Asymmetrie synthesis of fluorinated flavanone derivatives by an organocatalytic tandem intramolecular oxa-michael Addition/electrophilic fluorination reaction by using bifunctional cinchona alkaloids

Article abstract of DOI:10.1002/chem.200902303

"Chemical Equation Presented" A bifunetional quinidine derivative, containing a trifluoromethyl group, was found to catalyze a tandem intramolecular oxa-Michael addition/electrophilic fluorination reaction of acti-vated α,β-unsaturated ketones (see scheme). A series of chiral fluorinated flavanone derivatives were obtained in excellent yields and with high enantioselectivities.

Full text of DOI:10.1002/chem.200902303

COMMUNICATION
DOI: 10.1002/chem.200902303
Asymmetric Synthesis of Fluorinated Flavanone Derivatives by an
Organocatalytic Tandem Intramolecular Oxa-Michael Addition/Electrophilic
Fluorination Reaction by Using Bifunctional Cinchona Alkaloids
Hai-Feng Wang,[a] Hai-Feng Cui,[a] Zhuo Chai,[a] Peng Li,[a] Chang-Wu Zheng,[a]
Ying-Quan Yang,[b] and Gang Zhao*[a, b]
Flavanones are a large family of natural products with
many important biological activities, such as antitumor and
anti-inflammatory properties.[1,2] However, despite intensive
research devoted to the synthesis of flavanone derivatives,[3]
only a limited number of methods, particularly catalytic
asymmetric methods, are available for the asymmetric syn-
thesis of this class of compound.[4] Structurally, the asymmet-
ric, intramolecular oxa-Michael addition reaction of
a
phenol to chalcone would provide an easy access to chiral
flavanones due to the ready availability of the starting mate-
rials. However, it was not until 2007 that a breakthrough
based on this strategy, by using an organocatalytic method,
was accomplished, by Scheidt and co-workers,[4d] probably
due to the low reactivity of the substrates. They addressed
this challenge by utilizing an activated, unsaturated ketone,
1, as the substrate and bifunctional chiral thioureas as cata-
lysts (Scheme 1). Recently, Feng and co-workers[4g] reported
a metal-catalyzed version of the same reaction employing
chiral N,N’-dioxide nickel(II) complexes with excellent re-
sults. In view of these results, there is still the potential for
the development of new organocatalysts to effect an asym-
metric intramolecular oxa-Michael addition as a route to
synthesize chiral flavanones.
Scheme 1. Organocatalyzed tandem intramolecular oxa-Michael addition/
electrophilic fluorination reaction to access chiral fluorinated flavanones.
biological activity, which can lead to potential applications
in medicinal chemistry and the pharmaceutical industry.[5]
One of the most challenging subjects in the field of synthetic
fluorine chemistry is the enantioselective construction of the
[6]
À
C F bond at a stereogenic carbon center. Since the first
asymmetric fluorination reagents were reported by Differd-
[7a]
ing and Lang
in 1988 and the first catalytic enantioselec-
tive fluorination was disclosed by Hintermann and Togni[7b]
in 2000, this intriguing field of catalytic asymmetric fluorina-
tion has been blooming.[8,9] Our group has developed a one-
pot tandem reaction for the synthesis of fluorinated flava-
nones, from b-ketoesters and aldehydes, with excellent dia-
stereoselectivities.[10] On the basis of these results, we envis-
aged that by using an appropriate bifunctional catalyst, an
organocatalytic, asymmetric, intramolecular oxa-Michael ad-
dition of 1 would produce enantioenriched 2, which could
then be subjected to electrophilic fluorination to provide
novel, chiral, fluorinated flavanone derivatives (Scheme 1).
Herein, we report the details of this research.
On the other hand, the introduction of a fluorine atom
into a compound often results in important changes in its
[a] H.-F. Wang, H.-F. Cui, Z. Chai, P. Li, C.-W. Zheng, Prof. Dr. G. Zhao
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
345 LingLing Lu, Shanghai, 200032 (China)
Fax : (+86)21-64166128
E-mail: zhaog@mail.sioc.ac.cn
[b] Y.-Q. Yang, Prof. Dr. G. Zhao
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
Cinchona alkaloids and their derivatives were selected as
catalysts to be investigated due to their easy availability and
well-documented power as bifunctional organocatalysts in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902303.
Chem. Eur. J. 2009, 15, 13299 – 13303
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13299

various asymmetric reactions.[11] As a model substrate, the
activated a,b-unsaturated ketone 1a first underwent an in-
tramolecular oxa-Michael addition in the presence of a cin-
chona alkaloid followed by electrophilic fluorination with
[12]
Na2CO3 and N-fluorobenzenesulfonimide (NFSI) to deliv-
er the desired product 3a. Table 1 summarizes the results of
Table 1. Evaluation of different cinchona alkaloids as catalysts in the
asymmetric synthesis of flavanones.[a]
Entry
Catalyst
t1 [h]
t2 [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4 f
4g
4h
4i
72
72
240
240
84
156
36
10
10
12
12
11
17
17
17
17
3
17
16
12
12
4
83
76
73
73
89
83
76
70
54
99
99
80
99
À24
16
À57
24
À81
42
86
83
88
81
84
85
92
Scheme 2. Cinchona alkaloid catalysts used in this study.
Table 2. Screen of catalyst loading and solvents.[a]
9
10
11
12
13
4j
4k
4l
4.5
12
5
4m
12
[a] Unless otherwise noted, the reaction was carried out with 1a
(0.1 mmol), catalyst 4 (0.02 mmol), and toluene (1.0 mL) at room temper-
ature, then Na2CO3 (1.2 equiv) and NFSI (1.5 equiv) were added and the
reaction was stirred for 3–17 h. [b] Yield of the isolated product after
column chromatography on silica gel. [c] Determined by HPLC analysis
on a chiral phase. Only a single diastereoisomer was observed by 1H and
13C NMR spectroscopy.
Entry 4m [mol%] Solvent
t1 [h] t2 [h] Yield [%][b] ee [%][c]
1
2
3
4
20
15
10
5
toluene
toluene
toluene
toluene
toluene
xylene
12
12
15
17
72
9
5
6
8
99
99
92
89
92
99
99
99
99
70
89
70
35
99
51
99
96
96
92
93
93
94
93
93
93
87
87
91
86
94
71
89
95
20
62
60
8
5[d]
6
15
15
15
15
15
15
15
15
15
15
15
15
15
15
10
12
8
the catalyst evaluation. First, commercially available quinine
(4a) and quinidine (4b) both provided encouraging results
(Table 1, entries 1 and 2). Subsequent structural modifica-
tions on these two compounds led to the optimal catalyst
4m, which gave the desired product in 99% yield and 92%
enantiomeric excess (ee) (Table 1, entry 13). It is of note
that several sterically more demanding catalysts, such as 4 f–
4i (Scheme 2) all provided inferior results (Table 1, en-
tries 6–9), which highlighted the uniqueness of this novel tri-
fluoromethyl-group-containing catalyst 4m. Interestingly,
the organocatalysts also seemed to play a role in the electro-
philic fluorination step because different reaction times
were required for this step in each case. In all of the cases
examined, only one diastereoisomer of the product 3a was
observed.
Next, we examined the influence of catalyst loading on
the overall yield and enantioselectivity. Lowering the
amount of 4m from 20 to 15 mol% increased the ee value
to 93% while maintaining the excellent yield (Table 2, en-
tries 1 and 2). However, decreasing the amount of 4m fur-
ther to 10 or 5 mol% led to a drop in the yield, while similar
ee values were obtained (Table 2, entries 3 and 4). As a com-
promise of both yield and enantioselectivity, a catalyst load-
ing of 15 mol% was selected for the ensuing study. Lower-
7
8
9
PhCF3
48
9
10
10
9
CH2Cl2
CHCl3
CCl4
ClCH2CH2Cl
MTBE
n-hexane
THF
Et2O
EtOH
CH3CN
CH3CN
12
12
48
8
10
11
12
13
14
15
16
17
18[e]
48
48
48
48
9
24
24
8
24
6
8
6
8
8
[a] Unless otherwise noted, the reaction was carried out with 1a
(0.1 mmol) and 4m in solvent (1.0 mL) at room temperature for 8–48 h,
then Na2CO3 (1.2 equiv) and NFSI (1.5 equiv) were added and the reac-
tion was stirred for 5–48 h. [b] Yield of the isolated product after column
chromatography on silica gel. [c] Determined by HPLC analysis on a
chiral phase. Only a single diastereoisomer was observed by 1H and
13C NMR spectroscopy. [d] The reaction was carried out at 08C. [e] Se-
lectfluor was used instead of NFSI.
ing the reaction temperature to 08C brought no improve-
ment in enantioselectivity, but led to a decrease in the yield
and a prolonged reaction time (Table 2, entry 5). Other
arene solvents, such as xylene and PhCF3, provided compa-
13300
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Chem. Eur. J. 2009, 15, 13299 – 13303

Asymmetric Synthesis of Fluorinated Flavanone Derivatives
COMMUNICATION
rable results in terms of yield and ee value, but with longer
reaction times (Table 2, entries 6 and 7). Slightly lower ee
values and yields were obtained with the use of chlorine-
containing solvents, such as CH2Cl2, CHCl3, CCl4, and
ClCH2CH2Cl (Table 2, entries 8–11). Although higher ee
values were obtained in Et2O or methyl tert-butyl ether
(MTBE), the yields were markedly diminished probably due
to the poor solubility of NFSI in these two solvents (Table 2,
entries 12 and 15). A similar reason may be invoked to ex-
plain the low yields in apolar CCl4 and n-hexane (Table 2,
entries 10 and 13). Additionally, Selectfluor, another com-
monly used electrophilic fluorinating reagent, was also
tested (in CH3CN for reasons of solubility) but did not give
improved results (Table 2, entry 18). To summarize, the
present tandem reaction was best performed with 15 mol%
of 4m in toluene at room temperature (Table 2, entry 2).
Having established the optimal conditions for the intra-
molecular oxa-Michael addition/electrophilic fluorination
cascade reaction, we next explored the scope of the reaction
and representative results are listed in Table 3. For sub-
strates with different R1 substituents, excellent yields and
high ee values were generally obtained irrespective of the
electronic nature or positions of the substituents on the
arene ring (Table 3, entries 2–15), except for the heterocyclic
substrate 1p (R1 =furan-2-yl; Table 3, entry 16). Notably,
the reactions of substrates with electron-donating substitu-
ents generally required longer reaction times than those
with electron-withdrawing groups. The ee value of product
3d could be increased to >99% after a single recrystalliza-
tion (Table 3, entry 4). While changing the ester moiety (R2)
of substrate 1a to a less bulky methyl group resulted in a
slightly lower yield and ee value, the use of a more sterically
demanding tert-butyl group improved the enantioselectivity
to 96% ee and still with an excellent yield, although a
longer reaction time was required (Table 3, entries 17 and
18). The cyclohexyl-substituted substrate 1s with a tert-butyl
ester group also afforded the desired product 3s with high
enantioselectivity and yield (Table 3, entry 19). When R1
was an ethyl group, the reaction still proceeded efficiently to
give the desired product in excellent yield, but a sharp de-
crease in enantioselectivity was observed, which may be at-
tributable to its decreased steric hindrance (Table 3,
entry 20). The absolute configuration of product 3d was de-
termined as 2R, 3R by X-ray crystallographic analysis
(Figure 1).[13]
Table 3. Scope of the catalytic synthesis of chiral fluorinated flava-
ACHTUNGTRENNUNG
nones.[a]
Entry R1, R2, 1
t1
t2
3
Yield ee
[h] [h]
[%][b] [%][c]
1
2
3
C6H5, Et, 1a
12
12
12
12
12
12
12
12
12
6
7
7
7
7
7
7
7
7
3a
3b
3c
99 93
99 92
99 92
p-FC6H4, Et, 1b
p-ClC6H4, Et, 1c
p-BrC6H4, Et, 1d
p-NO2C6H4, Et, 1e
p-CNC6H4, Et, 1 f
p-CF3C6H4, Et, 1g
o-BrC6H4, Et, 1h
m-BrC6H4, Et, 1i
p-PhC6H4, Et, 1j
2-naphthyl, Et, 1k
p-MeC6H4, Et, 1l
p-MeOC6H4, Et, 1m
p-BnOC6H4, Et, 1n
3-BnO-4-MeO-C6H3, Et, 1o
furan-2-yl, Et, 1p
C6H5, Me, 1q
4[d]
5
3d >99 90 (>99)[e]
3e
3 f
3g
3h
3i
99 90
99 92
97 92
99 89
99 93
97 93
96 92
95 91
96 90
98 90
89 92
56 73
93 88
94 96
86 88
93 17
6
7
8
9
Figure 1. ORTEP structure of compound 3d. Ellipsoids at 30% probabili-
ty.
10
11
12
13
14
15
16
17
18
19
20
15 12 3j
15 12 3k
15 12 3l
15 12 3m
15 12 3n
24 12 3o
72 12 3p
15 12 3q
To propose a mechanism for the reaction, we assumed
that the oxa-Michael addition was the enantiodiscriminating
step and the stereocenter thus formed would govern the ste-
reoselectivity of the electrophilic fluorination process as we
have previously demonstrated.[10] Based on the experimental
results and previous studies,[11] we proposed a transition-
state model to explain the ste-
C6H5, tBu, 1r
cyclohexyl, tBu, 1s
Et, tBu, 1t
24
6
3r
144 48 3s
24 20 3t
reochemical outcome of the re-
[a] Unless otherwise noted, the reaction was carried out with
1
action (Scheme 3). The bifunc-
(0.1 mmol), 4m (0.015 mmol), and toluene (1.0 mL) at room temperature
for 12–144 h, then Na2CO3 (1.2 equiv) and NFSI (1.5 equiv) were added
and the reaction was stirred for 6–48 h. [b] Yield of the isolated product
after column chromatography on silica gel. [c] Determined by HPLC
analysis on a chiral phase. Only a single diastereoisomer was observed by
1H and 13C NMR spectroscopy. The absolute configuration of 3d was de-
termined as 2R, 3R by X-ray crystallographic analysis, and the other
products, 3a–3c and 3e–3t, were assigned by assuming that a similar cat-
alytic mechanism was followed. [d] The reaction was carried out on a
0.2 mmol scale. [e] The enantioselectivity was determined after a single
recrystallization.
tional catalyst may activate
both the nucleophile and the
electrophilic acceptor through a
hydrogen-bonding interaction,
directing the oxygen nucleo-
phile to attack the Re face of
the double bond to form the R-
configured product.
Scheme 3. Proposed transition-
state model for the oxa-Mi-
chael addition step.
Chem. Eur. J. 2009, 15, 13299 – 13303
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13301

G. Zhao et al.
ski, A. A. Reszka, D. Kimmel, F. DiNinno, S. P. Rohrer, L. P. Freed-
man, J. M. Schaeffer, M. L. Hammond, Bioorg. Med. Chem. Lett.
2005, 15, 1675–1681.
In conclusion, we have developed a novel, organocatalyt-
ic, intramolecular oxa-Michael addition/electrophilic fluori-
nation tandem reaction for the synthesis of a series of chiral
monofluorinated flavanones. By using the new quinidine-de-
rived bifunctional catalyst 4m, high enantioselectivities (up
to 96% ee) and excellent yields were obtained for most of
the substrates under mild conditions. Further applications of
the present reaction as well as the use of the bifunctional or-
ganocatalysts in other reactions are in progress in our labo-
ratories.
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Experimental Section
Typical procedure: A mixture of (E)-ethyl 2-(2-hydroxybenzoyl)-3-phe-
nylacrylate 1a (0.1 mmol) and catalyst 4m (7 mg, 0.015 mmol) in toluene
(1.0 mL) was stirred at room temperature for the appropriate time until
1a was consumed (as monitored by TLC). Then Na2CO3 (12.7 mg,
0.12 mmol) and NFSI (47.3 mg, 0.15 mmol) were added and the mixture
was stirred at room temperature for 6–12 h (as monitored by TLC). The
reaction mixture was then concentrated and the residue was purified by
flash column chromatography on silica gel (ethyl acetate/petroleum ether
1:20, v/v) to give the desired products 3a as a white solid (31.1 mg, 99%).
[a]2D4 =À166.5 (c=1.03 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.02
(t, J=6.9 Hz, 3H), 4.03–4.09 (m, 2H), 5.54 (d, J=8.4 Hz, 1H), 7.13–7.19
(m, 2H), 7.38–7.52 (m, 5H), 7.62 (t, J=7.5 Hz, 1H), 8.00 (d, J=7.5 Hz,
1H); 19F NMR (282 MHz, CDCl3): d=À175.30 (d, J=7.9 Hz, 1F). The ee
value was determined by HPLC analysis by using a chiralcel OD column,
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, tR (minor)=
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Acknowledgements
This research was supported by the National Natural Science Foundation
of China (nos. 20172064, 203900502, and 20532040), theQT Program,
Shanghai Natural Science Council, and the Excellent Young Scholars
Foundation of National Natural Science Foundation of China (20525208).
Keywords: asymmetric catalysis
· cinchona alkaloids ·
domino reactions · fluorination · oxa-Michael addition
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Received: August 20, 2009
Published online: November 6, 2009
Chem. Eur. J. 2009, 15, 13299 – 13303
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13303