Metal-Free, Visible-Light-Promoted Synthesis of 3-Phosphorylated Coumarins via Radical C?P/C?C Bond Formation

Article abstract of DOI:10.1002/adsc.201700293

A metal-free, visible-light-promoted direct difunctionalization of alkynoates was achieved under mild conditions. By employing catalytic quantities of the commercially available Eosin Y (EY) as the photocatalyst and tert-butyl-hydroperoxide (TBHP) as the oxidant, we developed a radical tandem phosphorylation/cyclization reaction to synthesize various 3-phosphorylated coumarins with high functional group tolerance, moderate to good yields, and excellent regioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201700293

Title: Metal-Free, Visible-Light-Promoted Synthesis of 3-
Phosphorylated Coumarins via Radical C-P/C-C Bond Formation
Authors: Dan Liu, Jian-Qiang Chen, Xing-Zhi Wang, and Peng-Fei Xu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700293
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10.1002/adsc.201700293
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free, Visible-Light-Promoted Synthesis of 3-
Phosphorylated Coumarins via Radical C-P/C-C Bond
Formation
Dan Liu,a Jian-Qiang Chen,a Xing-Zhi Wang,a and Peng-Fei Xua,*
a
A State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, People’s Republic of China
Fax: (+86)-931-891-5557; e-mail: xupf@lzu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
technology for versatile organic transformations,[9]
Abstract.
A metal-free, visible-light-promoted direct
difunctionalization of alkynoates was achieved under mild which offers an exciting opportunities to generate the
conditions. By employing catalytic quantities of the
commercially available Eosin Y (EY) as the photocatalyst
and tert-butyl-hydroperoxide (TBHP) as the oxidant, we
developed a radical tandem phosphorylation/cyclization
reaction to synthesize various 3-phosphorylated coumarins
with high functional group tolerance, moderate to good
yields, and excellent regioselectivities.
P-centered radicals under mild conditions without
using toxic precursors (scheme 1a).[10]
Keywords: cascade reaction; P-centered radicals; metal-
free; 3-phosphorylated coumarins; visible light
In the past few decades, extensive and continuous
efforts have been devoted to the formation of the C–P
bond, since phosphorus-containing compounds have
found wide applications in materials science,
pharmaceuticals,[1] and biological research.[2]
Michaelis–Arbuzov[3]
and
Michaelis–Becker[4]
reactions are general and powerful approaches for the
C(sp3)–P bond formation. The construction of
C(sp2)–P bonds was first reported by Hirao et al.
employing Pd as the catalyst,[5] which was modified
and improved by Yu and other groups (scheme 1a).[6]
Several general and effective approaches for
constructing C(sp2)–P bonds have also been
developed through the addition of P–centered radicals
to unsaturated systems (scheme 1b).[7] However, the
main drawback associated with the generation of the
P–centered radicals employed in these protocols is
the stoichiometric use of radical initiators (such as
peroxides, azo compounds, R3B/O2, and metal salts)
at high temperature or with the use of high-energy
UV light, which hinders their widespread
applications.[8] Therefore, a generally useful strategy
to effectively produce P-centered radicals under mild
conditions without using metal salts would be highly
desirable.
Scheme 1. Construction of C(sp2)-P bond through the
transition-metal or visible light catalysis.
The coumarin skeletons are commonly found in
natural products and pharmaceuticals. Various
strategies have been developed for their synthesis.[11]
The construction of 3-functionalized coumarin
derivatives by the cascade radical addition to aryl
propiolates and cyclization has also been reported.[12]
Nevertheless, the synthesis of 3-phosphorylated
coumarins, potential pharmaceutically active
compounds, through the difunctionalization of readily
available alkynoates via a cascade radical cyclization
is often plagued with the use of metal salts at high
temperature.[13] To address this challenge, we
proposed that photoredox catalysis, which provides
an efficient metal-free approach under mild
conditions for accessing P-centered radicals, would
Visible light photoredox catalysis has emerged as
an ecologically benign and sustainable synthetic
1
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10.1002/adsc.201700293
Advanced Synthesis & Catalysis
be an ideal approach for constructing 3-
phosphorylated coumarins. (scheme 1c)
Our initial investigation commenced with the
reaction of phenyl 3-phenylpropiolate 1a and the
radical precursor diphenylphosphine oxide 2a with
TBHP as the oxidant in the presence of an organic
photocatalyst under the irradiation of the visible light.
Table 2. Visible-light-promoted reactions of various R1-
substituted
alkynoates
with
phosphoryl
radical
precursors.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry PC
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
K2S2O8
CCl3Br
Air
Solvent
MeCN
MeCN
MeCN
DMF
Acetone
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Yield (%)[b]
70
61
55
33
12
trace
87
74
n.r.
53
33
57
trace
trace
n.r.
1
2
EY
RhB
MB
EY
EY
EY
EY
EY
EY
EY
EY
EY
EY
-
3[c]
4
5
6
7
8
9
10
11
12[d]
13[e]
14
O2
TBHP
TBHP
TBHP
-
15
EY
[a]
Standard conditions: 1a (0.1 mmol), 2a (0.2 mmol),
PC (4 mol%), oxidant (0.2 mmol) in dry DMSO under
o
the irradiation of a 25 W green LED strip at 25 C for
12 h under a N2 atmosphere.
Isolated yield.
25 W White LED.
[b]
[c]
[d]
[e]
Under air atmosphere.
The reaction was carried out in the dark.
n.r. = no reaction, PC = photocatalyst, EY = Eosin Y,
RhB = Rhodamine B, MB = Methylene blue.
We were pleased to find that the desired
transformation was realized in the presence of several
organic dyes (Table 1, entries 1–3). Moreover, it was
noted that the solvents had significant influence on
the reaction. The use of DMF, NMP, and acetone all
decreased the yield of 3a sharply (Table 1, entries 4–
6). Oxidant screening confirmed that TBHP was an
optimal oxidant for this transformation (Table 1,
entries 7–11). BrCCl3 failed to deliver the desired
product (Table 1, entry 9), since phosphoryl radical
could react with BrCCl3 to give the corresponding
halogenated phosphine oxide.[14] It was also noted
that the reaction could proceed with either air or O2 as
the oxidant, but the yields of the reactions were lower
since O2 could quench some phosphoryl radical.
Similarly, the desired product was produced in a low
yield of 57% under air atmosphere (Table 1, entry 12).
[a]
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), EY
(4 mol%), TBHP (0.2 mmol) in dry DMSO under
o
irradiation of a 25 W green LED strip at 25 C for 12
h under a N2 atmosphere.
Isolated yield.
n.r. = no reaction.
[b]
Finally, control experiments (Table 1, entries 13–15)
confirmed the requirement of the visible light,
photocatalyst and oxidant for the reaction to proceed.
Having identified the optimal conditions for the
synthesis of the 3-phosphorylated coumarins, we next
surveyed the scopes of the substrates and investigated
2
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10.1002/adsc.201700293
Advanced Synthesis & Catalysis
the limitations of this domino radical cyclization
reaction. Investigations using representative R1-
substituted alkynoates demonstrated that various
substituted phenyl rings (R1) worked well in this
reaction (3b–3n), but phenyl non-2-ynoate failed to
work in this protocol (3o). Other P–centered radical
precursors were also able to participate in the cascade
radical cyclization, providing the corresponding
product 3p and 3q in high yields. It should be noted
that diethyl phosphonate was a viable substrate, too,
giving the product 3r in a yield of 35%.
Table 3. Visible-light-promoted reactions of various R3-
substituted alkynoates with the phosphoryl radical
precursor.[a,b]
We next turned our attention to exploring various
substituents on the phenoxy ring under the standard
conditions. Substrates containing moderately
electron-rich phenoxy ring such as those with methyl,
ethyl and tert-butyl group on the para-position
reacted well under the reaction conditions (see Table
3, 4a–4c). Notably, the substrates with strong
electron-rich phenoxy ring containing methoxy group
on the para-position (4d) gave a slightly lower yield.
Phenoxy rings containing various electron-
withdrawing groups (4e–4h) were well tolerated.
Extended aromatic system (4i) also gave desired
product, albeit with a lower yield. We then explored
some sterically encumbered substrates. The substrate
with methyl group on the meta-position of the
phenoxy ring provided the desired products in a total
yield of 64%, which were formed as two
regioisomers (4j:4j’ = 1:2). In the similar way, the
substrate with the tert-butyl group on the meta-
position of the phenoxy ring also delivered two
regioisomers 4l and 4l’ in a total yield 67% with good
regioselectivity (4l:4l’ = 1:9). These results revealed
that the radical cyclization preferred to take place at
the position which was distal to the steric hindrance.
Furthermore, when substrates with the substitutes at
the ortho-position of the phenoxy ring did not work
in the reaction (4k, 4m), which demonstrated the
significant influence of the steric hindrance on the
reaction.
Notably, when the reaction was carried out under
natural sunlight irradiation, the desired products were
obtained with good yield (scheme 2a). Moreover,
when air was used as the oxidant, 3-phosphorylated
coumarin was obtained in a yield of 53% under
sunlight (scheme 2b). This protocol was also
successfully applied to the synthesis of
benzo[b]phosphole oxide (scheme 2c), which is an
important compound for the burgeoning fields of
organic light-emitting diodes (OLEDs) and
[a]
Reaction conditions: 1 (0.1 mmol), 2a (0.2 mmol), EY
(4 mol%), TBHP (0.2 mmol) in dry DMSO under
o
irradiation of a 25 W green LED strip at 25 C for 12
h in a N2 atmosphere.
Isolated yield.
A total yield of two isomers is shown.
n.r. = no reaction.
[b]
[c]
photovoltaic cells[15]
.
Furthermore, gram-scale-
synthesis of 3a was performed and the reaction
proceeded smoothly affording the corresponding
product with a slightly decreased yield (Scheme 2d).
When the reaction was conducted in the presence
This result supported the assumption that the reaction
involved the radical intermediates. Moreover, Stern-
Volmer fluorescence quenching experiments showed
that the photoexcited state EY* was quenched by 2a
(see supporting information).
of
a
radical scavenger, 2,2,6,6-tetramethyl-1-
piperidinyloxyl (TEMPO), the reaction was
completely inhibited (see supporting information).
3
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10.1002/adsc.201700293
Advanced Synthesis & Catalysis
D by oxidation and deprotonation affords the final
-
●
product 3a. TBHP is readily reduced by EY to
regenerate the ground state EY and furnish the tert-
butoxyl radical (A). However, we could not exclude
the possibility that the tert-butoxyl radical (A) can
also generate the phosphoryl radical (B) through a
HAT process [16]
.
In summary, we have developed a metal-free
photocatalytic protocol for the synthesis the 3-
phosphorylated coumarins with a wide range of
substrate scope. The reaction proceeds smoothly at
room temperature without using transient metals. Its
environmentally friendly and mild reaction conditions
allow the synthesis of valuable phosphorus-
containing compounds.
Experimental Section
t-BuOOH (0.2 mmol) were added to a solution of
alkynoates 1 (0.10 mmol, 1 equiv.), secondary
phosphine oxide 2 (0.2 mmol, 2 equiv.), and Eosin Y
(0.004 mmol, 0.04 equiv.) in dry DMSO (2 mL) at
room temperature. The mixture was degassed by
three cycles of freeze-pump-thaw and then placed in
the irradiation apparatus equipped with a 25 W green
light-emitting diode (LED) strip. The resulting
o
mixture was stirred at 25 C for 12 h. The mixture
Scheme 2. Further applications.
was diluted with ethyl acetate (4 mL) and saturated
NaHCO3 solution (8 mL), which was followed by
extraction with ethyl acetate (10 mL x 3 times). The
combined organic phase was washed with brine (10
mL), dried with Na2SO4 and the solvent was
evaporated. The crude product was purified by
column chromatography (silica gel, EtOAc : n-
Hexane = 1:1) to afford the desired product.
Based on the data, a mechanistic hypothesis was
[16]
proposed and outlined in Scheme 3.
Initially, the
irradiation of Eosin Y by visible light (Green LED or
sunlight) at room temperature produced the
photoexcited state of Eosin Y* (EY*). Phosphinous
acid 2a’ could be oxidized by excited EY* (E1/2
-
[17]
●
(EY*/EY ) = + 0.83 V)
to access phosphoryl
radical (B). The radical B then adds to the α-position
of the C = O bond of alkynoate 1a and produces the
vinyl radical C, which is highly reactive and can be
trapped by the aryl ring rapidly to form the
intermediate D. The rearomatization of intermediate
Acknowledgements
We are grateful to the NSFC (21632003, 21372105 and
21572087), and the “111” program from the MOE of P. R. China
for financial support.
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5
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10.1002/adsc.201700293
Advanced Synthesis & Catalysis
COMMUNICATION
Metal-Free, Visible-Light-Promoted Synthesis of
3-Phosphorylated Coumarins via Radical C-P/C-C
Bond Formation
Adv. Synth. Catal. Year, Volume, Page – Page
Dan Liu, Jian-Qiang Chen, Xing-Zhi Wang, and
Peng-Fei Xu*
6
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