Photo-induced phosphorus radical involved semipinacol rearrangement reaction: Highly synthesis of γ-oxo-phosphonates

Article abstract of DOI:10.1016/j.cclet.2019.08.011

Hydroxyphosphoric acids display the unique biological activities, and they have some attractive prospects as clinical drug moleculars. Herein, a new approach for the synthesis of γ-oxo-phosphonates (the precursor of hydroxyphosphoric acid) has been established through the semipinacol rearrangement tactic involved the photo-induced phosphorus radical process. Most important, this transformation is avoid of the external oxidants, and occurs very well under the sunlight irradiation, meanwhile the γ-oxo-phosphonate was easily derivatized to obtain γ-hydroxyphosphoric acid, thus highlights the synthesis value of this method.

Full text of DOI:10.1016/j.cclet.2019.08.011

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CCLET 5162 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Photo-induced phosphorus radical involved semipinacol
rearrangement reaction: Highly synthesis of -oxo-phosphonates
g
Chunhai Wanga, Xiaoling Huanga, Xueting Liua, Suqian Gaoa, Bin Zhaoa,
Shangdong Yanga,b,
*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 5 June 2019
Received in revised form 23 July 2019
Accepted 8 August 2019
Available online xxx
Hydroxyphosphoric acids display the unique biological activities, and they have some attractive
prospects as clinical drug moleculars. Herein, a new approach for the synthesis of g-oxo-phosphonates
(the precursor of hydroxyphosphoric acid) has been established through the semipinacol rearrangement
tactic involved the photo-induced phosphorus radical process. Most important, this transformation is
avoid of the external oxidants, and occurs very well under the sunlight irradiation, meanwhile the
g
-oxo-
phosphonate was easily derivatized to obtain
value of this method.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
g-hydroxyphosphoric acid, thus highlights the synthesis
Keywords:
Photo catalysis
Phosphorus radical
Semipinacol rearragement
g
-Oxo-phosphonate
Organophosphine compounds are common in medicinal
mild condition, but external oxygen was essential to complete the
catalytic cycle and the phosphorus precursors were limited to
phosphine oxides [6]. Our group has always been focused on the
chemistry of phosphorus, and hope to construct CꢀꢀP bond under
mild conditions without external oxidants either for metal-
catalyzed reaction or photo-catalyzed reaction [3h,3k,3s,3u]. In
2018, we discovered that the oxime phosphonates were easily
converted to P radical under visible-light irradiation by using fac-Ir
(ppy)3 as photo-catalyst, therefore constructing the new CꢀꢀP bond
chemistry and biochemistry [1]. Among the members of the
organophosphine family, hydroxyphosphoric acids display the
unique biological activitives, and they have some attractive
prospects as clinical drug molecules (Scheme 1a) [2]. Therefore,
the development of effective and simple tactics to synthesize the
hydroxyphosphoric acid or its precursor has attracted much
attention [[3]]. So far, great efforts have been devoted to construct
CꢀꢀP bond including metal/photo-catalyzed CꢀꢀP bond formation
[[3]]. The common point of these two tactics is the way to form
CꢀꢀP bond through the phosphorus radical intermediate [3h,3k].
While, the main drawbacks of these synthesis strategies were
using the stoichiometric base or stoichiometric oxidant to
complete the transformation [3j]. And more, the high temperature
was essential to promote the reaction, especially for the metal-
catalyzed reactions [3g].
[3k]. So, wequestioned whether it would be possible toform g-oxo-
phosphonates, which could be easily converted to hydroxyphos-
phoricacidbyusingthisoximephosphonatesasphosphorusradical
precursor through photo-catalyzed reaction. Herein, we reported
the method for the synthesis of g-oxo-phosphonates via phospho-
rus radical involved semipinacol rearrangement process. Most
important, thistransformationis avoidof the externaloxidants, and
occurs very well under the sunlight irradiation, meanwhile the
In 2014, Ji group reported the method for the synthesis of g-oxo-
phosphine oxide by using stoichiometric Ag salt to introduce the
phosphorus radical involved semipinacol rearrangement process,
while the high reaction temperature was essential [4]. In the same
year, Wu group fulfilled the similar transformation by using Ag salt
as catalyst [5]. Last year, Zhang group successfully prepared various
g-oxo-phosphonate was easily derivatized to obtain g-hydrox-
yphosphoric acid, thus highlights the synthesis value of this
method.
In the initial study, we first selected 1,1-diphenylprop-2-en-1-ol
(1a) [8] and oxime phosphonate (2a) as substrates and fac-Ir(ppy)3
as photo catalyst to explore various solvents irradiated with 5 W
blue LEDs. We were delighted to obtain the desired product 3a in
11% and 61% yield by using CH3CN and dioxane as the solvent
(Table 1, entries 2 and 3). According to the previous work, we
increased the reaction concentration to 0.2 mol/L, and the yield
was up to 84% (Table 1, entries 4 and 5). Decreasing the loading of
g
-oxo-phosphine oxides through photo-catalyzedreaction under
* Corresponding author at: State Key Laboratory of Applied Organic Chemistry,
Lanzhou University, Lanzhou 730000, China
E-mail address: yangshd@lzu.edu.cn (S. Yang).
https://doi.org/10.1016/j.cclet.2019.08.011
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: C. Wang, et al., Photo-induced phosphorus radical involved semipinacol rearrangement reaction: Highly
synthesis of
g-oxo-phosphonates, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.011

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C. Wang et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
Scheme 1. Photoredox catalysis for the synthesis of
g-oxo-phosphonates.
Table 1
Scheme 2. Substrate scope for oxime phosphonates. All reactions were carried out
with 1a (0.3 mmol), 2 (0.2 mmol), fac-Ir(ppy)3 (0.002 mmol), and dioxane (1.0 mL),
irradiated with 5 W blue LEDs for 14 h under Ar at 25 ꢁC. Isolated yields.
Investigation of the reaction conditions.a
electron-donating group (2j-2k, 2n-2o) could be present on each
aryl group (R2 and OBz), and good to excellent yields of 57% to 83%
were obtained. These results demonstrated that the reaction
tolerated various of oxime phosphonates very well.
We then investigated the use of substituted allylic alcohol
substrates. As shown in Scheme 3, when electron-donating groups
(methyl or methoxy group) were introduced to the para-position of
allylic alcohol, the yields dropped to 78% and 54% (3b and 3c).
These results may be caused by the more electron-rich aryl group
was more difficult to migrate compare to benzene group. To our
delight, for the more electron-rich aryl group, we could also obtain
the desired product in 48% yield (3g). Next, when electron-
withdrawing groups (CF3, F, Cl) were introduced to the para-
position of allylic alcohol, and moderate to good yields of 69% to
81% were obtained. Furthermore, when methyl group or methoxy
group was introduced to the orth-position of allylic alcohol, good
yields of 73% to 76% were obtained (3h-3i). And more, for the meta-
position of allylic alcohol, either electron-withdrawing group (3l)
or electron-donating group (3j–3k) could be tolerated, and good
yields of 63% to 76% could be obtained. Moreover, good yields of
65% could be obtained for the non-terminal allylic alcohol
substrate 3m.
Entry
1a:2a
PC (1 mol%)
Solvent
Yield (%)b
1c
2d
3e
4
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.2:1
1.5:1
1.5:1
1.5:1
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
—
DCM
CH3CN
NR
11
61
84
78
74
75
NR
NR
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
5f
6
7g
8
9h
fac-Ir(ppy)3
a
All reactions were carried out with 1a (0.3 mmol), 2 (0.2 mmol), fac-Ir(ppy)3
(0.002 mmol), and the solvent (1.0 mL), irradiated with 5 W blue LEDs for 14 h under
Ar at 25 ꢁC.
b
Isolated yields. NR = no reaction.
DCM (2.0 mL).
CH3CN (2.0 mL).
Dioxane (2.0 mL).
Dioxane (0.5 mL).
fac-Ir(ppy)3 (0.001 mmol).
No light.
c
d
e
f
g
h
Next, to understand the influence of migration caused by the
electronic nature of aryl group, unsymmetrical allylic alcohols
carrying two different aryl groups were investigated (Scheme 4,
3n-3u). We were delighted that the reactions proceeded in good
yields of 81% and 80% when thiophene and pyridine were used
instead of benzene group (3n, 3o, 3o0). And more, we could get two
isomers, which could be separated by chromatography for the
pyridine case. These results demonstrated that the more electron-
deficient aryl group migrated preferentially [6]. It was noteworthy
that methyl group was introduced to the orth-position of one
benzene group, the single isomer could be obtained in good yield of
71% (3p). More important, not only high regioselectivity but also
functional-group tolerance was demonstrated for the successful
realization of 3u with a lower yield of 29%.
fac-Ir(ppy)3 or changing the proportion of the two substrates was
not helpful (Table 1, entries 6 and 7). Finally, control experimental
run in the absence of either photo catalyst or a visible light source
did not give the desired product 3a (Table 1, entries 8 and 9).
Having identified optimal conditions, a wide range of oxime
phosphonates were submitted to this photo catalysis protocol
(Scheme 2) [3k]. First, we investigated the influence of OPG group.
When the OBz was changed to OAc or OPiv, we were delighted that
the desired product could be obtained in 64% or 47% yields (2b and
2c). Next, we investigated the influence of substituent group on
phosphorus atom (methoxy or isopropyl), we were also able to
obtain the target product in moderate to excellent yields (2d, 61%;
2e, 81%). Most important, the R2 substituent was changed to alkyl
group, the reaction also proceeded smoothly (2f-2i, 12%-58%).
Furthermore, both electron-withdrawing groups (2l, 2m, 2p) and
Several experiments were implemented to highlight the
synthesis value of this method. The reaction proceeded very well
with gram-scale yield of 88% (Scheme 5a). Furthermore, when the
Please cite this article in press as: C. Wang, et al., Photo-induced phosphorus radical involved semipinacol rearrangement reaction: Highly
synthesis of -oxo-phosphonates, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.011
g

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3
Scheme 3. Substrate scope for allylic alcohols. All reactions were carried out with 1a (0.3 mmol), 2 (0.2 mmol), fac-Ir(ppy)3 (0.002 mmol), and dioxane (1.0 mL), irradiated
with 5 W blue LEDs for 14 h under Ar at 25 ꢁC. Isolated yields.
Scheme 5. Applied experiments.
Scheme 4. Substrate scope for unsymmetrical allylic alcohols.All reactions were
carried out with 1a (0.3 mmol), 2 (0.2 mmol), fac-Ir(ppy)3 (0.002 mmol), and
dioxane (1.0 mL), irradiated with 5 W blue LEDs for 14 h under Ar at 25 ꢁC. Isolated
result suggested that it was the substrate 2a that quenched the
yields.
excited photocatalyst *Ir(III) [7].
Based on the experimental results of the mechanistic investi-
gation and previous mechanistic studies, details of the mechanism
of the proposed phosphorus radical involved semipinacol rear-
rangement reaction are outlined in Scheme 6. Irradiation of photo
catalyst fac-Ir(ppy)3 Ir(III) with visible light leads to the formation
of excited-state *Ir(III), which could be oxidized by oxime
phosphonate 2a with producing the P radical A [3k]. Then P
radical A is rapidly trapped by alkene of the substrate 1a to
generate alkyl radical B, which immediately forms benzyl radical D
through semipinacol rearrangement process. Finally, we expected
that oxidation of the resulting benzyl radical D should generate
benzyl cation with deprotonation to give the final product 3a and
regenerate the ground-state photo catalyst Ir(III), completing the
proposed catalytic cycle.
sunlight was used instead of 5 W blue LEDs, the desired product
could also be obtained with 82% yield (Scheme 5b). Meanwhile the
g
-oxo-phosphonate was easily derivatized to obtain g-hydrox-
yphosphoric acid 5 (Scheme 5c) [9]. These results highlight the
synthesis value of this tactic in drug discovers.
In the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEM-
PO, 2.0 equiv.) or 2,6-di-tert-butyl-4-methylphenol (BHT, 2.0
equiv.), the observed inhibition of thereaction indicated that a
radical process might be involved (Scheme S1 in Supporting
information) [10]. According to our previous work, oxime
phosphonate could be a suitable oxidant to be reduced by *Ir
(III), therefore converting to the active
P radical [3k]. So,
In summary, we have demonstrated a new, mild approach for
fluorescence spectra were collected on Cary Eclipse Fluorescence
Spectrophotometer. A significant decrease of fac-Ir(ppy)3 lumines-
cence was successfully observed in the presence of 2a (Fig. 1). This
the synthesis of
g-oxo-phosphonates (the precursor of hydrox-
yphosphoric acid) through the semipinacol rearrangement
Please cite this article in press as: C. Wang, et al., Photo-induced phosphorus radical involved semipinacol rearrangement reaction: Highly
synthesis of -oxo-phosphonates, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.011
g

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Acknowledgments
We are grateful for the National Natural Science Foundation of
China (No. 21532001) and International Joint Research Centre for
Green Catalysis and Synthesis, Gansu provincial Sci. & Tech.
Department (No. 2016B01017) for financial support.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.08.011.
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tactics involved the photo-induced phosphorus radical process.
Most important, this transformation is avoid of the external
oxidants, and occurs very well under the sunlight irradiation,
meanwhile the
obtain -hydroxyphosphoric acid, thus highlights the synthesis
value of this method.
g-oxo-phosphonate was easily derivatized to
g
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Please cite this article in press as: C. Wang, et al., Photo-induced phosphorus radical involved semipinacol rearrangement reaction: Highly
synthesis of -oxo-phosphonates, Chin. Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.011
g