Copper-Catalyzed Direct Oxyphosphorylation of Enamides with P(O)-H Compounds and Dioxygen

Article abstract of DOI:10.1002/cjoc.201700189

A simple and convenient copper-catalyzed direct oxyphosphorylation of enamides with P(O)-H compounds and dioxygen has been developed under mild conditions. This methodology can allow the synthesis of a series of valuable β-ketophosphine oxides/β-ketophosphonates in moderate to good yields with a broad substrate scope simply by using readily-available starting materials.

Full text of DOI:10.1002/cjoc.201700189

COMMUNICATION
DOI: 10.1002/cjoc.201700189
Copper-Catalyzed Direct Oxyphosphorylation of Enamides
with P(O)-H Compounds and Dioxygen
Wu Liang,a,b Zhijie Zhang,a,b Dong Yi,a,b Qiang Fu,a,b Suyuan Chen,a,b Lu Yang,a,b
Fengtian Du,*,a Jianxin Ji,a,b and Wei Wei*,c
a Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, Sichuan 610041, China
b University of the Chinese Academy of Sciences, Beijing 100049, China
c School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, Shandong 273165, China
A simple and convenient copper-catalyzed direct oxyphosphorylation of enamides with P(O)-H compounds and
dioxygen has been developed under mild conditions. This methodology can allow the synthesis of a series of valua-
ble β-ketophosphine oxides/β-ketophosphonates in moderate to good yields with a broad substrate scope simply by
using readily-available starting materials.
Keywords oxyphosphorylation, enamides, P(O)-H compounds, radical reaction, dioxygen
Introduction
various important organic compounds.[11] As part of our
continued interest in difunctionalization reaction of un-
saturated hydrocarbons[12] and the synthesis of phos-
phorus-containing compounds,[4a,5f,12a] herein, we wish
to present a simple and efficient copper-catalyzed oxy-
phosphorylation of enamides with P(O)-H compounds
and dioxygen leading to β-ketophosphine oxides/β-keto-
phosphonates under mild conditions (Scheme 1).
Phosphorus-containing molecules are a very im-
portant class of compounds, which are extensively used
in various pharmaceuticals,[1] organic synthesis,[2] and
functional materials.[3] Thus, the introduction of phos-
phorus-functionality into organic frameworks to con-
struct various organophosphorus compounds has drawn
great interests of chemists. On the other hand, the di-
functionalization reaction of unsaturated hydrocarbons
such as alkenes or alkynes has attracted great interests
of chemists in the construction of various valuable or-
ganic compounds because of its high efficiency in the
cascade formation of carbon-carbon and carbon-het-
eroatom bonds. Recently, the oxyphosphorylation of
alkenes,[4] alkynes,[4b,5] cinnamic acids,[6] alkynylcar-
boxylic acids,[5d,7] cinnamyl/alkynylcarboxylates,[8] and
α,β-unsaturated carbonyl compounds[9] with P(O)-H
compounds and dioxygen has emerged as a fascinating
and powerful protocol for the synthesis of β-keto-
phosphine oxides/β-ketophosphonates, which are an
important class of phosphorus-containing compounds
especially used as key synthetic precursors to access
olefins via the well-known Horner-Wadsworth-Emmons
(HWE) reaction.[10] Despite the significance of these
reactions, the development of simple, convenient and
efficient alternative oxyphosphorylation strategy to ac-
cess to β-ketophosphine oxides/β-ketophosphonates is
still highly desirable.
Scheme 1 Copper-catalyzed oxyphosphorylation of enamides
Experimental
General
All solvents were distilled before use by standard
1
methods. H NMR, 13C NMR and 31P NMR were rec-
orded in CDCl3 on a Bruker Advance III 400 M NMR
with TMS as internal standard at room temperature.
HRMS and LC-MS analyses were obtained on a Bruker
microTOF Q II mass spectrometer and a Waters UPLC-
Xevo TQ MS (PDA Detector)/Quattro Premier XE tri-
quadrupole mass spectrometer by ESI method respec-
tively. Flash column chromatography was carried out on
silica gel (200－300 mesh). Commercial reagents from
TCI (Shanghai) Development Co., Ltd., Alfa Aesar and
Sigma Aldrich were used without further purification.
Enamides, readily obtained from the reductive acyl-
ation of ketoximes, are widely employed as versatile
and powerful building blocks in the construction of
*
E-mail: weiweiqfnu@163.com, fengtiandu@163.com
Received March 16, 2017; accepted April 11, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700189 or from the author.
Chin. J. Chem. 2017, XX, 1—5
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Liang et al.
Table 1 Optimization of reaction conditionsa
COMMUNICATION
Typical experimental procedure for the oxyphos-
phorylation of enamides
To a solution of enamides 1 (0.5 mmol), CuBr2 (6
mg, 5 mol%), Et3N (0.5 mmol) in DCE (2 mL) was
added H-phosphine oxides 2 (H-phosphonates 2') (1.25
mmol). The reaction mixture was stirred at 25 ℃ for 2
h under dioxygen (2' was operated at 70 ℃ for 5 h).
After completion of the reaction, the reaction mixture
was concentrated and the residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl
acetate) to afford the products 3a－3u (4a－4k).
Entry Catalyst
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
t-BuOK
K2CO3
－
Solvent Temp./℃ Yieldb/%
1
2
FeCl3
Mn(OAc)3
AgNO3
AuCl3
CuBr
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCE
DMF
CH3CN
DCE
DCE
DCE
DCE
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
0
12
3
40
4
Trace
76
5
Results and Discussion
6
CuCl2
CuBr2
－
71
Based on our previous study on the oxyphosphoryla-
tion of alkenes,[4a] we wondered whether we could con-
struct β-ketophosphine oxides through oxyphosphoryla-
tion of enamides. In term of this conjecture, the enamide
1a and diphenylphosphine oxide 2a were chosen as
model substrates to optimize the reaction conditions
under air. Initially, a series of transition-metal catalysts
such as Fe, Mn, Ag, Au and Cu salts were screened in
THF at room temperature. Among them, we were de-
lighted to find copper salts, especially CuBr2, to be the
best catalyst to promote this reaction (Table 1, Entries
1－7, and supporting information). None of the desired
product was detected in the absence of catalyst (Table 1,
Entry 8). Further optimization of bases demonstrated
that triethylamine was the best choice, while other bases
were all less effective in this transformation (Table 1,
Entries 9－11). Only a trace amount of product was de-
tected without base (Table 1, Entry 12). Also, among the
solvents tested, 1,2-dichloroethane (DCE) was the opti-
mized one for mediating the formation of the product 3a
(Table 1, Entries 7, 13－15). In addition, the lowering or
elevating of reaction temperature had a detrimental ef-
fect on the reaction efficiency (Table 1, Entries 16 and
17). Notably, when the reaction was performed under
dioxygen, the best yield (89%) was obtained (Table 1,
Entry 18). Furthermore, when the reaction was operated
under N2 atmosphere, only a trace amount of the prod-
uct was detected (Table 1, Entry 19), which indicated
that dioxygen was essential for the formation of
β-ketophosphine oxides.
With the optimized conditions in hand, the substrate
scope of this reaction was investigated (Table 2). To our
delight, this oxyphosphorylation reaction displayed high
functional group tolerance and was proved to be quite a
general procedure. A variety of aryl enamides substitut-
ed with methoxyl, methyl, fluoro, chloro, trifluorome-
thyl, and ester on the aromatic rings all gave the corre-
sponding β-ketophosphine oxides 3b－3k in moderate
to excellent yields. Aryl enamides bearing an ortho and
meta substituted groups on the aromatic ring revealed
different reactivity resulting from their steric effect (3d
－3f). N-(1-(Naphthalen-2-yl)vinyl)acetamide, and het-
eroaromatic substituted enamides could also be trans-
formed into the corresponding β-ketophosphine oxides
7
78
8
0
9
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
60
10
11
12
13
14
15
16
17
18
19
40
46
Trace
84
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
61
71
63
40
25
25
71
89c
Traced
a Reaction conditions: 1a (0.5 mmol), 2a (1.25 mmol), catayst (5
mol%), base (0.5 mol), solvent (2 mL), under air, 2 h; DBU: di-
azabicycloundecene; DCE: 1,2-dichloroethane. Isolated yields
based on 1a. c Under O2. d Under N2.
b
3l － 3n in good yields. Notably, N-(1H-inden-3-
yl)acetamide, N-(3,4-dihydronaphthalen-1-yl)acetamide
and N-(1-cyclohexen-1-yl)acetamide could also deliver
the desired products 3o－3r in reasonable yields. The
scope of this reaction was further expanded to other
H-phosphine oxides, aryl groups bearing electron-do-
nating and electron-withdrawing groups could also be
used in the reaction to give the expected products 3s－
3u in good yields.
Subsequently, the substrate scope was further inves-
tigated by reacting enamides 1 with different dialkyl
phosphonates. Initially, lower yield was obtained under
the optimized conditions when diethyl phosphonate was
used as the H-P(O) coupling partner due to its low reac-
tivity. To our delight, the desired product 4a was suc-
cessfully obtained in 53% yield simply by elevating the
reaction temperature to 70 ℃ for 5 h. As shown in Ta-
ble 3, upon optimization of the reaction conditions, the
oxyphosphorylation reactions of various aryl enamides
with H-phosphonates afforded the corresponding
β-ketophosphonates in moderate yields.
To further understand the reaction mechanism, two
2
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Chin. J. Chem. 2017, XX, 1—5

Copper-Catalyzed Direct Oxyphosphorylation of Enamides
Table 2 Oxyphosphorylation of enamides with H-phosphine
oxidesa,b
Table 3 Oxyphosphorylation of enamides with H-phosphonatesa,b
O
P
OR5
O
Ac
O
P
OR5
CuBr2 (5 mol%)
OR6
HN
H
OR6
O2
+
+
Ar
Et3N (1 equiv.)
DCE, 70 oC
Ar
4a 4k
－
1
2'
O
O
O
O
O
O
P(OEt)2
O
MeO
O
P(OEt)2
O
O
PPh2
PPh2
PPh2
4a, 53%
4b, 44%
Me
MeO
O
O
O
3a, 89%
O
3c, 73%
3b, 63%
P(OEt)2
P(OEt)2
O
Me
O
O
O
O
OMe O
PPh2
Me
PPh2
PPh2
F3C
4c, 50%
4d, 46%
O
O
O
O
P(OEt)2
P(OEt)2
3f, 73%
3e, 58%
3d, 69%
O
O
O
O
PPh2
O
O
O2N
MeO2C
PPh2
PPh2
4e, 47%
4f, 43%
O
O
O
O
Cl
Cl
F
Cl
P(OEt)2
P(OEt)2
3i, 80%
3g, 86%
3h, 79%
N
O
O
PPh2
O
O
4g, 37%
O
4h, 63%
O
PPh2
O
PPh2
O
O
O
O
O
P
OEt
P(OBu)2
P(OMe)2
MeO2C
F3C
Ph
3l, 86%
3j, 57%
3k, 78%
4i, 53%
O
O
, 46%
4j
O
O
O
O
4k, 53%
PPh2
PPh2
PPh2
N
a Reaction conditions: 1 (0.5 mmol), CuBr2 (5 mol%), Et3N (1.0
equiv), DCE (2 mL), 2' (2.5 equiv.), O2, 70 ℃, 5 h; b Isolated
yields based on 1.
S
N
3m, 84%
3o, 63%
3n, 63%
O
O
O
O
O
O
the carbonyl oxygen atom of β-ketophosphine oxides
originated from dioxygen (Eq. 1). Subsequently, when
the radical scavenger 2,2,6,6-tetramethylpiperidine-
1-oxyl (TEMPO) was added to the model reaction sys-
tem, the reaction was completely inhibited (Eq. 2). This
result suggested that the present reaction might proceed
through a radical pathway.
PPh2
PPh2
PPh2
3q, 64%
3r, 31%
3p, 62%
O
P
O
O
P
O
OMe
OMe
3t, 78%
3s, 71%
O
P
O
F
N
.
F
O
Ac
O
HN
O
TEMPO
O
3u, 65%
+
H
PPh2
(2)
PPh2
Ph
1a
O
a Reaction conditions: 1 (0.5 mmol), CuBr2 (5 mol %), Et3N (1.0
equiv.), DCE (2 mL), 2 (2.5 equiv.), O2, 25 ℃, 2 h. b Isolated
yields based on 1.
CuBr2, Et3N, O2
DEC, 25 oC, 2 h
Ph
2a
3a (0%)
Based on the above experiments and previous re-
ports,[4a,4b,5f,13] a tentative mechanism for this oxyphos-
phorylation is illustrated in Scheme 3. Firstly, the reac-
tion proceeds by single electron transfer (SET) from
Ph2P(O)H (2a) to CuII species forming diphenyl
control experiments were investigated. Firstly,
18O-labeled product 3a was isolated in 86% yield when
the model reaction was performed in the presence of
18O2 under the standard conditions, which indicated that
Chin. J. Chem. 2017, XX, 1—5
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3

Liang et al.
COMMUNICATION
Scheme 3 Possible reaction pathway
phosphine oxide cation radical A and CuII-(OO•-) (hy-
droperoxide) species under dioxygen. With the help of
Et3N, the H＋ of A is grabbed to release the P-radical B,
which attacks N-(1-phenylvinyl) acetamide to give alkyl
radical C. Then, the unstable radical C undergoes the
intramolecular elimilation of acetamide leading to vinyl
radical D. Next, the formed vinyl radical D interacts
with CuII-(•OOH) to produce hydroperoxide intermedi-
ate E. Finally, the hydroperoxide intermediate E is re-
duced by diphenylphosphine oxide 2a to give the eno-
late F, which eventually transforms into product 3a via
a quick tautomerization. Fortunately, the intermediates
(B, D, and E) and the by-product acetamide are all de-
tected by LC-MS spectra (see supporting information,
Figures S5－S7).
oped for the synthesis of β-ketophosphine oxides/β-
ketophosphonates via copper catalyzed oxyphosphory-
lation of enamides with P(O)-H compounds and dioxy-
gen. This methodology, which utilizes simple and read-
ily available starting materials, provides a convenient
and highly attractive route to various β-ketophosphine
oxides/β-ketophosphonates with a broad substrate scope.
A possible mechanism is proposed on the basis of iso-
tope-labeling and radical trapping experiments. Further
studies on the mechanism details of oxyphosphorylation
reaction and synthetic applications of enamide chemis-
try are underway in our laboratory.
Acknowledgement
We gratefully acknowledge financial support from
the National Natural Science Foundation of China (Nos.
21572217, 21402184, 21172213, and 21302109).
Conclusions
A convenient and efficient method has been devel-
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