An efficient one-pot synthesis of indanone fused heterocyclic compounds via SeO2/FeCl3 promoted intramolecular Friedel-Craft acylation reaction

Article abstract of DOI:10.1016/j.tetlet.2021.153070

Indanones have been shown to exhibit a broad range of biological activities. An efficient and straightforward synthetic method for generating indanone fused heterocyclic compounds which contains a unique tetracyclic isoflavone moiety was developed. This unprecedented one-pot route utilizes a wide spread of substrates through three-step tandem Riley oxidation/Friedel-Crafts reaction/oxidation with SeO₂/FeCl₃ in moderate yield. Moreover, some of the synthesized heterocyclic compounds have shown moderate anticancer activities.

Full text of DOI:10.1016/j.tetlet.2021.153070

Tetrahedron Letters 72 (2021) 153070
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient one-pot synthesis of indanone fused heterocyclic
compounds via SeO2/FeCl3 promoted intramolecular Friedel-Craft
acylation reaction
⇑
⇑
Huan Zhang, Qi Wang, Lu Huang, Ziye Tian, Shunguang Zhang , Youlai Zhang
Tianjin Key Laboratory of Drug Targeting and Bioimaging, School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Indanones have been shown to exhibit a broad range of biological activities. An efficient and straightfor-
ward synthetic method for generating indanone fused heterocyclic compounds which contains a unique
tetracyclic isoflavone moiety was developed. This unprecedented one-pot route utilizes a wide spread of
substrates through three-step tandem Riley oxidation/Friedel-Crafts reaction/oxidation with SeO2/FeCl3
in moderate yield. Moreover, some of the synthesized heterocyclic compounds have shown moderate
anticancer activities.
Received 5 February 2021
Revised 24 March 2021
Accepted 6 April 2021
Available online 9 April 2021
Keywords:
Indanone
Ó 2021 Elsevier Ltd. All rights reserved.
Fused heterocyclic compounds
SeO2
Friedel-Crafts reaction
One-pot reaction
Introduction
arylalkynes [12], radical cyclization [13], and base-promoted
cyclization of b-alkynyl ketones [14].
In recent years, indanones and their structural analogues
behave as key intermediates in medicine, agriculture and natural
products synthesis, which display a broad spectrum of biological
and pharmaceutical properties [1]. The extensive research on the
biological activities of indanones has opened up more and more
new application prospects (Fig. 1), such as anticancer [2], antibac-
terial [3], antiviral and antimicrobial agents [4], agents for Alzhei-
mer’s disease [5] and hepatitis C treatment [6]. In addition,
indanone derivatives can be used as pesticides, fungicides and her-
bicides in agriculture [7]. In natural products synthesis, the inda-
none moieties are found in several natural compounds and also,
can be used as intermediate in the synthesis of many different
types of medicinally important molecules [8].Fig. 2
Consequently, the development of efficient methods for the
synthesis of the indanone frameworks and the unique tetracyclic
isoflavone derivatives is a topic of considerable importance. Known
powerful and reliable syntheses for indanone formation include
classical intramolecular Friedel-Crafts acylations [9], intramolecu-
lar [4 + 2] cycloaddition reactions of conjugated enynes [10], Grig-
nard reactions [11], transition metal-catalyzed annulation of
In our previous study, an unexpected indanone byproduct
excited our interest [15]. Driven by the need for a more efficient
synthetic route to indanone derivatives, we were particularly
interested in exploring
a one-pot intramolecular cyclization
(Scheme 1). In this paper, we disclose a one-pot pathway through
Scheme 2.
Riley oxidation/Friedel-Crafts reaction/oxidation promoted by
SeO2/FeCl3 to provide an efficient and straightforward protocol
for the preparation of indanone fused heterocyclic compounds.
In line with our hypothesis, the 2-methyl-thiochromones 1 [16]
was prepared and converted to aldehyde following Riley selenium
dioxide oxidation. Next acid promoted intramolecular Friedel-
Crafts reaction to generate the tetracyclic core and then subsquent
aromatization and oxidation of the resulting benzyl alcohol gave
corresponding indanone. To demonstrate its utility, we also
describe a short and efficient total synthesis of Wrightiadione
which exhibits a broad range of biological and pharmaceutical
activities, especially the cytotoxicity against leukemia cell lines
[17].
Based on the one-pot strategy, we studied the feasibility of the
process to determine the most compatible conditions. For the fun-
damental study, our efforts began by exploring possible conditions
using methyl thiochromone as model substrate. Oxidation/F-C
reaction was conducted in the presence of SeO2 with various Lewis
⇑
Corresponding authors.
E-mail addresses: zsg@tjut.edu.cn (S. Zhang), youlaimail@163.com (Y. Zhang).
https://doi.org/10.1016/j.tetlet.2021.153070
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H. Zhang, Q. Wang, L. Huang et al.
Tetrahedron Letters 72 (2021) 153070
Scheme 2. Synthesis of Wrightiadione.
yield, entry 3) and Sc(OTf)3 also gave unsatisfactory result (31.0%
yield, entry 4). Further regulating the reaction conditions were
achieved with FeCl3, which worked to yield 2a in moderate yield
(entry 5). To our delight, when FeCl3 reagent was increased to
0.5 equivalent, a dramatic improvement in the yield was achieved
(87.7% yield, entry 6). Then, considering the impact of water, FeCl3
(0.5 eq) was added separately after reaction time 8 h, the yield was
no obvious improved (entry 7). It should be noted that, increasing
equivalent of FeCl3, prolonging reaction time and increasing reac-
tion temperature did not improve the yield, but rather led to a
decreased yield (entry 8, 9 and 10). Finally, the optimal condition
was carried out in O-DCB with 2.4 eq. SeO2 and 0.5 eq. FeCl3 at
150 °C, after 12 h the desired transformation was successfully
demonstrated.
Fig. 1. Biologically active indanone derivatives.
With optimal conditions determined, our focus was directed
toward studying the substrates in the presence of 2.4 eq. SeO2
and 0.5 eq. FeCl3. The substituents on R1 and R2 were investigated
to see the substituent effect on the reactivity (Table 2). The tetra-
cyclic scaffold could be easily equipped with an additional sub-
stituent at R1 and R2 by this one-pot process. It was noticed that
even the present of aryl group bearing either electron-donating
or withdrawing group at R2, such as an alkyl (methyl and ethyl
group), methoxy (2f, 2j) and halogen (2e), the reactions were
well-tolerated and generated the respective heteroindanones in
moderate yields. The molecular structure of compound 2g was
independently confirmed by X-ray crystal structure analysis [18].
Evidently, the effect of the steric and electronic charactersof the
substituent R1 was not distinct on the course of the reaction (2h-
2u). In addition, amenable to this protocol, nitrogen-containing
derivatives were also investigated, and the expected products
(2v-2y) were obtained in moderate yields (Table 2).
Fig. 2. X-ray crystal structure of 2g.
Specially, Wrightiadione which is an indanone derivative
including a similar indanone fused heterocyclic structure, isolated
from the bark of Wrightia tomentosa medicinally in Thailand.
Based on the above studies, we envisioned that application of this
one-pot approach reaction to produce the natural product starting
from simple starting materials such as readily available 2-Methyl-
chromone. In the synthetic route, iodination with CAN and I2 was
occurred firstly. Then, the Suzuki-Miyaura coupling of the resulting
iodide with phenylboronic acid gave the desired compound in 90%
overall yield. Satisfactorily, the desired product was produced
smoothly via this one-pot procedure.
With these results, the reaction mechanism was shown in
Scheme 3. Formation of the generated aldehyde (a) was carried
out with the corresponding 2-methyl-thiochromones (1) following
Riley selenium dioxide oxidation. The selenous acid generated
from SeO2 and H2O, which was provided during Riley allylic
oxidation. Next, under acid condition, promoted by FeCl3 and
selenous, the tetracyclic core (b) was generated by intramolecular
Scheme 1. One-pot pathway to access indanone fused heterocyclic compounds.
acids in order to produce indanone fused heterocyclic compounds
(Table 1).
In the initial attempt, As shown in entry1, in the presence of 2.4
equiv SeO2 and 0.1 equiv BF3ꢀOEt2 in o-dichlorobenzene (O-DCB)
the reaction proceeded at 150 °C within 12 h to give desired inda-
none 2a as a sole product (34.7% yield, entry 1). AlCl3 showed sim-
ilar reactivity and gave similar result (41.0% yield, entry 2). Tin
tetrachloride (SnCl4) resulted in a much lower yield of 2a (17.2%
2

H. Zhang, Q. Wang, L. Huang et al.
Tetrahedron Letters 72 (2021) 153070
Table 1
Optimization of reaction conditions.
Entry
SeO2 (eq)
Additive (eq)
Temp (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
2.4
BF3ꢁOEt2, 0.1
AlCl3, 0.1
SnCl4, 0.1
Sc(OTf)3, 0.1
FeCl3, 0.1
FeCl3, 0.5
FeCl3, 0.5
FeCl3, 1.0
FeCl3, 0.5
FeCl3, 0.5
150
150
150
150
150
150
150
150
150
180
12
12
12
12
12
12
12
12
48
12
34.7
41.0
17.2
31.0
52.7
87.7
88.3b
82.1
87.1
84.3
a
Reaction conditions unless specified otherwise: 1a (0.3 mmol) and SeO2 (2.4 eq) in dichlorobenzene (4.0 mL) Under an Ar atmosphere. The reaction was stirred at 150 °C
under an Ar atmosphere for 12 h. Isolated yields.
b
FeCl3 was added separately, after reaction time 8 h.
Table 2
Scope of substituents leading to quaternary heteroindanones.a,b
a
Reaction condition: 1 (0.3 mmol), SeO2 (2.4 eq) and FeCl3 (0.5 eq) in dichlorobenzene (4.0 mL) Under an Ar atmosphere. The reactionmixture was stirred at 150 °C for 12 h.
Isolated yield.
b
3

H. Zhang, Q. Wang, L. Huang et al.
Tetrahedron Letters 72 (2021) 153070
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153070.
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Acknowledgments
[18] Crystallographic data of 2g has been deposited with Cambridge
Crystallographic Data Centre as supplementary publication No. CCDC-
2013442. Copies of the data can be obtained free of charge via http://www.
ccdc.cam.ac.uk/data_request/cif.
This work was financially supported by the Natural Science
Foundation of Tianjin (Grant No. 18JCYBJC28500; 20JCYBJC00410).
Thanks to Prof Xiangtai Meng and Xuguang Liu for the discussion.
4