Exploration on asymmetric synthesis of flavanone catalyzed by (S)-pyrrolidinyl tetrazole

Article abstract of DOI:10.1002/chir.20951

An improved method of the synthesis of flavanones catalyzed by pyrrolidine and BF₃·Et₂O has been developed and a lot of flavanones could be easily synthesized via this method. The asymmetric synthesis of flavanone from benzaldehyde a

Full text of DOI:10.1002/chir.20951

CHIRALITY 23:504–506 (2011)
Exploration on Asymmetric Synthesis of Flavanone Catalyzed
by (S)-Pyrrolidinyl Tetrazole
1
1
2
SHUBAO ZHOU,1,2 YUQIANG ZHOU,1,2 YALAN XING, NAIXING WANG, AND LINGHUA CAO
*
1Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, China
2College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi, China
ABSTRACT
An improved method of the synthesis of flavanones catalyzed by pyrrolidine
and BF3ÁEt2O has been developed and a lot of flavanones could be easily synthesized via this
method. The asymmetric synthesis of flavanone from benzaldehyde and 5-fluoro-2-hydroxyace-
tophenone has been studied and flavanone with moderate enantioselectivity was obtained in
C
VV
one step. Chirality 23:504–506, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: asymmetric catalysis; flavanones; BF3ÁEt2O; aromatic aldehydes; organocatalyst
from Daicel Chemical Industries, LTD. Analytical Thin Layer Chroma-
INTRODUCTION
tography was carried out on precoated plates (silica gel 60, F254), visual-
ized with UV light. All the reagents are used directly from commercial
sources and all melting points are uncorrected.
The flavanone is a key structure that presents in a lot of nat-
ural products with a broad array of biological activity,1 such as
antioxidant,2 antiestrogen,3 and anticancer.4 Moreover, these
kinds of compounds are important intermediates in the syn-
thesis of flavanone glycosides and 2-aryl chromans.5,6 There-
fore, much attention has recently been paid to design and syn-
thesize flavanone derivaties due to their various applications.
The methodology of preparing flavanones involves intra-
molecular oxa-Michael addition reactions of 2-hydroxy chal-
cones.7–9 Chandrasekhar reported the synthesis of flava-
nones catalyzed by L-proline recently, but the products are
mixtures of flavanone and chalcone.10 Herein, we would like
to report an improved method of the synthesis of flavanones
from aldehydes and 5-fluoro-2-hydroxyacetophenone 1 in the
presence of pyrrolidine and BF3ÁEt2O. The flavanones could
be obtained with moderate yields when pyrrolidine and
BF3ÁEt2O (1:5) were used as catalysts.
The Reactions of 5-Fluoro-2-hydroxyacetophenone 1 with
Aromatic Aldehydes 2 Catalyzed by Pyrrolidine and
BF3ÁEt2O; General Procedure
A mixture of 5-fluoro-2-hydroxyacetophenone 1 (77 mg, 0.5 mmol)
and the corresponding aldehyde 2 (0.75 mmol) in anhydrous EtOH (1
ml) was stirred at room temperature for 5 min. Then, pyrrolidine (7 mg,
0.2 equiv.) was added. The mixture was stirred at room temperature for
18 h. Then BF3ÁEt2O (71 mg, 1.0 equiv.) was added and the mixture was
refluxed. The mixture was filtered by short column and resulting solu-
tion was evaporated under vacuum, and the residue was purified by
chromatography (petroleum ether and EtOAc) to afford the desired
product 3.
6-fluoro-2-phenylchroman-4-one 3a. White solid; mp 75.0–
76.08C. 1H NMR (400 MHz, CDCl3): d 5 7.59–7.57 (m, 1 H), 7.50–7.38
(m, 5 H), 7.26–7.21 (m, 1 H), 7.05–7.02 (m, 1 H), 5.46 (dd, J 5 13.3, 2.9
Hz, 1 H), 3.08 (dd, J 5 17.0, 13.3 Hz, 1 H), 2.90 (dd, J 5 17.0, 3.0 Hz, 1
H). 13C NMR (100 MHz, CDCl3, Coupling of 19F-13C is not shown here):
d 5 191.3, 158.7, 157.9, 156.3, 138.6, 129.0 (2C), 126.3 (2C), 123.9, 121.5,
120.0, 112.2, 80.0, 44.4.
With a prochiral center at the C2, the asymmetric synthe-
sis of flavanones with organocatalysts presents a continuing
challenge. In recent years, many studies were focused on
the asymmetric synthesis of flavanones.11–19 However, only a
limited number of strategies have been developed to synthe-
size the C2 stereocenter flavanones, such as the synthesis of
chiral flavanones by natural chiron,11–13 and by the kinetic re-
solution with the lipase,14,15 and by chiral catalysts.16–19 In
view of these results, there is still the potential for the devel-
opment of new strategies to synthesize chiral flavanones.
Herein, we would like to report an asymmetric synthesis of
flavanone in the presence of (S)-pyrrolidinyl tetrazole cataly-
sis in 51% ee. To the best of our knowledge, one-step asym-
metric synthesis of flavanones from aromatic aldehydes and
2-hydroxy- acetophenones by chiral catalysts has not been
reported and it is the first time to find that chiral flavanone
3a could be obtained by (S)-pyrrolidinyl tetrazole catalysis.
6-fluoro-2-(4-nitrophenyl)chroman-4-one 3b. White solid; mp
174.0–176.08C. 1H NMR (400 MHz, CDCl3): d 5 8.30 (d, J 5 8.4 Hz, 2
H), 7.67 (d, J 5 8.4 Hz, 2 H), 7.66–7.57 (m, 1 H), 7.30–7.26 (m, 1 H),
7.10–7.07 (m, 1 H), 5.61–5.57 (m, 1 H), 3.01–2.97 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d 5 190.0, 159.0, 157.3, 148.2, 145.6, 126.9, 124.3,
124.0, 121.6, 120.0, 112.5, 78.7, 44.5. HRMS (EI): m/z [M]1 calcd
C15H10FNO4: 287.0594; found: 287.0494.
6-fluoro-2-(2,4-dichlorophenyl)chroman-4-one 3c. White solid;
1
mp 137.0–138.08C. H NMR (400 MHz, CDCl3): d 5 7.68 (d, J 5 8.4 Hz,
1 H), 7.61–7.58 (m, 1 H), 7.44 (d, J 5 2.0 Hz, 1 H), 7.39–7.36 (m, 1 H),
7.27–7.06 (m, 1 H), 7.07–7.03 (m, 1H), 5.78 (dd, J 5 13.6, 2.64 Hz, 1 H),
3.02 (dd, J 5 17.0, 2.7 Hz, 1 H), 2.82 (dd, J 5 17.0, 13.6 Hz,1 H). 13C
NMR (100 MHz, CDCl3): d 5 190.5, 158.9, 157.7, 156.5, 135.3, 135.3,
132.4, 129.7, 128.3, 124.0, 121.6, 119.9, 112.5, 76.5, 43.2. HRMS (EI): m/z
[M]1 calcd C15H9Cl2FO2: 309.9964; found: 309.9968.
EXPERIMENTAL
Additional Supporting Information may be found in the online version of this
article.
*Correspondence to: Naixing Wang, Technical Institute of Physics and
Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
E-mail: nxwang@mail.ipc.ac.cn
Received for publication 23 March 2010; Accepted 17 January 2011
DOI: 10.1002/chir.20951
Published online 15 April 2011 in Wiley Online Library
(wileyonlinelibrary.com).
Nuclear Magnetic Resonance spectroscopy was performed on an
Bruker DPX-400 spectrometer operating at 400 MHz (1H NMR) and 100
MHz (13C NMR). Tetramethylsilane was used an internal standard and
CDCl3 was used as the solvent. Mass spectra were recorded on a Bruker
Microflex mass spectrometer. High Performance Liquid Chromatogra-
phy analysis was performed on Hitachi (L-7420 Dual Absorbance Detec-
tor and L-7110 HPLC Pump). Chiralpak OD-H columns was purchased
C
VV
2011 Wiley-Liss, Inc.

ASYMMETRIC SYNTHESIS OF FLAVANONE
505
TABLE 1. The reactions of 1 with aromatic aldehydes
RESULTS AND DISCUSSION
catalyzed by pyrrolidine and BF3ÁEt2Oa
The synthesis of compounds 3a–3e was achieved from 5-
fluoro-2-hydroxyacetophenone and the derivatives of benzal-
dehyde in the presence of pyrrolidine and BF3ÁEt2O (1:5)
with moderate yields (Table 1). As can be seen from the ta-
ble, all the substrates could be carried out smoothly. The
use of benzaldehyde gave a yield of 68 % (Table 1, entry 1).
Although benzaldehydes with electron withdrawing group
were used, moderate yield products could be successfully
obtained, such as, benzaldehydes with nitro group could
give a product with yield of 54 % (Table 1, entry 2), benzalde-
hydes with chlorine atoms could give a product with yield of
63 % (Table 1, entry 3), benzaldehydes with ester group
could give a product with yield of 65% (Table 1, entry 4) and
benzaldehydes with formacyl could give a product with yield
of 60 % (Table 1, entry 5).
Entry
1
Substrate
Product Reflux time (h) Yield (%)b
3a20
36
68
2
3
3b
36
54
The one-step asymmetric synthesis of flavanone was also
studied, and the reaction of 5-fluoro-2-hydroxyacetophenone
1 with benzaldehyde 2a was investigated at room tempera-
ture in the presence of organocatalyst (Table 2). Several
chiral catalysts were surveyed firstly for the reaction of syn-
thesis of chiral flavanone. We found that 1 did not react with
benzaldehyde in EtOH when (1)-Quinidine 4 and L-prolinol
5 were respectively used as catalyst (Table 2, entries 1 and
2). (S)-Pyrrolidinyl tetrazole 6 showed better reactivity than
(1)-Quinidine 4 and L-prolinol 5, and the flavanone 3a was
obtained in 44% ee when we changed the catalyst to 6 (Table
2, entry 3). Therefore, catalyst 6 was chosen for further opti-
mization of the reaction conditions. A survey of different sol-
vents revealed EtOH to be the most suitable one for this
reaction with an improved yield and ee (Table 2, entries 3–5).
The effect of the catalyst loading of 6 was also studied, and
we found that increasing of the catalyst 6 loading could
afford a higher ee (Table 2, entry 6).
3c
36
63
4
5
3d
3e
36
48
65
60
aReaction conditions: 1 (0.5 mmol), 2 (0.75 equiv.), pyrrolidine (0.2 equiv.),
anhydrous EtOH (1.0 ml), stirred at r.t. for 18 h, then BF3ÁEt2O (1.0 equiv.)
was added, reflux.
bIsolated yields. Absolute configuration of 3a was determined according to
the literature21
.
TABLE 2. Organocatalytic asymmetric reactions of 1 with 2aa
Methyl 4-(6-fluoro-4-oxochroman-2-yl)benzoate 3d. Yellow
solid; mp 133.0–134.08C. 1H NMR (400 MHz, CDCl3): d 5 8.10 (d, J 5
8.3 Hz, 2 H), 7.58–7.56 (m, 1 H), 7.55 (d, J 5 8.3 Hz, 2 H), 7.27–7.22 (m,
1 H), 7.07–7.04 (m, 1 H), 5.52 (dd, J 5 12.9, 3.1 Hz, 1 H), 3.93 (s, 3 H),
3.03 (dd, J 5 17.0, 13.0 Hz, 1 H), 2.92 (dd, J 5 17.0, 3.2 Hz,1 H). 13C
NMR (100 MHz, CDCl3): d 5 190.6, 166.6, 158.7, 157.5, 143.4, 130.2,
126.0, 124.0, 121.5, 119.9, 112.3, 79.3, 52.3, 44.4. HRMS (EI): m/z [M]1
calcd C18H15FO4: 300.0798; found: 300.0682.
4-(6-fluoro-4-oxochroman-2-yl)benzaldehyde 3e. White solid;
1
mp 136.0–138.08C. H NMR (400 MHz, CDCl3): d 5 10.05 (s, 1 H), 7.96
(d, J 5 8.1 Hz, 2 H), 7.66 (d, J 5 8.1 Hz, 2 H), 7.59–7.56 (m, 1 H), 7.29–
7.24 (m, 1 H), 7.09–7.06 (m, 1 H), 5.56 (dd, J 5 12.7, 3.4 Hz, 1 H), 3.03
(dd, J 5 17.0, 12.8 Hz, 1 H), 2.94 (dd, J 5 17.0, 3.5 Hz,1 H). 13C NMR
(100 MHz, CDCl3): d 5 191.7, 190.5, 158.9, 157.5, 145.0, 136.7, 130.9,
126.7, 124.2, 121.5, 120.0, 112.4, 79.2, 44.5. HRMS (EI): m/z [M]1 calcd
C16H11FO3: 270.0692; found: 270.0485.
Entry
Chiral catalyst
Solvent
Yield (%)b
Ee (%)c
1
2
3
4
4
5
6
6
6
6
EtOH
EtOH
EtOH
Toulene
i-PrOH
EtOH
n.r.d
n.r.d
21
n.d.e
n.d.e
44 (R)
Organocatalytic Asymmetric Reaction of 5-Fluoro-2-hydroxyace-
tophenone 1 with Benzaldehyde 2a; Procedure. A mixture of 5-flu-
oro-2-hydroxyacetophenone 1 (31 mg, 0.2 mmol) and benzaldehyde 2a
(21 mg, 0.2 mmol) in anhydrous EtOH (1 ml) was stirred at room tem-
perature for 6 d. The mixture was evaporated under vacuum, and the
residue was purified by chromatography (petroleum ether and EtOAc)
to afford the desired product 3a.
The enantiomeric excess was determined by HPLC analysis using a
chiracel OD-H column (eluent: n-heptane/i-PrOH, 95:5, flow rate: 0.7
mL/min, wave length: 254 nm, temperature: 258C. Peaks 1, retention
time: 18.15 min, integral 23.94 %; Peaks 2, retention time: 25.52 min; inte-
gral 72.90%.)
n.r.d
14
n.d.e
5
43 (R)
51 (R)
6g
22
aReaction conditions: a mixture of 1 (0.2 mmol), 2a (0.2 mmol) and a catalyst
(20 mol%) in solvent (1.0 ml) was stirred at r.t. for 6 d.
bIsolated yields. Absolute configuration is determined according to the litera-
ture.21
cDetermined by HPLC analysis (Chiralcel OD-H).
dNo reaction.
eNot determined.
g30% catalyst was used.
Chirality DOI 10.1002/chir

506
ZHOU ET AL
9. Kumar D, Patel G, Mishra BG, Varma RS. Eco-friendly polyethylene gly-
CONCLUSIONS
col promoted Michael addition reactions of a,b-unsaturated carbonyl
In summary, we have developed an improved method for
the synthesis of flavanones catalyzed by pyrrolidine and
BF3ÁEt2O and a lot of flavanones could be easily synthesized
via this method. The one-step asymmetric synthesis of flava-
none from benzaldehyde and 5-fluoro-2-hydroxyacetophe-
none was studied and chiral flavanone 3a was obtained with
moderate enantioselectivity. More investigations of the reac-
tions are currently in progress.
compounds. Tetrahedron Lett 2008;49:6974–6976.
10. Chandrasekhar S, Vijeender K, Reddy KV. New synthesis of flavanones
catalyzed by L-proline. Tetrahedron Lett 2005;46:6991–6993.
11. Kevin JH. Approaches to 2-substituted chroman-4-ones: synthesis of (-)-
pinostrobin. Tetrahedron Lett 2001;42:3763–3766.
12. Kawasaki M, Kakuda H, Goto M, Kawabataa S, Kometanic T.
Asymmetric synthesis of 2-substituted chroman-4-ones using lipase--
catalyzed kinetic resolutions. Tetrahedron: Asymmetry 2003;14:
1529–1534.
13. Kawasaki M, Asano Y, Katayama K, Inoue A, Hiraoka C, Kakudac H,
Tanaka A, Goto M, Toyooka N, Kometani T. Asymmetric synthesis of 2-
substituted 4-chromanones using enzyme-catalyzed reactions. J Mol Catal
B: Enzym 2008;54:93–102.
ACKNOWLEDGMENTS
We thank the National 973 Program (NO. 2010CB732202)
Foundation for financial support.
14. Ramadas S, Krupadanam GLD. Enantioselective acylation of (6)-cis-fla-
van-4-ols catalyzed by lipase from Candida cylindracea (CCL) and the
synthesis of enantiopure flavan-4-ones. Tetrahedron: Asymmetry
2004;15:3381–3391.
LITERATURE CITED
1. Harborne JB, Williams CA. Anthocyanins and other flavonoids. Nat Prod
Rep 1995;12:639–657.
15. Todoroki T, Saito A, Tanaka A. Lipase-catalyzed kinetic resolution of (6)-
cis-flavan-4-ol and its acetate: synthesis of chiral 3-hydroxyflavanones.
Biosci Biotechnol Biochem 2002;66:1772–1774.
2. Tripoli E, La Guardia M, Giammanco S, Di Majo D, Giammanco M. Cit-
rus flavonoids: molecular structure, biological activity and nutritional
properties: a review. Food Chem 2007;104:466–479.
16. Dittmer C, Raabe G, Hintermann L. Asymmetric cyclization of 2’-hydroxy-
chalcones to flavanones: catalysis by chiral Brønsted acids and bases.
Eur J Org Chem 2007;35:5886–5898.
3. Shinkaruk S, Lamothe V, Schmitter JM, Manach C, Morand C, Berard A,
Bennetau B, Bennetau-Pelissero C. Development and validation of two
new sensitive ELISAs for Hesperetin and Naringenin in biological fluids.
Food Chem 2010;118:472–481.
17. Biddle MM, Lin M, Scheidt KA. Catalytic enantioselective synthesis of
flavanones and chromanones. J Am Chem Soc 2007;129:3830–3831.
4. Bulzomi1 P, Bolli1 A, Galluzzo1 P, Leone1 S, Acconcia1 F, Marino1 M.
Naringenin and 17b-Estradiol coadministration prevents hormone-
induced human cancer cell growth. IUBMB Life 2010;62:51–60.
18. Wang L, Liu X, Dong Z, Fu X, Feng X. Asymmetric intramolecular oxa-
Michael addition of activated a,b-unsaturated ketones catalyzed by a chi-
ral N,N’-dioxide nickel(II) complex: highly enantioselective synthesis of
flavanones. Angew Chem Int Ed Engl 2008;47:8670–8673.
5. Oyama K, Kondo T. Total synthesis of flavocommelin, a component of the
blue supramolecular pigment from Commelina communis, on the basis of
direct 6-C-glycosylation of flavan. J Org Chem 2004;69:5240–5246.
19. Wang HF, Cui HF, Chai Z, Li P, Zheng CW, Yang YQ, Zhao G. Asymmet-
ric synthesis of fluorinated flavanone derivatives by an organocatalytic
tandem intramolecular oxa-Michael addition/electrophilic fluorination
reaction by using bifunctional cinchona alkaloids. Chem Eur J 2009;15:
13299–13303.
6. Hodgetts KJ. Inter- and intramolecular Mitsunobu reaction based
approaches to 2-substituted chromans and chroman-4-ones. Tetrahedron
2005;61:6860–6870.
7. Chen DU, Kuo PY, Yang DY. Design and synthesis of novel diphena-
coum-derived, conformation-restricted vitamin K 2,3-epoxide reductase
inhibitors. Bioorg Med Chem Lett 2005;15:2665–2668.
20. Chang CT, Chen FC, Chen TS, Hsu KK, Ueng T, Hung M. Synthesis of
6-halogenoflavones and related compounds. J Chem Soc 1961;83:3414–
3417.
8. Moorthy NSHN, Singh RJ, Singh HP, Gupta SD. Synthesis, biological
evaluation and In Silico metabolic and toxicity prediction of some flava-
none derivatives. Chem Pharm Bull 2006;54:1384–1390.
21. Arakawa H, Nakazaki M. Die absolute Konfiguration der optisch aktiven
flavanone. Justus Liebigs Ann Chem 1960;636:111–117.
Chirality DOI 10.1002/chir