Visible Light-Promoted Selenylation/Cyclization of Enaminones toward the Formation of 3-Selanyl-4H-Chromen-4-Ones

Article abstract of DOI:10.1002/adsc.202001474

A simple and efficient visible-light-promoted selenylation/cyclization of enaminones have been realized for the practical synthesis of 3-selanyl-4H-chromen-4-ones. This reaction is performed in the mild conditions, no transition metal catalyst or photocatalysts and no additional oxidants are required. In addition, the 3-selanyl-4H-chromen-4-ones could be easily converted to selanyl-functionalized pyrimidines by reacting with benzamidine substrates. (Figure presented.).

Full text of DOI:10.1002/adsc.202001474

COMMUNICATIONS
DOI: 10.1002/adsc.202001474
Visible Light-Promoted Selenylation/Cyclization of Enaminones
toward the Formation of 3-Selanyl-4H-Chromen-4-Ones
a
a
b
a,
Hao-Yang Liu, Jia-Rong Zhang, Guo-Bao Huang, Yi-Huan Zhou, *
a,
a, b,
Yan-Yan Chen, * and Yan-Li Xu *
a
Pharmacy School of Guilin Medical University
Guilin, 541004 People’s Republic of China
E-mail: zyh8312020@163.com; chenyy269614@163.com; yanli.xu@163.com
Key Laboratory of Agricultural Resources Chemistry and Biotechnology
b
College of Chemistry and Food Science of Yulin
Normal University
Yulin 537000, People’s Republic of China
Manuscript received: November 26, 2020; Revised manuscript received: January 19, 2021;
Version of record online: Februar 4, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001474
chromones containing selenyl-substituents show
Abstract: A simple and efficient visible-light-pro-
unique bioactivities and chemical properties, and
moted selenylation/cyclization of enaminones have
widely adopted in drug design and regulation of
been realized for the practical synthesis of 3-
[6]
biological processes.
selanyl-4H-chromen-4-ones. This reaction is per-
formed in the mild conditions, no transition metal
catalyst or photocatalysts and no additional oxidants
are required. In addition, the 3-selanyl-4H-chromen-
As 3-selenochromones are an important class of
compounds, much efforts has been devoted to the
[7]
assembly of this compound. Among them, the
reactions based on the featured chromone annulation
of easily available 2-hydroxyphenyl enaminones have
been proved to be the most reliable and broadly
4
-ones could be easily converted to selanyl-func-
tionalized pyrimidines by reacting with benzamidine
substrates.
[8]
applicable one. For example, Zhou’s group reported a
metal-free approach to 3-selenocyanochromone via α-
CÀ H selenocyanation of enaminones using PhI(OAc)
2
Keywords: 2-hydroxyphenyl enaminones; selenyla-
tion; 3-selanyl-4H-chromen-4-ones; selanyl-function-
alized pyrimidines; visible-light-promoted
as an oxidant in an aqueous medium (Scheme 1a).
[9]
[10]
Wan’s group and Braga’s group
reported KIO3-
catalyzed synthesis of 3-selenochromones from 2-
hydroxyphenyl enaminones and diorganyl diselenides,
in which using ethyl lactate and glycerol as solvent,
[11]
Chromone moiety is a well-documented privileged respectively (Scheme 1b). Blond’s group have devel-
structure in the natural products and pharmaceuticals oped AgOTf-mediated synthesis of 3-selenochromones
[1]
for discovering lead compounds and medicines. In through the reaction of 2-hydroxy-phenyl enaminones
particular, C3-substituted chromones are recently and phenylselenyl chloride (Scheme 1c). Although
drawing considerable attention as they exhibit a variety diverse approaches toward the synthesis of 3-seleno-
[2]
of physiological and biological activities. Several
[3]
representative compounds with anti-cancer, anti-
oxidant, and anti-inflammatory activities, are shown in
Figure 1.
Organoselenium compounds have attracted consid-
erable attention in medicinal chemistry owing to their
[4]
well-known biological activities, which mainly attrib-
uted to the fact that the selenium atom may serve as an
electron donor or a hydrogen bond acceptor in these
applications, altering the chemical characteristics of
Figure 1. Biologically Active Molecules including C3-Substi-
tuted Chromones Moiety.
[5]
enzyme active sites. Recent studies revealed that
Adv. Synth. Catal. 2021, 363, 1656–1661
1656
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
[a]
Table 1. Optimization of Reaction Conditions.
Entry
1
Solvent
Yield
DMF
DMF
DMF
33
38
40
50
81
86
73
80
75
63
10
0
[b]
2
3
4
5
6
7
8
9
1
[
c]
DMF:HOAc (v/v=1:1)
DMF:HOAc (v/v=5:1)
DMF:HOAc (v/v=10:1)
DMF:HOAc (v/v=20:1)
CH CN:HOAc (v/v=10:1)
3
DMSO:HOAc (v/v=10:1)
THF:HOAc (v/v=10:1)
Ethanol:HOAc (v/v=10:1)
DMF:HOAc (v/v=10:1)
DMF:HOAc (v/v=10:1)
DMF:HOAc (v/v=2:1)
0
1
1
[d]
[e]
[f]
12
13
14
83
79
[
a]
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), solvent
(1.0 mL), 60 W white LEDs, air, at room temperature for 3 h,
isolated yield base on 1a.
Scheme 1. Different Methods to 3-Selenochromones from 2-
Hydroxyphenyl Enaminones.
[b]
[c]
[d]
[e]
[f]
2
2
equiv. K CO was added.
2 3
equiv. K CO and 1 equiv. H O were added.
2
3
2
2
chromones have been exploited, the development of
efficient, practical and green synthetic methods for
constructing 3-selenochromones are still in high
demand.
Reaction in the dark.
60 W blue LEDs was used.
The reaction of 1a (5.24 mmol) and 2a (5.24 mmol) in the
mixture of DMF (10 mL)/HOAc (5 mL), 60 W white LEDs,
air, at room temperature for 14 h.
Visible-light photoredox catalysis using O as the
2
oxidant is regarded as an ideal methodology for the
oxidative functionalization reactions because (1) the
light is abundant and available in nature, appreciating that the yield of 3a was increased as the reaction
[12]
as a mild energy source; (2) O is a green oxidant performed in acid conditions, and the best yield (86%)
2
with it[s economical, safe and environmentally was obtained when the reaction was carried out in the
13]
friendly. As our continued interest in visible light presence of DMF:HOAc (v/v=10:1) (Table 1, entries 6
[
14]
photoredox catalysis
and the formation of CÀ Se vs 4–7). Then, the investigation of various solvents
[15]
bond, herein, we developed a simple and efficient such as CH CN, DMSO, THF, and ethanol, revealing
3
method for the preparation of 3-selanyl-4H-chromen- that DMF was the optimal solvent for this reaction and
4
-one compounds from enaminones and diselenides, in afforded 3a in 86% yield (Table 1, entries 6 vs 8–11).
+
which phenylselenyl cation (PhSe ) was formed first Moreover, when the reaction performed in the dark
under irradiation of visible-light in the air atmosphere, condition, no product of 3a was detected and the most
followed by the electrophilic substitution/intramolecu- of materials were recovered, which indicated that the
lar nucleophilic cyclization of enaminones to afford 3- light is essential for this transformation (Table 1,
selanyl-4H-chromen-4-one in the acid conditions entry 12). The reaction was performed under irradi-
(Scheme 1d).
ation by 60 W blue LEDs, and 3a was obtained in
At the beginning, the reaction of enaminone 1a and 83% yield (Table 1, entry 13). Besides, the reaction
diselenide 2a was chosen as a model system for the was scalable and practical since a satisfactory yield
optimization studies and the results are summarized in (79%) could be obtained when the reaction was
Table 1. The reaction was performed in DMF under performed on a 5.24 mmol scale (Table 1, entry 14).
irradiation by 60 W white LEDs in the air atmosphere, Therefore, the best conditions for the synthesis of 3a
3
3% yield of 3a was obtained (Table 1, entry 1). No involving in DMF at room temperature under the
significant increase in yields of 3a was observed when irradiation of 60 W white LEDs in the air atmosphere.
the reactions were carried out in the presence of With the optimal reaction conditions identified, the
K CO or in the presence of K CO /H O system scope and generality of this reaction were firstly
2
3
2
3
2
2
(Table 1, entries 2 and 3). We were pleased to observe investigated using divergent enaminones (Scheme 2).
Adv. Synth. Catal. 2021, 363, 1656–1661
1657
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
Scheme 3. Substrate Scope of 3-Selanyl-4H-Chromen-4-Ones
[a]
and Benzamidines.
2
equiv. K CO in DMSO at 80°C performed smoothly
2
3
to provide the desired selanyl- functionalized pyrimi-
dines products 4a–4i in excellent yields. This result
confirmed the high application potential of the 3-
selanyl functionalized chromones in the synthesis of
other diverse selanyl functionalized organic product by
acting as the main building blocks.
In order to gain insight into the reaction mecha-
nism, control experiments were conducted as shown in
Scheme 4. This photoreaction cannot be fully inhibited
and the desired product (3a) was obtained in 86%
yield even though 10 equiv. of TEMPO was added
Scheme 2. Substrate Scope of 2-Hydroxyphenyl Enaminones
and Diselenides.
[a]
[16]
(Scheme 4, eqn. 1). The reaction of 1a and 2a with
In general, the process is compatible enaminones with 2 equiv. of ethene-1,1-diyldibenzene was added, pro-
1
different R groups at the benzene ring containing viding 3a in 70% yield with a trace amount of 5 (5
electron-donating (Me, OMe) and electron-withdraw- was detected by HRMS) (Scheme 4, eqn. 2). The
ing (F, Cl, Br, NO ) substituents, which reacted with reaction of 1a and 2a with 2 equiv. of N-phenyl-
2
1
,2-di-p-tolyldiselane (2b) gave the corresponding methacrylamide was added, providing 3a in 60% yield
products 3b–3o in 72%–89% yields. And the diary- with a trace amount of 6 (6 was detected by HRMS)
ldiselenides with electron-donating (OMe, Me) and (Scheme 4, eqn. 3). These results suggest that the
electron-withdrawing (F, Cl, CF ) substituents reacted phenylselenyl free radical was first formed under the
3
smoothly to provide the desired products 3p–3t in irradiation of diphenyl diselenide (2a). The reaction
7
0%–89% yields. In addition, the substrate 1,2-di- performed in the nitrogen atmosphere and no product
(naphthalen-2-yl)diselane was performed smoothly, of 3a was detected, in which most of materials 1a and
and afforded the desired product of 3u in 78% yield. 2a were recovered with a trace mount of 4H-chromen-
Unfortunately, the reaction of 1a and 1, 2-di(thiophen- 4-one (7) was formed (Scheme 4, eqn. 4). This result
2
-yl)diselane under the standard condition, a trace indicated that O is essential for this transformation.
2
amount of product 3v was detected by HRMS. The The reaction of 1a and PhSeCl under the standard
substrates 1,2-dibenzyldiselane and 1,2-diphenyldisul- condition offered 3a was obtained in 83% yield,
+
fane failed to afford the desired products 3w–3x.
indicating that PhSe is a possible intermediate for the
Besides, to disclose the application of 3-selanyl- formation of 3a (Scheme 4, eqn. 5). In addition, the
H-chromen-4-one compounds, we investigated the reaction of enaminone 8 and 2a under the standard
4
reactions of compounds 3 with the readily available condition, leading the formation of 9 (9 were detected
benzamidine (Scheme 3). To our delight, the reaction by HRMS) (Scheme 4, eqn. 6). The mixture of 1a
of 3 and benzamidine hydrochloride in the presence of under the standard condition without 2a, affording the
Adv. Synth. Catal. 2021, 363, 1656–1661
1658
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
Scheme 5. Proposed Reaction Mechanism.
On the basis of these experimental results and the
[17]
previous reports,
a plausible mechanism for the
reaction was proposed in Scheme 5. Firstly, the
irradiation of diphenyl diselenide (2a) produced
phenylselenyl free radicals, which would suffer oxida-
+
tion by air to afford phenylselenyl cation (PhSe ). The
+
addition of PhSe (A) to the C=C bond in the
enaminone 1a gives rise to selenium ion B, which
underwent intramolecular electrophilic substitution by
NMe2 to afford intermediate C. Then, the intra-
molecular cyclization of C via nucleophilic addition of
OH group to imine cation to give intermediate E.
Finally, the elimination of dimethylamine from E in
the acid conditions leading the formation of the desired
product 3a.
In summary, we have developed a simple and
efficient visible-light-promoted metal-free selenyla-
tion/cyclization of enaminones with diselenides for the
synthesis of 3-selanyl-4H-chromen-4-one compounds,
which could be easily converted to selanyl-functional-
ized pyrimidines. These reactions performed in the
mild conditions, no transition metal catalyst or photo-
catalysts and no additional oxidants are required. And
exhibited potent anticancer activities in vitro and
further applications of this transformation are currently
underway in our laboratory.
Scheme 4. Controlled Experiments.
Experimental Section
Synthesis of 3-Selanyl-4H-Chromen-4-Ones Deriva-
product of 4H-chromen-4-one (7) in 20% yield with tives
a was recovered (Scheme 2, eqn. 7). Finally, the
1
A solution of 2-hydroxyphenyl enaminones 1 (0.2 mmol),
diselenides 2 (0.2 mmol), DMF:HOAc (v/v=10:1) (2 mL) in a
reaction of 7 and 2a under the standard condition, a
trace amount of 3a was formed and most of materials
were recovered (Scheme 4, eqn. 8). Besides, the reac-
tion on the light proceeded smoothly and gave the
2
5 mL test tube was stirred at room temperature under 60 W
white LEDs in the air atmosphere. The progress of the reaction
was monitored by TLC. After the reaction was complete,
desired product of 3a, while no product of 3a was quenched with water (3 mL), and the mixture was extracted
formed as the reaction performed in the dark, which with EtOAc (3×5 mL). The resulting orange solution was dried
suggest that the continuous light is needed for the over Na SO , evaporated under reduced pressure, and the
2 4
residue was purified by column chromatography (SiO , ethyl
formation of 3a (Scheme 4, eqn. 9).
2
Adv. Synth. Catal. 2021, 363, 1656–1661
1659
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
acetate/hexane gradient) yielding the desired 3-selanyl-4H-
chromen-4-ones products 3.
Huang, K. Lee, H. W. Yu, C. Chen, C. Hsu, H. Chen, F.
Tsai, C. Y. Chen, J. Biomol. Struct. Dyn. 2010, 28, 23–
7.
3
[
4] For selected reviews, see: a) L. Kursvietiene, A. Mon-
girdiene, J. Bernatoniene, J. Sulinskiene, I. Staneviciene,
Antiox. 2020, 9, 80–90; b) E. E. Frieben, S. Amin, A. K.
Sharma, J. Med. Chem. 2019, 62, 5261–5275; c) Q.
Miao, J. Xu, A. Lin, X. Wu, L. Wu, W. Xie, Curr. Med.
Chem. 2018, 25, 2009–2033.
Synthesis of Selanyl-Functionalized Pyrimidines
Derivatives
A
stirred solution of 3-selanyl-4H-chromen-4-ones
3
(
0.2 mmol), benzamidine hydrochloride (0.2 mmol), K CO3
2
(0.4 mmol), DMSO (2.0 mL) in a 25 mL test tube was stirred at
8
0°C or 3 h. After the reaction was complete, quenched with
[5] Z. Chen, H. Lai, L. Hou, T. Chen, Chem. Commun. 2020,
6, 179–196.
water (3 mL), and the mixture was extracted with EtOAc (3×
5
5
mL). The resulting orange solution was dried over Na SO ,
2 4
[6] a) Z. Song, L. Zhan, C. Ding, Y. Yu, W. Zhang, J. Qian,
G. Liang, 2019, CN 109180625; b) S. F. Fonseca, N. B.
Padilha, S. Thurow, J. A. Roehrs, L. Savegnago, M. N.
de Souza, M. G. Fronza, T. Collares, J. Buss, F. K.
Seixas, D. A. Eder, J. Lenardão, Ultrason. Sonochem.
evaporated under reduced pressure, and the residue was purified
by column chromatography (SiO , ethyl acetate/hexane gra-
2
dient) yielding the desired selanyl-functionalized pyrimidines
products 4.
2
017, 39, 827–836; c) X. Meng, P. Zhong, Y. Wang, H.
Wang, H. Tang, Y. Pan, Adv. Synth. Catal. 2020, 362,
06–511.
Acknowledgements
5
We would like to thank the National Natural Science
Foundation of China (21861015), Guangxi Science and Tech-
nology Base and Talents Program (AD18281035,
AD18281028), Guangxi Key Laboratory of Agricultural Re-
sources Chemistry and Biotechnology (2019KF07) and Culti-
vation Plan of Thousands of Young and Middle-aged Backbone
Teachers in Guangxi Colleges and Universities for financial
support.
[7] Other reported methods to 3-selenochromones, see: a) B.
Godoi, A. Speranca, C. A. Bruning, D. F. Back, P. H.
Menezes, C. W. Nogueira, G. Zeni, Adv. Synth. Catal.
2011, 353, 2042–2050; b) C. Ding, Y. Yu, Q. Yu, Z. Xie,
Y. Zhou, J. Zhou, G. Liang, Z. Song, ChemCatChem
2
018, 10, 5397–5401; c) J. Zhu, B. Xu, J. Yu, Y. Ren, J.
Wang, P. Xie, C. U. Pittman, A. Zhou, Org. Biomol.
Chem. 2018, 16, 5999–6005; d) T. Guo, Synth. Commun.
2
017, 47, 2053–2061; e) Z. Song, C. Ding, S. Wang, Q.
Dai, Y. Sheng, Z. Zheng, G. Liang, Chem. Commun.
020, 56, 1847–1850.
References
2
[
8] Z. Yang, L. Hu, T. Cao, L. An, L. Li, T. Yang, C. Zhou,
New J. Chem. 2019, 43, 16441–16444.
[
1] For selected reviews, see: a) A. Nazhand, A. Durazzo,
M. Lucarini, R. Romano, M. A. Mobilia, A. A. Izzo, A.
Santini, Nat. Prod. Res. 2020, 34, 137–152; b)
Sakagami, H. Watanabe, T. Hoshino, T. Suda, N. Mori,
K. Yasui, T. Yamauchi, N. Kashiwagi, H. Gomi, T.
Oizumi, T. J. Nagai, Y. Uesawa, K. Takao, Y. Sugita,
Medicine 2019, 6, 4–32; c) R. S. Keri, S. Budagumpi,
R. K. Pai, R. G. Balakrishna, Eur. J. Med. Chem. 2014,
[9] S. Zhong, Y. Liu, X. Cao, J. Wan, ChemCatChem 2017,
9
, 465–468.
[
[
[
10] J. Rafique, S. Saba, A. R. Schneider, M. S. Franco, S. M.
Silva, A. L. Braga, ACS Omega 2017, 2, 2280–2290.
11] J. Suffert, G. Blond, J. Joussot, A. Schoenfelder, L.
Larquetoux, M. Nicolas, Synthesis 2016, 48, 3364–3372.
12] For selected reviews on visible-light photoredox cataly-
sis, see: a) F. Hong, L. Ye, Acc. Chem. Res. 2020, 53,
7
8, 340–374; d) A. Gaspar, M. J. Matos, J. Garrido, E.
Uriarte, F. Borges, Chem. Rev. 2014, 114, 4960–4992.
2] For selected examples, see: a) Y. Li, G. Li, M. Zhou, L.
Xiang, D. Ren, H. Lou, X. Wang, T. Shen, Bioorg. Med.
Chem. 2018, 26, 5140–5150; b) M. Cosentino, F.
Marino, E. Rasini, M. Legnaro, R. Bombelli, A. Luini,
B. Pacchetti, Biomed. Pharmacother. 2019, 111, 91–98;
c) Y. Chen, S. L. Cass, S. K. Kutty, E. M. H. Yee,
D. S. H. Chan, C. R. Gardner, O. Vittorio, E. Pasquier,
D. S. C. Black, N. Kumar, Bioorg. Med. Chem. Lett.
2
003–2019; b) Z. Zhang, J. Ye, T. Ju, L. Liao, H. Huang,
Y. Gui, W. Zhou, D. Yu, ACS Catal. 2020, 10, 10871–
0885; c) A. Peter, G. J. P. Perry, D. J. Procter, Adv.
[
1
Synth. Catal. 2020, 362, 2135–2142; d) A. A. Festa,
L. G. Voskressensky, E. V. Van der Eycken, Chem. Soc.
Rev. 2019, 48, 4401–4423; e) T. Zhang, Y. Zhang, S.
Das, ChemCatChem 2020, doi: 10.1002/cctc.202001195.
[
13] For selected reviews on O as a green oxidant, see: a) S.
2
Fukuzumi, Y. Lee, W. Nam, ChemSusChem 2019, 12,
2
015, 25, 5377–5383; d) M. A. Rahman Mazumder, P.
Hongsprabhas, Biomed. Pharmacother. 2016, 82, 379–
92; e) B. Feng, X. Li, J. Xia, S. Wu, J. Enzyme Inhib.
3
931–3940; b) X. Tang, W. Wu, W. Zeng, H. Jiang, Acc.
Chem. Res. 2018, 51, 1092–1105.
3
[
14] a) H. Chen, R. Ding, H. Tang, Y. Pan, Y. Xu, Y. Chen,
Chem. Asian J. 2019, 14, 3264–3268; b) R. Ding, H.
Chen, Y. Xu, H. Tang, Y. Chen, Y. Pan, Adv. Synth.
Catal. 2019, 361, 3656–3660; c) X. Huang, R. Ding, Z.
Mo, Y. Xu, H. Tang, H. Wang, Y. Chen, Y. Pan, Org.
Lett. 2018, 20, 4819–4823; d) X. Huang, H. Chen, Z.
Med. Chem. 2017, 32, 968–977; f) P. Miksatkova, P.
Lankova, L. Huml, O. Lapcik, Nat. Prod. Res. 2014, 28,
6
90–697.
[
3] a) G. Yan, X. Li, B. Ge, X. Shi, Y. Chen, X. Yang, J. Xu,
S. Liu, P. Zhao, Z. Zhou, C. Zhou, W. Chen, Eur. J. Med.
Chem. 2015, 90, 251–257; b) J. Edwards, R. F. Raffauf,
P. W. Le Quesne, J. Nat. Prod. 1979, 42, 85–91; c) H.
Adv. Synth. Catal. 2021, 363, 1656–1661
1660
© 2021 Wiley-VCH GmbH

COMMUNICATIONS
asc.wiley-vch.de
Huang, Y. Xu, F. Li, X. Ma, Y. Chen, J. Org. Chem.
2017, 359, 3950–3961; e) X. Wang, Y. Zhong, Z. Mo, S.
2
019, 84, 15283–15293.
Wu, Y. Xu, H. Tang, Y. Pan, Adv. Synth. Catal. 2021,
363, 208–214.
[
15] a) X. Ma, Q. Wang, X. Feng, Z. Mo, Y. Pan, Y. Chen, M.
Xin, Y. Xu, Green Chem. 2019, 21, 3547–3551; b) X. [16] TEMPO could be used as an oxidant, see: J. Chen, A.
Zhou, H. Liu, Z. Mo, X. Ma, Y. Chen, H. Tang, Y. Pan,
Y. Xu, Chem. Asian J. 2020, 15, 1536–1539; c) F. Cui, J.
Wasim, M. Li, Z. Li, Z. Cui, R. Tang, Adv. Synth. Catal.
2020, 362, 269–276.
Chen, Z. Mo, S. Su, Y. Chen, X. Ma, H. Tang, H. Wang, [17] Q. Zhang, Y. Ban, P. Yuan, S. Peng, J. Fang, L. Wu, Q.
Y. Pan, Y. Xu, Org. Lett. 2018, 20, 925–929; d) F. Cui, J.
Chen, S. Su, Y. Xu, H. Wang, Y. Pan, Adv. Synth. Catal.
Liu, Green Chem. 2017, 19, 5559–5563.
Adv. Synth. Catal. 2021, 363, 1656–1661
1661
© 2021 Wiley-VCH GmbH