Copper-catalyzed direct oxyphosphorylation of alkynes with H-phosphine oxides and dioxygen: A convenient approach to β-ketophosphine oxides

Article abstract of DOI:10.1080/00397911.2016.1205196

A simple and facile copper-catalyzed synthesis of β-ketophosphine oxides via direct oxyphosphorylation of alkynes with H-phosphine oxides and dioxygen has been developed under mild conditions without any base or cocatalyst. A radical reaction pathway for

Full text of DOI:10.1080/00397911.2016.1205196

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Copper-Catalyzed Direct Oxyphosphorylation of
Alkynes with H-Phosphine Oxides and Dioxygen: A
Convenient Approach to β-Ketophosphine Oxides
Wen-Wu Zhong, Qiang Zhang, Meng-Shun Li, Dong-Yan Hu, Ming Cheng,
Feng-Tian Du, Jian-Xin Ji & Wei Wei
To cite this article: Wen-Wu Zhong, Qiang Zhang, Meng-Shun Li, Dong-Yan Hu, Ming Cheng,
Feng-Tian Du, Jian-Xin Ji & Wei Wei (2016): Copper-Catalyzed Direct Oxyphosphorylation of
Alkynes with H-Phosphine Oxides and Dioxygen: A Convenient Approach to β-Ketophosphine
Oxides, Synthetic Communications, DOI: 10.1080/00397911.2016.1205196
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1205196
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Date: 20 July 2016, At: 01:54

Copper-Catalyzed Direct Oxyphosphorylation of Alkynes with H-Phosphine oxides
and Dioxygen: a Convenient Approach to β-Ketophosphine oxides
Wen-Wu Zhong1,2, Qiang Zhang1, Meng-Shun Li2,3, Dong-Yan Hu2,3, Ming Cheng4,
Feng-Tian Du1, Jian-Xin Ji1, Wei Wei5
1Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
2University of the Chinese Academy of Sciences, Beijing, China 3Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, Chengdu, China 4Chengdu Diao
Pharmaceutical Group co., ltd, Chengdu, Sichuan, China 5School of Chemistry and
Chemical Engineering, Qufu Normal University, Qufu, Shandong, China
Corresponding author: Wei Wei, School of Chemistry and Chemical Engineering, Qufu
Normal University, Qufu 273165, Shandong, China E-mail: weiweiqfnu@163.com;
Feng-Tian Du, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu
610041, China; E-mail: fengtiandu@163.com
Abstract
A simple and facile copper-catalyzed synthesis of β-ketophosphine oxides via direct
oxyphosphorylation of alkynes with H-phosphine oxides and dioxygen has been
developed under mild conditions without any base or cocatalyst. A radical reaction
pathway for the formation of β-ketophosphine oxides is proposed. 18O labeling
experiment suggested that the carbonyl oxygen atom of β-ketophosphine oxides
originated from dioxygen.
Graphical Abstract
KEYWORDS: β-ketophosphine oxides, copper-catalysis, alkynes, dioxygen, H-
phosphine oxides
1

INTRODUCTION
Phosphorus-containing molecules exhibited a wide range of applications in organic
synthesis,[1] medicinal chemistry,[2] and materials science.[3] In particular, β-
ketophosphine oxides are extremely versatile intermediates, which can be used for
various organic transformations toward many useful compounds such as olefins,[4]
cyclopropanes,[5] and α, β-unsaturated ketones.[6] Furthermore, they can also serve as
potential bidentate ligands and metal-extracting agents.[7] As a result, the synthesis of β-
ketophosphine oxides has gained much attention.[8-12] The conventional synthetic
methods usually relied on acylation of alkyl phosphine oxides with carboxylic acid
derivatives by employing stoichiometric amounts of the hazardous organometallic
reagents.[8] Alternative methods including the hydrolysis of enamine phosphine oxides,[9]
base-promoted substitution reaction of hydrophosphoryl compounds with
chloroacetophenone,[10] palladium-catalyzed hydration of alkynylphosphine oxides,[11]
and copper-catalyzed Csp3-H/P-H cross-coupling reaction of aryl ketone O-acetyl oximes
with phosphine oxides have also been developed.[12] However, most of these methods
suffered from limitations such as relatively harsh or complex reaction conditions,
multistep reactions, preformed starting materials, toxic wastes, or requiring excess
amounts of organometallic reagents.
Recently, the methods for the synthesis of β-ketophosphine oxides through the
oxyphosphorylation of terminal alkynes and alkynylcarboxylic acids have been reported
by several groups.[13-18] Zhao reported a AgNO3/CuSO4 co-catalyzed direct
2

oxyphosphorylation of terminal alkynes for the construction of β-ketophosphine oxides in
the presence of K2S2O8 (4.0 equiv) (Scheme 1, Eq (1)).[13] Song and He developed
copper/iron co-catalyzed aerobic oxyphosphorylation of terminal alkynes and alkynyl
carboxylic acids to access β-ketophosphine oxides in the presence of Et3N (Scheme 1, Eq
(2),(3)).[14,15] Tang reported a CuSO4·5H2O-catalyzed coupling of alkynyl acids with H-
phosphine oxides leading to β-ketophosphine oxides by using TBHP as the oxidant and
NH3·H2O as the base.[16] Wang described a novel method for the synthesis of β-
ketophosphine oxides through the silver-catalyzed oxidative decarboxylative coupling of
arylpropiolic acids with H-phosphine oxides.[17] Nevertheless, bimetallic catalysts, base,
or stoichiometric amounts of oxidants such as K2S2O8 and TBHP were inevitably used in
above well-developed reaction systems. Herein, we wish to report a simple approach for
the synthesis of β-ketophosphine oxides via copper catalyzed direct oxyphosphorylation
of alkynes with H-phosphine oxides and dioxygen (Scheme 1, Eq (4)). The present
reaction provides a convenient and efficient approach to various β-ketophosphine oxides
in moderate to good yields with excellent functional group tolerance, which make it
unnecessary for any metal co-catalyst or additives.
RESULT AND DISCUSSION
In an initial experiment, under an oxygen atmosphere, phenylacetylene (1a) and
diphenylphosphine oxide (2a) were chosen as the model substrates to examine the
catalytic activity of various transition metal complexes such as Cu, Ag, Au, Fe, Ni and
Co salts in CH3CN at 55 °C (Table 1, entries 1-11). Among various metals screened (5
mol%), copper salts especially CuCN was found to catalyze the formation of the desired
3

product 3aa, albeit in low yield (Table 1, entry 5). The screening of a range of solvents
showed that the reaction performed in DMSO was better than those in MeCN, THF,
DME, DMF, toluene and 1,4-dioxane (Table 1, entries 5, 12-17). A low yield (33%) was
obtained when the reaction was carried out at room temperature, and the best yield was
obtained at 55 °C (Table 1, entries 17, 21-22). In addition, the proportion of the substrates
also exerted the influences on the efficiencies. The optimal proportion of phenylacetylene
(1a) to diphenylphosphine oxide (2a) was 1 : 2, and the decrease of the amount of 2a
(Table 1, entry 23) or increase of 1a (Table 1, entry 24) would inhibit this transformation.
Moreover, no desired product was observed in the absence of catalyst or dioxygen (Table
1, entries 25 and 26). After an extensive screening of the reaction parameters, the best
yield of 3aa (65%) was obtained by employing 5 mol% CuCN in DMSO at 55 °C under
oxygen atmosphere (Table 1, entry 17).
With the optimized conditions in hand, the scope and limitations of this
oxyphosphorylation reaction were investigated, with the results shown in Table 2.
Generally, aromatic alkynes bearing both electron-rich and electron-poor groups on the
aryl rings were all suitable for this process, producing the corresponding products in
moderate to good yields (3aa-3na). It was found that this oxyphosphorylation was not
significantly affected by the steric effect. The sterically congested ortho- or meta- methyl
substituted aromatic alkynes could also be suitable for the reactions to deliver products
(3ea and 3fa) in good yields. Notably, various functional groups such as fluoro, chloro,
bromo, ester, acetyl, cyano, and nitro groups were also found to be tolerated in this
reaction to give the corresponding products (3ga-3na), which could be employed in
4

further transformations. Naphthyl alkyne such as 1-ethynylnaphthalene and heteroaryl
alkyne such as 3-ethynylthiophene were also compatible with this reaction, providing the
desired products in 60% and 54% yields, respectively (3oa and 3pa). In addition, when
internal alkyne such as 1-phenyl-1-propyne was employed in the present reaction system,
the desired product 3qa was obtained in 17% yield. Nevertheless, when aliphatic alkynes
such as 3-cyclohexyl-1-proyne and 4-phenyl-1-butyne were used as the substrates, none
of the corresponding products were obtained. The scope of this reaction was further
expanded to other H-phosphine oxides, in addition to diphenylphosphine oxide (2a),
other diarylphosphine oxides bearing electron-donating and electron-withdrawing groups
could also be used in the reaction to give the expected products (3ab-3ae) in moderate
yields.
A number of control experiments were performed to gain some insights into the reaction
mechanism. Initially, the 18O isotope-labeled product was obtained in 61% yield when
isotope labeling experiment using 18O2 was performed in the reaction of phenylacetylene
(1a) and diphenylphosphine oxide (2a), indicating that the carbonyl oxygen atom of the
β-ketophosphine oxide originated from dioxygen (Scheme 2).
Subsequently, the addition of the radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) to model reaction completely inhibited the reactivity (Scheme 3). Furthermore,
when the reaction of 2a and TEMPO was performed in the absence of phenylacetylene
(1a), a TEMPO-trapped compound (4a′) was obtained in 13% yield (Scheme 3). These
results suggested that the present reaction should proceed through a radical pathway.
5

On the basis of above experiments and previous reports,[13-19] a tentative mechanism was
proposed in the Scheme 4. Firstly, the reaction of CuΙ and O2 would form CuII-(O2·),
which interacted with diphenylphosphine oxide 2a leading to phosphonyl radical 4a and
CuII-(OOH).[19] Subsequently, the selective addition of the resulting phosphonyl radical
4a to alkyne 1a gave vinylradical 5a.[13-15] Then, the reaction of vinylradical 5a with CuII-
(OOH) would lead to the formation of vinylperoxyl intermediate 6a.[14] Next, the O-O
bond of vinylperoxyl intermediate 6a produced vinyloxy radical 7a and hydroxyl
radical ·OH. The coupling of hydroxyl radical ·OH with 4a gave diphenylphosphinic
acid 9a.[13] Finally, vinyloxy radical 7a would abstract the hydrogen of
diphenylphosphine oxide 2a to afford enolated phosphonate 8a, which underwent
tautomerization to yield the desired product 3aa. [13-15]
Fortunately, the proposed vinylperoxyl intermediate 6a, the diphenylphosphinic acid 9a,
and TEMPO-trapped radical 4a, 5a, 7a were all detected by LC-MS analysis when
TEMPO was added to the model reaction system after 2h (CuCN (5 mol%), DMSO (1
mL), 55 oC, O2 (balloon)) (Fig. 1). The above results indicated that the proposed
vinylperoxyl intermediate 6a and radical 4a, 5a, 7a should be involved in the present
reaction system .
EXPERIMENTAL
All the reagents were bought from Alfa Aesar, TCI and J&K chemical companies. The
products were purified by column chromatography using silica gel (200-300 mesh) and
6

aluminum oxide (neutral). 1H NMR, 13C NMR and 31P NMR were recorded on a Bruker
Avance 400 spectrometer. 1H NMR were recorded on 400 MHz in CDCl3 with TMS
(tetramethylsilane) as internal standard, 13C NMR were recorded on 100 MHz in CDCl3
with TMS (tetramethylsilane) as internal standard and 31P NMR were recorded on 162
MHz in CDCl3 with H3PO4 (phosphoric acid) as internal standard. HRMS were
performed on a Brucker Daltonics Bio-TOF-Q mass spectrometer by the ESI method and
LC-MS were obtained on a Waters Acquity HPLC (PDA Detector) Quattor Premier XE
triquadrupole mass spectrometer. IR spectra were obtained with a PerkinElmer Spectrum
One FTIR Spectrometer. Melting points were obtained with a WRS-100 melting point
apparatus.
General Procedure For Construction Of Β-Ketophosphine Oxides
An oven-dried flask with the mixture of CuCN (0.025 mmol), alkynes 1 (0.5 mmol), H-
phosphine oxides 2 (1.0 mmol) and DMSO (1.0 ml) was charged with O2. The reaction
mixture was stirred at 55 °C for 24 hours. After completion of the reaction, water (10 ml)
was added and extracted with EtOAc (5.0 ml×3). The combined organic layers were
dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The
resulting mixture purified by flash column chromatography using a mixture of petroleum
ether and ethyl acetate as eluent to give the desired products 3.
Spectral Data For The Product (Table 2, 3aa) [16,17]
2-(Diphenylphosphoryl)-1-Phenylethanone (3aa)
7

White solid; mp: 139.5-140.4 °C; 1H NMR (400 MHz, CDCl3) δ (ppm): 7.99 – 7.97 (m,
2H), 7.83 – 7.78 (m, 4H), 7.55 – 7.50 (m, 3H), 7.48 – 7.39 (m, 6H), 4.14 (d, J = 15.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ (ppm): 192.9 (d, JC-P = 5.5 Hz), 137.1 (s), 133.7 (s),
132.3 (d, JC-P = 2.8 Hz), 132.0 (d, JC-P = 102.8 Hz), 131.2 (d, JC-P = 9.8 Hz), 129.3 (s),
128.7 (d, JC-P = 12.3 Hz), 128.6 (s), 43.4 (d, JC-P = 58.0 Hz); 31P NMR (162 MHz, CDCl3)
δ (ppm): 26.9 (s); IR (KBr) ν (cm-1): 1682 (C=O), 1435 (P-Ph), 1178 (P=O); ESI HRMS
calcd for C20H18O2P [M+H]+ 321.1039, found 321.1039.
CONCLUSION
In conclusion, a simple and convenient method for the synthesis of β-ketophosphine
oxides has been developed via copper-catalyzed direct oxyphosphorylation of alkynes
with H-phosphine oxides and dioxygen. Preliminary mechanistic studies suggested that
the present reaction might involve a radical process and the carbonyl oxygen atom of β-
ketophosphine oxides came from the dioxygen. This simple reaction system is expected
to expand the potential applications of β-ketophosphine oxides in the synthetic and
pharmaceutical chemistry. Further studies of the detailed mechanism of this process and
its application are underway in our laboratory.
SUPPLEMENTARY INFORMATION
Full experimental detail, 1H NMR, 13C NMR, 31P NMR, IR spectra, melting point,
HRMS and LC-MS for this article can be accessed in the “Supplementary Information”
section of this article’s webpage.
8

Supplementary information for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from the National Natural Science
Foundation of China (no. 21172213, 21302109, 21402184, and 21572217) and the
Natural Science Foundation of Shandong Province (ZR2015JL004).
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12

Table 1. Optimization of the reaction conditionsa
Entry Catalyst (mol%)
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
T(oC)
55
55
55
55
55
55
55
55
55
55
55
55
55
55
55
Yield（%)b
trace
1
CuBr2 (5)
CuBr (5)
CuF (5)
2
23
24
17
33
26
trace
26
trace
19
28
30
33
19
32
29
65
58
62
56
33
53
34c
39d
0
3
4
CuI (5)
5
CuCN (5)
Cu(AcO)2 (5)
AuI (5)
6
7
8
AgNO3 (5)
FeBr3 (5)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
NiCl2 (5)
.
Co(OAc)2 4H2O (5) CH3CN
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (2.5)
CuCN (10)
CuCN (20)
CuCN (5)
CuCN (5)
CuCN (5)
CuCN (5)
--
THF
DMF
DME
toluene
1,4-dioxane 55
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
55
55
55
55
25
80
55
55
55
55
CuCN (5)
0e
13

a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), Catalyst (2.5-20 mol%), Solvent
(1.0 ml), O2 (balloon), 24 h.
b Isolated yields based on 1a.
c 1a (0.5 mmol), 2a (0.5 mmol).
d 1a(1.0 mmol), 2a (0.5 mmol), isolated yields based on 2a.
e under N2.
14

Table 2. Copper catalyzed oxyphosphorylation of alkynes to form β-ketophosphine
oxides.a,b
a Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), CuCN (5 mol%), DMSO (1.0 ml),
55 °C, 24 h, O2 (balloon).
b Isolated yields based on 1.
15

Scheme 1. Synthesis of β-ketophosphine oxides via oxyphosphorylation of alkynes 14
16

Scheme 2. Isotope labeling experiment 14
17

Scheme 3. Radical capture experiment 15
18

Scheme 4. Postulated reaction pathway 15
19

Figure 1. LC-MS spectrum of 6a, 9a , 3aa and TEMPO-trapped 4a, 5a, 7a 16
20