A metal-free radical cascade reaction of phosphine oxides with 2-aryloxy phenylacetylenes to synthesize diphosphonyl xanthene derivatives

Article abstract of DOI:10.1039/d1ob01045j

A radical cascade reaction of 2-aryloxy phenylacetylenes with phosphine oxides promoted by K₂S₂O₈was developed, which provided diphosphonyl xanthenes as products. This reaction proceeds under transition metal-free and mild conditions with simple operation and good yields. The mechanistic study indicated that phosphine oxide was induced into a phosphonyl radical, and then the following double radical addition/cyclization with 2-aryloxy phenylacetylenes generated bisphosphonyl xanthenes.

Full text of DOI:10.1039/d1ob01045j

Organic &
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A metal-free radical cascade reaction of phosphine
oxides with 2-aryloxy phenylacetylenes to
synthesize diphosphonyl xanthene derivatives†
Cite this: Org. Biomol. Chem., 2021,
19, 6609
Received 29th May 2021,
Accepted 7th July 2021
Tao Fan, Yan Liu, Caina Jiang,* Yanli Xu * and Yanyan Chen
*
DOI: 10.1039/d1ob01045j
rsc.li/obc
A radical cascade reaction of 2-aryloxy phenylacetylenes with
Xanthene is a common structural scaffold with diverse bio-
phosphine oxides promoted by K2S2O8 was developed, which pro- logical activities, and widely exists in natural products.11 The
vided diphosphonyl xanthenes as products. This reaction proceeds introduction of different substituents in position
9 of
under transition metal-free and mild conditions with simple oper- xanthenes has a strong influence on their chemical properties
ation and good yields. The mechanistic study indicated that phos- and biological applications; therefore, substantial attention
phine oxide was induced into a phosphonyl radical, and then the has been devoted to modify the 9 position of xanthenes during
following double radical addition/cyclization with 2-aryloxy phe- the past decades. Different groups such as acylamino,12 thio,13
nylacetylenes generated bisphosphonyl xanthenes.
carbonyl,14 heteroaryl,15 monophosphonyl,16 etc. are intro-
duced at the 9 position via the direct coupling of xanthenes;
however, diphosphonyl xanthene derivatives have not been
reported. Alkynes are considered as important building blocks
and have been widely used in the construction of hetero-
cycles.17 Meanwhile, the couplings of alkynes with phosphine
oxides are commonly used for the preparation of organopho-
sphorous compounds.18 Herein, we developed a metal-free
cascade reaction of 2-aryloxy phenylacetylenes with phosphine
oxides initiated by K2S2O8 leading to diphosphonyl xanthene
derivatives.
Organophosphorous compounds exhibit valuable applications
in organic synthesis,1 materials chemistry,2 and medicinal
chemistry.3 During the past years, great breakthroughs have
been made in the development of efficient synthetic
methods for the construction of organic monophosphorous
compounds; however, facile methods for the preparation of
diphosphonyl compounds are rare. Ananikov’s group reported
the nickel-catalyzed double addition of the P(O)–H bond with
alkynes to prepare 1,2-bisphosphorylethanes.4 Ogawa’s
group achieved the phosphinylphosphination of alkenes
initiated by V-40.5 Han and co-workers developed palladium-
catalyzed dehydrogenative bisphosphorylation of alkynes with
H-phosphonate.6 The nucleophilic reaction of amides with
phosphites promoted by Tf2O provided α-amino bisphospho-
nates with high chemoselectivity.7 The tandem reaction of
P(O)–H with N-containing heterocycles such as 1,10-phen-
anthrolines,8 quinolones,9 and benzoxazoles10 led to
double hydrophosphonylated compounds (Fig. 1). The above
reported methods mainly focus on the bisphosphonylation of
simple alkenes, alkynes and limited nitrogen-containing het-
erocycles; hence, efficient and green methods for the syn-
thesis of diverse diphosphonyl compounds are still highly
desired.
Initially, the reaction of 2-phenoxyphenylacetylene 1a,
diphenylphosphine oxide 2a and (NH4)2S2O8 in CH3CN at
70 °C was studied, and a diphosphorylated product 3a was
obtained in 62% yield and its structure was confirmed by X-ray
College of Pharmacy, Guilin Medical University, Guilin 541004,
People’s Republic of China. E-mail: chenyy269614@163.com, yanli.xu@163.com,
jiangcaina@glmc.edu.cn
†Electronic supplementary information (ESI) available. CCDC 2079136. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob01045j
Fig. 1 The reported bisphosphonylations.
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of 2a and 2.5 equivalents of K2S2O8 in CH3CN at 70 °C under
an air atmosphere.
With the optimal conditions in hand, the substrate scope of
2-aryloxy phenylacetylenes 1 was studied and the results are
shown in Scheme 1. Firstly, different groups such as 4-Cl, 4-Br,
4-Me and 4-MeO were introduced into the R1 position on the
benzene ring, and 3b–3e were obtained in 76–82% yields.
4-Trifluoromethoxy and 3,5-dimethyl slightly decreased the
yields of the desired products, giving 3f and 3g in 65% and
75% yields, respectively. Introduction of 2-tert-butyl provided
3h in 79% yield, indicating that steric hindrance does not have
a significant impact on this reaction. When 1-(2-ethynylphe-
noxy)naphthalene was used, it reacted smoothly with 2a,
giving 3i in 76% yield. In the moiety of the R2 group, methyl,
methoxy and chloro were tolerant, generating the corres-
ponding products 3j–3m in moderate yields. When oxygen was
replaced, 2-(4-methylphenylthio) phenylacetylene reacted well
with 1a, providing 3n in 60% yield. Unfortunately, heterocycle
groups were not compatible with this reaction, and only gener-
ated a trace amount of the desired products. When 1o and 1p
were used as substrates, the reactions were complicated and
no main product could be isolated. The reaction of 1q and 1a
Fig. 2 The X-ray crystal structure of 3a.
Table 1 Optimized conditionsa
Entry
Oxidant
Solvent
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
(NH4)2S2O8
K2S2O8
t-BuOOt-Bu
AgNO3
Mn(OAc)3
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-Dioxane
EtOAc
Toluene
DCE
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
70
70
70
70
70
70
70
70
70
70
80
60
70
70
70
62
85
20
0
0
52
Trace
38
45
10
83
78
Trace
64
9
10
11
12
13c
14d
15e
K2S2O8
K2S2O8
K2S2O8
K2S2O8
73
a Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol) and oxidant
(0.5 mmol) in solvent (2.0 mL) were stirred under a nitrogen atmo-
sphere at 70 °C for 7 h. b Yields of the isolated products. c The reaction
was performed under an air atmosphere. d 2a (0.8 mmol) was used.
e K2S2O8 (0.4 mmol) was used.
crystal structure analysis (Fig. 2). Then, the reaction conditions
were further screened and the results are shown in Table 1.
Oxidants such as K2S2O8, t-BuOOt-Bu, AgNO3 and Mn(OAc)3
were investigated, and K2S2O8 was proven as the best radical
initiator which provided 3a in 85% yield (entries 2–5, Table 1).
Other solvents were unsuitable for this reaction and they led to
a serious decrease of the yield (entries 6–10, Table 1). Higher
and lower temperatures were unfavorable, affording 3a in 83%
and 78% yields, respectively (entries 11 and 12, Table 1). Only
a trace amount of 3a (entry 13, Table 1) was obtained under an
air atmosphere. When smaller loadings of 2a and K2S2O8 were
used, lower yields were obtained (entries 14 and 15, Table 1).
Scheme 1 The substrate scope of 2-aryloxy phenylacetylenes.
Reaction conditions: 1 (0.2 mmol), 2a (1.0 mmol) and K2S2O8 (0.5 mmol)
in CH3CN (2.0 mL) were stirred under a nitrogen atmosphere at 70 °C
Finally, the optimal conditions are as follows: 5.0 equivalents for 7 h. aThe reaction was carried out on a 1 mmol scale.
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afforded 1-(3-phenoxythiophen-2-yl)ethenone as the main
product (see the ESI†). We also studied the reaction of 1a and
2a on a 1 mmol scale, and to our delight, 3a was obtained in
83% yield.
The scope of phosphine oxides was also explored as shown
in Scheme 2. The benzene ring bearing 4-methyl and 4-fluoro
produced the corresponding products 4a and 4b in 85% and
63% yields, respectively. However, 4-CF3 was not tolerant and
only a trace amount of 4c was detected. 3-Methoxy and 3,5-
dimethyl gave 4d and 4e in 70% and 49% yields, respectively.
To our delight, thienyl was suitable, affording 4f in 64% yield.
However, diethyl phosphonate was not suitable, and only a
trace amount of 4g was observed.
Scheme 3 Control experiments.
To investigate the possible pathway of this bisphosphonyla-
tion, several control experiments were conducted. Firstly, the
reaction of 1a and 2a was carried out under an air atmosphere;
3a′ was isolated as the main product and only a trace amount
of 3a was observed (Scheme 3a). When the standard reaction
was carried out for 2 h, 3a was obtained in 32% yield with a
trace amount of 3aa detected by LC-MS (Scheme 3b). We
speculated that 3aa was the key intermediate; however, 3aa
readily reacted with 2a to afford the final product 3a which led
to the low loading of 3aa in the reaction solution. When the
radical scavenger TEMPO was added, 3a was completely inhib-
ited, and the radical addition products 5a and 5b were
detected by LC-MS, indicating that this reaction is probably
initiated by a radical pathway (Scheme 3c).
Scheme 4 The proposed possible mechanism.
Based on the control experiments, a possible reaction
pathway was proposed (Scheme 4). At first, potassium persul-
fate underwent homolytic cleavage under heating conditions,
providing a sulfate radical anion which abstracted a hydrogen
from 2a generating the diphenylphosphine oxide radical and
HSO4−. After the coupling of the diphenylphosphine oxide
radical with 1a, a vinyl radical A was obtained which readily
underwent intramolecular cyclization to give B. Subsequently,
oxidation of B by the sulfate radical anion afforded intermedi-
ate C. C attacked by diphenylphosphine oxide radical gave an
intermediate D. Finally, the hydrogen abstraction of D from 1a
generated the product 3a.
Conclusions
In conclusion, we have developed a cascade reaction of
2-aryloxy phenylacetylenes with phosphine oxides promoted by
K2S2O8, producing diphosphonyl xanthenes in moderate to
good yields. A possible reaction pathway involving the double
addition/cyclization of a phosphonyl radical with 2-aryloxy
phenylacetylenes was proposed. This reaction features metal-
free conditions, simple operation and good yields.
Scheme 2 The substrate scope of phosphine oxides.Reaction con- Conflicts of interest
ditions: 1a (0.2 mmol), 2 (1.0 mmol) and K2S2O8 (0.5 mmol) in CH3CN
(2.0 mL) were stirred under a nitrogen atmosphere at 70 °C for 7 h.
There are no conflicts to declare.
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Acknowledgements
We thank the National Natural Science Foundation of
China (21861015), the Special Fund for Talents of Guangxi
(AD18281028 and AD18281035), and the Cultivation Plan of
Thousands of Young and Middle-aged Backbone Teachers
in Guangxi Colleges and Universities for the financial
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