TABLE 1. Effect of Catalysts and Additives on the Knoevenagel
Reaction of 1a and Benzaldehydea
Facile Stereoselective Synthesis of Fluorinated
Flavanone Derivatives via a One-Pot Tandem
Reaction
Haifeng Cui, Peng Li, Zhuo Chai, Changwu Zheng,
Gang Zhao,* and Shizheng Zhu*
yield (%)b
entry
catalyst
solvent
2
3
Laboratory of Modern Synthetic Organic Chemistry and Key
Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, People’s Republic of China
1
L-proline
L-proline
pyrrolidine
piperidine
piperidine
L-proline
L-proline
L-proline
L-proline
L-proline
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
toluene
THF
90
trace
90
87
83
85
trace
trace
8
trace
trace
2c
3
trace
trace
trace
trace
trace
trace
82
4
5d
6
7
8
9
10
ReceiVed October 23, 2008
CH3CN
H2O
59
trace
a 1a/benzaldehyde ) 1:1 in 1.5 mL of solvents. b Isolated yield after
flash chromatography. c 60 mg of MS 4 Å was used as additive. d 20
mol % of CH3COOH was added as additive.
potential utility in biological and pharmaceutical studies, and
the development of tandem procedures would well serve this
purpose.
A series of fluorinated flavanones were synthesized in
moderate to good yields with excellent diastereoselectivities
under mild reaction conditions via a one-pot tandem proce-
dure involving a proline-catalyzed Knoevenagel condensa-
tion, a Michael addition, and an electrophilic fluorination
by NFSI.
Recently, Ma has reported the synthesis of fluorinated
indanones via a triple cascade Knoevenagel condensation/
Nazarov cyclization/electrophilic fluorination reaction of aro-
matic ꢀ-ketoesters and aldehydes.5 However, stoichiometric
Lewis acids were required in this system to effect the reaction.
On the other hand, Scheidt has reported the organocatalyzed
enantioselective synthesis of flavanones via the use of alkylidene
ꢀ-ketoesters 2a (preformed via Knoevenagel condensation),
which was presumed to be able to enhance the reactivity of the
conjugate acceptor and favor the flavanone products over the
acyclic chalcones.6 Moreover, a number of electrophilic fluori-
nating agents with a N-F structure have been employed to
introduce the fluorine atom into organic molecules,7 and the
electrophilic fluorination reaction of ꢀ-ketoesters with these
fluorinating reagents is also well-documented.8 On the basis of
these studies and as a part of our continued interests in the
synthesis of fluorinated heterocyclic compounds,9 we reasoned
Flavanones represent an important structural motif occurring
in many natural products with a variety of biological activities
such as antitumor and anti-inflammatory properties.1 Therefore,
a large number of methods have been developed for the
synthesis of flavanones and their derivatives.2 On the other hand,
the introduction of the fluorine atom is often adopted as a
measure to usher in great changes in the physicochemical and
biological properties of the protio molecules;3 however, to the
best of our knowledge, only one fluoro-containing flavanone
has been reported to be synthesized from its direct protio
compound 2,3-dihydro-4H-1-benzopyranone in the literature.4
As a result, it is desirable to devise novel methods to allow
easy access to fluoro-containing flavanones in view of their great
(5) (a) Cui, H.-F.; Dong, K.-Y.; Zhang, G.-W.; Wang, L.; Ma, J.-A. Chem.
Commun. 2007, 2284–2286. (b) Nie, J.; Zhu, H. W.; Cui, H.-F.; Hua, M.-Q.;
Ma, J.-A. Org. Lett. 2007, 9, 3053–3056.
(6) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129,
3830–3831.
* Corresponding author. Fax: 0086-21-64166128.
(7) For excellent reviews, see: (a) Wilkinson, J. A. Chem. ReV. 1992, 92,
505–519. (b) Rozen, S. Acc. Chem. Res. 1996, 29, 243–248. (c) Lal, G. S.; Pez,
G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737–1755. (d) Rozen, S. Chem.
ReV. 1996, 96, 1717–1736. (e) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron
1999, 55, 12431–12477. (f) Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119–
6146. (g) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996.
(8) (a) Barnette, W. E. J. Am. Chem. Soc. 1984, 106, 452–454. (b) Umemoto,
T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. J. Am.
Chem. Soc. 1990, 112, 8563–8575. (c) Takeuchi, Y.; Suzuki, T.; Satoh, A.;
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L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359–4362. (e) Hamashima, Y.;
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1011. (g) Shibata, N.; Ishimura, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004,
1703–1706. (h) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2004, 125, 1357–1361.
(i) Hamashima, Y.; Sodeoka, M. Synlett 2006, 1467–1478.
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10.1021/jo8023818 CCC: $40.75 2009 American Chemical Society
Published on Web 01/02/2009