Synthesis of stilbene-fused 2′-hydroxychalcones and flavanones

Article abstract of DOI:10.1016/j.bioorg.2010.04.001

Synthesis of stilbene-fused chalcones and flavanones were successfully completed. Molecules were designed in a way to mimic the structural features of both stilbene and chalcones or stilbene and flavanones at the same time, and synthesized by three steps. Heck reactions of 3-bromobenzaldehyde with styrene derivatives gave corresponding (E)-stilbenes, which were reacted with acetophenones to furnish stilbene-fused 2′-hydroxychalcones under basic conditions. Finally, intramolecular cyclization reactions were performed to produce stilbene-fused flavanones.

Full text of DOI:10.1016/j.bioorg.2010.04.001

Bioorganic Chemistry 38 (2010) 139–143
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis of stilbene-fused 20-hydroxychalcones and flavanones
_
*
Ismail Akçok, Ali Çag˘ır
_
_
Izmir Institute of Technology, Faculty of Science, Department of Chemistry, Urla-Izmir 35430, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 November 2009
Available online 9 April 2010
Synthesis of stilbene-fused chalcones and flavanones were successfully completed. Molecules were
designed in a way to mimic the structural features of both ‘‘stilbene and chalcones” or ‘‘stilbene and
flavanones” at the same time, and synthesized by three steps. Heck reactions of 3-bromobenzaldehyde
with styrene derivatives gave corresponding (E)-stilbenes, which were reacted with acetophenones to
furnish stilbene-fused 20-hydroxychalcones under basic conditions. Finally, intramolecular cyclization
reactions were performed to produce stilbene-fused flavanones.
Keywords:
Stilbene
Chalcone
Flavanone
Ó 2010 Elsevier Inc. All rights reserved.
Claisen–Schmidt reaction
Michael addition
Heck reaction
1. Introduction
biological environment) is desirable. Such inhibitors will require
only one synthesis, one formulation and a single set of metabolism
One of the goals of medicinal chemistry research and drug dis-
covery is to develop compounds that both show desired biological
activities and are easily accessible. Such compounds should be
either isolated from natural resources or they should be easily syn-
thesized in large amounts in the laboratory. To this end, the time
and resources required to bring such biologically active com-
pounds to the market can be minimized.
Flavanones (1), stilbenes (2), and chalcones (3), which are
secondary metabolites of plants [1,2], are relatively simple
molecules. Of significant importance, derivatives of these secondary
metabolites can possess a variety of biological activities such as anti-
tumor [3–7] antiviral [5,7], antileishmanial [8], antimalarial [9],
anti-inflammatory [3,4,7,10,11], antiangiogenic [12], antioxidant
[3,4,7] antibacterial [3,5] antimitotic [13], aromatase, and metasta-
sis inhibition [14,15] activities (Fig. 1).
Alopecurones have been isolated from the extracts of the roots
of Sophora alopecuroides in 1995 by Iinuma et al., who classified
these compounds as flavanostilbenes because they have both fla-
vanone and stilbene subunits in their structure [16]. The antibacte-
rial activities of three isolated flavanostilbenes (alopecurones A–C)
against the strains of Stphylococcus aureus, which are known for
their methicillin-resistant property, have also been reported [17].
In general, enzyme inhibitors are designed such that they only
interact with one enzyme. Design and synthesis of pharmaceutical
compounds that possess dual acting enzyme inhibitors (i.e. single
compounds that inhibit two different enzymes in the same
studies. Two drugs may have different pharmacokinetic rates and
metabolic profiles; therefore, it might be difficult to optimally ad-
just their concentrations simultaneously [18]. Similarly, in cancer
treatments a so-called ‘combination chemotherapy’ involving two
different simultaneous medications, may have advantages over
single-agent treatment [19]. It is logical to presume that similar
success can be achieved by anticancer drugs which work not via
two different compounds, but rather by a single compound pro-
gressing through two alternate mechanisms at the same time.
In this work, stilbene-fused flavanone (4) and chalcone (5)
structures were proposed as potentially biologically active com-
pounds (Fig. 1). The aim of this work is to optimize a synthesis
route for the preparation of stilbene-fused flavanones (4) and chal-
cones (5). Ultimately the goal is to find compounds which have the
benefits of both stilbene and chalcones, or the benefits of both
stilbene and flavanones.
2. Results and discussion
The products, stilbene-fused flavanone (4) or stilbene-fused
chalcone (5), can be readily converted to another one in the pres-
ence of acids or bases as shown in Fig. 1. Retro-synthetic analysis
(Fig. 2), shows that the synthesis of the target compounds requires
three steps: Claisen–Schmidt, Heck, and Michael addition reactions.
All of these reactions can be carried out under basic conditions.
The noted tolerance of the substituents in these reactions allowed
us to attempt the synthesis of the target compounds by two differ-
ent proposed approaches. The first starts with a Claisen–Schmidt
reaction between 3-bromobenzaldehyde and acetophenones to
* Corresponding author. Fax: +90 232 7507509.
E-mail address: alicagir@iyte.edu.tr (A. Çag˘ır).
0045-2068/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.bioorg.2010.04.001

_
140
I. Akçok, A. Çag˘ır / Bioorganic Chemistry 38 (2010) 139–143
Table 1
O
O
Synthesis of 20-hydroxychalcone derivatives (13–18).
R1
O
R1
O
O
R2
R3
O
OH
R2
R3
Br
Conditions
18-24 h.
CH3
Br
+
1
2
3
OH
OH
R4
6-11
R4
12
13-18
.
O
O
O
Acetophenone
Conditions
Product Yield
(%)
R1
R2
R3
R4
OH
6
7
8
9
10
11
H
H
OCH3
OCH3
H
OCH3
Cl
H
H
H
H
H
OCH3
H
OH
H
H
H
H
H
NaOH, EtOH, RT
NaOH, EtOH, RT
NaOH, EtOH, RT
NaOH, EtOH, RT
13
14
15
16
17
18
48
95
91
91
NR
15
4
5
CH3 NaOH, EtOH, RT
NO2
Fig. 1. Structures of flavanone (1), stilbene (2), 20-hydroxychlacones (3), stilbene-
fused flavanone (4), and stilbene-fused chalcone (5).
H
CH3
L
-Proline, DMF,
80 °C
NR: no reaction.
O
Claisen-Schmidt
In the next step, cyclization reactions of 20-hydroxychalcones
were studied under acidic and basic conditions. Results of intramo-
lecular Michael addition reactions are summarized in Table 2. For
20-hydroxychalcones (13, 14, and 16) refluxing acetic acid worked
quite well and gave the expected products in high yields (81–90%).
Conversely, the same reaction conditions did not work at all for the
dimethoxy-substituted chalcone 15. All attempts to convert chal-
cone 15 into flavanone 21 in refluxing ethanol in the presence of
a sodium acetate trihydrate as a mild basic catalyst failed. Later,
a similar transformation was successfully achieved for chalcone
16 in refluxing ethanol containing anhydrous sodium acetate as
catalyst. Although the yield for this reaction was almost half of
the yields of the acetic acid catalyzed reactions, it was performed
under milder conditions, an easier workup procedure, and gave
clean TLC results.
In the last step, Heck reactions of synthesized flavanones
(19–20) with selected styrenes (23–27) were performed separately
in the presence of palladium (II) acetate either with or without the
triphenylphosphene ligand. Previously Li and Wang showed that
the Heck reaction can successfully produce stilbene when per-
formed in a mixture of 1% palladium (II) acetate in triethanolamine
at 100 °C in the absence of a ligand [21]. The same procedure was
applied to synthesize stilbene-fused flavanones (28–33) in the
presence of varying amounts of palladium (II) acetate (first six en-
tries in Table 3). All reactions were monitored by TLC and many
R'
R
O
Michael
addition
Heck
reaction
O
O
Br
R
H
+
+
R
OH
Fig. 2. Retro-synthetic analysis of stilbene-fused flavanones.
form 20-hydroxy-3-bromochalcone derivatives. Then intramolecu-
lar Michael addition reaction would give brominated flavanones,
which can be reacted with styrenes in the presence of a palladium
catalyst to yield stilbene-fused 20-hydroxycalcones, which can be
transformed to corresponding stilbene-fused chalcones under
acidic or basic conditions.
As an alternative second route, synthesis can be initiated with a
Heck reaction between 3-bromobenzaldehyde and a styrene deriv-
ative to form a trans-stilbene. Then the formed product can be
transformed into stilbene-fused 20-hydroxycalcones and later to
stilbene-fused flavanones by sequential Claisen–Schmidt and Mi-
chael addition reactions.
Applying the first route, Claisen–Schmidt reactions of different
2-hydroxyacetophenones (6–11) with 3-bromobenzaldehyde (12)
were studied as shown in Table 1. These reactions were performed
at room temperature in sodium hydroxide containing ethanol.
Condensation reaction between acetophenone 11 and 3-bromo-
Table 2
Synthesis of flavanone derivatives (19–22).
R1
O
R1
O
R2
R3
R2
R3
Br
Conditions
24-72 h.
benzaldehyde (12) was carried out in DMF, and L-proline was used
Br
O
as the catalyst [20]. Except compound 11, all 2-hydroxy acetophe-
nones have electron donating substituents on them. All reactions
were monitored by TLC until no difference was observed. Hydrox-
ide catalyzed reactions involving all starting materials, except 2,4-
dihydroxy-3-methyl acetophenone (10), produced quite high (91–
OH
R4
R4
19-22
13-16
.
20-Hydroxychalcone
Conditions
Product Yield
(%)
R1
R2
R3
R4
95%) isolated yields. Alternatively, the
also gave the chalcone 18 in 15% yields. At the same time,
also catalyzed the transformation of the 20-hydroxychlacone into
corresponding flavanone with a yield of 21%. Although, -proline
L
-proline catalyzed reaction
L
-proline
13
14
H
H
OCH3
Cl
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
Acetic acid, reflux
Acetic acid, reflux
Acetic acid, reflux
Acetic acid, reflux
NaOAc, EtOH, reflux
NaOAc.3H2O, EtOH,
reflux
19
20
21
22
22
21
81
90
NR
90
45
NR
L
15 OCH3
16 OCH3
16 OCH3
15 OCH3
can catalyze both Claisen–Schmidt and Michael addition reactions
at the same time, total yields of products was much lower com-
pared with the yield of the hydroxide catalyzed reaction. Hence,
H
OCH3
the
L-proline catalyzed chalcone synthesis route was abandoned
NR: no reaction.
for the rest of this work.

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I. Akçok, A. Çag˘ır / Bioorganic Chemistry 38 (2010) 139–143
141
Table 3
Table 4
Attempts to synthesize stilbene-fused flavanones (28–34) from bromoflavanones (19
and 20).
Synthesis of stilbene derivatives (35–39) by ligand free Heck reaction.
R''
R'
R'
Pd(OAc)2, NaOAc,
NMP, 135 oC
Br
O
O
O
+
R
R
R''
R'
R''
R'
O
R''
Conditions
+
Br
O
O
12
23-27
35-39
.
19-20
23-27
28-34
Styrene
R0
R00
Product
Yield (%)
.
23
25
24
26
27
H
H
CH3
F
OCH3
CH3
H
H
NH2
35
36
37
38
39
92
80
90
75
NR
Flavanone
R
Stilbene
R0
Conditions
Product Yield
(%)
43
IM
IM
IM
IM
IM
IM
IM
IM
R00
19 OCH3 23
20 Cl 23
H
H
OCH3 12% Pd(OAc)2,
N(C2H4OH)3, 10 h
OCH3 0,1% Pd(OAc)2,
N(C2H4OH)3, 15 h
28
29
30
31
32
33
28
28
34
H
NR: no reaction.
19 OCH3 24 CH3
H
1% Pd(OAc)2,
N(C2H4OH)3, 14 h
1% Pd(OAc)2,
N(C2H4OH)3, 15 h
20% Pd(OAc)2,
N(C2H4OH)3, 48 h
4% Pd(OAc)2,
Only compound 28 was obtained in sufficiently high purity after
being applied to many silica gel columns (43% yield). As discussed
earlier, when flavanones were treated with bases, they reached
equilibrium with their chalcone counterparts. It might be possible
that triethanolamine can cause such a problem.
Alternatively, Heck reactions were performed in the presence of
triphenylphosphine as the ligand. Flavanone 19 was reacted with
styrenes 23 and 25 in the presence of 1% palladium (II) acetate
and 2% triphenylphosphine. Reactions were carried out in either
acetonitrile or toluene, and catalyzed by different bases such as tri-
ethylamine or potassium carbonate. TLC analyses of these experi-
ments were not different than those of the triethanolamine
results. The reactions ended up as inseparable mixtures, making
this route not useful. Therefore, further work continued using the
alternative route where the Heck reaction was involved in the ini-
tial step.
20 Cl
25
H
H
H
H
H
H
CH3
F
19 OCH3 26
19 OCH3 27
19 OCH3 23
19 OCH3 23
19 OCH3 25
NH2
N(C2H4OH)3, 48 h
OCH3 1% Pd(OAc)2, 2%P(Ph)3,
Et3N, CH3CN 24 h
OCH3 1% Pd(OAc)2, 2%P(Ph)3,
Na2CO3, Toluene, 24 h
CH3
1% Pd(OAc)2, 2%P(Ph)3,
Na2CO3, Toluene, 24 h
IM: inseparable mixture.
new spots were seen as an indication of new product formation for
all cases. We found it extremely difficult to purify these mixtures.
Table 5
Synthesis of stilbene-fused chalcones (41–57). Numbers in parentheses are isolated yields.
R1
O
R2
R3
CH3
OH
Ar1
R1
O
R2
R3
R''
R'
NaOH, EtOH
rt., 24 h.
6-9, 40
Ar1
Ar2
+
OH
R''
R'
O
Ar2
41-57
35-38
.
Aldehyde(Ar2)?
;ketone (Ar1)
35
36
37
38
OMe
F
6
7
9
41 (80%)
45 (60%)
49 (55%)
42 (72%)
46 (54%)
50 (44%)
43 (10%)
47 (41%)
51 (77%)
44 (57%)
48 (23%)
52 (77%)
MeO
Cl
OH
OH
OMe
OH
40
8
53 (20%)
57 (44%)
54a
55a
56a
MeO
MeO
OH
OH
OMe
a
Could not be purified from 2-hydroxy-4-methoxyacetophenone (40) on silica gel column.

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I. Akçok, A. Çag˘ır / Bioorganic Chemistry 38 (2010) 139–143
Table 6
Synthesis of stilbene-fused flavanones (58–73). Numbers in parentheses are isolated yields.
R1
O
O
R1
O
R2
R3
R''
R'
R2
R3
R''
R'
NaOAc, EtOH
reflux, 24 h.
Ar1
Ar2
Ar1
Ar2
OH
41-57
58-73
.
Ar2?
;Ar1
OMe
F
–
58 (73%)
62 (26%)
66 (64%)
59 (71%)
63 (76%)
67 (61%)
60 (76%)
64 (76%)
68 (56%)
MeO
Cl
OH
61a (62%)
65 (79%)
OH
OMe
OH
69 (67%)
73 (65%)
70 (32%)
71 (73%)
72 (49%)
MeO
MeO
OH
OMe
OH
a
Conditions of entry 5: potassium tert-butoxide, EtOH, rt, 24 h.
Firstly, Heck reactions between 3-bromobenzaldehyde (12) and
the same reaction conditions to show the applicability of the route.
Synthesis of compound 73 was successfully done at an overall yield
of 29% for the two steps (Tables 5 and 6).
commercially available styrenes (23–27) were performed in N-
methylpyrrolidone containing palladium (II) acetate (0.06% mole)
as catalyst and anhydrous sodium acetate as base [22]. Except for
the reactant 4-aminostyrene 27, all styrenes (23–26) gave corre-
sponding stilbenes (35–38) in good yields (Table 4).
3. Conclusions
Our work involving the first route had allowed us to understand
the necessary reaction conditions for the Claisen–Schmidt and Mi-
chael addition reactions which could in turn also be applied to the
alterative route. Sodium hydroxide in ethanol was used as a reac-
tion medium for the Claisen–Schmidt reactions, while anhydrous
sodium hydroxide in refluxing ethanol was used for cyclization
reactions. Four commercially available acetophenones (6, 7, 9
and 40) and stilbenes (35–38), obtained from Heck reactions, were
used to form stilbene-fused chalcones (41–56) and stilbene-fused
flavanones (58–72). Yields for these reactions are given in Tables
5 and 6.
As it can be seen from these tables, the yields for transforma-
tions from stilbenes (35–38) to stilbene-fused chalcones (41–56)
are relatively low because of the difficulties we have met during
the purification step. We have found the purification step is extre-
mely difficult for stilbene-fused chalcone products produced from
2-hydroxy-4-methoxy acetophenone (40). Only compound 53 was
successfully purified from the unreacted acetophenone 40. Com-
pounds 54–56 could not be purified at all from their corresponding
unreacted acetophenone (40) and they were used as a mixture for
the following step.
In conclusion, synthesis of two small matrices (4 ꢀ 4) of stil-
bene-fused chalcones and flavanones were completed successfully.
Work on the biological activities for these matricies is underway
and will be reported in a separate paper.
Acknowledgments
We are grateful to Mrs. Isßın Özçelik and Dr. Ritchie Eanes for
their kind help with the NMR experiments and manuscript proof-
reading, respectively. This work was supported by DPT Research
Grant DPT-2003K120690 (DPT10) awarded by the State Planning
Organization of the Republic of Turkey.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bioorg.2010.04.001.
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