Polyphosphoric acid-promoted synthesis of coumarins lacking substituents at positions 3 and 4

Article abstract of DOI:10.1080/00397911.2020.1792498

Coumarins have recently emerged as a hot topic of research due to their diverse pharmacological properties. This work described a method for the synthesis of 3,4-diunsubstituted coumarins promoted by polyphosphoric acid (PPA) from salicylaldehydes and acetic anhydride. Various coumarins were produced in good to excellent yields.

Full text of DOI:10.1080/00397911.2020.1792498

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Polyphosphoric acid-promoted synthesis of
coumarins lacking substituents at positions 3 and
4
Li-Shou Yang , Yu Wang , En-Hua Wang , Jan Yang , Xiong Pan , Xiu Liao &
Xiao-Sheng Yang
To cite this article: Li-Shou Yang , Yu Wang , En-Hua Wang , Jan Yang , Xiong
Pan , Xiu Liao & Xiao-Sheng Yang (2020): Polyphosphoric acid-promoted synthesis of
coumarins lacking substituents at positions 3 and 4, Synthetic Communications, DOI:
10.1080/00397911.2020.1792498
To link to this article: https://doi.org/10.1080/00397911.2020.1792498
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https://doi.org/10.1080/00397911.2020.1792498
Polyphosphoric acid-promoted synthesis of coumarins
lacking substituents at positions 3 and 4
a,b
a,b
c
a,b
a,b
Ã
Ã
Li-Shou Yang
, Yu Wang , En-Hua Wang , Jan Yang , Xiong Pan ,
a,b
a,b
Xiu Liao , and Xiao-Sheng Yang
a
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University,
b
Guiyang, P. R. China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and
Chinese Academy of Sciences, Guiyang, P. R. China; Department of Medicine and Food, Guizhou
c
Vocational College of Agriculture, Guiyang, PR China
ABSTRACT
ARTICLE HISTORY
Coumarins have recently emerged as a hot topic of research due to
their diverse pharmacological properties. This work described a
method for the synthesis of 3,4-diunsubstituted coumarins promoted
by polyphosphoric acid (PPA) from salicylaldehydes and acetic
anhydride. Various coumarins were produced in good to excellent
yields.
Received 26 April 2020
KEYWORDS
Condensation; coumarin;
polyphosphoric acid;
salicylaldehyde
GRAPHICAL ABSTRACT
Introduction
Coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in numerous
[
1]
natural and synthetic products, displays varied bioactivities such as anti-oxidant, anti-
[
2]
[3]
[4]
[5]
[6]
inflammatory, anti-HIV, anti-microbial, anti-cancer, anti-tuberculosis, anti-
[
7]
[8]
convulsant, and anti-coagulant (Fig. 1). Therefore, the synthesis and applications of
the coumarin skeleton have gained widespread attention.
The general synthetic routes reported for coumarin derivatives involving Pechmann
[
9]
[10]
[11]
reaction,
tions
Knoevenagel condensation,
are all well documented in the literature.
is perhaps the most simple method used to produce coumarins.
Perkin condensation,
and Wittig reac-
[
12]
[13]
The classical Perkin condensation
[
14]
However, most
methods suffer from drawbacks including limited substrate scope and sometimes the
necessity of multi-step reactions. Modifications have been done to the classical Perkin
CONTACT Xiao-Sheng Yang
gzcnp@sina.cn
State Key Laboratory of Functions and Applications of Medicinal
Plants, Guizhou Medical University, Guiyang, P. R. China.
Ã
These authors are co-first authors.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
L.-S. YANG ET AL.
Figure 1. Selected bioactive coumarins.
condensation to prepare 3-substitutedcoumarins by using Mukaiyama esterification
[
15]
protocol to broad substrate and functional group tolerance.
Herein, we describe a convenient procedure promoted by PPA for the preparation of
coumarins from salicylaldehydes and acetic anhydride.
Results and discussion
Our initial studies were carried out with readily available salicylaldehyde 1a and
acetic anhydride 2 as test substrates. A mixture of 1a (1 equiv.), 2 (4 equiv.), PPA
ꢀ
(
2 equiv.) in DMF was stirred at 120 C for 2 h under a nitrogen atmosphere to give
the desired product 3a in 30% yield (Table 1, entry 2). Increasing the amount of
PPA had no obvious effect on the reaction (Table 1, entry 1). However, decreasing
the amount of PPA to 1 equiv. resulted in lower yield (Table 1, entry 3). We then
investigated the temperature impact on the efficiency of the reaction and found that
ꢀ
1
45 C was the best choice (Table 1, entries 4–7). Subsequently, a decreased yield
was observed upon reducing the reaction time to 1 h (Table 1, entry 8). To our
delight, further screening of the reaction time showed that the yield could be
improved when the reaction time increased to 3 h (Table 1, entry 9). However, pro-
longing the reaction time (4 h) had very a slight reduction in yield (Table 1, entry
10). Unfortunately, the reaction performed in EtOH, THF, 1,4-dioxane or DMSO
did not give the desired product 3a (Table 1, entries 11–14). The optimized reaction
conditions were determined as 1a (1 equiv.), 2 (4 equiv.), PPA (2 equiv.) in DMF at
ꢀ
1
45 C for 3 h under a nitrogen atmosphere (Table 1, entry 9). With the optimized
reaction conditions in hand, a gram scale reaction was carried out and provided the
product 3a in 72% yield (Table 1, entry 15).
Under the optimized conditions, the scope of the substrates was investigated by vary-
ing salicylaldehyde 1 (Table 2). As shown in Table 2, desired products 3b–3j were suc-
cessfully obtained in good to excellent yields (Table 2, entries 2–10). The electronic
properties of the substituents had an obvious effect on the reaction. Electron-withdraw-
ing groups (F, Cl, Br and NO ) on salicylaldehyde 1 led to lower yields (Table 2, entries
2
6–10). Additionally, fluoro-, dichloro- or nitro-substituted salicylaldehyde had limited
influence on the reactivity (Table 2, entries 6, 9 and 10). The classical Perkin

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3
a
Table 1. Optimization of the reaction conditions .
o
b
Entry
PPA (equiv.)
Solvent
T ( C)
Time (h)
Yield 3a (%)
1
2
3
4
5
6
7
8
9
3
2
1
2
2
2
2
2
2
2
2
2
2
2
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
110
140
145
150
145
145
145
75
2
2
2
2
2
2
2
1
3
4
3
3
3
3
3
31
30
14
9
60
77
76
41
91
90
/
1
1
1
1
1
1
a
0
1
2
3
4
5
DMF
EtOH
THF
65
/
/
/
72
1,4-dioxane
DMSO
DMF
100
145
145
c
Reagents and conditions: 1a (0.3 mmol), 2 (1.2 mmol), solvent (0.3 mL).
b
Isolated yield.
c
Reagents and conditions: 1a (8.4 mmol), 2 (33.6 mmol), solvent (6.0 mL).
a
Table 2. Evaluation of substrate scope .
b
Entry
R
Time (h)
Product 3
Yield 3 (%)
1
2
3
4
5
6
7
8
9
H
3
3
3
3
3
4
3
3
4
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
91
88
92
87
85
80
82
77
80
71
3-Me
4-Me
3-tBu
3-allyl
4-F
5-Cl
5-Br
3,5-Cl
5-NO
2
1
a
0
2
3j
Reagents and conditions: 1 (0.3 mmol), 2 (1.2 mmol), DMF (0.3 mL).
b
Isolated yield.
condensation involves the use of simple starting materials in the presence of basic con-
[
16]
densing agents including NaOAc, KOAc, CsOAc and Cs CO
The same coumarins
2
3.
[18]
[
16 ]
[17]
[19]
3
a, 3b, 3f, and 3h were formed in 79%, d 85%,
88%,
and 56%
yields under
ꢀ
the classical conditions (heated at 145–180 C for 6–48 h) from salicylaldehydes and
acetic anhydride.

4
L.-S. YANG ET AL.
Conclusion
In summary, we have developed a simple and practicable reaction for the synthesis of
3
,4-diunsubstituted coumarins promoted by PPA from accessible salicylaldehydes and
acetic anhydride.
Experimental section
General procedure for the preparation of coumarins 3 (3a–3j)
To the solution of polyphosphoric acid (PPA, 0.6 mmol) in DMF (0.3 mL) were added
salicylaldehydes 1 (0.3 mmol) and acetic anhydride 2 (1.2 mmol) under a nitrogen
ꢀ
atmosphere. The reaction mixture was stirred at 145 C 3–6 h. The reaction mixture was
quenched with water and extracted with ethyl acetate. The organic layer was washed
with saturated sodium bicarbonate solution, dried over Na SO and evaporated. The
2
4
resulting crude compound was purified by silica gel column chromatography, affording
the pure coumarins 3.
Detailed procedures and spectral characterization data for all compounds reported
herein can be accessed on the publisher’s website.
Acknowledgment
The authors 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.
Funding
The work here was supported by the National Natural Science Foundation of China [No.
8
1860609], the Guizhou Provincial Natural Science Foundation [No. QKHJC[2019]1213], the
High-level Innovative Talents Training in Guizhou Province [No. 2015-4027] and the Project of
Guizhou Science and Technology Platform and Talent Team Under Grant [No.
QKHPTRC[2017]5614].
ORCID
Li-Shou Yang
http://orcid.org/0000-0002-7148-9291
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