A novel cyclization/oxidation strategy for a two-step synthesis of (Z)-aurone

Article abstract of DOI:10.1016/j.tetlet.2017.02.074

An efficient and facile two-step strategy for the synthesis of (Z)-aurone from arylacetylenes and salicyladehydes, via silver(I) nitrate mediated cyclization/oxidation in the presence of potassium carbonate has been developed. The key feature of our metho

Full text of DOI:10.1016/j.tetlet.2017.02.074

Accepted Manuscript
A novel cyclization/oxidation strategy for a two-step synthesis of (Z)-aurone
Siyuan Li, Feng Jin, Mayavan Viji, Hyeju Jo, Jaeuk Sim, Hak Sung Kim,
Heesoon Lee, Jae-Kyung Jung
PII:
S0040-4039(17)30261-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.074
TETL 48685
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 January 2017
18 February 2017
24 February 2017
Please cite this article as: Li, S., Jin, F., Viji, M., Jo, H., Sim, J., Sung Kim, H., Lee, H., Jung, J-K., Anovel cyclization/
oxidation strategy for a two-step synthesis of (Z)-aurone, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.02.074
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A novel cyclization/oxidation strategy for a
two-step synthesis of (Z)-aurone
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Siyuan Lia, b, †, Feng Jina, †, Mayavan Vijib, Hyeju Job, Jaeuk Simb, Hak Sung Kima ∗, Heesoon Leeb, Jae-Kyung
Jungb ∗

1
Tetrahedron Letters
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A novel cyclization/oxidation strategy for a two-step synthesis of (Z)-aurone
Siyuan Lia, b, †, Feng Jina, †, Mayavan Vijib, Hyeju Job, Jaeuk Simb, Hak Sung Kima ∗, Heesoon Leeb, and
Jae-Kyung Jungb ∗
a College of Pharmacy, Wonkwang University, Iksan 54538, Republic of Korea
b College of Pharmacy and Medicinal Research Center (MRC), Chungbuk National University, Cheongju 28644, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient and facile two-step strategy for the synthesis of (Z)-aurone from arylacetylenes and
salicyladehydes, via silver(I) nitrate mediated cyclization/ oxidation in the presence of
potassium carbonate has been developed. The key feature of our method was delicate cascade
reaction, to provide the corresponding (Z)-aurone in high yield and good regio- and stereo
selectivity.
Received in revised form
Accepted
Available online
Keywords:
(Z)-aurone
2009 Elsevier Ltd. All rights reserved.
Silver (I) nitrate
Fétizon oxidation
Regio-selectivity
Oxygen heterocycles
Cascade reaction
A number of naturally occurring aurone which possess various
hydroxylation patterns, such as sulfuretin (3), aureusidin (4),
maritimetin (5), and bracteatin (6), have numerous biological
activities.4 Therefore, formidable efforts have been made on
the synthesis of (Z)-aurone and its derivatives.5,6,7
Introduction
Flavonoids and their derivatives have drawn much
attention because many compounds with this skeleton display
pronounced biological and pharmaceutical activities.1 (Z)-
aurone (1) [(Z)-2-benzylidenebenzofuran-3(2H)-one] is a well-
known natural product belonging to the sub class of flavonoid
family (Figure 1), that contributes to the pigmentation of
flowers and fruits.2 Aurones have a broad range of bioactivities
including antifungal, antioxidation, tyrosinase inhibition,
iodothyronine deiodinas inhibition, antitumor and anti-cancer,
etc.3
O
O
O
O
Flavone ( )
2
1
(Z)-Aurone ( )
Scheme 1. One-pot strategy for synthesis of (Z)-aurone
R1
O
3
R1 = R2 = R3 = H; Sulfuretin ( )
4
5
R1 = OH, R2 = R3 = H; Aureusidin ( )
However, some of these approaches suffered from various
limitations such as side reaction,5a low yield,6 and long reaction
time.7 Although few studies have reported the synthesis of
aurones from the precursor 7, they typically used toxic MnO2
as an oxidant at a later stage as illustrated in Scheme 1.
Moreover, the above methods also required complex silver
R1= R3 = H, R2 = OH; Maritimetin ( )
O
HO
6
R1= R3 = OH, R2 = H; Bracteatin ( )
OH
OH
R2
R3
Figure 1. Representative aurones
———
† These authors contributed equally to this work
∗ Corresponding author. Tel.: +82-63-850-6818; fax: +82-63-850-6818; e-mail: hankidad@wku.ac.kr (H .S .Kim)
∗ Corresponding author. Tel.: +82-43-261-2635; fax: +82-43-268-2732; e-mail: orgjkjung@chungbuk.ac.kr (J .-K. Jung)

2
Tetrahedron
catalysts and expensive gold catalyst in the cyclization
demonstrated by use of 1.0 equivalent of AgNO3 (Table 1,
entry 9), which resulted in the appearance of silver mirror.
step.5c-e, 7 Consequently, it is necessary to find the way to use a
simple silver catalyst for the synthesis of aurones without
adding any external oxidizing agents.
Table 1. Optimization of cyclization/ oxidationa
Over the past decades considerable progress have been
made in the development of transition metal catalyzed domino
reactions, which are an ideal approach in organic synthesis.8 In
such reactions, at least two consequent steps occur in one
synthetic operation and need not isolate intermediates.
Furthermore, these methods hold advantages such as low cost
and time saving. Thus, finding a suitable catalyst which can
also act as oxidant is highly desirable.
Entry
AgNO3
(equiv.)
Solvent
Temp
(°C)
Time
(h)
Yieldb
(%)
In this manuscript, we describe a simple and an efficient
way to synthesize of (Z)-aurone derivatives from easily
available starting materials via Ag(I) mediated 5-exo-dig
cyclization and subsequent oxidation. This method is
advantageous in high yield and good stereoselectivity.
1c
2
2.2
2.2
2.2
5.0
0.2
2.2
2.2
2.2
1.0
2.2
2.2
2.2
0.0
MeOH
rt
3
SRd
MeOH
rt
2
15
3
MeOH/H2O
MeOH
rt
30 min
13
4
rt
20 min
17
2. Results and discussions
5
MeOH
rt
2
Tracee
SR/NRg
trace
94
6
Solventsf
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
rt
2
To explore a suitable reaction conditions to probe the
feasibility of cyclization/oxidation reaction, 2-(1-hydroxy-3-
phenylprop-2-ynyl)phenol (7) was selected as a representative
substrate; and the results are summarized in Table 1. Our
initial effort using AgNO3 in methanol at room temperature
resulted in the formation of a new product. However, it was
unsatisfactory because the benzyl propargylic hydroxyl group
was converted to a methoxy group to afford compound 10
(Table 1, entry 1). We realized that a base can influence the
stability of benzyl propargylic alcohol. Therefore, we
successfully utilized 2.2 equiv of potassium carbonate (K2CO3)
and 2.2 equiv of AgNO3 to afford the desired product 9 in 15%
yield (Table 1, entry 2). The silver catalyst plays a dual role in
this cascade reaction; it activates alkyne during 5-exo-dig
addition (cyclization) and subsequently oxidizes the benzylic
alcohol to ketone in the presence of K2CO3. Encouraged by the
results above, we attempted to find appropriate conditions, in
the previous study water triggered the synthesis of aurone
derivatives,5c,e we have added 1 drop of water, but it could not
accelerate the reaction; the yield was only 13% (Table 1, entry
3). The use of 5.0 equiv of AgNO3 afforded expected product
in only 17 %, and rest of the starting material was converted to
side products (Table 1, entry 4). Reducing the catalyst loading
to 20 mol % it quantitatively afforded the compound 8 with a
trace amount of 9 (Table 1, entry 5). The above results
suggested that changing methanol to other solvent would be a
good option for reducing the generation of side products.
Using other polar solvents like DMF, THF, and CH3CN was
not beneficial in the cascade reaction (Table 1, entry 6).
Inspired by Fétizon oxidation10 we realized the importance of
using non-polar solvent and avoiding the influence of water.
Because cyclization was required, we chose the commonly
used solvent toluene (Table 1, entries 7-9).
7
rt
24
2
8
120
120
120
120
120
140
9
2
37
10h
11i
12c
2
90
2
92
24
24
trace
--
13c
a
conditions: Unless otherwise stated, all the reactions were
conducted in 1.0 equiv. of starting material, 2.2 equiv. of
b
AgNO3, 2.2 equiv. of K2CO3 under nitrogen atmosphere.
c
d
isolated yield of 9, absence of base, side reaction, mainly
10. e monitored by TLC. f DMF, THF, or CH3CN was used as a
g
solvent. side reaction or no reaction. 10 mol% TBAI was
h
used as an additive. i 10 mol% Celite was used as an additive.
This experiment indicates initial cyclization with the formation
of 8, followed by oxidation; in the case of oxidation followed
by cyclization, we would not obtain final product 9 because the
reaction would stop at the oxidation step, resulting in 11.
Additives did not increase the reaction yield; for instance,
the yield was somewhat lowered when we used TBAI11 or
celite12 (Table 1, entries 10, 11). The Fétizon oxidant (Ag2CO3)
was found to be not suitable for this transformation, as the
product was obtained only in trace amount. No desired product
was obtained with other catalysts examined such as Cu2SO4,
FeSO4 (entries not shown). This reaction also depended on the
choice of base. The replacement of K2CO3 with NaHCO3
proved to be inefficient and only trace amount of product was
obtained. In the case Et3N and DIPEA no product formation
was observed even the reaction was carried out for a longer
time 24 h (entries not shown). From the experiment shown in
entry 12, K2CO3 is a mandatory base in this reaction, as in its
absence only trace amount of product was detected. Omitting
both the catalyst and base resulted in no product formation;
and the starting material remains intact even at a prolonged
reaction time and elevated temperature (Table 1, entry 13). As
a result of these finding, we considered the optimal reaction
conditions are as follows: 7 (1.0 mmol, 1.0 equiv) with AgNO3
(2.2 equiv.), K2CO3 (2.2 equiv.) in toluene (2.0 mL) under
nitrogen atmosphere at reflux temperature for 2 h.
We found that the use of 2.2 equiv. of AgNO3 and 2.2
equiv of K2CO3 in toluene at 120 °C under nitrogen
atmosphere afforded the formation of 9 in a higher yield (Table
1, entry 8). We were interested in finding the reaction pathway;
the entire pathway is depicted in Scheme 2, which shows that
(Z)-aurone can be synthesized from 2-(1-hydroxy-3-
phenylprop-2-ynyl)phenol (7) and the key step is a one-pot
cyclization/oxidation reaction. We assumed two possible
alternate pathways: oxidation followed by cyclization and,
cyclization followed by oxidation. We monitored the reaction
by TLC and NMR (supplementary information), which found
that the second pathway was dominant; this was also

3
Having established most promising conditions in our
hand, we next evaluated substrates with different substitution
patterns. We synthesized a variety of substituted aurone
precursors 12a-22a13 to establish the scope of the cascade
system and its applicability for synthesizing a wide range of
or electron-withdrawing substituent groups on the
phenylacetylene or salicyladehydes were well tolerated. A
variety of halogen containing substrates (Cl, Br) were
compatible under the standard conditions, providing the
expected products in good yields. It is noteworthy that the
alkyl-substituted substrates also provide the corresponding
products in good yields. For instance, bulky t-butyl group on
the salicylaldehyde ring could afford the desired product in
high yields. It was pleased to find that the substrates bearing
strong electron-withdrawing groups such as NO2 group were
also suitable for the reaction, although the yield of the product
was lower (31%). An electron-donating group on arylacetylene
disfavored the reaction: with MeO- as the substitute, only
about 70% of yields of the desired products were observed.
While MeO- group on salicylaldehyde ring complete
conversion occurred, but the product was decomposed even
when it stored at low temperature (-20 °C). Configuration of
the aurones was established with the help of NMR spectral
data by comparison with the data reported in the literature. All
though we did not try all possible substitutions in all positions,
it is reasonable to predict on the basis of the previous
reported5c,d,e, 7 and our limited data that most compounds would
be synthesized.15
Scheme 2. Synthetic pathway of our strategy
Table 2. Substrate scopea
OH
O
R1
R1
AgNO3 (2.2 equiv)
K2CO3 (2.2 equiv)
O
OH
Toluene, reflux, 2 h
R2
R2
Conclusion
O
O
O
O
We have developed a novel method for the synthesis of
(Z)-aurones via silver mediated cascade reaction from readily
available 2-(1-hydroxy-3-phenylprop-2-ynyl)phenols. It is an
example of how to utilize a cascade reaction to solve problems
wisely. A series of diversely substituted aurones were
synthesized in good yields and shorter reaction time rendering
this methodology highly valuable.
O
O
, 93%
12
, 94%
9
13, 84%
Cl
O
O
O
O
Br
O
O
OMe
Acknowledgments
, 70%
16
, 79%
14
, 71%
15
OMe
This work was supported by the National Research
Foundation of Korea grant funded by the Korea Government
(MSIP) (No. MRC, 2008-0062275), the ministry of trade,
Industry, & Energy (MOTIE) through the R&D project of
Osong Academy-Industry Convergence (BAIO), the
International Science and Business Belt Program through the
Ministry of Science, ICT and Future Planning (2015K000284),
and China Scholarship Council (CSC, File No. 201608260086,
to S. L.). This research was also conducted during the research
year of Chungbuk National University in 2013.
O
O
O
Br
O
O
O
OMe
17, 63%
18, 92%
19, 64%
OMe
Cl
O
O
O
Br
Br
O
O
O
O2N
OMe
20, 92%
21, 68%
22, 31%
Cl
O
References and notes
O
23, 90%
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4
Tetrahedron
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13. To a solution of arylacetylene (1.6 mmol) in THF (4.0 mL) was
dropwise added n-BuLi (1.5 mmol, 2.5 M in n-hexane) at
-40 °C. After 0.5 h stirring, a solution of corresponding
salicylaldehyde (1.0 mmol in 4.0 mL anhydrous THF) was
dropwise added at -40°C The reaction mixture was stirred at
-40 °C for 2 h and then heated up to 0 °C for 5 min followed by
quenched with water. The organic solvent was removed by
rotary evaporator and the rest was extracted with EtOAc twice.
The collected EtOAc layer was washed with brine, dried over
Na2SO4, filtered, and evaporated. The crude product was
purified by flash column chromatography.
14. To the precursors (12a-22a, 0.5 mmol) in anhydrous toluene
was added K2CO3 (2.2 equiv., 1.1 mmol) at room temperature
and then heated to 50 °C. The reaction mixture was stirred for
10 min and AgNO3 (2.2 equiv., 1.1 mmol) was added, which
was rapidly heated till reflux. The reaction was stopped within
2 h, and silver mirror was observed. After cooling down, the
solid was removed by filtration with celite, and remove solvent
by rotary evaporator. The crude product was purified by flash
column chromatography.
15. The limitation of our strategy is that the product yield would
decrease, when the 6 or 4’ position was substituted.

5
Highlights
• Two-step synthesis of (Z)-Aurones through cyclization/oxidation cascade reaction
• A novel AgNO3-promoted synthesis of diversely substituted aurones was developed.
• (Z)-Aurones were obtained in good yields with excellent regio- and diastereoselectivity.