Dioxygen-induced oxidative activation of a P-H bond: Radical oxyphosphorylation of alkenes and alkynes toward β-oxy phosphonates

Article abstract of DOI:10.1039/c6cc06881b

The dioxygen-induced radical oxyphosphorylation of alkenes and alkynes is presented, wherein a P-H bond was activated by molecular oxygen. Various β-oxy phosphonates could be facilely synthesized without the assistance of any transition metals or extra or

Full text of DOI:10.1039/c6cc06881b

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Dioxygen-induced oxidative activation of P-H bond: radical
oxyphosphorylation of alkenes and alkynes toward β-oxy
phosphonates
Received 00th January 20xx,
Accepted 00th January 20xx
Pan Peng,a Qingquan Lu,a Long Peng,a Chao Liu,a Guangyu Wanga and Aiwen Lei*ab
DOI: 10.1039/x0xx00000x
www.rsc.org/
Hydrogenatom transfer
Oxidative activation
The dioxygen-induced radical oxyphosphorylation of alkenes and
alkynes is present while P-H bond was activated by molecular
oxygen. Various β-oxy phosphonates could be facilely synthesized
without assistance of any transition metals or extra organic
initiators. Mechanistic studies showed that HP(O)Ph2 act as a
reductant to accelerate oxyphosphorylation.
O
O
P
O
P
O
SET
R1
Organic initiators
R1
R2
R1
R2
PT
R1
R2
P
H
P
H
R2
R1, R2 = Ar, OR, R
Scheme 1. Strategies for phosphorus-centered radical initiation.
R
Reactions involving phosphorus-centered radicals play a vital
OH
O
PPh2
Ar1
R
role in the construction of
π-conjugated materials,
Ar1
organophosphorus ligands and biologically active molecules.1
Homolytic cleavage of P-H bonds is a common route to
phosphorus-centered radicals. This process usually promoted
by organic radical initiators such as azo compounds, peroxides
and so on,2 and known as hydrogen atom transfer process.3
Another methods for the generation of phosphorus-centered
radicals go through single electron oxidation of P-H
compounds then lose the proton (Scheme 1).4 This methods
can be seen as “oxidative activation”. In oxidative activation
process, the decreases in the P-H bond dissociation energies
(BDEs) are associated with acidities increases of radical cation
derived from P-H compounds.5 So the P-H bond was activated
after oxidation process, and the oxidants mostly are metal
salts such as sliver, iron and manganese salts. However,
introduction of these transition metal salts often results in the
β−hydrophosphonates
O
-H+
O
P
O2
O
HPPh2
HPPh2
Ph
Ph
O
O
Ar2
PPh2
Ar2
β
-ketophosphonates
Scheme 2. Synthesis of β-oxy phosphonates
As a result of its inherent features of environmental
friendliness, cleanliness and sustainability,6 radical reactions
with dioxygen as the initiator have received increasing
attentions.7 Given the importance of organophosphorus
compounds in organic synthesis, we questioned whether
dioxygen could be also employed to initiate phosphinoyl
radicals through oxidative activation process. Then generated
residual catalysts and diverse by-products, limiting their phosphinoyl radicals further react with a variety of radical
applications in the chemical and pharmaceutical industries.
Therefore, it is extraordinarily important to find greener and
more sustainable oxidant to update these processes.
linkages such as alkenes and alkynes, furnish the valuable β-
oxy phosphonates (Scheme 2).8 Although β-oxy phosphonates
are valuable synthons in synthetic community, the synthetic
methods towards these compounds are quite limited,
especially for green and sustainable ones.8d, 9 Compared to the
traditional synthetic methods of β-oxy phosphonates,10 this
protocol features synthetic simplicity and mild conditions,
which would enable the potential application for academic
community and pharmaceutical industry in the future.
To verify whether dioxygen could initiate phosphinoyl
radicals through oxidative activation process, EPR experiment
was performed to detect the phosphinoyl radical intermediate.
As shown in Figure 1, when free radical spin trapping agent
DMPO (5,5-dimethyl-1-pyrroline N-oxide) was mixed with
diphenylphosphine oxide (Ph2POH) under air atmosphere, an
obvious EPR signal was identified, and assigned to stable
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radical
Journal Name
A
(aN=14.0 G, aH=17.8 G, aP=36.7 G).11 Suggested that Nevertheless, bis(4-chlorophenyl)phosphine oxide (3da) and
phosphinoyl radical was generated, then quickly trapped by diethyl phosphite (3ea) were not amenable to this procedure,
DMPO, formed the radical A. This result showed that probably owing to the higher oxidative potential.
Table 1. Radical oxyphosphorylation of alkenesa
phosphinoyl radicals could be induced by the dioxygen.
2a+DMPO
3300
3320
3340
3360
3380
3400
Filed / G
Figure 1. The electron paramagnetic resonance (EPR) spectra
Inspired by this result, the reaction of
α
-methylstyrene (1a)
with 2-fold Ph2P(O)H (2a) was firstly performed under air
atmosphere using THF (tetrahydrofuran) as solvent, giving 34%
yield of the expected product 3aa (for details, see Table S1,
ESI†). A higher Ph2P(O)H loading proved to be optimal and 94%
isolated yield could be obtained. While the decrease in the
temperature inhibited the oxyphosphorylation reaction.
Solvents proved to have huge influence in this radical
oxyphosphorylation reaction. Conducting the reaction in DMF,
DCE, CH3CN, DMSO and toluene gave the product 3aa in lower
yield. Notably, just 18% yield could be obtained under oxygen
atmosphere. And no product was detected when the reaction
was performed under N2 atmosphere. To probe the role of O2,
the model reaction between 1a and 2a under N2/18O2 (4:1) was
carried out. And the 18O-labeled product 3aa’ was isolated in
80% yield with 85% isotopic purity, indicating that molecular
oxygen acted not only as initiator to induce the radical
a
Unless otherwise specified, all reactions were carried out using 1 (0.2 mmol), 2 (0.6
mmol) in THF (2.0 mL) at 45 oC for 2 h under air, isolated yield.
To investigate the reaction mechanism, in-situ NMR was
performed to monitor the reaction of 1a and 2a under the
optimized conditions. The amount of 3aa and byproduct
HOP(O)Ph2 increased steadily with decrease of 2a during the
reaction process. Meanwhile, an intermediate
increased and then decreased with time going on (Figure 2, A),
this intermediate was proposed as β-peroxylphosphonates,
it decreased due to reduction by HP(O)Ph2. ESI-MS was further
applied to verify β-peroxylphosphonate intermediate . To our
delight, a strong peak (m/z=353.30) was detected, which
identified as [
+H]+. Besides, the over oxidative product
V firstly
V
transformation but also as
a terminal oxygen source
V
introduced into final products (for details, see ESI†).
With the optimized condition in hand, we next explored the
V
scope of the reaction between various
diphenyl phosphine oxides, and the results are summarized in
Table 1. A series of -methylstyrenes bearing both electron-
α-methylstyrene and
HOP(O)Ph2 (m/z=219.25) of 2a was also detected (for details,
see ESI†). To gain more information, the reaction was also
monitored by operando IR spectroscopy. The kinetic profile
clearly showed that HOP(O)Ph2 and 3aa increased
proportionally (Figure 2, B). These results indicated that
HP(O)Ph2 served not only as phosphorus source but also as
α
donating groups (R= Me, OMe) and electron-withdrawing
group (R= CF3) furnished the desired tertiary β-
hydrophosphonates in moderate to excellent yields (3ab-3ac,
3ae). It is noteworthy that halogen (such as Br) group was well
tolerated, which enabled a potential application in further
functionalization (3ad). Additionally, a wide range of functional
groups such as naphthyl (3af), thioether (3ag), and phenyl
reductant, and the reduction of the intermediate
accelerate the reaction.
V can
On the basis of the aforementioned experimental results
and previous reports,12 a potential mechanism was proposed.
(
3ah) were demonstrated to be tolerated in this protocol. 1,1-
As shown in scheme 3, radical cation I derives from 2a through
Diphenylethylene was also well applicable to give the desired
single electron transfer with dioxygen with the generation of
superoxide radical anion at the same time.13 Then radical
product 3ai in 89% yield. When submitting (1-
cyclopropylvinyl)benzene
to
standard
condition
cation I loses a proton to radical II, which further reacts with α-
oxyphosphorylation product 3aj was afforded in 43% yield.
Aliphatic alkene generated 3ak in trace amount of product
with major hydrophosphorylation by-product. Moreover, the
scope of phosphine oxides were also examined. p-Methyl
substituted phosphine oxide and m-methyl substituted
phosphine oxide could deliver the desired products with
methylstyrene (1a) in a radical addition process to form the
carbon-centered radical III. III reacts with dioxygen, produces
an alkylhydroperoxy radical intermediate IV. And then the
generated intermediate IV affords β-peroxylphosphonates
V
through hydrogen atom abstraction from 2a. Finally,
moderated yield of 71% and 66% respectively (3ba, 3ca).
2 | J. Name., 2012, 00, 1-3
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subsequent reduction of
V by diphenylphosphine oxide gives
Table 2. Substrate scope of the radical oxyphosphorylation of various alkynesa
the oxyphosphorylation product 3aa
.
A
2a
OOHO
ESI-MS,
PPh2 m/z=353.30
Ph
ESI-MS,
m/z=219.25
HOP(O)Ph2
V
3aa
10 min
20 min
30 min
40
min
90 min
16
18
20
22
24
26
28
30
32
δ
ppm
0.30
0.25
0.20
0.15
0.10
0.05
0.00
B
HOP(O)Ph2
2a
3aa
a
Unless otherwise specified, all reactions were carried out using 4 (0.2 mmol), 2a (0.6
mmol) in NMP (2.0 mL) at 60 oC for 2 h under a balloon of O2:N2 = 1:1, isolated yield.
Based on our proposed mechanism, we proposed if leaving
group was introduced to
α-position of styrene, β-
ketophosphonates could also be obtained.7d, 16 So we applied
several α-substituted styrene derivatives to this protocol. To
our delight, corresponding β-ketophosphonate 3aa was
obtained in moderate to excellent yields after simply changing
the reaction temperature and solvent (Table 3). Intriguingly,
Cvinyl-heteroatom bonds cleavage including C-Br and C-N were
proven to be amenable to this protocol. Notably,
decarboxylation which was deemed to need high energy was
occurred under this mild condition due to ingenious substrate
design. These transformations further highlight the synthetic
utility of this method and broaden the scope of this reaction.
0
20
40
60
80
100
120
Time / min
Figure 2. A) In situ NMR, reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol) in THF (2.0
mL) at 45 oC for different reaction time under air. B) The kinetic profile of the reaction
of 1a (0.4 mmol), 2a (1.2 mmol) in THF (4.0 mL) at 45 oC under air.
Table 3. Substrate scope of various substituted styrenesa
Scheme 3. Potential mechanism
With the better understanding of reaction mechanism, we
turned to explore whether alkynes could be convert to β-
ketophosphonates under this condition. The reaction of
phenylacetylene 4a with diphenylphosphine oxide 2a was
conducted under the foregoing condition, and 24% yield was
obtained (for details, see Table S2, ESI†). Rising temprature
and changing solvent slightly increased the yield to 30% yield.
We considered the O2 concentration might have great
influence in this reaction, so when we increased oxygen
concentration to 50%, an increased yield of 39% could be
obtained. We speculated the generation of vinyl peroxide
radical is difficult, which resulted in a low yield.14 So we added
phenylboronic acid to reduce the generated vinyl peroxide
radical, forced the equilibrium to desired product in 71%
isolated yield.15 Besides, phenylboronic acid was oxidized to
phenol in 93% GC yield.
a Unless otherwise specified, all reactions were carried out using styrene (0.2 mmol), 2a
b
(0.6 mmol) in DMF (2.0 mL) at 60 oC for 2 h, isolated yield. DCE (2.0 mL) instead of
DMF (2.0 mL) for 5 h.
Conclusions
In summary, we have disclosed an environmentally friendly
radical oxyphosphorylation reaction without assistance of any
transition metals or extra organic radical initiators. Various β-
oxy phosphonates were facilely obtained with a wide range of
functional group tolerance. EPR experiment showed that
dioxygen could be employed to initiate phosphinoyl radicals
through SET oxidative activation. Isotopic labeling experiment
showed that the oxygen atom of hydroxyl comes from
dioxygen. Mechanistic studies concluding in-site NMR and
operando IR showed that diphenylphosphine oxide served not
only as substrate but also as reductant. Besides, several kinds
Furthermore, reactions of the corresponding phenylacetylene
derivatives was investigated, furnished corresponding ketones
in moderated yields
phenylacetylene gave the same 48% yield (3ab
substituents such as fluorine and bromine were also tolerated,
(
5ab
-5ae). p-Methyl and m-Methyl
,
3ac). Halogen
giving the corresponding products in 58% and 51% yield (5ad
,
5ae), respectively.
of alkynes and
π
-substituted styrene derivatives could also
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convert to β-ketophosphonates. Radical oxyphosphorylation of
alkyne can be promoted by phenylboronic acid. Further studies
on mechanistic details and expanding the substrate scope are
currently underway in our laboratory.
Acknowledgements
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21520102003, 21272180, 21302148), the Hubei Province
Natural Science Foundation of China (2013CFA081), the
Research Fund for the Doctoral Program of Higher Education
of China (20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
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