Synthesis of chiral flavanones from tricarbonyl (η6- Arylbenzaldehyde)chromium(0)

Article abstract of DOI:10.14233/ajchem.2013.14634

A synthesis of chiral flavanones via the condensation of tricarbonyl(η⁶-arylbenzaldehyde)chromium(0) and o-hydroxyacetophenone in a shorter time at room temperature have been developed. The tricarbonylchromium(0) group was removed by virtue of light and the enantioenriched flavanones was formed with highly enantioselectivity (> 95 % ee).

Full text of DOI:10.14233/ajchem.2013.14634

Asian Journal of Chemistry; Vol. 25, No. 14 (2013), 7828-7830
http://dx.doi.org/10.14233/ajchem.2013.14634
Synthesis of Chiral Flavanones from Tricarbonyl (η6-Arylbenzaldehyde)chromium(0)
1
2
1
1
1
1
1,2,*
GUI-XIANG LIU , YU WAN , LING-LING ZHAO , HAI-YING WANG , ZHOU XU , JIN-LONG QI and HUI WU
1School of Chemistry and Chemical Engineering, Jiangsu Normal University, Jiangsu Key Laboratory of Green Synthesis of Functional Material,
Xuzhou 221116, P.R. China
2Jiangsu Key Laboratory of Biotechnology on Medical Plant, Xuzhou 221116, P.R. China
*Corresponding author: Fax: +86 516 83500164; Tel: +86 516 83403163; E-mail: wuhui72@yahoo.com.cn
(Received: 29 September 2012;
Accepted: 18 July 2013)
AJC-13819
A synthesis of chiral flavanones via the condensation of tricarbonyl(η6-arylbenzaldehyde)chromium(0) and o-hydroxyacetophenone in a
shorter time at room temperature have been developed. The tricarbonylchromium(0) group was removed by virtue of light and the
enantioenriched flavanones was formed with highly enantioselectivity (> 95 % ee).
Key Words: Synthesis, Chiral flavanones, Chiral tricarbonylchromium(0) aromatic aldehydes.
glass backed plates precoated with silica gel and examined
under UV (254 nm).
INTRODUCTION
Flavanones constitute a large number of natural products
with many medicinal applications1. Because of their broad
range of biological activities such as anti HIV2, anticancer3,
antioxidant4, gastro-protective5, antibacterial and antifungal6,7,
a variety of approaches have been developed to synthesize
flavanones. The most commonly one was the intramolecular
cyclodehydration of 1-(2-hydroxyphenyl)-1,3-diketones8.
Although the diastereoselective flavanones has been shown to
proceed, in some cases, with high to excellent diastereo-
selectivities, the enantioselective variation of this reaction is
less developed. A limited number of strategies have been
developed to obtain chiral flavanones, such as resolution of
the related alcohols9 or substitution reactions10. Due to its
difficult synthesis and harsh experimental conditions, it is
needed to find efficient method for the synthesis of chiral
flavanones.
Experimental process: Synthesis of racemic flavanones
(Scheme-I): Compound 3 (2-hydroxychalcones) was prepared
through condensation of aromatic aldehyde 1 (5 mmol) and
o-hydroxyacetophenone 2 (5 mmol) in 20 % NaOH aqueous
solution (2 mL), using TBAB (tetrabutylammonium bromide,
0.15 mmol, 0.05 g) as phase transfer catalyst under microwave
irradiation for 5 min. Then the reaction mixture was poured
into ethyl acetate (20 mL) and washed with water for 2-3 times.
The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo and purified by chromato-
graphy on silica gel (petroleum ether:ethyl acetate = 3:1) to
give 3.
CHO
OH
O
OH
O
20%NaOH
MW/TBAB
R1
R2
+
R1
R2
Herein we report an efficient synthesis of chiral flavanones
via the reaction of tricarbonylchromium(0) and o-hydroxy-
acetophenone.
3
1
2
O
O
Pyridine
H2O
R1
R2
EXPERIMENTAL
4
Solvents were dried and liquid aromatic aldehydes were
distilled prior to use. NMR spectra were recorded on a Bruker
Avance DMX400 spectrometer in DMSO-d6 with TMS as an
internal standard. Infrared spectra were recorded on Bruker
FTIR-Tensor27 spectrometer expressed in cm-1 (KBr). Mass
was determined by using a Bruker Micro TOF-MS high reso-
lution mass spectrometer. TLC analysis was performed with
Scheme-I: Synthesis of enantiomers 2-phenychroman-4-ones
The mixture of 3 (2 mmol), hexahydropyridine (1 mL)
and water (10 mL) was taken in a 50 mL round bottom flask
and stirred at room temperature for 5-6 h. Then by filtering
flavanones 4 was obtained (Table-1).

Vol. 25, No. 14 (2013)
Synthesis of Chiral Flavanones from Tricarbonyl (η6-Arylbenzaldehyde)chromium(0) 7829
OH
O
TABLE-1
SYNTHETIC RESULTS OF RACE-FLAVANONE 4
OH
O
OH
OH
H+
O
H
Entry
4a
R
Formula
C16H14O3
m.p. (ºC) Time Yield (%)
Condensation
OCH3
OCH3
OCH3
2 -OCH3
106-107
92-93
73-74
97-98
95-96
81-82
70-72
3.0
3.0
3.5
3.0
3.0
2.0
2.0
85
80
85
89
90
92
90
(OC)3Cr
(OC)3Cr
(OC)3Cr
2,3(-OCH3)2 C17H16O4
3,4(-OCH3)2 C17H16O4
4b
4c
O
O
hv/O2
H
O
2-Br
3-Br
4-Cl
–
C15H11O2Br
C15H11O2Br
C15H11O2Cl
C15H12O2
4d
4e
OCH3
H
OCH3
(OC)3Cr
O
4f
Scheme-III: Probable mechanism
4g
Spectral data for new compounds
Synthesis of chiral flavanones (Scheme-II): In N2
atmosphere the chiral tricarbonylchromium(0) aromatic
aldehydes 5 (based on our previous work11) (5 mmol) and o-
hydroxyacetophenone 2 (5 mmol) were stirred with 20 %
NaOH solution (2 mL) in 95 % ethanol (10 mL) and THF
(tetrahydrofuran 10 mL) at room temperature for 1 h. Then
the reaction mixture was poured into ethyl acetate (20 mL)
and washed with water for 2-3 times. The combined organic
layers were dried over anhydrous Na2SO4, concentrated in
vacuo and purified by chromatography on silica gel (petroleum
ether:ethyl acetate = 3:1) to give chiral tricarbonylchromium(0)
2-hydroxychalcones 6.
2,3-Dihydro-2-(2-methoxyphenyl)chromen-4-one (4a):
colourless crystals, IR (KBr, νmax, cm-1): 3030, 2960, 2920,
2870, 1680, 1600, 1500, 1460, 1380, 1260. 1H NMR (δ ppm,
DMSO-d6): 2.86 (dd, J1 = 2.4Hz, J2 = 16.8 Hz, C3-H), 3.33 (t,
J = 13.6Hz, C3-H), 3.89 (s, 3H, CH3O), 5.84 (dd, J1 = 2.8 Hz,
J2 = 13.2 Hz, 1H, C2-H), 7.70-7.13 (m, 8H, ArH). Anal. calcd.
(%) for C16H14O3: C 63.0, H 5.5; found (%): C 63.2, H 5.6.
2,3-Dihydro-2-(2,3-dimethoxyphenyl)chromen-4-one
(4b): IR (KBr, νmax, cm-1): 3030, 2960, 2920, 2860, 1680, 1600,
1500, 1450, 1380, 1260, 1120. 1H NMR (δ ppm, DMSO-d6):
2.86 (dd, J1 = 2.4 Hz, J2 = 16.8 Hz, C3-H), 3.32 (t, J = 13.6 Hz,
C3-H), 3.83 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 5.84 (dd, J1 =
2.8 Hz, J2 = 13.2 Hz, 1H, C2-H), 7.70-7.13 (m, 7H, ArH).
Anal. calcd. (%) for C17H16O4: C 71.8, H 5.6; found (%): C
71.9, H 5.7.
CHO
OH
O
OH
O
20%NaOH
EtOH/THF
R1
R2
Cr(CO)3
R2
R1
+
(OC)3Cr
5
2
6
2,3-Dihydro-2-(3,4-dimethoxyphenyl)chromen-4-one
(4c): IR (KBr, νmax, cm-1): 3030, 2960, 2920, 2870, 1680, 1600,
1500, 1450, 1380, 1260, 1130. 1H NMR (δ ppm, DMSO-d6):
2.85 (dd, J1 = 2.4 Hz, J2 = 16.8 Hz, C3-H), 3.32 (t, J = 13.6 Hz,
C3-H), 3.83 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 5.84 (dd, J1 =
2.8 Hz, J2 = 13.2 Hz, 1H, C2-H), 7.70-7.13 (m, 7H, ArH).
Anal. calcd. (%) for C17H16O4: C 71.8, H 5.6; found (%): C
71.8, H 5.7.
O
O
CH3COONa
EtOH
hv
R1
R2
R1
R2
O
O
(OC)3Cr
7
8
Scheme-II: Synthesis of chiral 2-phenychroman-4-ones
2,3-Dihydro-2-(2-bromo)chromen-4-one (4d): IR (KBr,
1
The mixture of 6 (2 mmol), sodium acetate and 95 %
ethanol (10 mL) was taken in a 50 mL round bottom flask and
stirred at room temperature for 5-6 h. Then by filtering we got
chiral tricarbonylchromium(0) flavanones 7. By virtue of light,
the tricarbonylchromium(0) group was removed and obtained
the chiral flavanones 8 (Table-2).
ν
max, cm-1): 3030, 2920, 1680, 1600, 1500, 1450, 1260. H
NMR (δ ppm, DMSO-d6): 3.33 (t, J = 13.6 Hz, C3-H), 2.84
(dd, J1 = 2.4 Hz, J2 = 16.8 Hz, C3-H), 5.86 (dd, J1 = 2.8, J2 =
13.2 Hz, 1H, C2-H), 8.27-7.00 (m, 8H, ArH). Anal. calcd. (%)
for C15H11O2Br: C 59.4, H 3.6; found (%): C 59.5, H 3.4.
2,3-Dihydro-2-(2-chloro)chromen-4-one (4e): IR (KBr,
1
ν
max, cm-1): 3030, 2920, 1680, 1600, 1500, 1450, 1260. H
TABLE-2
SYNTHETIC RESULTS OF CHIRAL FLAVANONES
NMR (δ ppm, DMSO-d6): 3.33 (t, J = 13.6 Hz, C3-H), 2.84
(dd, J1 = 2.4 Hz, J2 = 16.8 Hz, C3-H), 5.86 (dd, J1 = 2.8, J2 =
13.2 Hz, 1H, C2-H), 8.27-7.00 (m, 8H, ArH). Anal. calcd. (%)
for C15H11O2Cl: C 59.4, H 3.6; found (%): C 59.5, H 3.4.
2,3-Dihydro-2-(4-chloro)chromen-4-one (4f): IR (KBr,
Entry
+8a
-8a
Time
2.0
Yield (%)a
e.e (%)b
Config.
65
65
60
96
R
S
R
S
2.0
98
2.0
95
+8b
-8b
2.0
60
94
ν
max, cm-1): 3030, 2920, 1680, 1600, 1500, 1450, 1260, 1130.
b
aIsolated yields after chromography. Determinede by chiral-HPLC
1H NMR (δ ppm, DMSO-d6): 2.83 (dd, J1 = 2.4 Hz, J2 = 16.8
Hz, C3-H), 3.35 (t, J = 13.6 Hz, C3-H), 5.82 (dd, J1 = 2.8 Hz, J2
= 13.2 Hz, 1H, C2-H), 7.70-7.13 (m, 8H, ArH). Anal. calcd.
(%) for C15H11O2Cl: C 69.6, H 4.3; found (%): C 69.7, H 4.4.
using AD-H coloum.
Probable mechanism (Scheme-III): Firstly, the starting
chalcone was accessed via Knoevenagel condensation, the
chiral tricarbonylchromium(0) aromatic aldehydes reacted
with o-hydroxyacetophenone in alkaling condition. Then,
based on acid catalyzed the flavanones was formed upon
intramolecular cyclization.At last the tricarbonylchromium(0)
group was removed by virtue of light and the enantioenriched
flavanones was formed (Scheme-III).
RESULTS AND DISCUSSION
In this work, it was found that the ee % of products were
high when chiral tricarbonylchromium(0) aromatic aldehydes
were used as chiral reactant. The results indicated that both
(-)-tricarbonylchromium(0) aromatic aldehydes and (+)-

7830 Liu et al.
Asian J. Chem.
tricarbonylchromium(0) aromatic aldehydes played the same
activity and stereoselective role in the synthesis of chiral
flavanones.
for Higher Education Institutions in Jiangsu Province (Pre-
development of medicinal microbial resources) for financial
support.
Conclusion
REFERENCES
In summary, we have developed an efficient method for
the synthesis of chiral flavanones. This is a novel application
of chiral tricarbonylchromium(0) aromatic aldehydes. Shorter
total times (5-6 h) were taken with highly enantioselective
(> 95 % ee) at room temperature comparing with previous
methods. Our method for the synthesis of these natural products
provided an efficient way and made significant improvment.
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(No. 10KJA430050, 11KJB150017), the Graduate Innovation
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