.;
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(14) The use of 6 equiv of base was necessaryfor the first step addition
reaction to complete without the occurrence of the cross-coupling
reaction.
(15) (a) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043–5045.
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Our study began with the reaction condition screening
by examining the reaction of 2-bromobenzaldehyde and
phenylboronic acid with palladacycle 3 as the catalyst. Our
results are summarized in Table 1. We found that by using
toluene as solvent, the addition reaction step (step I)
occurred smoothly with K3PO4, K2CO3, or KF as bases,14
but the cyclization via CÀH activation/oxidation (step II)
did not go well (Table 1, entries 1À3). Rather benzophe-
none (C) was obtained. DMA was then examined as the
solvent for the reaction because it has been used as solvent
for cross-coupling reactions via CÀH activation.15 We
found when DMA was used, step I could not occur, rather
cross-coupling reaction was observed (Table 1, entries 4
and 5). Wethencarried outthe addition reaction in toluene
first and thenthe cyclization/oxidation inDMA. Wefound
by using trimethylacetic acid as an additive,16 very en-
couraging results were observed (Table 1, entries 6À10).
Gratifyingly, we found that by carrying out the reaction in
air, the desired fluorenone was obtained in an excellent
yield (Table 1, entry 11).17
After establishing the reaction conditions, the scope of
the reaction was examined. We found that high yields of an
array of structurally diversified substituted fluorenones
were obtained with arylboronic acids including sterically
hindered, electron-rich and electron-poor ones (Table 2,
entries 1À13). When m-substituted-phenylboronic acids
such as m-methylphenylboronic acid and m-methoxy-
phenylboronic acid were used, two isomeric products were
obtained, and the ratio of 2-substituted fluorenones
to 4-substituted fluorenones was observed to be 30:1
and 9:1, respectively (Table 2, entries 8 and 9). Other
(17) Fluorenol was observed as the intermediate (GC-MS analysis)
when the reaction was stopped after 2 h.
Org. Lett., Vol. 13, No. 9, 2011
2453

Table 1. Palladacycle 3-Catalyzed Sequential Reactions of
Phenylboronic Acid with 2-Bormobenzaldehydea
Table 2. Type I Palladacycle 3-Catalyzed Sequential Reactions
of Arylboronic Acids with 2-Bromobenzaldehydesa
conv (%)b
temp for
step I/
ratioc
entry base solvent additive
step II step I step II of B:C
1
2
3
4
5
6
K3PO4 toluene
K2CO3 toluene
55/120
55/120
55/120
55/120
55/120
55/120
100
100
94
100d
100d
100
100
100
14
1:99
1:99
KF
toluene
K3PO4 DMA
K2CO3 DMA
K2CO3 toluene/
DMA
54
8:92
7
8
9
K2CO3 toluene/ t-BuCO2H 55/120
100
100
100
100
16 29:71
61 44:56
83 42:58
100 57:33 f,g
100 92:8
DMA
K2CO3 toluene/ t-BuCO2H 55/140
DMA
K2CO3 toluene/ t-BuCO2H 55/120 e
DMA
10 K3PO4 toluene/ t-BuCO2H 55/120
DMA
11 K2CO3 toluene/ t-BuCO2H 55/120e,f 100
DMA
a Reaction conditions: aldehyde (1.0 equiv), phenylboronic acid (1.1
equiv), toluene (1.5 mL), base (6 equiv), 55 °C for 5 h, and then DMA (5
1
mL), 120 °C for another 5 h. b Conversion based on H NMR. c Con-
version based on GC-MS analysis. d Biphenyl-2-carbonylaldehyde as the
only product. e Reaction time: 10 h. f Reaction carried out under air.
g 10% 2-phenylbenzophenone was observed.
2-bromobenzaldehydes were also found to be suitable
substrates, and high yields of a variety of substituted
fluorenones were obtained (Table 2, entries 14À21).
We have further tested the sequential reaction of 2,5-
dibromoterephthalaldehyde with phenylboronic acid and
4-tert-butylphenylboronic acid. We found the sequential
reaction occurred smoothly, and indenofluorenediones
5a and 5b were obtained in 49% and 58% yields, respec-
tively (Scheme 2). Substituted indenofluorenediones are
useful building blocks for materials synthesis18 and are
recently of interest as n-type semiconductors/field-effect
transistors.19
(18) For recent examples, see: (a) Park, Y.; Lee, J.-H.; Jung, D. H.;
Liu, S.-H.; Lin, Y.-H.; Chen, L.-Y.; Wu, C.-C.; Park, J. J. Mater. Chem.
2010, 20, 5930–5936. (b) Yen, W.-C.; Pal, B.; Yang, J.-S.; Hung, Y.-C.;
Lin, S.-T.; Chao, C.-Y.; Su, W.-F. J. Polym. Sci., Part A: Polym. Chem.
2009, 47, 5044–5056. (c) Lin, T.-C.; Hsu, C.-S.; Hu, C.-L.; Chen, Y.-F.;
Huang, W.-J. Tetrahedron Lett. 2009, 50, 182–185. (d) Poriel, C.; Liang,
J.-J.; Rault-Berthelot, J.; Barriere, F.; Cocherel, N.; Slawin, A. M. Z.;
Horhant, D.; Virboul, M.; Alcaraz, G.; Audebrand, N.; Vignau, L.;
Huby, N.; Wantz, G.; Hirsch, L. Chem.;Eur. J. 2007, 13, 10055–10069.
(e) Reisch, H.; Wiesler, U.; Scherf, U.; Tuytuylkov, N. Macromolecules
1996, 29, 8204–8210.
(19) For examples, see: (a) Usta, H.; Risko, C.; Wang, Z.; Huang, H.;
Deliomeroglu, M. K.; Zhukhovitskiy, A.; Facchetti, A.; Marks, T. J. J.
Am. Chem. Soc. 2009, 131, 5586–5608. (b) Usta, H.; Facchetti, A.;
Marks, T. J. J. Am. Chem. Soc. 2008, 130, 8580–8581. (c) Usta, H.;
Facchetti, A.; Marks, T. J. Org. Lett. 2008, 10, 1385–1388. (d) Nakaga-
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Mater. 2008, 20, 2615–2617.
a Reaction conditions: aldehyde (1.0 equiv), arylboronic acid (1.1
equiv), toluene (1.5 mL), K2CO3 (6 equiv), 55 °C for 5 h, and then DMA
(1.5 mL), 120 °C for another 10 h. b Isolated yields. c Based on GC-MS
analysis. d Reaction was carried out at 80 °C for 25 h and then 120 °C for
another 10 h with a 5 mol % catalyst loading.
In summary, we have demonstrated that type I palla-
dacycles can function as both Pd(II) and Pd(0) catalysts
for a new sequential reaction of 2-bromobenzaldehydes
with arylboronic acids based on the addition reaction,
cyclization via CÀH activation, and oxidation se-
quence. Our study provided an efficient access to a
2454
Org. Lett., Vol. 13, No. 9, 2011

with the transition metal-catalyzed addition reaction as
a key reaction component.
Scheme 2. Type I Palladacycle-Catalyzed Indenofluorenedione
Preparation by the New Sequential Reaction
Acknowledgment. We gratefully thank the NSF
(CHE0719311) and NIH (1R15 GM094709) for funding.
Partial support from PSC-CUNY Research Award Pro-
grams is also acknowledged. We thank Frontier Scien-
tific for its generous gifts of Pd(OAc)2 and arylboronic
acids.
Supporting Information Available. General procedures
and product characterization for type I palladacycle-
catalyzed sequential reactions of 2-bromobenzalde-
hydes with arylboronic acids. This material is available
free of charge via the Internet at http://pubs.acs.org.
variety of substituted fluorenones/indenofluorene-
diones from readily available arylboronic acids and
2-bromobenzaldehydes. Our study may also lead to
the development of other one-pot, multistep reactions
Org. Lett., Vol. 13, No. 9, 2011
2455