Activation of phenolic oxygen atom using polyphosphoric acid: Synthesis of carbonyl-containing dihydrobenzofurans/dihydrobenzopyrans

Article abstract of DOI:10.1080/00397911.2021.1902537

Carbonyl-containing dihydrobenzofurans/dihydrobenzopyrans were prepared from carbonyl-containing ortho-allyl/prenylphenols by activation of phenolic oxygen atom using polyphosphoric acid (PPA). Various substrates were investigated, and the corresponding d

Full text of DOI:10.1080/00397911.2021.1902537

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Activation of phenolic oxygen atom
using polyphosphoric acid: Synthesis of
carbonyl-containing dihydrobenzofurans/
dihydrobenzopyrans
Qian Yang, Yu Wang, Juan Yang, Yi Wu, Liang-qun Li, Fa-ju Chen, En-hua
Wang, Li-lang Li, Yan Yang, Yan-fang Yan, Li Wang, Li-juan Ge, Li-shou Yang &
Xiao-sheng Yang
To cite this article: Qian Yang, Yu Wang, Juan Yang, Yi Wu, Liang-qun Li, Fa-ju Chen, En-hua
Wang, Li-lang Li, Yan Yang, Yan-fang Yan, Li Wang, Li-juan Ge, Li-shou Yang & Xiao-sheng
Yang (2021) Activation of phenolic oxygen atom using polyphosphoric acid: Synthesis of carbonyl-
containing dihydrobenzofurans/dihydrobenzopyrans, Synthetic Communications, 51:11, 1723-1730,
DOI: 10.1080/00397911.2021.1902537
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Published online: 01 Apr 2021.
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2021, VOL. 51, NO. 11, 1723–1730
https://doi.org/10.1080/00397911.2021.1902537
Activation of phenolic oxygen atom using polyphosphoric
acid: Synthesis of carbonyl-containing dihydrobenzofurans/
dihydrobenzopyrans
Qian Yanga, Yu Wangb,c, Juan Yangb,c, Yi Wub,c, Liang-qun Lib,c, Fa-ju Chenb,c
,
En-hua Wangd, Li-lang Lib,c, Yan Yangb,c, Yan-fang Yanb,c, Li Wangb,c, Li-juan Geb,c
Li-shou Yangb,c , and Xiao-sheng Yangb,c
,
b
aSchool of Pharmaceutical Sciences, Guizhou University, Guiyang, PR China; State Key Laboratory of
c
Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, PR China; The
Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of
d
Sciences, Guiyang, PR China; Department of Medicine and Food, Guizhou Vocational College of
Agriculture, Guiyang, PR China
ABSTRACT
ARTICLE HISTORY
Received 25 January 2021
Carbonyl-containing dihydrobenzofurans/dihydrobenzopyrans were
prepared from carbonyl-containing ortho-allyl/prenylphenols by acti-
vation of phenolic oxygen atom using polyphosphoric acid (PPA).
Various substrates were investigated, and the corresponding dihydro-
benzofurans/dihydrobenzopyrans were obtained in good to excellent
yields.
KEYWORDS
Cyclization; dihydrobenzo-
furans; dihydrobenzopyrans;
ortho-allyl/prenylphenols;
polyphosphoric acid
GRAPHICAL ABSTRACT
Introduction
Dihydrobenzofuran/dihydrobenzopyran system is found in a variety of biologically
active compounds[1] and exhibit significant biological activity, such as antigenotoxic,[2]
antiproliferative,[3] anticancer,[4] and antiinflammatory.[5] The most common synthetic
method reported for the preparation of dihydrobenzofurans/dihydrobenzopyrans is the
cyclization of ortho-allyl/prenylphenols.[6]
Recently, we disclosed a procedure promoted by PPA for the preparation of coumar-
ins from salicylaldehydes and acetic anhydride,[7] wherein the intramolecular cyclization
of 3-allyl-2-hydroxybenzalde was occurred to generate the dihydrobenzofuran (Scheme
1(a)). This cyclization of ortho-allylphenol had attracted our interests, and found that
carbonyl-containing substrates could undergo the cyclization yielding desirable products
in good yields (Scheme 1(b)). Carbonyl group on the nucleophilic component of the
CONTACT Li-shou Yang
1039160204@qq.com; Xiao-sheng Yang
gzcnp@sina.cn
State Key Laboratory of
Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, PR China
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Q. YANG ET AL.
Scheme 1. (a) Intramolecular cyclization of 3-allyl-2-hydroxybenzalde was occurred during the Perkin
condensation promoted by PPA; (b) cyclization of carbonyl-containing ortho-allylphenols gave dihydro-
benzofurans in good yields.
reaction would, theoretically, appear detrimental to the reaction sequence, but in this
case, the phenolic oxygen nucleophilicity was reversed. We envisioned that it would be
possible to generate phosphorylated adduct and then formed phenoxy anion due to the
carbonyl-aromatic p-stacked interaction.
Carbonyl-containing dihydrobenzofurans/dihydrobenzopyrans also have varied bioac-
tivities including anticancer activity,[8] antiproliferative activity,[9] and inhibitory activity
on D-amino acid oxidase[10] (Fig. 1). To the best of our knowledge, methods to accom-
plish the cyclization of carbonyl-containing ortho-allyl/prenylphenols include the use of
[11]
[12]
I2,
H2SO4,
HCl,[13] p-TsOH,[14] TFA[8b], AlCl3[8b], and ZrCl4[6d]. However, these
reported methods suffer some disadvantages, such as unsatisfactory products
yields,[11–14] relatively long reaction time[13,6d], and narrow substrate scope[11–13,14b,8b,6e]
maybe because of the decrease of phenolic oxygen nucleophilicity.
Herein, we report an efficient procedure for the preparation of carbonyl-containing
dihydrobenzofurans/dihydrobenzopyrans from ortho-allyl/prenylphenols by activation of
phenolic oxygen atom using PPA.
Results and discussion
Our initial studies were carried out with the commercially available 3-allyl-2-hydroxy-
benzaldehyde 1a as test substrate. A mixture of 1a (1 equiv.) and PPA (3 equiv.) in
N,N-dimethylformamide (DMF) was stirred at 130 ꢀC for 10 h under an air atmosphere
to give the desired product 2a in 52% yield (Table 1, entry 1). To further improve the

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Figure 1. Selected bioactive carbonyl-containing dihydrobenzofurans and dihydrobenzopyrans.
Table 1. Optimization of reaction conditionsa.
Entry
PPA (equiv.)
Solvent
2a (%)b
1
2
3
3
1
5
7
5
5
5
5
5
DMF
DMF
DMF
DMF
THF
52
27
81
79
/
18
/
4
5c
6d
7
1,4-Dioxane
DMSO
DMA
8
23
8
9e
Toluene
aReaction conditions: 1a (0.2 mmol), solvent (0.3 mL).
bIsolated yield.
cReaction temperature: 66 ꢀC.
dReaction temperature: 106 ꢀC.
eReaction temperature: 110 ꢀC.
reaction yield, control experiment was performed. Decreasing the amount of PPA
resulted in a lower yield (Table 1, entry 2). To our delight, we found that increasing the
amount of PPA to 5 equiv. further increased the yield (Table 1, entry 3). However, fur-
ther increased the amount of PPA had no obvious effect on the reaction (Table 1, entry
4). Subsequently, we investigated the effect of solvents on the efficiency of the cycliza-
tion. Unfortunately, the reaction performed in THF, 1,4-dioxane, DMSO, DMA, or tolu-
ene exerted detrimental effect on the yield (Table 1, entries 5–9). Therefore, the
optimized reaction conditions were determined as 1a (1 equiv.) and PPA (5 equiv.) in
DMF at 130 ꢀC for 10 h under a normal atmosphere (Table 1, entry 3).
With the optimized reaction conditions in hand, the substrate scope of this cycliza-
tion was examined by varying carbonyl-containing ortho-allyl/prenylphenols 1a–k
(Table 2). Notably, ortho-allylphenol containing two carbonyl substituents was obtained
in excellent yield (2a, 2b, 2c, and 2d vs. 2e). When an electron-donating group

1726
Q. YANG ET AL.
Table 2. Evaluation of substrate scopea.
aReaction conditions: 1a (0.2 mmol), PPA (1.0 mmol), and DMF (0.3 mL).
bPPA (20 equiv., 4.0 mmol).
cPPA (30 equiv., 6.0 mmol).
(OMe or OH) was bonded to the benzene ring, the cyclization proceeded to give the
corresponding dihydrobenzofurans in lower yields (2b and 2d). Next, we selected some
available prenylated flavonoids and anthraquinones as substrates, which led to the for-
mation of dihydrobenzopyrans in good to excellent yields, and no five-membered cyclic
ether was observed (2f–k). This indicated that the conditions we developed tolerate fla-
vonoids and anthraquinones and the cyclization reaction proceeded at the double bond
carbon atom with more substituents that follows Markovnikov selectivity. Obviously,
anthraquinones reacted better and gave excellent yields (2j–k vs. 2f–i). Besides, it was
observed that dihydroflavone had lower reactivity than chalcone or flavone (2i vs.
2f–h). Gratifyingly, we only observed the regioselective cyclization of allyl/prenyl group
with the p-hydroxy of the carbonyl group (2d, 2g, 2j, or 2k) based on NMR spectra
and in accordance with literature reports[14a,15] In addition, regioselective cyclization of
the prenyl group occurred to give exclusively chromanochalcone from prenylated chal-
cone, but we did not observe formation of the corresponding flavanone (Scheme 2; 2f
and 2g).
A plausible mechanism for the synthesis of carbonyl-containing dihydrobenzofurans/
dihydrobenzopyrans is depicted in Scheme 3. Firstly, phosphorylated adduct 3 is formed

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Scheme 2. Regioselective cyclization of prenylated chalcone using PPA.
Scheme 3. Plausible mechanism for the synthesis of carbonyl-containing dihydrobenzofurans/
dihydrobenzopyrans.
from 1c and PPA under elevated reaction temperature. Electron delocalization within
p–p conjugated 3 due to more polarized the O–H bond and better stabilization of the
negative charge on the oxygen atom[16] forming intermediate 4. Finally, the nucleophilic
attack leads to the desired product 2c.
Conclusion
In summary, we have developed an efficient method for the synthesis of dihydrobenzo-
furans/dihydrobenzopyrans from ortho-allyl/prenylphenols by activation of phenolic
oxygen atom using PPA.
Experimental section
General procedure for the preparation of carbonyl-containing
dihydrobenzofurans/dihydrobenzopyrans 2 (2a–2k)
To a stirred solution of N,N-DMF (0.3 mL) were added PPA (1 mmol) and carbonyl-
containing ortho-allyl/prenylphenols 1 (0.2 mmol) in 5 mL pressure-resistant reaction
bottle. The reaction mixture was stirred at 90–160 ꢀC until all starting materials were
consumed (2–10 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 Na2SO4, and evaporated. The resulting crude compound was purified by

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Q. YANG ET AL.
silica gel column chromatography, affording the pure dihydrobenzofurans/dihydroben-
zopyrans 2.
Detailed procedures and spectral characterization data for all compounds reported
herein can be accessed on the publisher’s website.
Acknowledgments
The authors are grateful for 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.
81860609], the Guizhou Provincial Natural Science Foundation [No. QKHJC[2019]1213], the
High-level Innovative Talents Training in Guizhou Province [No. 2015-4027], the Project of
Guizhou Science and Technology Platform and Talent Team Under Grant [No.
QKHPTRC[2017]5614], and the Plan Project of Science and Technology in Guizhou Province
[No. QKHFQ[2020]4013].
ORCID
Li-shou Yang
http://orcid.org/0000-0002-7148-9291
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