New synthesis of flavanones catalyzed by L-proline

Article abstract of DOI:10.1016/j.tetlet.2005.08.066

L-Proline is utilized as an efficient organocatalyst for the synthesis of substituted flavanones and chalcones in good yields. The efficiency of the catalyst was proved with a variety of substrates ranging from electron-deficient to electron-rich aryl aldehydes and 2-hydroxyacetophenones.

Full text of DOI:10.1016/j.tetlet.2005.08.066

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6991–6993
New synthesis of flavanones catalyzed by L-prolineI
S. Chandrasekhar,* K. Vijeender and K. Venkatram Reddy
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 12 July 2005; revised 2 August 2005; accepted 12 August 2005
Abstract—L-Proline is utilized as an efficient organocatalyst for the synthesis of substituted flavanones and chalcones in good yields.
The efficiency of the catalyst was proved with a variety of substrates ranging from electron-deficient to electron-rich aryl aldehydes
and 2-hydroxyacetophenones.
Ó 2005 Elsevier Ltd. All rights reserved.
There is a resurgence in research activity in the flavanoid
class of molecules due to excellent biological profiles
reported in the recent times. This class of New Chemical
Entities show activity in cancer, AIDS, bacterial and
inflammatory diseases.
whereas in the case of ketones spirocyclic flavanones
were the exclusive products.
In the first instance, 2-hydroxyacetophenone and benz-
aldehyde in equimolar quantities were stirred together in
the presence of L-proline (30 mol %) in DMF (0.02 M)
at 80 °C for 18 h. The usual work up viz extracting with
ether followed by a water wash and chromatography
furnished flavanone 1 along with chalcone in a 7:3 ratio
with combined yield of 70%. To further substantiate this
result, various substituted aldehydes and substituted
2-hydroxy acetophenones were subjected to L-proline
catalysis and good yields of flavanones and chalcones
were obtained. The various aldehydes included benz-
aldehyde (Table 1, entries 1–3), 4-nitrobenzaldehyde
(entry 4), 4-chlorobenzaldehyde (entry 5), mono- and
dimethoxy benzaldehydes (entries 6–10), p-tolualdehyde
(entry 11), pyridine aldehydes (entries 12–14) and furfur-
aldehyde (entry 14). The substituted 2-hydroxy aceto-
phenones are represented by 2-hydroxyacetophenone
(entries 1, 4, 5, 6, 11, 12, 14 and 15), 5-chloro-4-
methyl-2-hydroxyacetophenone (entries 2, 7 and 9)
and 3-methoxy 2-hydroxyacetophenone (entries 3, 8,
10 and 13). In total, 15 flavanones and 15 chalcones
were synthesized (Scheme 1).
The methodology most widely used to prepare flava-
nones involves the isomerization of appropriately substi-
tuted 2-hydroxy chalcones, in turn obtained by an aldol
condensation reaction between a 2-hydroxyacetophe-
none and an aldehyde. These cyclizations have been car-
ried out under numerous conditions using acids,1 bases,2
silica gel,3 heat,4 light,5 electrolysis,6 Ni/Zn/K halides7
and others.8 Other alternative procedures to synthesize
flavanones include oxidation of flavan-4-ol.9 Reacting
benzaldehydes with 1-(2-hydroxyphenyl)-3-phenyl pro-
pane-1,3-diones in basic medium10 and transformation
of 3-bromo-1-phenylprop-2-ynyl aryl ethers in the pres-
ence of mercury(II) trifluoroacetate.11
As part of an exploration of the possibility of utilizing
L-proline as organocatalyst12 for aldol and related
reactions, herein we disclose syntheses of flavanones
from aryl aldehydes and substituted 2-hydroxyacetophe-
nones in one step. Also, the synthesis of spiroflavanones
were achieved from ketones and substituted 2-hydroxy-
acetophenones in the presence of L-proline (30 mol %) in
DMF as solvent. In the case of aldehydes, mixtures of
flavanones and chalcones were isolated with ease,
Next, cyclohexanone was used as partner in the flava-
none synthesis (Scheme 2). The unsubstituted (Table 2,
entries 1–3) mono- (entry 4) and disubstituted (entry
5) 2-hydroxyacetophenones underwent very easy spiro-
cyclization to generate novel tricyclic flavanones in very
high yields.
Keywords: L-Proline; Flavanone; Chalcone; 20-Hydroxyacetophenone;
Isomerization.
q IICT Communication No. 050711.
*
In conclusion, L-proline has been shown to be an efficient
organocatalyst for the synthesis of various substituted
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail addresses: srivaric@iict.res.in; srivaric@gmail.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.066

6992
S. Chandrasekhar et al. / Tetrahedron Letters 46 (2005) 6991–6993
Table 1. L-Proline catalyzed synthesis of flavanonesa
Table 2. Synthesis of spiroflavanones
Entry R0
R
R00
Ratio of
Combined
Entry
R0
R
Ketone
Flavanonea (%)
80b
flavanone/ yieldb (%)
chalcone
O
1
H
H
1
2
3
4
5
6
7
8
H
Cl
H
H
H
H
Cl
H
H
7/3
7/3
7/3
8/2
8/2
7/3
7/3
6/4
70
68
65
73
72
60
63
65
O
2
3
4
5
H
H
H
Cl
H
93
95
96
92
CH3
OCH3
H
N
Bn
O
H
O2N
Cl
N
Boc
H
O
OCH3
CH3
H
MeO
MeO
N
Bn
O
CH3
OCH3
N
MeO
MeO
Bn
a Isolated yields after column chromatography.
9
Cl
H
CH3
7/3
6/4
62
60
b Reaction carried out for 20 h.
MeO
MeO
MeO
10
OCH3
flavanones and chalcones. The biological application of
these flavanones as aldose reductase inhibitors will be
described elsewhere.
11
12
H
H
H
H
7/3
6/4
64
H3C
(
63c
OMe
OMe
N
N
Acknowledgements
(
(
13
14
15
H
H
H
OCH3
H
6/4
7/3
6/4
61c
65c
67
K.V. thanks CSIR for financial assistance.
References and notes
N
O
(
H
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O
O
R'
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L-Proline
+
DMF, 80 oC,
18 h
R"
H
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OH
R''
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Scheme 1.
O
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R'
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O
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(Ketone)
X=CH2, NBn, NBoc
Scheme 2.

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