Copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with H-phosphine oxides and dioxygen

Article abstract of DOI:10.1016/j.tetlet.2017.04.042

A copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with H-phosphine oxides and dioxygen is reported. The present reaction, proceeds under mild reaction conditions with good functional group tolerance, affording the facile and efficient synthesis of various β-hydroxyphosphine oxides in a scaled-up manner with moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2017.04.042

Accepted Manuscript
Copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes
with H-phosphine oxides and dioxygen
Dong Yi, Qiang Fu, Su-Yuan Chen, Ming Gao, Lu Yang, Zhi-Jie Zhang, Wu
Liang, Qiang Zhang, Jian-Xin Ji, Wei Wei
PII:
S0040-4039(17)30482-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.042
TETL 48834
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 March 2017
11 April 2017
13 April 2017
Please cite this article as: Yi, D., Fu, Q., Chen, S-Y., Gao, M., Yang, L., Zhang, Z-J., Liang, W., Zhang, Q., Ji, J-
X., Wei, W., Copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with H-phosphine
oxides and dioxygen, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.042
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Copper-catalyzed direct hydroxyphosphorylation
of electron-deficient alkenes with H-phosphine oxides and dioxygen
Dong Yi, Qiang Fu, Su-Yuan Chen, Ming Gao, Lu Yang, Zhi-Jie Zhang, Wu Liang, Qiang Zhang, Jian-Xin Ji
and Wei Wei
An efficient copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with H-phosphine
oxides and dioxygen leading to β-hydroxyphosphine oxides has been realized at room temperature.

1
Tetrahedron Letters
journal homepage: www.els evier.com
Copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with
H-phosphine oxides and dioxygen
Dong Yia,b, Qiang Fua,b, Su-Yuan Chena,b, Ming Gaoa,b, Lu Yanga,b, Zhi-Jie Zhanga,b, Wu Lianga,b, Qiang
Zhanga,∗, Jian-Xin Jia, Wei Weic,∗
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b University of the Chinese Academy of Sciences, Beijing 100049, China
c School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A copper-catalyzed direct hydroxyphosphorylation of electron-deficient alkenes with H-
phosphine oxides and dioxygen is reported. The present reaction, proceeds under mild reaction
conditions with good functional group tolerance, affording the facile and efficient synthesis of
various β-hydroxyphosphine oxides in a scaled-up manner with moderate to good yields.
Received in revised form
Accepted
Available online
Keywords:
Electron-deficient alkenes
Hydroxyphosphorylation
β-Hydroxyphosphine oxide
Copper catalysis
2017 Elsevier Ltd. All rights reserved.
Dioxygen
Phosphorus-containing molecules are valuable compounds,
which have been widely used in organic synthetic chemistry,1
pharmaceutical chemistry,2 and materials science.3 Among them,
β-hydroxyphosphine oxide compounds have attracted increasing
research interest from synthetic chemists, because they could not
only act as the key synthetic intermediates in the well-known
Horner–Wittig reaction,4 but also serve as the versatile building
blocks for the synthesis of various important products in organic
chemistry.5 Up to date, many synthetic strategies have been
developed to construct β-hydroxyphosphine oxide scaffolds.
Traditionally, β-hydroxyphosphine oxides have been prepared by
the hydrogenation of β-ketophosphine oxides,6 the nucleophilic
addition of the anions of alkyl(diphenyl)phosphine oxides to
carbonyl compounds,7 and the nucleophilic addition of
organolithium reagents to β-ketophosphine oxides.8 Alternative
procedures include the ring-opening reaction of epoxy
compounds with phosphorus nucleophiles,9 the ring-opening of
α,β-epoxy phosphine oxides with LiAlH4,10 and the oxidation of
β-hydroxyphosphines with H2O2.11 However, almost all of these
methods suffer from one or more drawbacks, such as relatively
harsh reaction conditions, tedious procedures, lack of
functionality tolerance, excess amounts of hazardous
organometallic reagents, and low atom economy.
phosphorus-containing compounds.12 In 2014, Tang and co-
workers disclosed a new hydroxyphosphorylation of alkenes with
H-phosphine oxides leading to β-hydroxyphosphine oxides in the
presence of stoichiometric Mn(OAc)3·2H2O under nitrogen
atmosphere (Scheme 1a).13 Very recently, our group14 and Lei
group15 independently developed dioxygen-induced direct
hydroxyphosphorylation of alkenes under metal-free and heating
conditions (Scheme 1b and 1c). These strategies are well suited
for electron-rich alkenes, however, the hydroxyphosphorylation
of electron-deficient alkenes with H-phosphine oxides has
remained unexplored to date. As part of our continued interest in
difunctionalization of alkenes and the construction of
phosphorus-containing compounds,14,16 herein, we wish to report
a
simple
and
practical
copper-catalyzed
direct
hydroxyphosphorylation of electron-deficient alkenes with H-
phosphine oxides and dioxygen at room temperature.
The difunctionalization of carbon-carbon unsaturated bonds is
one of the powerful and attractive synthetic tools toward
∗ Corresponding authors.
E-mail addresses: cibzhangq@outlook.com (Q. Zhang), weiweiqfnu@163.com (W. Wei).

2
Tetrahedron Letters
b Isolated yields based on 1a.
c 2a (1.25 mmol), THF (2 mL), 65°C, 12 h.
d 1a (0.2 mmol), 2a (0.6 mmol), THF (2 mL), air, 45°C, 2 h.
e 12 h.
f
0°C.
g 40°C.
h 80°C.
of ethyl 2-phenylacrylate (1a) and diphenylphosphine oxide (2a)
was performed under the standard conditions of
hydroxyphosphorylation of electron-rich alkenes according to
previous reports.14,15 As shown in Table 1, only a trace amount of
the hydroxyphosphorylation product β-hydroxyphosphine oxide
(3aa) was detected at 45°C or 65°C (entry 1). To our delight,
significantly improved reaction efficiency was obtained when
CuBr2 (5 mol%) and Et3N (1 equiv) were introduced as the
catalyst and base into the reaction at room temperature (entries 2
and 3). Furthermore, a range of reaction solvents were screened
(entries 4-8), with N,N-dimethylformamide (DMF) being the
superior for the formation of product 3aa (73%). The effects of
other catalysts, such as Cu, Fe, Ag, Pd, Au, In, Ni, and Ru salts,
were also investigated and copper salts, especially CuBr2, were
found to be the best catalyst to afford the desired product 3aa
(entries 9-17). A relatively lower yields of 3aa was obtained,
when the loading of Et3N was reduced to 0.1 equiv or 0.5 equiv,
indicating that the stoichiometric amount of Et3N is essential for
this oxyphosphorylation (entries 18 and 19). It was noteworthy
that this hydroxyphosphorylation reaction could also proceed
smoothly even at 0°C (entry 21), whereas the relatively lower
yields were obtained under higher temperatures (entries 22 and
23). After a series of detailed investigations (Table 1 and the
supplementary information), the best yield of 3aa (73%) was
obtained by employing 1a (0.5 mmol), 2a (1 mmol), CuBr2 (5
mol%), and Et3N (0.5 mmol) in DMF at room temperature under
dioxygen atmosphere (Table 1, entry 6).
Scheme 1. Hydroxyphosphorylation of alkenes with H-phosphine oxides
In order to realize the hydroxyphosphorylation of electron-
deficient alkenes with H-phosphine oxides, initially, the reaction
Table 1
Optimization of reaction conditionsa
Entry
1
Catalyst
—
Solvent
THF
Et3N(equiv)
—
Yield(%)b
tracec,d
2
3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl
THF
THF
—
1
tracee
69
Table 2
Results for the hydroxyphosphorylation of α,β-unsaturated esters 1 with H-
phosphine oxides 2a,b
4
CHCl3
1,4-Dioxane
DMF
EtOH
AcOH
DMF
1
72
5
1
72
6
1
73
7
1
25
8
1
trace
72
9
1
10
11
12
13
14
15
16
17
18
19
20
21
CuCN
FeCl2
DMF
1
72
DMF
1
11
AgF
DMF
1
trace
18
PdCl2
DMF
1
AuCl3
InCl3
DMF
1
ND
ND
ND
ND
41
DMF
1
NiCl2·6H2O
RuCl3·H2O
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
DMF
1
DMF
1
DMF
0.1
0.5
1
DMF
49
DMF
70f
62g
61h
DMF
1
22
DMF
1
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst (5 mol%),
Et3N (0.5 mmol), solvent (1 mL), O2 (balloon), r.t., 1 h. ND = not
detected.

3
a Reaction conditions: 4 (0.5 mmol), 2a (1 mmol), CuBr2 (5 mol%), Et3N
(0.5 mmol), DMF (1 mL), O2 (balloon), r.t., 1 h.
b Isolated yields based on 4.
Furthermore, to develop a more general and useful method,
other electron-deficient alkenes including α,β-unsaturated
amides, α,β-unsaturated ketone and α-CF3-substituted alkene, as
well as electron-rich alkenes, were surveyed by using
diphenylphosphine oxide (2a) as the test substrate under the
standard conditions. As shown in Table 3, to our satisfaction, all
of these alkenes reacted well with 2a to afford the corresponding
hydroxyphosphorylation products (5aa−5ha) in moderate to good
yields. The above results demonstrated that this synthesis system
could present a general method for the hydroxyphosphorylation
of various alkenes, overcoming limitations of the preceding
reports.
a Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), CuBr2 (5 mol%), Et3N
(0.5 mmol), DMF (1 mL), O2 (balloon), r.t., 1 h.
b Isolated yields based on 1.
To demonstrate the practicality of this hydroxy-
phosphorylation reaction of electron-deficient alkenes, a scaled-
up experiment was investigated by using the model reaction
between 1a and 2a under the standard conditions. As shown in
Scheme 2, β-hydroxyphosphine oxide 3aa was achieved in 73%
yield (1.63 g) without any significant loss of its efficiency. Thus,
this method could serve as a practical and efficient protocol to
synthesize β-hydroxyphosphine oxides.
Upon optimization of the reaction conditions, the scope of this
As
hydroxyphosphorylation
reaction
was
evaluated.
demonstrated in Table 2, in general, 2-arylacrylate and its
derivatives containing electron-rich or electron-poor groups on
the aryl rings were suitable for this process to provide the
corresponding products (3aa−3qa) in moderate to good yields.
Various functional groups, such as methoxy, fluoro, chloro,
bromo, nitro, and sulfonyl groups, were demonstrated to be well
tolerated in this reaction, whose corresponding products can be
applied in further transformation. Notably, the heteroaryl
substrate such as ethyl 2-(pyridin-2-yl)acrylate was also
compatible with this protocol to give the desired product (3ra) in
53% yield. Importantly, 2-alkylacrylate derivatives, such as ethyl
2-benzylacrylate, methyl methacrylate, methyl 2-methylbut-2-
enoate, and 2-methylenebutyrolactone, could also be used in the
reaction, providing the corresponding products (3sa−3va) in
moderate to good yields. With regard to the H-phosphine oxides,
electron-withdrawing groups substituted diarylphosphine oxide
(3ac) showed lower activity in comparison with that bearing
electron-donating groups (3ab).
Scheme 2. Gram scale experiment
To have a better understanding of this transformation, several
control experiments were conducted (Scheme 3). When the
model reaction was performed under nitrogen, none of desired
product 3aa was detected. It indicates that dioxygen plays the
key role in the formation of β-hydroxyphosphine oxides.
Furthermore, the 18O-labeled product 3aa could be obtained in
70% yield when the reaction was performed in the presence of
18O2, indicating that the hydroxyl oxygen atom of β-hydroxy-
phosphine oxide might originate from the dioxygen. In addition,
the model reaction was significantly inhibited when TEMPO
Table 3
Results for the hydroxyphosphorylation of other electron-deficient alkenes
and electron-rich alkenesa,b
(2,2,6,6-tetramethyl-1-piperidinyloxy, a well-known radical
scavenger) was added into the reaction system, which suggested

4
that the present reaction might involve a radical process.
Tetrahedron Letters
Acknowledgements
We gratefully acknowledge financial support from the Chinese
National Natural Science Foundation (No. 21402184, 21572217, and
21302109).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.****
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On the basis of the above control experiments and previous
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Scheme 4. Possible reaction mechanism
In conclusion, a simple and convenient copper-catalyzed
direct hydroxyphosphorylation of electron-deficient alkenes with
H-phosphine oxides and dioxygen has been developed. A series
of structurally diverse β-hydroxyphosphine oxide derivatives
could be effectively obtained from various readily available
starting materials under very mild conditions. Preliminary
mechanistic studies indicated that this reaction might involve a
radical process and the hydroxyl oxygen atom of β-
hydroxyphosphine oxide was derived from dioxygen. Further
studies on the mechanism details and synthetic applications of
this methodology are underway in our laboratory.
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6
Tetrahedron Letters
•
•
Direct hydroxyphosphorylation of electron-deficient
alkenes
The hydroxyl oxygen atom of β-
hydroxyphosphine oxide originated from
dioxygen
•
•
The reaction can be performed in scaled-up
manner under very mild conditions
A radical process might be involved in this
hydroxyphosphorylation