Novel and Efficient Access to Flavones under Mild Conditions: Aqueous HI-Mediated Cascade Cyclization/Oxidative Radical Reaction of 2-Propynolphenols

Article abstract of DOI:10.1002/ejoc.201801154

Herein we disclose a metal-free and efficient method for the direct conversion of 2-propynolphenols to biologically important flavones using aqueous HI as the promoter. This transformation was proved via 4-iodo-2H-chromenes intermediate, which was simultaneously conversed to corresponding flavones by a C_sp2?I bond cleavage and a C–O bond formation under air.

Full text of DOI:10.1002/ejoc.201801154

A Journal of
Accepted Article
Title: Novel and Efficient Access to Flavones under Mild Conditions:
Aqueous HI-Mediated Cascade Cyclization/Oxidative Radical
reaction of 2-Propynolphenols
Authors: Xian-Rong Song, Ren Li, Tao Yang, Xi Chen, Haixin Ding,
Qiang Xiao, and Yong-Min Liang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801154
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10.1002/ejoc.201801154
European Journal of Organic Chemistry
COMMUNICATION
Novel and Efficient Access to Flavones under Mild Conditions:
Aqueous HI-Mediated Cascade Cyclization/Oxidative Radical
Reaction of 2-Propynolphenols
Xian-Rong Song, [a] Ren Li, [a] Tao Yang,[a] Xi Chen,[a] Haixin Ding,[a] Qiang Xiao,*[a] and Yong-Min
Liang[b]
Dedication ((optional))
Abstract: Herein we disclose a metal-free and efficient method for
the direct conversion of 2-propynolphenols to biologically important
flavones using aqueous HI as the promoter. This transformation was
proved via 4-iodo-2H-chromenes intermediate, which was
simultaneously converted to corresponding flavones by a Csp2−I
bond cleavage and a C−O bond formation under air.
Introduction
Flavonoids are important scaffolds present occurring in
numerous plant secondary metabolites and natural products.[1]
Figure 1. Representative bioactive natural products
Such compounds exhibit latent pharmacologically and
biologically activity, especially with anti-inflammatory,[2]
antiestrogenic,[3] antioxidant,[4] antimicrobial,[5] cardiovascular, [6]
and chemo preventative activities.[7] Figure 1 lists several
representative natural product molecules containing flavonoid
skeletons. Many efforts have been made to construct flavonoids
due to their significant biological activities. Until now, various
methods have been established for the preparation of flavones,
such as the cyclization of 1-(o-hydroxyphenyl)-1,3-diketones,[8]
the cyclization of 2-chalconesphenols,[9] the cyclization of
alkynones,[10] the reaction of 2-iodophenols with alkynes [11] and
the oxidation reaction of flavanones.[12] Although these
approaches are highly efficient and innovative, some of them
have one or more disadvantages, such as low yield, long
reaction times, expensive catalyst and microwave radiation.
Thus, to develop an effective synthetic approach for the
construction of flavones is extremely attractive and challenging.
Cascade cyclization is one of the most important and
synthetic intermediates in synthetic methodology,[14] which has
made great achievements in the synthesis of carbo- and
hetrocyclic compounds. Over the past few years, our group had
reported numerous effective synthetic strategies for the
synthesis of heterocyclic compounds by tandem cyclization of
propargylic alcohols, such as 2H-chromenes, 4-chromanones
and benzoxazoles (Scheme 1). [15]
powerful tactics for constructing cyclic compounds and has
[13]
attracted the attention of many chemists.
Recently,
propargylic alcohols with two mutual activated functional groups
have served as versatile synthons for the construction of various
Scheme 1. Our previous work and new strategy towards the synthesis of
flavone derivatives
[a]
[b]
Dr. X.-R. Song, R. Li, X. Chen, H. Ding, Prof. Dr. Q. Xiao*
Institute of Organic Chemistry,
Jiangxi Science & Technology Normal University
Jiangxi Province, Nanchang 330013, China.
E-mail: xiaoqiang@tsinghua.org.cn
Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China
By taking into consideration our continuous interest in the
potential reactivity of propargylic alcohols, we herein report an
efficient strategy for the synthesis of flavones through Brønsted
acid promoted cascade cyclization of 2-propynolphenols
(Scheme 1). It is worth noting that the efficient transformation of
2-propynolphenols to flavones through C−O bond formation and
Csp2−I bond cleavage has rarely been reported in previous
literature.[10d] Compared with the established methods, our
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201801154
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developed strategy have the advantages of atomic economy,
high yield and simple operation, which provide potential
possibilities for the application of this method in medicinal
chemistry.
can be successfully converted to the corresponding flavone
derivatives (3a-3s) in good to excellent yields. Firstly, various
substituted 2-propynolphenols were performed with aqueous HI
to examine the electron effects of substituents. Propargylic
alcohols bearing electron-rich and –poor substituents on the
Results and Discussion
Table 2. Transformation of propargylic alcohols to flavones[a]
Initially, 2-propynolphenols 1a was selected as representative
substrate using aqueous HI as promoter in CH2Cl2 at 30 ºC to
investigate this proposed transformation (Table 1). Only trace of
2-phenyl-4H-chromen-4-one (3a) was observed through TLC
analysis with almost whole of 4-iodo-2H-chromenes (2a)
detected after 2.0 h. 2a was found to be extremely unstable,
which could be transformed into 3a in a test tube during column
chromatography separation process, leading to the formation of
3a in 89% yield (entry 1). The existence of the resulting 2a was
confirmed by standard 1H NMR spectroscopy or TLC. So the
optimization of product 3a became the subsequent goal.
Subsequently, a series of solvents was tested and no better
results were obtained (entries 2-7). Furthermore, 73% yield of 3a
was isolated at ambient temperature because of the lower
activity (entry 8). Further screening of the loading of aqueous HI
proved that 1.5 equiv was the most effective for this
transformation (entries 9-10). Afterward, 78% yield of 3a was
also obtained when HBr was used instead of HI (entry 11).
However, 4-chloro-2H-chromene was isolated when HCl as acid
promoter was used for this transformation, and no desired
product 3a was obtained (entry 12). Finally, the use of aqueous
HI (1.5 equiv) in CH2Cl2 at 30°C was determined to be the best
conditions to form 2-phenyl-4H-chromen-4-one.
Table 1. Optimization of the reaction for the synthesis of 3a[a]
Entry
1
Solvent
CH2Cl2
HI (equiv)
1.5
T[ºC ]
Yield[%]
89
30
2
3
4
5
6
7
MeNO2
MeCN
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
1.2
1.5
1.5
30
30
30
30
30
30
rt
80
78
83
73
79
75
73
88
83
84
0
DCE
THF
1,4-dioxane
HOAc
8[b]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
30
30
30
30
10
[a] Unless otherwise noted, all reactions were performed with 1 (0.2 mmol)
11[c]
12[d]
and aqueous HI (1.5 equiv) in DCM (1.0 mL) at 30 °C for 2.0 h, and the
residue was further flashed by chromatography on silica gel, which then
allowed to stand for several hours in tube. Isolated yields.
[a] Unless otherwise noted, all reactions were performed with 0.2 mmol of
1a with aqueous HI, in solvent (2.0 mL) at 30 ºC. [b] 4.0 h. [c] HBr was
used instead of HI; [d] HCl was used instead of HI.
aromatic ring attached to the alcohol position were compatible
for this transformation, the target products were obtained in
good to high yields. Various substituents, including methyl,
methoxy, halogens, were tolerated at the different position of the
aromatic ring. Especially, substrates with halo-substituted can
proceed successfully to achieve the desired products (3d-3h
Subsequently, various 2-propynolphenols was investigated
to examine the scope of this transformation under the optimal
conditions (Table 2). Generally, a number of propargylic alcohols
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10.1002/ejoc.201801154
European Journal of Organic Chemistry
COMMUNICATION
and 3o), which offered an opportunity for further transformation
via cross-coupling reactions promoting the efficient synthesis of
complexes compounds. Notably, substrates with two or more
substituents were also tolerated to form the desired products in
good to high yields under optimal conditions (3l-3p). Moreover,
the cascade transformation proceeds easily when the substrates
with a poly-ring group, giving the target products in satisfied
yields (3q-3r). Finally, diverse substituents such as Me, OMe, Br,
and Cl at another aromatic ring could also comfortable with the
optimal conditions to obtain the target products in excellent
yields (3s-3v).
A clear merit of our established approach was that this
transformation was developed through a scale-up reaction
(Scheme 2); an 81% yield of desired product 3m was obtained
on the gram-scale under standard operations, which could
provide a potential application value in the field of medicinal
chemistry.
Figure 3. Reaction monitoring by precipitation phenomenon.
Furthermore, some experiments were performed under the
controlled conditions (Scheme 3). When the radical inhibitors
such as TEMPO or BHT were added to the reaction, we found
that the reaction was inhibited and more than 90% of the 2k was
recovered. This result indicated that the radical intermediate
may involve in this reaction (Scheme 3a). Moreover, to verity the
source of oxygen atom in flavone product, H2O18 (10.0 equiv)
was used as additive for this reaction, only untagged product 3k
can be detected by HRMS analysis (Scheme 3b). When the
reaction was performed under an air or O2 atmosphere, over
95% of 2k could be converted into product 3k for 2.0 h (Scheme
3c). By contrast, a similar reaction under an argon atmosphere
was difficult to be converted into product 3k, even the reaction
could not be completely transformed after 48 h (Scheme 3c).
The above two results demonstrate that the oxygen atom of
flavone product was probably originated from O2.
Scheme 2. Scale-up experiment.
To explore the reaction mechanism, the process of the
reaction of 4-iodo-2-(2-methoxyphenyl)-2H-chromene 2k16 was
monitored by 1HNMR spectroscopy (Figure 2). The signal
corresponding to the methoxy hydrogen in 3k (3k; δ=3.98 in d-
DMSO) appeared at 10 min after the transformation started. This
signal of 3k became strong at the end of the reaction. The
consumption of 2k and production of 3k could be easily
observed in the spectrum as the transformation proceeded.
These results strongly indicated that 4-iodo-2H-chromene 2a is
an intermediate of this transformation. Moreover, we recorded
the change process of 2k to 3k through the images (Figure 3).
The different colours of pictures were clearly demonstrated the
conversion process.
Scheme 3. Controlled experiments.
Followed by these preliminary mechanistic studies and the
previous reports,[15d],[17]
a
plausible mechanism of this
transformation is tentatively proposed as shown in Scheme 4.
The initial step involves the formation of 4-iodo-2H-chromene
intermediate 2a from the interaction of 2-propynolphenols 1a
with HI. Subsequently, the substitution reaction take place with
oxygen radical to give vinyl radical E, which can be successfully
Figure 2. Reaction monitoring by NMR spectroscopy. a = methoxy group in
2k. b = methoxy group in 3k.
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European Journal of Organic Chemistry
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captured by peroxy radical giving intermediate F. Finally, the
product 3a was obtained through the elimination of HOI.
557 ,221.
[3]
[4]
S. Gobbi, A. Cavalli, A. Rampa, F. Belluti, L. Piazzi, A. Paluszcak, R.W.
Hartmann, M. Recanatini, A. Bisi, J. Med. Chem, 2006, 49, 4777.
G. Maiti, R. Karmakar, R. N. Bhattacharya, U. Kayal, Tetrahedron Lett.
2011, 52, 5610.
[5] T. P. T. Cushnie, A. J. Lamb, Int. J. Antimicrob. Agents, 2005, 26, 343.
[6]
E. Middleton Jr., C. Kandaswami, T. C. Theoharides, Pharmacol. Rev.
2000, 52, 673.
[7]
J. M. Cassady, J. M. Baird, C.-J. Chang, J. Nat. Prod. 1990, 53, 23.
[8] a) W. Baker, J. Chem. Soc. 1933, 1381; b) H.S. Mahal, K. Venkataraman,
J. Chem. Soc. 1934, 1767; c) C. F. Chee, M. J. C. Buckle, N. A.
Rahman, Tetrahedron Lett. 2011, 52, 3120.
[9]
a) P. D. Lokhande, S. S. Sakate, K. N. Taksande, B. Navghare,
Tetrahedron Lett. 2005, 46, 1573; b) A. S. Zambare, J. N. Sangshetti, N.
D. Kokare, D. B. Shinde, Chin. Chem. Lett. 2009, 20, 171; c) N. Ahmed,
H. Ali, J. E. van Lier, Tetrahedron Lett. 2005, 46, 253; d) K. H. Kumar,
P. T. Perumal, Tetrahedron 2007, 63, 9531; e) S. R. Sarda, W. N.
Jadhav, R. P. Pawar, Int. J. ChemTech. Res. 2009, 3, 539; f) S. Kumar,
D. Sharma, Orient. J. Chem. 2011, 27, 761; g) Z. Du, H. Ng, K. Zhang,
H. Zeng, J. Wang, Org. Biomol. Chem. 2011, 9, 6930; h) P. S. Kulkarni,
D. D. Kondhare, R. Varala, P. K. Zubaidha, J. Serb. Chem. Soc. 2013,
78, 909; i) Y. K. Rao, S.-H. Fang, Y.-M. Tzeng, Bioorg. Med. Chem.
2005, 13, 6850; j) A. Lahyani, M. Trabelsi, Ultrason. Sonochem. 2016,
31, 626; k) K. V. Sashidhara, M. Kumar, A. Kumar, Tetrahedron Lett.
2012, 53, 2355.
Scheme 4. Proposed mechanism
Conclusions
In
conclusion,
we
have
disclosed
a
cascade
[10] For selected examples on cyclization of alkynones to synthesize
flavones, see: a) M. Yoshida, Y. Fujino, T. Doi, Org. Lett. 2011, 13,
4526; b) M. Yoshida, K. Saito, Y. Fujino, T. Doi, Chem. Commun.
cyclization/oxidative radical reaction of propynols in aqueous HI-
air system to construct flavones. Various flavones were formed
with high yield and efficiency under mild conditions. These
compounds exhibit latent pharmacologically and biologically
activity. The interesting mechanistic aspects of this reaction
have showed enough potential attraction for chemists working
on alkynols and radical chemistry. These findings in this paper
show significant progress in the synthesis of flavones and
develop a new reaction strategy for investigation.
2012, 48, 11796; c) K. Saito, M. Yoshida, T. Doi, Chem. Lett. 2015
44, 141; d) D. Zhai, L. Chen, M. Jia, S. Ma, Adv. Synth. Catal. 2018
360, 153.
,
,
[11] a) H. Miao, Z. Yang, Org. Lett. 2000, 2, 1765; b) E. Awuah, A. Capretta,
Org. Lett. 2009, 11, 3210; c) C. F. Barnard, J. Organometallics 2008,
27, 5402; d) B. Liang, M. Huang, Z. You, Z. Xiong, K. Lu, R. Fathi, J.
Chen, Z. Yang, J. Org. Chem. 2005, 70, 6097; e) Q. Yang, H. Alper, J.
Org. Chem. 2010, 75, 948; f) P. G. Ciattini, E. Morera, G. Ortar, S. S.
Rossi, Tetrahedron 1991, 47, 6449.
Experimental Section
[12] a) M. Muthukrishnan, P. S. Patil, S. V. More, R. A. Joshi, Mendeleev
Commun. 2005, 15, 100; b) P. R. Mahalle, T. Khaty, E-J. Chem. 2010,
7, 1359.
Aqueous HI (1.5 equiv) was added to a solution of 2-
propynolphenol 1a (0.2 mmol) in DCM (2.0 mL), and the
resulting mixture was stirred at 30°C in a sealed tube for 2.0 h.
The residue was further flashed by chromatography on silica gel,
which then allowed to stand for several hours in tube. The
solution was evaporated under reduced pressure to afford the
desired product 3a in 89% yield.
[13] J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005,
105, 1001.
[14] a) L. Zhang, G. Fang, R. K. Kumar, X. Bi, Synthesis 2015, 47, 2317; b)
Y. Zhu, L. Sun, P. Lu, Y. G. Wang, ACS Catal. 2014, 4, 1911. c) Y.-m.
Pan, F.-j. Zheng, H.-x. Lin, Z.- p. Zhan, J. Org. Chem. 2009, 74, 3148; d)
T. Wang, X.-l. Chen, L. Chen, Z.-p. Zhan, Org. Lett. 2011, 13, 3324; c)
X. Huang, N. Jiao, Org. Biomol. Chem. 2014, 12, 4324; e) Z. Liu, J. Liu,
L. Zhang, P. Liao, J. Song, X. Bi, Angew. Chem. Int. Ed. 2014, 53, 5305.
[15] a) Y.-F. Qiu, Y.-Y. Ye, X.-R. Song, X.-Y. Zhu, F. Yang, B. Song, J. Wang,
H.-L. Hua, Y.-P. Han, X.-Y. Liu, Y.-M. Liang, Chem. Eur. J. 2015, 21,
3480; b) X.-R. Song, Y.-F. Qiu, B. Song, X.-H. Hao, Y.-P. Han, P. Gao,
X.-Y. Liu, Y.-M. Liang, J. Org. Chem. 2015, 80, 2263; c) X.-R. Song, R.
Li, H. Ding, R. Yang, Q. Xiao, Y.-M. Liang, Tetrahedron Lett. 2016, 57,
4519; d) R. Li, X.-R. Song, X. Chen, H. Ding, Q. Xiao, Y.-M. Liang,
Tetrahedron Lett. 2017, 58, 3049; e) R. Li, X. Chen, X.-R. Song, H.
Ding, P. Wang, Q. Xiao, Y.-M. Liang, Adv. Synth. Catal. 2017, 359,
3962.
Acknowledgements ((optional))
We acknowledge the National Natural Science Foundation of
China (no. 21676131 and no. 21462019), the Science
Foundation
20161BAB213085, 20143ACB20012), and Jiangxi Science &
Technology Normal University (2017QNBJRC004, Doctor
Startup Fund) for financial support.
of
Jiangxi
Province
(20181BAB203005,
Keywords: 2-propynolphenols • cascade cyclization • flavones •
Brøsted acids •synthetic methods
[16]
For the preparation of 2k: Aqueous HI (1.5 equiv) was added to a
solution of 2-propynolphenol 1k (0.2 mmol) in DCM (2.0 mL), and the
resulting mixture was stirred at 30°C in a sealed tube for 2.0 h. The
[1]
[2]
S. Martens, A. Mithöfer, Phytochemistry, 2005, 66, 2399.
V. García-Mediavilla, I. Crespo, P. S. Collado, A. Esteller, S. Sánchez-
Campos, M.J. Tuñón, J. González-Gallego, Eur. J. Pharmacol, 2007,
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10.1002/ejoc.201801154
European Journal of Organic Chemistry
COMMUNICATION
residue was further flashed by chromatography on silica gel to obtain
[17] Z. Xu, C. Zhang, N. Jiao, Angew. Chem. Int. Ed. 2012, 52, 11367.
2k, which should be quickly analyzed by 1HNMR spectroscopy.
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Entry for the Table of Contents (Please choose one layout)
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Dr. X.-R. Song, R. Li, T. Yang, X. Chen,
H. Ding, Prof. Dr. Q. Xiao*, Prof. Dr. Y.-M
Liang
Page No. – Page No.
Novel and Efficient Access to Flavones
under Mild Conditions: Aqueous HI-
Mediated
Cascade
Cyclization/
Oxidative Radical Reaction of 2-
Propynolphenols
Herein we disclose a metal-free and efficient method for the direct conversion of 2-
propynolphenols to biologically important flavones using aqueous HI as the promoter.
This transformation was proved via 4-iodo-2H-chromenes intermediate, which was
simultaneously conversed to corresponding flavones by a Csp2−I bond cleavage and a
C−O bond formation under air.
This article is protected by copyright. All rights reserved.