One-pot synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophenones and aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2019.151180

An efficient and practical PPA/H₂SO₄ promoted synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophenones and aromatic aldehydes was developed. Various (E)-3-benzylideneflavanones were produced in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2019.151180

Journal Pre-proofs
One-pot synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophe-
nones and aromatic aldehydes
Lishou Yang, Enhua Wang, Yanhua Fan, Juan Yang, Zhongsheng Luo, Yu
Wang, Mei Peng, Tingfei Deng, Xiaosheng Yang
PII:
S0040-4039(19)30954-2
DOI:
https://doi.org/10.1016/j.tetlet.2019.151180
TETL 151180
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 July 2019
14 September 2019
17 September 2019
Please cite this article as: Yang, L., Wang, E., Fan, Y., Yang, J., Luo, Z., Wang, Y., Peng, M., Deng, T., Yang, X.,
One-pot synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophenones and aromatic aldehydes,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151180
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2
Graphical Abstract
One-pot
synthesis
of
(E)-3-
Leave this area blank for abstract info.
benzylideneflavanones
from
2-
hydroxyacetophenones and aromatic
aldehydes
Lishou Yanga,b, Enhua Wangc, Yanhua Fana,b, Juan Yanga,b, Zhongsheng Luoa,b, Yu Wanga,b, Mei Penga,b,
Tingfei Denga,b, Xiaosheng Yanga,b,

5
3
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot synthesis of (E)-3-benzylideneflavanones from 2-hydroxyacetophenones and
aromatic aldehydes
Lishou Yanga,b, Enhua Wangc, Yanhua Fana,b, Juan Yanga,b, Zhongsheng Luoa,b, Yu Wanga,b, Mei Penga,b,
Tingfei Denga,b, Xiaosheng Yanga,b,*
a State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medcial University, Guiyang 550014, China
b The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guiyang 550014, China
c Department of Medicine and Food, Guizhou Vocational College of Agriculture, Guiyang 551400, China
 Corresponding author. Tel.: +86-0851-83809055; fax: +86-0851-83809055; e-mail address: gzcnp@sina.cn (X. Yang).
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and practical PPA/H2SO4 promoted synthesis of (E)-3-benzylideneflavanones
from 2-hydroxyacetophenones and aromatic aldehydes was developed. Various (E)-3-
benzylideneflavanones were produced in good to excellent yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
PPA/H2SO4
Condensation
One-pot synthesis
(E)-3-Benzylideneflavanones
Herein, we describe a convenient and efficient one-pot
procedure promoted by polyphosphoric acid (PPA) and H2SO4
for the preparation of (E)-3-benzylideneflavanones from 2-
Introduction
3-Benzylideneflavanones are a significant architectural motif
found in biologically active compounds and natural products.1
For example, they are building blocks in the synthesis of
spiroheterocycles,2 and are also present in biologically active
flavones.3 These compounds exhibit various pharmacological
activities such as anti-cancer,4 anti-oxidant, anti-inflammatory,
analgesic and anti-bacterial5a-b properties (Fig. 1). Therefore, the
synthesis and applications of these scaffolds have gained
widespread attention.
hydroxyacetophenones and aromatic aldehydes.
The most common synthetic method reported for the
preparation of 3-benzylideneflavanones is the condensation of
flavanones with aromatic aldehydes catalyzed either by an acid or
base.6 In addition, they are also formed as co-products during the
condensation of 2-hydroxyacetophenones and aromatic
aldehydes.7 To the best of our knowledge, only two protocols
have reported the one-pot synthesis of 3-benzylideneflavanones
8
via either the NaOH5 or SiCl4 catalyzed condensation of 2-
hydroxyacetophenones and aromatic aldehydes.

34
Figure 1. Selected bioactive 3-benzylideneflavanones.
Table 1. Optimization of the reaction conditions.a
Entry
Additive 1 (equiv.)
Additive 2 (equiv.)
Solvent
T (oC)
Time (h)
Yield 3a (%)b
1c
2
3
4
5
6
7
8
9
10
11
12d
13
14
15
16
17
18
19
PPA (15)
PPA (0)
H2SO4 (4)
H2SO4 (4)
H2SO4 (0)
H2SO4 (4)
H2SO4 (4)
H2SO4 (12)
H2SO4 (16)
H2SO4 (12)
H2SO4 (12)
H2SO4 (12)
H2SO4 (12)
HCl (12)
H3PO4 (12)
HNO3 (12)
AcOH (12)
H2SO4 (12)
H2SO4 (12)
H2SO4 (12)
H2SO4 (12)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
EtOH
90
90
90
90
90
90
90
40
60
60
60
60
60
60
60
60
60
60
60
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
28
/
PPA (15)
PPA (20)
PPA (25)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
PPA (20)
11
39
38
58
56
40
84
92
91
3
9
2
10
/
/
THF
DMSO
DMF
/
/
a Reagents and conditions: 1a (0.1 mmol), 2a (0.16 mmol), solvent (2 mL). b Isolated yield. c H2SO4 (98% concentrated sulfuric acid). d HCl (36.5% concentrated
hydrochloric acid).
Results and Discussion
OH) on the 2-hydroxyacetophenones and/or the aromatic
aldehydes provided the highest yields (Table 2, entries 1-2, 6-8).
2-Hydroxyacetophenone also reacted with benzaldehyde to give
the desired product 3e in good yield (Table 2, entry 5). However,
electron-withdrawing groups, such as F, Cl and Br, led to slightly
lower yields (Table 2, entries 3-4, 9-16). Aromatic aldehydes
with electron-donating or electron-withdrawing groups at the
ortho-position gave the corresponding products in similar yields
compared with aromatic aldehydes substituted at the para-
position (Table 2, 3c vs. 3d, 3f vs. 3g vs. 3h, 3i vs. 3j, 3l vs. 3m
and 3n vs. 3o). Substrates with electron-withdrawing groups gave
lower yields (Table 2, entries 12-13 and 16).
Our initial studies were carried out with readily available 2-
hydroxy-5-methyacetophenone 1a and benzaldehyde 2a as test
substrates. A mixture of 1a (1 equiv.), 2a (1.6 equiv.), PPA (15
o
equiv.) and H2SO4 (4 equiv.) in 1,4-dioxane was stirred at 90 C
for 1 h under an air atmosphere to give the desired product 3a in
28% yield (Table 1, entry 1). Control experiments were
performed in the absence of either PPA or H2SO4 (Table 1,
entries 2-3). The results showed that PPA and H2SO4 were
essential for the formation of the desired product 3a. Increasing
the amount of PPA resulted in a higher yield (Table 1, entry 4).
However, further increasing the amount of PPA to 25 equiv. had
no obvious effect on the reaction (Table 1, entry 5). To our
delight, we found that increasing the amount of H2SO4 to 12
equiv. further increased the yield (Table 1, entry 6). However, a
decreased yield was observed upon increasing the amount of
H2SO4 to 16 equiv. (Table 1, entry 7). We then investigated the
The stereochemistry of the 3-benzylideneflavanone derivatives
1
was unambiguously determined from their H NMR spectra. The
product 3 exist in the E form, based on their NMR spectra and in
accordance with literature reports.9 The arylidene proton signal of
3 resonates at a lower field (around 8.00) and was more shielded
than the Z-isomer. In addition, the NOEs of selected products 3
are shown in the ESI.
o
impact of the temperature and found that 60 C was the best
choice (Table 1, entries 8-9). Subsequently, further screening of
the reaction time showed that the yield could be improved when
the reaction time was increased to 1.5 h (Table 1, entry 10).
However, further increasing the reaction time (2.0 h) led to a
slight reduction in the yield (Table 1, entry 11). When
concentrated hydrochloric acid (HCl), H3PO4, HNO3 or AcOH
was used instead of H2SO4, product 3a was obtained in low
yields (Table 1, entries 12-15). Unfortunately, the reactions
performed in EtOH, THF, DMSO or DMF did not give the
desired product 3a (Table 1, entries 16-19). The optimized
reaction conditions were determined as 1a (1 equiv.), 2a (1.6
equiv.), PPA (20 equiv.) and H2SO4 (12 equiv.) in 1,4-dioxane at
60 oC for 1.5 h under an air atmosphere (Table 1, entry 10).
As shown in Table 2, the reaction represents a general method
to construct different substituted 3-benzylideneflavanones.
Notably, the electronic properties of the substituents have an
effect on the reaction. Electron-donating groups (Me, OMe and
Table 2. Evaluation of substrate scope.a
Product
Entry
R1
R2
3
Yield 3 (%)b
1
2
3
4
6-Me
6-Me
6-Me
6-Me
H
3a
3b
3c
3d
92
87
80
79
4'-OH
2'-Cl
4'-Br
5
6
7
8
9
H
H
H
H
H
H
3e
3f
3g
3h
3i
85
84
83
86
75
4'-OH
2'-OMe
4'-Me
2'-Cl

5
10
11
12
13
14
15
16
H
4'-Br
4'-OH
2'-Cl
4'-Br
4'-OH
4'-Me
4'-Br
3j
3k
3l
3m
3n
3o
3p
78
77
70
72
75
79
66
1. (a) Subramaniyan G, Raghunathan R, Castro AMM. Synthesis.
2002;2002:2440-2444;
6-Cl
6-Cl
6-Cl
6-F
6-F
6-F
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2007;48:8562-8565;
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b Isolated yield.
(c) Subramaniyan G, Raghunathan R. Tetrahedron. 2001;57:2909-
2913;
(d) Manikandan S, Shanmugasundaram M, Raghunathan R.
Heterocycles. 2000;53:579-584.
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Scheme 1. Plausible mechanism for the one-pot synthesis of (E)-3-
benzylideneflavanones.
A plausible mechanism for the one-pot synthesis of (E)-3-
benzylideneflavanones is depicted in Scheme 1. PPA promotes
the condensation of 2-hydroxyacetophenone 1a with
benzaldehyde 2a to form intermediate 4, which after subsequent
cyclisation gives intermediate 5. Finally, the PPA promoted
condensation of intermediate 5 with benzaldehyde 2a leads to the
desired product 3a.
(b) Joseph L, George M, Gopal N. Highland Med Res J. 2007;5:20-
22;
(c) Dhara MG, Mallik UK, Mallik AK. Indian
J Chem.
1996;35B:1214-1217.
6. (a) Mallik UK, Saha MM, Mallik AK.
1990;67:478-481;
J Indian Chem Soc.
(b) Krishnamurty HG, Parkash B, Sathyanarayana S. Indian J Chem
B. 1989;28:279-281.
7. (a) Chawla HM, Sharma SK. Heterocycles. 1987;18:1527-1534;
(b) Chawla HM, Sharma SK. Indian J Chem. 1987;16B:1075-1077;
(c) Széll T, Unyi RÉM. J Org Chem. 1963;28:1146-1147;
Conclusion
(d) Seikel MK, Lounsbury MJ, Wang SC.
1962;27:2952-2954.
J Org Chem.
In summary, we have developed an efficient one-pot method
for the preparation of (E)-3-benzylideneflavanones using 2-
hydroxyacetophenones and aromatic aldehydes as the starting
materials.
8. Salama AT, Ismail AM, Khalil MA, et al. Arkivo. 2012;2012:242-253.
(a) Manikandan S, Ashraf MM, Raghunathan R. Synth Commun.
2001;31:3593-3601;
(b) Salama AT, Ismail AM, Khalil MA, et al. Arkivo. 2012;2012:242-
9. 253.
Acknowledgments
We are grateful for the help provided by the staff at the Key
Laboratory of Chemistry for Natural Products of Guizhou
Province and the Chinese Academy of Sciences. The work here
was supported by the National Natural Science Foundation of
China (No. 81860609), the Guizhou Provincial Science and
Technology Foundation (No. QKHJC[2019]1213) and the High-
level Innovative Talents Training in Guizhou Province (No.
2015-4027).
Appendix A. Supplementary data
Supplementary material related to this article can be found, in
the online version, at doi:
References

6
 A one-pot protocol for the preparation of (E)-3-
benzylideneflavanones.
 Moderate to good yields of the products.
 Experimentally simple procedures working
under air.
 Simple starting materials.