Direct synthesis of β-ketophosphine oxides via copper-catalyzed difunctionalization of alkenes with H-phosphine oxides and dioxygen

Article abstract of DOI:10.1016/j.tetlet.2018.04.042

A simple copper-catalyzed direct difunctionalization of alkenes with H-phosphine oxides and dioxygen for the synthesis of β-ketophosphine oxides has been developed under mild conditions. The present protocol, which utilizes an inexpensive catalyst, readily available materials, and environmentally benign oxygen source, provides a convenient and cost-effective approach to construct various β-ketophosphine oxides.

Full text of DOI:10.1016/j.tetlet.2018.04.042

Accepted Manuscript
Direct synthesis of β-ketophosphine oxides via copper-catalyzed difunctional-
ization of alkenes with H-phosphine oxides and dioxygen
Guangming Nan, Huilan Yue
PII:
S0040-4039(18)30498-2
https://doi.org/10.1016/j.tetlet.2018.04.042
TETL 49905
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 February 2018
13 April 2018
17 April 2018
Please cite this article as: Nan, G., Yue, H., Direct synthesis of β-ketophosphine oxides via copper-catalyzed
difunctionalization of alkenes with H-phosphine oxides and dioxygen, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.04.042
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Direct synthesis of β-ketophosphine oxides
via copper-catalyzed difunctionalization of
alkenes with H-phosphine oxides and
dioxygen
Guangming Nan, Huilan Yue
A simple and convenient copper-catalyzed direct synthesis of β-ketophosphine oxide compounds from alkenes,
H-phosphine oxides and dioxygen has been developed under mild conditions.

1
Tetrahedron Letters
Direct synthesis of β-ketophosphine oxides via copper-catalyzed difunctionalization
of alkenes with H-phosphine oxides and dioxygen
Guangming Nana, Huilan Yueb,*
a University and College Key Lab of Natural Product Chemistry and Application in Xinjiang, School of Chemistry and Environmental Science, Yili Normal
University, Yining 835000, China
b Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences and Qinghai Provincial Key Laboratory of
Tibetan Medicine Research, Qinghai 810008, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple copper-catalyzed direct difunctionalization of alkenes with H-phosphine oxides
anddioxygen for the synthesis of β-ketophosphine oxides has been developed under mild
conditions. The present protocol, which utilizes an inexpensive catalyst, readily available
materials, and environmentally benign oxygen source, provides a convenient and cost-effective
approach to construct various β-ketophosphine oxides.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
copper-catalyzed
β-ketophosphine oxides
alkenes
dioxygen
H-phosphine oxides
 Corresponding author.
E-mail: nanguangming02@sohu.com; hlyue@nwipb.cas.cn

2
oxides and dioxygen (Scheme 1, (b)), in which copper-activated
As an important class of phosphorus-containing compounds, β-
ketophosphine oxides have drawn great attention of chemists
because of their widely applications in organic synthesis.1
Particularly, β-ketophosphine oxides can serve as the useful
intermediates for the construction of olefins via well-known
Wittig-Horner reaction.2 In addition, they have also been used in
the liquid-liquid extraction of metals due to their eminent metal-
complexing abilities.3 Traditionally, β-ketophosphine oxides are
prepared by the acylation of alkylphosphine oxides with esters in
the presence of n-BuLi,4 hydrolysis of enaminephosphine
oxides,5 or KOH promoted the reaction of hydrophosphoryl
compounds with chloroacetophenone.6 However, all these
methods suffer from limitations such as relatively harsh reaction
conditions, tedious procedures, unreadily-available starting
materials, or the use of excess amounts of organometallic
reagents. In 2012, Gao and Xu reported an efficient PdCl2-
catalyzed hydration of alkynylphosphine oxides for the synthesis
of β-ketophosphine oxides.7 In 2015, Lei described copper-
catalyzed radical/radical Csp3-H/P-H cross-coupling reaction of
aryl ketone o-acetyloximes with H-phosphine oxides leading to
dioxygen is essential for promoting this transformation. The
present reaction, which can be effectively scaled up, provides a
catalytic and attractive approach to various β-ketophosphine
oxides in moderate to good yields with favorable functional
group tolerance simply using inexpensive CuCN as a catalyst.
Table 1
Screening of the reaction conditionsa
Entry
1
2
3
4
5
6
7
8
Catalyst (mol % )
CuCl (5)
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
Toluene
1,4-dioxane
DCE
DME
DMSO
T(oC)
60
60
60
60
60
60
60
60
60
60
60
60
60
60
25
40
80
100
80
80
80
80
80
Yield(%)b
45
CuI (5)
CuBr (5)
37
49
28
32
47
53
46
32
60
37
38
47
36
32
48
62
CuCl2 (5)
CuBr2 (5)
Cu(OAc)2 (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN(20)
CuCN (10)
CuCN (2)
--
9
β-ketophosphine
oxides
in
the
presence
of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
tricyclohexylphosphine.8 Recently, some methods for the
construction of β-ketophosphine oxides from terminal alkynes,9
alkynylcarboxylic aids,9bc,10 cinnamic acid,11 ketones,12 or
CH3OH
enamides13 have also been developed. Gracefully successive as
these reactions could be, there is still a great demand for the
development of new, convenient, and environmentally-benign
methods to access β-ketophosphine oxides from simple and
easily accessible starting materials.
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
57
50
59
51
12
CuCN (5)
72c
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (0-20 mol%),
solvent (1 ml), 25-100oC, O2 (balloon), 12h.
b Isolated yields based on 1a.
c 1a (0.5 mmol), 2a (1.25 mmol).
Initially, styrene 1a and diphenylphosphine oxide 2a were
chosen as model substrates to optimize the reaction conditions
under oxygen atmosphere. Various transition-metal catalysts
such as Cu, Fe, Co, Ag, Pd, Zn, In and Bi salts were screened in
CH3CN at 60oC (see Table S1, in the Supporting Information).
To our delight, among the above metal salts examined, copper
salts especially CuCN was found to be the most effective catalyst
to give product 3a in 53% yield in the absence of a base (Table 1,
entry 7). Among the solvents tested, 1, 4-dioxane was shown to
be more effective than the others such as CH3CN, THF, toluene,
DME, DCE, DMSO, and CH3OH (Table 1, entries 7–14). The
reaction temperature could also affect this transformation (Table
1, entries 10, 15–18). The desired product was only obtained in
32% yield when the model reaction was carried out at room
temperature (Table 1, entry 15), and the reaction at 80oC gave the
best result (Table 1, entry 17). Furthermore, the screening of
catalyst loading found that 5 mol% of catalyst was the best
choice and the reaction efficiency was slightly low with the
decreasing or increasing of CuCN loading (Table 1, entries 19-
21). Moreover, the desired product was isolated in only 12%
yield when the reaction was conducted in the absence of copper
catalyst (Table 1, entry 22). After a series of detailed
investigations of the reaction parameters, we found that the best
result (72% yield) was obtained when the reaction was carried
Scheme
oxyphosphorylation of alkenes .
1 Methods for the synthesis of β-ketophosphine oxides via
Alkenes are inexpensive and
organic
reactants and chemical feedstocks, which difunctionalization is
one of the most powerful and reliable protocols for the
construction of various useful and fascinating compounds.14 In 2016,
Zou and co-workers reported an efficient solvent-controlled
Mn(OAc)3-mediated radical oxyphosphorylation of alkenes
leading to β-ketophosphine oxides, in which the phosphonyl
radical is initiated by stoichiometric amounts of Mn(OAc)3.15
Nevertheless, the utilization of an excess amount of Mn(OAc)3 (2
equiv) would lead to the generation of a large number of toxic
wastes, which might limit their wide applications on a large scale
in the synthetic and pharmaceutical chemistry. (Scheme 1, (a)).
Recently, Zhao and Chen reported acetonitrile-dependent CuSO4-
catalyzed oxyphosphorylation of α,β-alkenyl carboxylic acids or
alkenes with H-phosphonates leading to β-ketophosphonates.16
Herein, we wish to report a simple and convenient method for the
synthesis of β-ketophosphine oxides via CuCN (5 mol%)
catalyzed direct difunctionalization of alkenes with H-phosphine

3
out using 5 mol% of CuCN in 1,4-dioxane at 80 °C in the
heteroaromatic alkenes such as 2-vinylthiophene, 4-
presence of 2.5 equiv. of 2a (Table 1, entry 23).
vinylpyridine, and 2-vinylpyridine could also be used in the
reaction to give the expected products 3p-3r in moderate yields.
Nevertheless, when aliphatic alkenes such as 1-octene and 1-
hexene were used as the substrates, only a trace amount of the
desired products were obtained. With regard to the H-phosphine
oxides, in addition to diphenylphosphine oxide 2a, other
diarylphosphine oxides bearing both electron-donating and
electron-withdrawing groups were also compatible with this
reaction to give the corresponding products in moderate yields
(3s-3v).
Table 2
Results for copper-catalyzed synthesis of β-ketophosphine oxides from
alkenes, H-phosphine oxides and dioxygena,b
Furthermore, the synthetic applicability of this method was
investigated on a gram scale by using the model reaction between
1a and 2a. As shown in Scheme 2, the reaction could afford 2.21
g of 3a in 69% yield without significant loss of its efficiency.
Thus, this reaction could serve as a practical and efficient
protocol to synthesize β-ketophosphine oxides.
Scheme 2 Gram scale reaction
To gain some insights into this reaction mechanism, several
control experiments were carried out as shown in Scheme 3.
When the reaction of H(O)PPh2 (2a) with TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy, a well-known radical scavenger)
was performed under the standard conditions, TEPMO trapped
compound 2a' was detected (Scheme 3, Eq (1)). Furthermore,
when TEMPO was added into the model reaction system, the
reaction was completely inhibited and TEMPO trapped
compound 3a' was isolated in 25% yield (Scheme 3, Eq (2)). The
above results suggested that the present reaction might involve a
a
Reaction conditions: 1 (0.5 mmol), 2 (1.25 mmol), CuCN (5 mol%), 1,4-
dioxane (1 ml), 80oC, O2 (balloon), 12 h.
b Isolated yields based on 1.
With the optimized condition in hand, we next examined the
substrate scope of this transformation. Aromatic alkenes with
both electron-donating and electron-withdrawing groups worked
smoothly to afford β-ketophosphine oxides in moderate to good
yields under the standard conditions, whereas the electron-
withdrawing groups led to a negative effect on the yield (Table 2,
3a-3o). Also, functional groups such as chloromethyl, halogen,
acyloxy, cyano, and nitro groups (Table 2, 3f-3n) were all well
tolerated, whose corresponding products can be applied in further
modifications. It was observed that 2-vinylnaphthalene was also
tolerated to afford the product 3o in 60% yield. Notably,
Scheme 3 Control experiments.
radical reaction pathway. Moreover, when the reaction was
conducted under nitrogen atmosphere, only a trace amount of
product 3a was detected, indicating that dioxygen might play an

4
Chem. Soc. Perkin Trans. 1 1985, 2307; (d) Hutton, G.; Jolliff, T.;
important role in the formation of β-ketophosphine oxide (Scheme
3, Eq (3)). To elucidate the origin of the carbonyl oxygen atom of
β-ketophosphine oxides, 18O labeling experiment was performed
in the reaction of 1a and 2a (Scheme 3, Eq (4)). The
experimental result shows that the carbonyl oxygen atom of β-
ketophosphine oxide comes from dioxygen. In addition, the
desired product 3a was not obtained when β-hydroxyphosphine
oxide 4a was treated under the standard conditions, suggesting
that β-hydroxyphosphine oxide should not be an intermediate in
this reaction system (Scheme 3, Eq (5)).
Mitchell, H.; Warren, S. Tetrahedron Lett. 1995, 36, 7905; (e) Cavalla,
D.; Gueguen, C.; Nelson, A.; Russell, M. G.; Warren, S. Tetrahedron
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F. Adv. Synth. Catal. 2012, 354, 2427.
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Chem. Int. Ed. 2015, 54, 6604.
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Liu, Z. D.; Bi, W. Z.; Xia, Y. Y.; Wu, H. T.; Zhao, Y. F. Chem.
Commun. 2015, 51, 3846; (b) Yi, N. N.; Wang, R. J.; Zou, H. X.; He,
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D.-Y.; Cheng, M.; Du, F.-T.; Ji, J.-X.; Wei, W. Synth. Commun. 2016,
46, 1377; (e) Peng, P.; Lu, Q. Q.; Peng, L.; Liu, C.; Wang, G. Y.; Lei,
A. W., Chem. Commun. 2016, 52, 12338.
Based on the above results and previous reports 9-13,15-17, a
possible reaction pathway was proposed as shown in Scheme 4.
Firstly, diphenylphosphine oxide 2a was oxidized by copper-
activated dioxygen to generate phosphonyl radical 5a and CuII-
OOH.17 Subsequently, the resulting phosphonyl radical 5a
selectively added to alkene 1a gave alkyl radical 6a, which
interacted with CuII-OOH to produce alkylperoxy 7a. Finally, the
elimination of water from alkylperoxy 7a gave the desired
product 3a.15,17
10. (a) Zhang, P. B.; Zhang, L. L.; Gao, Y. Z.; Xu, J.; Fang, H.; Tang, G.;
Zhao, Y. F. Chem. Commun. 2015, 51, 7839; (b) Zeng, Y. F.; Tan, D.
H.; Lv, W. X.; Li, Q. J.; Wang, H. G. Eur. J. Org. Chem. 2015, 4335;
11. Zhou, M. X.; Zhou, Y.; Song, Q. L. Chem. Eur. J. 2015, 21, 10654.
12. (a) Fu, Q.; Yi, D.; Zhang, Z-J.; Liang, W. Chen, S-Y.; Yang, L.; Zhang,
Q.; Ji, J-X.; Wei, W. Org. Chem. Front, 2017, 4, 1385; (b) Zhang, Z-J.;
Yi, D.; Fu, Q.; Liang, W. Chen, S-Y.; Yang, L.; Du, F-T.; Ji, J-X.; Wei,
W. Tetrahedron Lett 2017, 58, 2417.
Scheme 4 Postulated reaction mechanism.
13. Liang, W.; Zhang, Z-J.; Yi, D.; Fu, Q.; Chen, S-Y.; Yang, L.; Du, F-T.;
Ji, J-X.; Wei, W. Chin. J. Chem. 2017, 35, 1378.
In summary, we have developed a new and straightforward
CuCN catalyzed method for the construction of a series of β-
ketophosphine oxides from alkenes, H-phosphine oxides and
dioxygen. The present protocol has the advantages of operation
simplicity, high atom efficiency, as well as ready availability of
materials and catalyst. Radical capture and isotope labeling
experiments showed that this reaction might proceed through a
radial process and carbonyl oxygen atom of β-ketophosphine
oxides originated from dioxygen. Further studies of the detailed
mechanism of this process and its application are underway in
our laboratory.
14. Selective examples: (a) Schmidt, V. A.; Alexanian, E. J. J. Am. Chem.
Soc. 2011, 133, 11402; (b) Xue, Q. C.; Xie, J.; Zhu, C. J. Acs Catalysis.
2013, 3, 1365; (c) Wang, Y.; Zhang, L.; Yang, Y. H.; Zhang, P.; Du, Z.
T.; Wang, C. Y. J. Am. Chem. Soc. 2013, 135, 18048; (d) Zhou, M. B.;
Wang, C. Y.; Song, R. J.; Liu, Y.; Wei, W. T.; Li, J. H. Chem.
Commun. 2013, 49, 10817; (e) Oh, S. H.; Malpani, Y. R.; Ha, N.; Jung,
Y. S.; Han, S. B. Org. Lett. 2014, 16, 1310; (f) Wei, W.; Wen, J.; Yang,
D.; Du, J.; You, J.; Wang, H. Green Chem. 2014, 16, 2988; (g) Wei,
W.; Wen, J.; Yang, D.; Liu, X.; Guo, M.; Dong, R.; Wang, H. J. Org.
Chem. 2014, 79, 4225.
15. Zhang, G-Y.; Li, C-K.; Li, D-P.; Zeng, R-S.; Shoberu, A.; Zou, J-P.
Tetrahedron, 2016, 72, 2972.
16. Chen, X.; Chen, X.; Li, X.; Qu, C.; Qu, L.; Bi, W.; Sun, K.; Zhao, Y.
Tetrahedron 2017, 73, 2439.
17. (a) Grotjahn, D. B.; Brewster, M. A.; Ziurys, L. M. J. Am. Chem. Soc.
2002, 124, 5895; (b) Kunishita, A.; Ishimaru, H.; Nakashima, S.; Ogura,
T.; Itoh, S. J. Am. Chem. Soc. 2008, 130, 4244; (c) Wei, W.; J. X. Ji
Angew. Chem., Int. Ed., 2011, 50, 9097; (d) Wei, W.; Liu, C.; Yang,
D.; Wen, J.; You, J.; Suo, Y.; Wang, H. Chem. Commun. 2013, 49,
10239; (e) Liu, C.; Zhu, M.; Wei, W.; Yang, D.; Cui, H.; Liu, X.; Wang,
H. Org. Chem. Front. 2015, 2, 1356; (f) Li, M.-S.; Zhang, Q.; Hu, D.-
Y.; Zhong, W.-W.; Cheng, M.; Ji, J.-X. Wei, W. Tetrahedron Lett 2016,
57, 2642.
Acknowledgements
This work was supported by the Opening Project of Key
Laboratory at Universities of Education Department of Xinjiang
Uygur Autonomous Region (No. 2018YSHXZD01).
References and notes
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Clarke, C.; Foussat, S.; Fox, D. J.; Pedersenc, D. S.; Warrena, S. Org.
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Chem. 2005, 3, 630.
2. (a) Hutton, G.; Jolliff, T.; Mitchel, H.; Warren, S. Tetrahedron Lett.
1995, 36, 7905; (b) Buss, A. D.; Cruse, W. B.; Kennard, O.; Warren, S.
J. Chem. Soc. Perkin Trans. 1 1984, 243; (c) A. D. Buss, S. Warren,J.

5

Catalytic synthesis of β-ketophosphine
oxides from alkenes and H-phosphine oxides
Gram scale


The carbonyl oxygen atom of β-
ketophosphine oxides originated from
dioxygen

A radical process is proposed
18.