Synthesis of aurones through silver-catalyzed intramolecular cyclization from o-Alkynonylphenols

Full text of DOI:10.1002/bkcs.11384

Note
DOI: 10.1002/bkcs.11384
BULLETIN OF THE
W. Hwang et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Aurones through Silver-catalyzed Intramolecular
Cyclization from o-Alkynonylphenols
Woonsang Hwang,†,§ Hyunseok Kim,‡,§ Hyuck Choi,† Jaehyun Kim,† Woo Hyung Jeon,‡
†,
Phil Ho Lee,‡, and Kooyeon Lee
*
*
†Department of Bio-Health Technology, Institute of Bioscience and Biotechnology, Kangwon National
University, Chuncheon 24341, Republic of Korea. *E-mail: lky@kangwon.ac.kr
‡Department of Chemistry, Kangwon National University, Chuncheon 24341, Republic of Korea.
*E-mail: phlee@kangwon.ac.kr
Received November 13, 2017, Accepted January 2, 2018
Keywords: Aurone, Silver(I) acetate, 5-exo Cyclization, o-Alkynonylphenol, Dual π-activation
Flavonoids and their derivatives are of particular impor-
tance due to their wide-ranging biological activities. For
example, aurone, a subclass of flavonoid, is a pigment com-
ponent present in fruits, vegetables, and flowers,1 as con-
firmed by the isolation of hydroxylated, methoxylated, and
glycosylated aurones from natural products.2 These aurone
derivatives have been reported to be important scaffolds
because of their anticancer, antitumor, antimalarial, and
antifungal activities (Scheme 1).3
To date, synthetic methods for aurone compounds have
been reported: the condensation of benzofuran-3(2H)-one
(3-coumaranone) with an aldehyde in the presence of alu-
mina, alumina-potassium fluoride, and barium hydroxide
(Eq. (1), Scheme 2),4 the oxidative cyclization of 20-
hydroxychalcone (Eq. (2)),5 2.2 equiv AgNO3-mediated
cascade reaction from 2-(1-hydroxy-3-phenylprop-2-ynyl)
phenol (Eq. (3)),6 and the 5-exo cyclization of o-
alkynonylphenol (3 equiv Cs2CO3, acetone, rt, or 30.0 mol
% AgNO3 in MeOH, rt, or approximately 2.5–5.0 mol %
Scheme 2. Representative synthetic methods towards aurones.
n-Bu3P, CH2Cl2, or EtOH, Eq. (4)).7 However, because
some of the previously reported synthetic methods demand
a strong base and excessive amount (0.3 or 2.2 equiv) of
expensive AgNO3, the development of real catalytic syn-
thetic approaches to overcome these shortcomings has been
highly required. Also, the cyclization reaction of o-
alkynonylphenol often produces a mixture of aurones
through the 5-exo cyclization reaction, in addition to fla-
vones through a 6-endo cyclization. In continuation with
our studies directed towards the cyclization of π-activated
alkynes using Brønsted and Lewis acids,8 we herein report
a selective and catalytic method for the synthesis of a vari-
ety of aurones through Ag-catalyzed intramolecular
Scheme 1. Examples of biologically active aurone derivatives.
§These authors contributed equally to this work.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
1

Note
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
Table 1. Optimization of the reaction conditions for preparation of the aurone derivatives.a
Yieldb (%)
Entry
Catalyst (mol %)
Solvent
Temp (ꢀC)
Time (h)
2a
3a
1
2
3
4
5
6
7
8
Bi(OTf)3 (10)
Fe(OTf)3 (10)
In(OTf)3 (10)
Hf(OTf)4 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
AgOTf (10)
Ag2CO3 (10)
Ag2O (10)
AgSbF6 (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (10)
AgOAc (3)
AgOAc (3)
—
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
PhCl
1,4-dioxane
THF
Toluene
DMSO
DMA
100
100
100
100
100
100
25
25
25
25
25
25
25
25
25
25
25
25
25
21
21
21
21
21
1
1
1
1
4
0
0
0
0
8
6
9
11
29
4
2
3
33
93
83
96
99
65
99
91
34
88
88
90
96
95
0
9
1
2
10
11
12
13
14
15
16
17
18
19
20
21
a
1
<1
<1
<1
<1
8
1
3
3
0
21
21
21
24
24
1
1
24
1
CH3NO2
DMF
DMF
25
100
99 (95)c
0
<1
99
14
Reaction conditions: 1a (0.22 mmol) in the presence of catalyst was reacted in solvent (2.5 mL) under N2 atmosphere.
Yields of 2a and 3a were determined by 1H NMR spectroscopic results using dibromomethane as the internal standard.
Isolated yield.
b
c
cyclization from o-alkynonylphenols under mild reaction
conditions (Eq. (5)).
AgSbF6, and AgOAc (entries 8–11), with the best results
being obtained using AgOAc (99%) in DMF at 25 C for
ꢀ
The synthesis of aurone (2a) through the 5-exo cycliza-
tion reaction was initially examined by reacting 1-(2-hydro-
xyphenyl)-3-phenylprop-2-yn-1-one (1a) in the presence of
a large number of metal triflates as a catalyst to determine
the optimal reaction conditions (Table 1). However, when
10.0 mol % Bi(OTf)3 was employed as the catalyst in nitro-
1 h (entry 11). The effect of the reaction solvent was exam-
ined using CH3CN, PhCl, 1,4-dioxane, tetrahydrofuran
(THF), toluene, dimethyl sulfoxide (DMSO), N,N-
dimethylacetamide (DMA), and nitromethane (entries
12–19) and lower reactivities and selectivities were
obtained compared to the reaction employing DMF. When
ꢀ
ꢀ
methane (CH3NO2) at 100 C for 21 h, flavone (3a) was
the reaction was carried out in DMF (25 C, 1 h), a reduc-
obtained in 8% yield instead of the desired aurone (2a)
(entry 1). Similar results were obtained with Fe(OTf)3,
In(OTf)3, and Hf(OTf)4 in CH3NO2 at 100 ꢀC for 21 h
(entries 2–4). In ꢀcontrast, when Cu(OTf)2 was employed in
CH3NO2 at 100 C for 21 h, aurone (2a) and 2-phenyl-4H-
chromen-4-one (3a) were obtained in 33 and 29% yields,
respectively (entry 5). To our delight, Cu(OTf)2 in DMF at
tion in the amount of catalyst from 10.0 to 3.0 mol % pro-
duced aurone (2a) in 99% (isolated yield of 95%) (entry
20). When 1a was heated to 100 ꢀC in DMF without
AgOAc, no aurone (2a) was observed and flavone (3a) was
produced in quantitative yield (entry 21). These results
indicate that AgOAc are essential for the 5-exo cyclization.
The substrate scope of the reaction was then examined
by application of the optimal reaction conditions to sub-
strates bearing a wide range of substituents at the R1 and
R2 positions (Table 2). In all cases, the desired aurone
derivatives were obtained in excellent yields. For example,
for substrates bearing methyl and tert-butyl groups at the
ꢀ
100 C for 1 h afforded aurone (2a) in 93% yield (entry 6).
Interestingly, AgOTf exhibited a high catalytic activity,
ꢀ
providing aurone (2a) in 83% yield at 25 C for 1 h (entry
7). To enhance the selectivity of this reaction, various silver
catalysts were examined, including Ag2CO3, Ag2O,
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
2

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
Table 2. AgOAc-catalyzed synthesis of aurone derivatives.a
Scheme 3. Examination of the reaction substrate scope and
selectivity.
alkyne moiety in o-alkynonylphenol (1). Therefore, we
expect that the Ag(I) catalyst, which is a soft metal catalyst,
coordinates the alkyne moiety as well as the adjacent aryl
ring to afford a partial positive charge at the α-position of
the carbonyl group, which essentially controls the selectiv-
ity of the 5-exo cyclization.
In summary, we successfully developed a selective and
catalytic synthetic method of aurone derivatives through the
cyclization of a wide range of o-alkynonylphenols in the
presence of AgOAc catalyst. This reaction exhibits a high
selectivity towards the 5-exo cyclization process under mild
conditions, and is suitable for the synthesis of various aur-
one derivatives in the presence of various functional groups
including methyl, tert-butyl, methoxy, chloro, and bromo
group.
a
Reaction conditions: o-Hydroxyaryl phenylethynyl ketone
(1, 0.45 mmol) in the presence of AgOAc (0.014 mmol, 3.0 mol %)
was reacted in DMF (2.0 mL) under N2 atmosphere.
R1- position, products 2b and 2c were obtained in 96 and
97% yields, respectively. The presence of methoxy or halo-
gen substituents (i.e., Cl and Br) at the R1-position gave the
desired products in excellent yields ranging from 90% to
97%. In addition, to confirm the substituent effect at the
R2-position, the reaction was carried out using substrates
bearing methyl, tert-butyl, methoxy, and chloro substituents
to afford the desired aurones in high yields varying from
86 to 99%.
Furthermore, to examine the suitability of our developed
system to different starting materials, the reaction was
applied to compounds 1m and 1n, which contained cyclo-
hexyl and n-butyl groups instead of an aryl group on the
alkyne moiety. When 1m was treated with AgOAc
Experimental
Typical Experimental Procedure. A mixture of o-
hydroxyarylphenyl ethynyl ketone (1) (0.45 mmol) and
AgOAc (0.015 mmol, 3.0 mol %) in DMF (2.0 mL) was
ꢀ
stirred at 25 C for 1 h. After completion of reaction as
indicated by TLC, the reaction mixture was poured into
H2O (20 mL), and extracted with CH2Cl2 (60 mL, 20 mL
× 3). The organic layers were dried over anhydrous
MgSO4, filtered and concentrated to remove solvent and
purified by column chromatography on silica gel (EtOAc/n-
hexane = 1/5) to give the desired product 2.
ꢀ
(3.0 mol %) at 25 C for 1 h, the cyclohexyl-containing
Acknowledgments. This work was supported by the
National Research Foundation of Korea (NRF) grant
funded by the Korea Government (MISP) (2015H1C1A1
035955 and 2011–0018355) and the 2015 Research Grant
from the Kangwon National University (No. 520150311).
benzofuran-3(2H)-one (2m) and 4H-chromen-4-one (3m)
were obtained in yields of 64% and 31%, respectively
(Scheme 3). In the case of the n-butyl-containing substrate
1n, only 2-n-butyl-4H-chromen-4-one (3n) was obtained in
55% yield. These results indicate that the regioselectivity
between the 5-exo and the 6-endo cyclization is determined
by the presence or absence of a phenyl ring close to the
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
3

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
1399. (h) D. Villemin, B. Martin, N. Bar, Molecules 1998, 3,
88. (i) R. S. Verma, M. Verma, Tetrahedron Lett. 1992, 33,
5937. (j) G. Stork, M. Tomasz, J. Am. Chem. Soc. 1964, 86,
471. (k) T. A. Geissman, J. B. Harborne, J. Am. Chem. Soc.
1955, 77, 4622.
References
1. (a) R. Haudecoeur, A. Boumendjel, Curr. Med. Chem. 2012,
19, 2861. (b) C. M. Sousa, J. Berthet, S. Delbaere,
P. J. Coelho, Dyes Pigments 2012, 92, 537. (c) A. Boumendjel,
Curr. Med. Chem. 2003, 10, 2621. (d) J. B. Harborne,
C. A. Williams, Phytochemistry 2000, 55, 481.
5. (a) S. Venkateswarlu, G. K. Panchagnula, A. L. Gottumukkala,
G. V. Subbaraju, Tetrahedron 2007, 63, 6909. (b) G. Bose,
E. Mondal, A. T. Khan, M. J. Bordoloi, Tetrahedron Lett.
2001, 42, 8907. (c) M. Bennett, A. Burke, W. Ivo O’Sullivan,
Tetrahedron 1996, 52, 7163. (d) K. Thakkar, M. Cushman,
J. Org. Chem. 1995, 60, 6499. (e) K. Thakkar, M. Cushman,
Tetrahedron Lett. 1994, 35, 6441. (f) H. Sekizaki, Bull. Chem.
Soc. Jpn. 1988, 61, 1407.
2. (a) G. M. V. Junior, C. M. D. M. Sousa, A. J. Cavalheiro,
J. H. G. Lago, M. H. Chaves, Helv. Chim. Acta 2008, 91,
2159. (b) P. Mohan, T. Joshi, Phytochemistry 1989, 28, 2529.
3. (a) C. Zwergel, F. Gaascht, S. Valente, M. Diederich,
D. Bagrel, G. Kirsch, Nat. Prod. Commun. 2012, 7, 389.
(b) M. Roussaki, S. Costa Lima, A.-M. Kypreou, P. Kefalas,
A. Cordeiro da Silva, A. Detsi, Int. J. Med. Chem. 2012, 2012,
196921. (c) H. M. Sim, K. Y. Loh, W. K. Yeo, C. Y. Lee,
M. L. Go, ChemMedChem 2011, 6, 713. (d) H. Cheng,
L. Zhang, Y. Liu, S. Chen, H. Cheng, X. Lu, Z. Zheng,
G. C. Zhou, Eur. J. Med. Chem. 2010, 45, 5950.
(e) B. P. Bandgar, S. A. Patil, B. L. Korbad, S. C. Biradar,
S. N. Nile, C. N. Khobragade, Eur. J. Med. Chem. 2010, 45,
3223. (f) A. Detsi, M. Majdalani, C. A. Kontogiorgis,
D. Hadjipavlou-Litina, P. Kefalas, Bioorg. Med. Chem. 2009,
17, 8073. (g) N. J. Lawrence, D. Rennison, A. T. McGown,
J. A. Hadfield, Bioorg. Med. Chem. Lett. 2003, 13, 3759.
(h) O. Kayser, A. F. Kiderlen, R. Brun, Planta Med. 2001,
67, 718.
4. (a) K. M. Taylor, Z. E. Taylor, S. T. Handy, Tetrahedron Lett.
2017, 58, 240. (b) K. Boussafi, D. Villemin, N. Bar,
M. Belghosi, J. Chem. Res. 2016, 40, 567. (c) S. Kumar,
Green Chem. Lett. Rev. 2014, 7, 95. (d) I. Hawkins,
S. T. Handy, Tetrahedron 2013, 69, 9200. (e) R. Steng, C. Hu,
J. Zhang, X. Lin, J. Li, B. Yang, Q. He, Y. Hu, Eur. J. Med.
Chem. 2009, 44, 7. (f) M. Morimoto, H. Fukumoto, T. Nozoe,
A. Hagiwara, K. Komai, J. Agric. Food Chem. 2007, 55, 700.
(g) D. Boiek, M. J. Gutschow, Heterocycl. Chem. 2005, 42,
6. S. Li, S. F. Jin, M. Viji, H. Jo, J. Sim, H. S. Kim, H. Lee, J.-
K. Jung, Tetrahedron Lett. 2017, 58, 1417.
7. (a) C. Taylor, Y. Bolshan, Tetrahedron Lett. 2015, 56, 4392.
(b) K. Saito, M. Yoshida, T. Doi, Chem. Lett. 2015, 44, 141.
(c) T.-T. Jong, S.-J. Leu, J. Chem. Soc. Perkin Trans. 1990, 1,
423. (d) C. Liu, Z. Zhang, J. Zhang, X. Liu, M. Xie, Chin.
J. Chem. 2014, 32, 1233.
8. (a) H. Choi, J. Kim, K. Lee, Tetrahedron Lett. 2016, 57, 3600.
(b) J. Park, H. Choi, D.-C. Lee, K. Lee, Tetrahedron Lett.
2015, 56, 7005. (c) J. Yun, J. Park, J. Kim, K. Lee, Tetrahe-
dron Lett. 2015, 56, 1045. (d) D. Eom, S. Park, Y. Park,
K. Lee, G. Hong, P. H. Lee, Eur. J. Org. Chem. 2013, 2013,
2672. (e) C.-E. Kim, T. Ryu, S. Kim, K. Lee, C.-H. Lee,
P. H. Lee, Adv. Synth. Catal. 2013, 355, 2873. (f) K. Lee,
P. H. Lee, Adv. Synth. Catal. 2007, 349, 2092. (g) S. Kim,
P. H. Lee, Adv. Synth. Catal. 2008, 350, 547. (h) C. Park,
P. H. Lee, Org. Lett. 2008, 10, 3359. (i) J. Park, S. H. Kim,
P. H. Lee, Org. Lett. 2008, 10, 5067. (j) S. Kim, D. Kang,
S. Shin, P. H. Lee, Tetrahedron Lett. 2010, 51, 1899.
(k) J. Mo, P. H. Lee, Org. Lett. 2010, 12, 2570. (l) P. H. Lee,
S. Kim, A. Park, B. C. Chary, S. Kim, Angew. Chem. Int. Ed.
2010, 49, 6806.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
4