Facile stereoselective synthesis of fluorinated flavanone derivatives via a one-pot tandem reaction

Article abstract of DOI:10.1021/jo8023818

A series of fluorinated flavanones were synthesized in moderate to good yields with excellent diastereoselectivities under mild reaction conditions via a one-pot tandem procedure involving a proline-catalyzed Knoevenagel condensation, a Michael addition,

Full text of DOI:10.1021/jo8023818

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
zhaog@mail.sioc.ac.cn
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.;
Shiragami, T.; Shibata, N. J. Org. Chem. 1999, 64, 5708–5711. (d) Hintermann,
L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359–4362. (e) Hamashima, Y.;
Yagi, K.; Takano, H.; Tamas, L.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
14530–14531. (f) Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007–
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.
(1) (a) Harborne, J. B., Ed. The FlaVonoids: AdVances in Research Since
1980; Chapman and Hall: New York, 1988. (b) Harborne, J. B.; Williams, C. A.
Nat. Prod. Rep. 1995, 12, 639–657. (c) Chang, L. C.; Kinghorn, A. D. In
BioactiVe Compounds from Natural Sources: Isolation Characterisation and
Biological Properties; Tringali, C., Ed.; Taylor & Francis Ltd.: London, UK,
2001; Chapter 5. (d) FlaVonoids: Chemistry, Biochemistry and Applications;
Andersen, L. M., Markham, K. R., Eds.; Taylor & Francis Ltd.: London, UK,
2006.
(2) (a) Kabbe, H. J.; Widdig, A. Angew. Chem., Int. Ed. 1982, 21, 247–256.
(b) Ramadas, S.; Krupadanam, G. L. D. Tetrahedron: Asymmetry 2004, 15, 3381–
3391. (c) Brown, M. K.; Degrado, S. J.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2005, 44, 5306–5310. (d) Hodgetts, K. J. Tetrahedron 2005, 61, 6860–6870.
(3) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV.
2008, 37, 320–330.
(4) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 2609–2615.
1400 J. Org. Chem. 2009, 74, 1400–1402
10.1021/jo8023818 CCC: $40.75 2009 American Chemical Society
Published on Web 01/02/2009

SCHEME 1. Electrophilic Fluorination of 2 or 3 To Form 4a
TABLE 2. Effect of Bases on the One-Pot Synthesis of
Monofluorinated Flavanone Derivative 4aa
a catalytic amount of L-proline was enough to catalyze the
reaction to give the desired product alkylidene ꢀ-ketoesters 2
in 90% yield (Table 1, entry 1) under very mild reaction
conditions. Surprisingly, when the reaction was performed in
the presence of molecular sieves 4 Å (MS 4 Å) or with
piperidine or pyrrolidine as the catalyst, only the trans cyclized
product 3 (the configuration of 3 was determined by 1H NMR)
was obtained (Table 1, entry 2). Subsequent screening of several
other solvents revealed that EtOH was the solvent of choice
(Table 1, entries 6-10). Notably, only a single diastereoisomer
of 4a was observed in both cases and its structure was confirmed
by X-ray crystallographic analysis.10 Moreover, it was found
in our subsequent investigation that compound 2 could be easily
converted to 3 under basic conditions and both compounds could
undergo facile electrophilic fluorination reaction to provide the
desired monofluoro-flavanone 4a in comparable yields and the
same excellent diastereoselectivity in the presence of inorganic
bases (Scheme 1); however, the product 4a is racemic.
Therefore, it is safe to say that the transformation of 2 to 4a
proceeded through 3 as an intermediate under the reaction
conditions (Scheme 1), which may then form a reactive enolate
I in the presence of bases, and the sterically hindered phenyl
group would drive the electrophilic fluorinating agent NFSI to
attack from the opposite plane accounting for the excellent
diastereoselectivity observed in this process. Encouraged by
these results, it was assumed that the Knoevenagel condensation,
cyclization, and electrophilic fluorination may be done in one
pot to deliver the desired monofluorinated product. The condi-
tions of entry 1 (Table 1), namely, 20 mol % L-proline as the
catalyst and EtOH as the solvent, were chosen for subsequent
studies for the simplicity of the reaction system.
entry
base
none
K2CO3
KOH
Li2CO3
NaOH
Na2CO3
yield (%)b
1
2
3
4
5
6
c
63
48
47
50
77
a 1a/benzaldehyde/NFSI ) 3:3:4 in 1.5 mL of EtOH. b Isolated yield
after flash chromatography. c 60 mg of MS 4 Å was used as additive.
TABLE 3. Scope of the One-Pot Reaction To Synthesize
Fluorinated Flavanone Derivativesa
entry substrate
R1
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
R2
R3
yield of 4/%b
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
4a: 77
4b: 50
4c: 52
4d: 79
4e: 63
4f: 81
4g: 74
4h: 57
4i: 64
4j: 74
4k: 73
4l: 57
4m: 85
4n: 67
4o: 40
4p: 58
4q: 50
4r: 61
2
3
4
5
6
7
8
9
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-Me-C6H4
p-Ph-C6H4
p-MeO-C6H4
p-BnO-C6H4
p-NO2-C6H4
o-Br-C6H4
m-Br-C6H4
3-BnO-4-MeO-C6H3
furan-2-yl
10
11
12
13
14
15
16
17
18
Next, we examined the one-pot synthesis of the monofluoro
flavanone 4a directly from ꢀ-ketoester 1a and benzaldehyde
using NFSI as the fluorinating reagent. After completion of the
proline-catalyzed Knoevenagel condensation of 1a and benzal-
dehyde (monitored by TLC), bases and NFSI were then added
to the reaction system (Table 2). The screening of a series of
inorganic bases revealed a pronounced influence on the overall
yield for the different bases used and the best yield was obtained
with Na2CO3 (Table 2, entry 6). Moreover, no desired fluorinated
product 4a was obtained in the absence of bases (Table 2, entry
pentyl
t-Bu
t-Bu
t-Bu
p-Me-C6H4
p-Br-C6H4
p-MeO-C6H4
t-Bu Me p-Me-C6H4
a 1a/benzaldehyde/NFSI ) 3:3:4 in 1.5 mL of EtOH. b Isolated yield
after flash chromatography.
that fluorinated flavanones may also be accessible through a
Knoevenagel condensation/Michael addition/electrophilic fluo-
rination sequence directly from ꢀ-ketoesters 1 and aldehydes.
Herein, we report our results with this strategy.
Initially, the Knoevenagel condensation reaction of 1a and
benzaldehyde was investigated. Delightfully, it was found that
(9) (a) Pang, W.; Zhu, S.; Jiang, H.; Zhu, S. J. Fluorine Chem. 2007, 128,
1379–1384. (b) Li, D.-M.; Song, L.-P.; Li, X.-F.; Xing, C.-H.; Peng, W.-M.;
Zhu, S.-Z. Eur. J. Org. Chem. 2007, 3520–3525. (c) Song, S.; Song, L.-P.; Dai,
B.; Yi, H.; Jin, G.; Zhu, S.; Shao, M. Tetrahedron 2008, 64, 5728–5735. (d) Li,
P.; Chai, Z.; Zhao, G.; Zhu, S.-Z. Synlett 2008, 2547–2551.
(10) See the Supporting Information for the ORTEP structure of 4a.
J. Org. Chem. Vol. 74, No. 3, 2009 1401

the filtrate gave the crude product, which was purified by column
chromatography on silica gel (hexane/ethyl acetate 10:1) to provide
the desired product 4a (80 mg, 77% yield) as a white solid: mp
128-129 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J ) 7.9 Hz,
1H), 7.63 (t, J ) 8.5 Hz, 1H), 7.52 (d, J ) 3.0 Hz, 2H), 7.44-7.42
(m, 3H), 7.17 (t, J ) 8.5 Hz, 2H), 5.54 (d, J ) 7.8 Hz, 1H),
4.11-4.03 (m, 2H), 1.03 (t, J ) 7.1 Hz, 3H); 19F NMR (282 MHz,
CDCl3) δ -175.48 (d, J ) 8.5 Hz, 1F); 13C NMR (100 MHz,
CDCl3) δ 185.0 (d, J ) 16.6 Hz), 163.6 (d, J ) 26.1 Hz), 161.2,
137.2, 133.2, 129.6, 128.5, 128.0, 126.9, 122.7, 119.5, 118.2, 91.6
(d, J ) 203.5 Hz), 81.7 (d, J ) 27.6 Hz), 62.5, 13.7; IR (KBr) ν
1766, 1733, 1704, 1607, 1475, 1465, 1307, 1226 cm-1; EI-MS (m/
z) 314 (M+, 11%), 120 (100), 92 (18), 121 (11), 194 (10), 241
(10), 165 (7), 101 (6). Anal. Calcd for C18H15FO4: C, 68.78; H,
4.81. Found: C, 68.46; H, 5.09.
trans-Ethyl 3-Fluoro-2-(4-fluorophenyl)-4-oxochroman-3-car-
boxylate, 4b (Table 3, entry 2). 4b was prepared according to the
general procedure as a white solid (50 mg, 50% yield): mp 110-111
°C; 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J ) 7.6 Hz, 1H), 7.53
(t, J ) 7.1 Hz, 1H), 7.42 (d, J ) 5.6 Hz, 2H), 7.10-7.00 (m, 4H),
5.43 (d, J ) 8.2 Hz, 1H), 4.03-3.92 (m, 2H), 0.95 (t, J ) 6.8 Hz,
3H); 19F NMR (282 MHz, CDCl3) δ -111.65 (m, 1F), -174.66
(d, J ) 8.1 Hz, 1F); 13C NMR (100 MHz, CDCl3) δ 184.7 (d, J )
17.0 Hz), 163.3 (d, J ) 246.9 Hz), 163.4 (d, J ) 25.7 Hz), 161.0,
137.2, 129.0 (d, J ) 2.6 Hz), 128.7 (d, J ) 8.4 Hz), 127.9, 122.7,
119.4, 118.0, 115.4 (d, J ) 21.9 Hz), 91.5 (d, J ) 201.0 Hz), 81.9
(d, J ) 27.9 Hz), 62.5, 13.7; IR (KBr) ν 2924, 1766, 1737, 1705,
1607, 1581, 1512, 1475, 1465, 1375 cm-1; EI-MS (m/z) 332 (M+,
24%), 120 (100), 92 (21), 259 (17), 212 (13), 121 (12), 268 (8),
183 (8). Anal. Calcd for C18H14F2O4: C, 65.06; H, 4.25. Found: C,
64.97; H, 4.46.
1) and in all the cases examined; the desired product 4a was
invariably obtained as a single diastereoisomer.
Subsequently, a selected spectrum of aldehydes were exam-
ined to test the scope of this tandem procedure (Table 3).
Diastereoisomerically pure trans- monofluorinated flavanones
4a-l were obtained in moderate to good yields for all the
substituted benzaldehydes examined, irrespective of the elec-
tronic nature or positions of the substituents on the phenyl ring
(Table 3, entries 1-12). Notably, heterocyclic furan-2-carbal-
dehyde and aliphatic aldehyde hexanal also proved to be a
suitable substrate for this transformation, giving the correspond-
ing products 4m and 4n in 85% and 67% yields, respectively
(Table 3, entries 13 and 14). On the other hand, when
ꢀ-ketoester 1b bearing a more sterically demanding tert-butyl
group on the ester moiety was subjected to similar reaction
conditions as its ethyl counterpart 1a, the same excellent
diastereosectivity could also be obtained with the desired
products 4o-r, albeit with a decrease in the yields (Table 3,
entries 15-18).
In conclusion, we have developed a novel one-pot tandem
procedure for the synthesis of a series of monofluorinated
flavanones derivatives. This method is featured with mild
reaction conditions, simple operation, and a good substrate
scope. Efforts on the asymmetric synthesis of these compounds
are underway in our laboratories.
Experimental Section
General Procedure for the One-Pot Tandem Reaction To
Synthesize Fluorinated Flavanone Derivatives. trans-Ethyl
3-Fluoro-4-oxo-2-phenyl-3,4-dihydro-2H-chromene-3-carboxy-
late, 4a (Table 3, entry 1). To a solution of 1a (69 mg, 0.3 mmol)
and benzaldehyde (32 mg, 0.3 mmol) in ethanol (1.5 mL) was added
L-proline (7 mg, 20 mol %) at room temperature and the mixture
was stirred for 12 h. Then sodium carbonate (37 mg, 0.4 mmol)
and NFSI (110 mg, 0.4 mmol) were added sequentially to the
reaction mixture. Upon completion of the reaction (monitored by
TLC), the solvent was removed in vacuum and the residue was
mixed with 2 mL of water, then extracted with CH2Cl2 (3 × 2
mL). The combined organic phases were washed with brine (5 mL)
and dried over anhydrous Na2SO4. Filtration and concentration of
Acknowledgment. The generous financial support from the
National Natural Science Foundation of China, QT Program,
Shanghai Natural Science Council, and Excellent Young
Scholars Foundation of NNSF is gratefully acknowledged.
Supporting Information Available: Experimental proce-
1
dures, copies of H NMR, 19F NMR, and 13C NMR spectra,
characterization data for all the new compounds, and a CIF file
and X-ray crystal structure data for 4a. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8023818
1402 J. Org. Chem. Vol. 74, No. 3, 2009