Copper/Iron-Catalyzed Aerobic Oxyphosphorylation of Terminal Alkynes Leading to β-Ketophosphonates

Article abstract of DOI:10.1021/acs.joc.5b00408

A copper/iron-catalyzed oxyphosphorylation of alkynes with H-phosphonates through a radical process was developed. The present protocol provides an attractive approach to β-ketophosphonates in moderate to good yields, with the advantages of readily available substrate, high functional group tolerance and operation simplicity. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b00408

Article
pubs.acs.org/joc
Copper/Iron-Catalyzed Aerobic Oxyphosphorylation of Terminal
Alkynes Leading to β‑Ketophosphonates
Niannian Yi, Ruijia Wang, Huaxu Zou, Weibao He, Wenqiang Fu, and Weimin He*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. China
*
S Supporting Information
ABSTRACT: A copper/iron-catalyzed oxyphosphorylation of alkynes
with H-phosphonates through a radical process was developed. The
present protocol provides an attractive approach to β-ketophosphonates
in moderate to good yields, with the advantages of readily available
substrate, high functional group tolerance and operation simplicity.
INTRODUCTION
of more efficient catalytic methods for the synthesis of α-
■
functionalized carbonyl compounds, keeping in mind their
diverse biological properties and versatile synthetic applications
in organic synthesis. Prompted by these facts and in
Oxyfunctionalization of simple organic compounds with
dioxygen through a radical pathway is a highly efficient and
rapidly growing novel strategy for the construction of oxygen-
containing compounds. Molecular oxygen, the linchpin of this
8
continuation of our interest in alkyne chemistry, we report
herein an efficient copper/iron catalyzed aerobic oxyphosphor-
ylation of alkynes with H-phosphonates to afford β-
ketophosphonates in moderate to good yields. β-Ketophosph-
strategy, is an ideal oxidant in organic synthesis because of its1
environmental friendliness, cleanliness, and sustainability.
Moreover, the activation of dioxygen finds important
applications in biochemistry and enzymology. As a result,
transition metals have been used to activate dioxygen. They
are also well-known for initiating radical reactions under mild
conditions. Merging the two roles of transition metals, that is,
dioxygen activation and radical initiation, is an exciting as well
as a challenging strategy for the development of new
synthetically important reactions.
9
1
,2
onates are valuable compounds in organic synthesis and
10
3
pharmaceutical industry. A number of methods have been
reported for their synthesis, but β-ketophosphonates have
11
rarely been obtained from alkynes. In 2011, Ji and co-workers
reported synthesis of β-ketophosphonates via dioxygen
11g
activation-based oxidative difunctionalization of alkene.
Inspired by this report, we envisaged the generation of
vinylphosphonate radical from alkynes and H-phosphonate
under Ji’s reaction conditions. To test our hypothesis, a model
reaction was performed under the conditions of Ji.
Over the past decade great progress has been made in
synthesis of α-functionalized carbonyl compounds via tran-
sition-metal-catalyzed aerobic oxidative radical reactions of
3a,4
alkenes,
but unactivated alkynes have seldom been used in
RESULTS AND DISCUSSION
this way. To the best of our knowledge, in literature only three
methods, reported by Jiao, Lei and Maiti, have been
described (Scheme 1). This definitely calls for the development
■
5
6
7
To our delight, the expected β-ketophosphonate was indeed
formed and, moreover, with 19% yield based on GC analysis
(
Table 1, entry 1). Increasing the loading of CuBr and FeBr
2 3
Scheme 1. Synthesis of α-Functionalized Carbonyl
Compounds via Direct Aerobic Difunctionalization of
Alkyne
to 10 mol % and 20 mol %, respectively, leads to a considerable
increase in the yield up to 30% (entry 2). A variety of
transition-metal salts were examined, and some results were
shown in entries 3−14. Among the salts tested, Cu(acac) and
2
FeCl3 performed better than other catalysts. As the next
optimization step we performed a solvent screening (entries
1
5−17). None of the other solvents was superior to DMSO.
Different bases were also examined, and the results showed that
Et N was still the best choice (entries 18−20). Moreover,
3
elevating the reaction temperature from 55 to 80 °C led to a
slightly improved yield (entry 21). Further exploration
Received: February 21, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00408
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of the Reaction Conditions
superior reaction efficiency to that of the electron-withdrawing
ones. The presence of other functional groups in the
phenylacetylene substrate, including tert-butyl, phenyl, me-
thoxy, benzyloxy, acetoxy, ester, acetyl and nitrile groups (3ka−
3ra), were tolerated under these reaction conditions. The
naphthyl alkyne was also a suitable substrate for this reaction
(3sa). Electron-rich heterocycle-containing alkynes were also
suitable substrates for this transformation (3ta−3va). However,
electron-poor alkynes, such as 2- and 3-ethynylpyridine, did not
undergo the reaction, likely caused by the low reactivity of the
C−C triple bonds. Moreover, estrone derivative (3wa) and
amino acid derivative (3xa) were also successfully prepared,
which highlights the good functional group tolerance and
potential applications of this method. This direct oxy-
phosphorylation of alkynes with H-phosphonates strategy
could also be extended to access the corresponding β-
ketophosphonates (3ab−3ae) when we used other phospho-
nates as the substrates. Morever, diphenylphosphine oxide was
suitable coupling partner (3af). Unfortunately, both internal
(dodec-6-yne and but-1-yn-1-ylbenzene) and aliphatic terminal
(dodec-1-yne) alkynes gave trace amount (<8%) of the desired
products.
yield
b
entry
catalyst
CuBr2
cocatalyst
base
condition
(%)
c
1
FeBr3
FeBr3
FeCl3
FeCl2
Fe(acac)3
ZnCl2
AlCl3
Et N
3
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMF, 55 °C
19
2
3
4
5
6
7
8
9
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr
CuCl
CuI
Et N
3
30
40
Et N
3
Et N
3
9
Et N
3
0
Et N
3
19
Et N
3
24
NiCl2
FeCl3
FeCl3
FeCl3
Et N
3
34
Et N
3
23
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
Et N
3
25
Et N
3
20
Cu(OTf)2
Cu(TFA)2
Cu(acac)2
Cu(acac)2
FeCl3
Et N
3
42
FeCl3
Et N
3
40
FeCl3
Et N
3
52
FeCl3
Et N
3
44
Cu(acac)2
FeCl3
Et N
3
DCE, 55 °C
THF, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 55 °C
DMSO, 80 °C
32
We also explored the reactivity of the Cu(acac) /FeCl -
2
3
Cu(acac)2
FeCl3
Et N
3
36
catalyzed oxyphosphorylation system for larger-scale synthesis
shown in Scheme 2. The reaction with (10 mmol, 1.02 g) of
phenylacetylene produced excellent yield (63%). The oxy-
phosphorylation proceeded smoothly even with a further
increased amount of substrate (50 mmol, 5.10 g), affording
β-ketophosphonates in 61% yield. These excellent results
showed the promise of the catalytic system for larger-scale
synthesis in the process of alkyne oxyphosphorylation.
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
−
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
−
Et NH
2
45
i
Pr NH
2
48
DBU
43
1
d
Et N
3
58
o
2
Et N
3
DMSO , 80 C
66 (63)
22
e
23
Et N
3
DMSO, 80 °C
DMSO, 80 °C
DMSO, 80 °C
24
Et N
3
0
25
FeCl3
Et N
3
trace
In order to gain reasonable insight into the reaction
mechanism, we conducted a number of experiments (Scheme
a
Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst (10 mol
), cocatalyst (20 mol %), base (0.5 mmol), solvent (1 mL), O2
%
(
3
). Initially, we studied the radical nature of the reaction using
b
balloon), 24 h. The yield was determined by GC with biphenyl as an
c d
diethyl phosphonate 2a and TEMPO under the standard
conditions. As expected, the TEMPO-trapped compound 5a
was observed (Scheme 3A). The radical nature of these
reactions was further confirmed by inclusion of catalytic
amounts of inhibitors TEMPO; product 3aa was formed only
to the extent of 24% (Scheme 3B). Studying the role of oxygen
in the reaction was also vital to unfold the intricacies of the
mechanism. The reaction was considerably inhibited under
internal standard. CuBr (2.5 mol %), FeBr (5 mol %). 2a (2
2
3
mmol) was used and the number in parentheses refers to the yield of
e
isolated product. Under air.
suggested that a good yield of 3aa was obtained when the
amount of H-phosphonate (2a) increased from 2 equiv to 4
equiv (entry 22). Unfortunately, the reaction did become
sluggish under an air atmosphere (entry 23). Finally, control
experiments showed that both copper salts and iron salts were
necessary for this reaction (entries 24 and 25).
The scope of the transformation was then investigated under
the optimized conditions. A variety of aromatic alkynes could
efficiently undergo oxyphosphorylation to the desired β-
ketophosphonates in moderate to good yields (Table 2).
Electron-donating and electron-withdrawing substituents at the
m-, o-, and p-positions on the phenyl ring of aromatic alkynes
all gave moderate to good yields of their corresponding
products. Oxyphosphorylation of m-, o-, and p-ethynyltoluenes
1
8
nitrogen (Scheme 3C). Further investigation under an O2
atmosphere proved the dioxygen activation, indicating that
oxygen atoms of the β-ketophosphonates originated from
molecular dioxygen (Scheme 3D). The results also revealed
that the DMSO was not the oxidant of the oxidative coupling
reaction. When diethyl (phenylethynyl)phosphonate (Scheme
3
E) and (E)-diethyl styrylphosphonate (Scheme 3F) were used
as the substrates, neither of them underwent the hydration
under the standard reaction.
Based on the results described above and previous
7
,11g,12
report,
a mechanism for this catalytic reaction is
(
3ba−3da) or m-, o-, and p-ethynylbromobenzenes (3ea−3ga)
proposed in Scheme 4. The generation of phosphonyl radical
proceeded well, and good yields were achieved, suggesting that
the steric effect of substituents on aromatic rings was negligible.
The intact bromo and chloro groups (3ea−3ha) are beneficial
for further functionalization at a later stage using cross coupling
protocols. What’s more, fluorine (3ia) and trifluoromethyl
II
I and Cu -(•OOH) (hydroperoxide) species is similar to the
mechanism first proposed by Ji and co-workers. The
phosphonyl radical I attacked the alkyne 1 and delivered a
reactive α-styrenyl radical intermediate II which interacted with
II
(
3ja) have come to be recognized as key elements in materials
Cu -(•OOH) species to form hydroperoxide intermediate III.
science, and many fluorine-containing biologically active agents
are finding applications as pharmaceuticals and agrochemicals.
The electron-donating substituted aromatic alkynes showed
Then, the intermediate III undergoes reduction by H-
phosphonate 2, producing phosphonyl radical I, water and
enolate IV. Finally, the enolate IV isomerizes and furnishes 3.
B
DOI: 10.1021/acs.joc.5b00408
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Reaction Scope
a
Reaction conditions: 1 (0.5 mmol), 2(2 mmol), Cu(acac) (10 mol %), FeCl (20 mol %), Et N (0.5 mmol), DMSO (1 mL), O (balloon), 80 °C,
2
3
3
2
2
4 h.
Scheme 2. Larger-Scale Synthesis of 3aa
EXPERIMENTAL SECTION
■
General Information. Commercially available reagents were of
reagent grade (AR grade) and were used without further purification.
Reactions were monitored by thin-layer chromatography (TLC) using
silicycle precoated silica gel plates. Flash column chromatography was
1
performed over silicycle silica gel (200−300 mesh). H NMR,
13
1
31
C{ H} NMR, and P NMR spectra were recorded on 400 MHz
NMR plus spectrometer using residue solvent peaks as internal
standards. Infrared spectra were recorded with IR spectrometer and
are reported in reciprocal centimeter (cm ). High-resolution mass
spectra were obtained using GCT-TOF instrument with EI or ESI
source.
CONCLUSIONS
■
−1
In conclusion, we have developed a generic approach to the
synthesis of complex β-ketophosphonates via the direct
copper/iron catalyzed oxidative coupling of alkynes and H-
phosphonates. The present methodology utilizes easily available
starting materials, offers operational simplicity, and enjoys a
broad substrate scope as well as functionality tolerance.
General Procedure for the Synthesis of 3aa. Phenylacetylene
(
(
51 mg, 0.5 mmol) was added to a mixture of H-diethyl phosphonate
276 mg, 2 mmol), Cu(acac) (13 mg, 0.05 mmol), FeCl (16 mg, 0.1
2
3
mmol), and Et N (50 mg, 0.5 mmol) in DMSO (1 mL) at room
3
Preliminary mechanism revealed that O not only participates
2
temperature under O (balloon). The reaction mixture was stirred at
2
as the ideal oxidant but also undergoes dioxygen activation
under ambient conditions via a radical process. Further studies
to clearly understand the reaction mechanism and the synthetic
applications are currently underway.
8
0 °C for 24 h. After completion of the reaction, water (5 mL) was
added to the reaction mixture, and the resulting mixture was extracted
with dichloromethane. The organic layer was washed with water (20
mL × 3) and brine (20 mL × 1), and the separated aqueous phase was
C
DOI: 10.1021/acs.joc.5b00408
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6
6
2.5 (d, J
= 6.5 Hz), 38.2 (d, JC−P = 129.0 Hz), 21.5, 16.1 (d, JC−P
=
Scheme 3. Mechanistic Studies
C−P
.5 Hz); 31P NMR (162 MHz, CDCl ) δ 20.2.
3
8
l
Diethyl (2-Oxo-2-(m-tolyl)ethyl)phosphonate (3ca). Yellow oil;
1
yield: 62% (83 mg). H NMR (400 MHz, CDCl ) δ 7.77−7.75 (m,
3
2
2
H), 7.37−7.30 (m, 2H), 4.13−4.06 (m, 4H), 3.58 (d, J
= 22.8 Hz,
H−P
H), 2.37 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H); 13C{ H} NMR (100 MHz,
1
CDCl ) δ 192.0 (d, J
= 6.5 Hz), 138.3, 136.5, 134.3, 129.3, 128.3,
3
C−P
1
26.2, 62.5 (d, J
= 6.6 Hz), 38.2 (d, JC−P = 129.8 Hz), 21.1, 16.0 (d,
C−P
JC−P = 6.6 Hz); 31P NMR (162 MHz, CDCl ) δ 20.1.
3
8
l
Diethyl (2-Oxo-2-(o-tolyl)ethyl)phosphonate (3da). Yellow oil;
1
yield: 62% (83 mg). H NMR (400 MHz, CDCl ) δ 7.67 (d, J = 7.2
3
Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.22−7.16 (m, 2H), 4.07−4.00 (m,
4
6
1
6
H), 3.52 (d, J
= 22.4 Hz, 2H), 2.44 (s, 3H), 1.18 (t, J = 7.0 Hz,
H−P
H); 13C{ H} NMR (100 MHz, CDCl ) δ 194.9 (d, J
1
= 6.6 Hz),
C−P
3
38.8, 137.1 (d, J = 2.2 Hz), 131.8, 131.7, 129.5, 125.6, 62.4 (d, J
.6 Hz), 40.9 (d, JC−P = 129.1 Hz), 21.2, 16.1 (d, JC−P =6.6 Hz);
=
P
C−P
3
1
NMR (162 MHz, CDCl ) δ 20.2.
3
8
l
Diethyl (2-(4-Bromophenyl)-2-oxoethyl)phosphonate (3ea).
1
Yellow oil; yield: 61% (102 mg). H NMR (400 MHz, CDCl ) δ
3
7
.87 (m, 2H), 7.61 (m, 2H), 4.16−4.08 (m, 4H), 3.58 (d, J
= 22.4
H−P
13
1
Hz, 2H), 1.27 (t, J = 7.2 Hz, 6H); C{ H} NMR (100 MHz, CDCl )
3
δ 190.9 (d, JC−P = 6.6 Hz), 135.2, 131.9, 130.5, 129.0, 62.7 (d, J
=
C−P
3
1
6
.6 Hz), 38.5 (d, JC−P = 128.3 Hz), 16.2 (d, JC−P = 6.6 Hz); P NMR
(
162 MHz, CDCl ) δ 19.4.
Diethyl (2-(3-Bromophenyl)-2-oxoethyl)phosphonate (3fa). Yel-
3
8
l
1
Scheme 4. Proposed Mechanism
low oil; yield: 56% (93 mg). H NMR (400 MHz, CDCl ) δ 8.11 (s,
3
1
H), 7.92 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 8.0
Hz, 1H), 4.14−4.10 (m, 4H), 3.58 (d, J = 22.4 Hz, 2H), 1.26 (t, J =
H−P
7
.2 Hz, 6H); 13C{ H} NMR (100 MHz, CDCl ) δ 190.6 (d, J
1
= 6.5
C−P
= 6.6 Hz),
3
Hz), 138.0, 136.4, 131.9, 130.1, 127.6, 122.8, 62.7 (d, J
C−P
8.5 (d, JC−P = 129.1 Hz), 16.1 (d, JC−P = 5.8 Hz); 3 P NMR (162
1
3
MHz, CDCl ) δ 19.3.
3
Diethyl (2-(2-Bromophenyl)-2-oxoethyl)phosphonate (3ga). Yel-
1
low oil; yield: 63% (105 mg). H NMR (400 MHz, CDCl ) δ 7.59 (m,
3
1
H), 7.53 (m, 1H), 7.39−7.35 (m, 1H), 7.32−7.28 (m, 1H), 4.13−
4
.06 (m, 4H), 3.68 (d, J = 22.4 Hz, 2H), 1.25 (t, J = 7.2 Hz, 6H);
H−P
13
1
C{ H} NMR (100 MHz, CDCl ) δ 195.0 (d, J
= 6.6 Hz), 140.6,
C−P
3
1
=
33.6, 132.1, 129.7, 127.4, 118.9, 62.6 (d, J
= 6.6 Hz), 41.8 (d, JC−P
C−P
127.6 Hz), 16.1 (d, JC−P = 6.6 Hz); 31P NMR (162 MHz, CDCl ) δ
3
−1
extracted with CH Cl (20 mL × 2). The combined organic layers
19.0; IR (neat): 2966, 1688, 1579, 1250, 1028, 966 cm ; HRMS
(ESI): m/z [M + H] calcd for C12H17BrO P: 335.0042, found:
2
2
+
were dried over Na SO , filtered, and concentrated in vacuo. The
4
2
4
residue was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate, 2:1) to afford the β-ketophosphonate 3aa as a
light-yellow oil (63%, 81 mg).
335.0032.
Diethyl (2-(4-Chlorophenyl)-2-oxoethyl)phosphonate (3ha). Yel-
low oil; yield: 45% (65 mg). H NMR (400 MHz, CDCl
1
) δ 7.94 (d, J
3
The Experimental Procedure for Larger-Scale Synthesis of
aa. Phenylacetylene (5.1 g, 50 mmol) was added to a mixture of H-
= 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.15−4.08 (m, 4H), 3.58 (d,
J
H−P
= 22.8 Hz, 2H), 1.26 (t, J = 7.2 Hz, 6H); 13C{ H} NMR (100
1
3
diethyl phosphonate (27.6 g, 200 mmol), Cu(acac) (1.31 g, 5 mmol),
MHz, CDCl ) δ 190.6 (d, J
= 6.5 Hz), 140.2, 134.7, 130.4, 128.9,
C−P
2
3
FeCl (1.62 g, 10 mmol), and Et N (5.05 g, 50 mmol) in DMSO (30
62.7 (d, J
= 6.5 Hz), 38.5 (d, JC−P = 129.0 Hz), 16.1 (d, JC−P = 6.6
3
3
C−P
Hz); 31P NMR (162 MHz, CDCl ) δ 19.5; IR (neat): 2955, 1696,
mL) at room temperature under O (balloon). The reaction mixture
2
3
−1
+
was stirred at 80 °C for 36 h. After completion of the reaction, water
1580, 1257, 1020, 975 cm ; HRMS (ESI): m/z [M + H] calcd for
(
30 mL) was added to the reaction mixture, and the resulting mixture
C H ClO P: 291.0547, found: 291.0545.
12
17
4
8
l
was extracted with dichloromethane. The organic layer was washed
Diethyl (2-(4-Fluorophenyl)-2-oxoethyl)phosphonate (3ia). Yel-
low oil; yield: 58% (79 mg). H NMR (400 MHz, CDCl ) δ 8.02 (m,
3
1
with 0.1 M HCl (50 mL × 1), water (50 mL × 3), and brine (50 mL ×
1
), and the separated aqueous phase was extracted with CH Cl (50
2H), 7.10 (t, J = 8.4 Hz, 2H), 4.13−4.06 (m, 4H), 3.57 (d, J
= 22.8
2
2
H−P
Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H); 13C{ H} NMR (100 MHz, CDCl )
1
mL × 2). The combined organic layers were dried over Na SO ,
2
4
3
filtered, and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate, 2:1) to
afford the β-ketophosphonate 3aa as a light-yellow oil (61%, 7.81 g).
δ 190.2 (d, JC−P = 6.6 Hz), 165.9 (d, JC−F = 254.4 Hz), 132.8, 131.7 (d,
JC−F = 9.5 Hz), 115.6 (d, JC−F = 21.9 Hz), 62.5 (d, J
= 6.6 Hz), 38.5
C−P
(d, JC−P = 128.4 Hz), 16.1 (d, JC−P = 5.8 Hz); 31P NMR (162 MHz,
1
1g
Diethyl (2-Oxo-2-Phenylethyl)phosphonate (3aa).
low oil; yield: 63% (81 mg). H NMR (400 MHz, CDCl ) δ 7.97 (d, J
Light-yel-
CDCl ) δ 19.6.
3
1
3
Diethyl (2-Oxo-2-(4-(trifluoromethyl)phenyl)ethyl)phosphonate
8l
1
=
7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 4.10
(3ja). Yellow oil; yield: 54% (87 mg). H NMR (400 MHz,
(
m, 4H), 3.60 (d, J = 22.8 Hz, 2H), 1.24 (t, J = 7.2 Hz, 6H);
CDCl ) δ 8.10 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 4.14−4.07
H−P
3
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 191.8 (d, J
= 6.5 Hz), 136.4,
C−P
(m, 4H), 3.62 (d, JH−P = 23.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 6H);
3
1
3
1
1
1
33.6, 128.9, 128.5, 62.5 (d, J
= 6.6 Hz), 38.2 (d, JC−P = 129.8 Hz),
C{ H} NMR (100 MHz, CDCl
134.2 (dd, JC−F =32.8 Hz, 32.0 Hz), 129.3, 125.5 (q, JC−F =3.7 Hz),
122.0, 62.7 (d, J =6.6 Hz), 38.8 (d, JC−P = 128.3 Hz), 16.1 (d, JC−P
3
) δ 191.0 (d, JC−P = 6.5 Hz), 139.0,
C−P
6.1 (d, JC−P = 6.6 Hz); 31P NMR (162 MHz, CDCl ) δ 20.0.
3
1
1e
Diethyl (2-Oxo-2-(p-tolyl)ethyl)phosphonate (3ba). Yellow oil;
C−P
1
31
yield: 63% (85 mg). H NMR (400 MHz, CDCl ) δ 7.88 (d, J = 8.0
= 6.6 Hz); P NMR (162 MHz, CDCl ) δ 19.0.
3
3
8
l
Hz, 2H), 7.24 (t, J = 8.4 Hz, 2H), 4.10 (m, 4H), 3.58 (d, J
= 22.4
Diethyl (2-(4-(tert-Butyl)phenyl)-2-oxoethyl)phosphonate (3ka).
H−P
Hz, 2H), 2.38 (s, 3H), 1.25 (t, J = 7.0 Hz, 6H); 13C{ H} NMR (100
1
Yellow oil; yield: 54% (84 mg). H NMR (400 MHz, CDCl ) δ 7.90
1
3
MHz, CDCl ) δ 191.4 (d, J = 6.5 Hz), 144.5, 133.9, 129.2, 129.0,
(d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.12−4.05 (m, 4H), 3.56
3
C−P
D
DOI: 10.1021/acs.joc.5b00408
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
d, J
= 22.8 Hz, 2H), 1.28 (s, 9H), 1.23 (t, J = 7.2 Hz, 6H);
1H), 8.06−8.03 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.0 Hz,
H−P
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 191.3 (d, J
= 6.6 Hz), 157.3,
2H), 7.62−7.53 (m, 2H), 4.18−4.11 (m, 4H), 3.76 (d, J
= 22.8 Hz,
3
C−P
H−P
2H), 1.26 (t, J = 7.2 Hz, 6H); 13C{ H} NMR (100 MHz, CDCl
1
) δ
3
1
3
2
34.1, 128.9, 125.4, 62.4 (d, JC−P = 6.6 Hz), 38.2 (d, J
= 129.1 Hz),
C−P
4.9, 30.8 16.0 (d, JC−P = 6.6 Hz); 3 P NMR (162 MHz, CDCl ) δ
1
191.7 (d, JC−P = 6.5 Hz), 135.7, 133.7, 132.3, 131.4, 129.7, 128.8,
3
0.2.
128.4, 127.7, 126.8, 124.0, 62.6 (d, JC−P = 6.5 Hz), 38.4 (d, JC−P =
129.0 Hz), 16.2 (d, JC−P = 6.0 Hz); 31P NMR (162 MHz, CDCl
) δ
Diethyl (2-([1,1′-Biphenyl]-4-yl)-2-oxoethyl)phosphonate (3la).
3
1
−1
Light-yellow oil; yield: 34% (56 mg). H NMR (400 MHz, CDCl )
20.2; IR (neat): 3015, 1678, 1621, 1248, 1047, 989 cm ; HRMS
3
+
δ 8.09 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0
Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 4.20−4.12
(ESI): m/z [M + H] calcd for C16H O P: 307.1094, found:
20 4
307.1103.
(
m, 4H), 3.67 (d, J
= 22.4 Hz, 2H), 1.29 (t, J = 7.2 Hz, 6H);
Diethyl (2-(Benzo[b]thiophen-3-yl)-2-oxoethyl)phosphonate
H−P
1
3
1
1
C{ H} NMR (100 MHz, CDCl ) δ 191.4 (d, J
= 5.8 Hz), 146.3,
(3ta). Light-yellow oil; yield: 44% (68 mg). H NMR (400 MHz,
3
C−P
CDCl ) δ 8.75 (d, J = 8.4 Hz, 1H), 8.55 (s, 1H), 7.86 (d, J = 8.0 Hz,
1
3
39.6, 135.1, 129.7, 128.9, 128.3, 127.2, 127.1, 62.7 (d, J
= 6.6 Hz),
3
C−P
8.5 (d, JC−P = 129.0 Hz), 16.2 (d, JC−P = 5.8 Hz); 31P NMR (162
1
4
H), 7.49 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 4.18−4.11 (m,
13 1
−1
H), 3.63 (d, J
= 22.4 Hz, 2H), 1.28 (t, J = 7.2 Hz, 6H); C{ H}
H−P
MHz, CDCl ) δ 20.1; IR (neat): 2922, 1686, 1241, 1038, 973 cm ;
3
+
NMR (100 MHz, CDCl ) δ 186.1 (d, J = 6.5 Hz), 140.1, 139.6,
HRMS (ESI): m/z [M + H] calcd for C H O P: 333.1250, found:
3
3
C−P
18
22
4
1
(
36.4, 134.7, 126.0, 125.6, 125.5, 122.2, 62.7 (d, J
= 6.6 Hz), 40.7
C−P
33.1249.
d, JC−P = 130.3 Hz), 16.2 (d, JC−P = 6.6 Hz); 31P NMR (162 MHz,
Diethyl (2-(4-Methoxyphenyl)-2-oxoethyl)phosphonate
1
1e
1
−1
(
3ma).
Yellow oil; yield: 65% (93 mg). H NMR (400 MHz,
CDCl
3
) δ 20.2; IR (neat): 3022, 1672, 1241, 1043, 981 cm ; HRMS
+
CDCl ) δ 7.98 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.15−4.08
(
(ESI): m/z [M + H] calcd for C14
H
18
O
4
PS: 313.0658, found:
3
m, 4H), 3.86 (s, 3H), 3.57 (d, J
= 22.8 Hz, 2H), 1.27 (t, J = 7.2
313.0648.
H−P
13
1
8l
Hz, 6H); C{ H} NMR (100 MHz, CDCl ) δ 190.1 (d, J
= 6.5
Diethyl (2-Oxo-2-(thiophen-3-yl)ethyl)phosphonate (3ua). Yel-
low oil; yield: 56% (73 mg). H NMR (400 MHz, CDCl
3
C−P
1
Hz), 163.9, 131.4, 129.5, 113.7, 62.6 (d, JC−P = 6.6 Hz), 55.4, 38.1 (d,
3
) δ 8.15 (m,
JC−P = 129.1 Hz), 16.1 (d, JC−P = 6.6 Hz); 31P NMR (162 MHz,
1H), 7.50 (m, 1H), 7.24 (m, 1H), 4.10−4.03 (m, 4H), 3.46 (d, J
=
H−P
22.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 6H); 13C{ H} NMR (100 MHz,
1
CDCl ) δ 20.5.
3
Diethyl (2-(4-(Benzyloxy)phenyl)-2-oxoethyl)phosphonate (3na).
CDCl ) δ 185.5 (d, J = 6.6 Hz), 141.7, 134.3, 127.2, 126.3, 62.6 (d,
JC−P = 6.6 Hz), 39.8 (d, JC−P = 129.0 Hz), 16.1 (d, JC−P = 6.5 Hz); P
3
C−P
1
31
Yellow oil; yield: 60% (108 mg). H NMR (400 MHz, CDCl ) δ 7.99
3
(
d, J = 8.8 Hz, 2H), 7.43−7.34 (m, 5H), 7.01 (d, J = 8.8 Hz, 2H), 5.13
NMR (162 MHz, CDCl ) δ 19.9.
3
(
s, 2H), 4.17−4.09 (m, 4H), 3.58 (d, J = 22.8 Hz, 2H), 1.28 (t, J =
Diethyl (2-Oxo-2-(thiophen-2-yl)ethyl)phosphonate (3va). Yellow
H−P
.2 Hz, 6H); 13C{ H} NMR (100 MHz, CDCl ) δ 190.2 (d, J
1
= 6.5
oil; yield: 50% (65 mg). H NMR (400 MHz, CDCl ) δ 7.79 (d, J =
1
7
3
C−P
3
3.6 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.12 (t, J = 4.4 Hz, 1H), 4.15−
4.08 (m, 4H), 3.52 (d, J
= 22.4 Hz, 2H), 1.26 (t, J = 7.2 Hz, 6H);
H−P
13
1
C{ H} NMR (100 MHz, CDCl ) δ 184.1 (d, J
= 6.5 Hz), 143.7,
C−P
3
135.1, 134.1, 128.2, 62.7 (d, J
= 6.5 Hz), 39.2 (d, JC−P = 129.8 Hz),
C−P
16.1 (d, JC−P = 5.9 Hz); 31P NMR (162 MHz, CDCl ) δ 19.4; IR
3
−1
(neat): 2956, 1672, 1524, 1253, 1036, 975 cm ; HRMS (ESI): m/z
+
[M + H] calcd for C H O PS: 263.0501, found: 263.0498.
10 16
4
D i e t h y l ( 2 - ( ( 8 R , 9 S , 1 3 S , 1 4 S ) - 1 3 - M e t h y l - 1 7 - o x o -
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-
phenanthren-3-yl)-2-oxoethyl)phosphonate (3wa). Light-yellow oil;
1
yield: 37% (80 mg). H NMR (400 MHz, CDCl
) δ 7.77 (d, J = 8.4
3
Hz, 1H), 7.74 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.17−4.10 (m, 4H),
3.59 (d, JH−P = 22.4 Hz, 2H), 2.98−2.94 (m, 2H), 2.50−2.42 (m, 2H),
2.36−2.33 (m, 1H), 2.18−1.97 (m, 4H), 1.64−1.49 (m, 6H), 1.29 (t, J
= 6.8 Hz, 6H), 0.91 (s, 3H); 13C{ H} NMR (100 MHz, CDCl
1
) δ
3
191.7 (d, JC−P = 6.5 Hz), 146.2, 137.0, 134.1, 129.6, 126.5, 125.6, 62.6
(d, JC−P = 6.5 Hz), 50.5, 47.8, 44.7, 38.3 (d, JC−P = 129.8 Hz), 37.7,
31
35.8, 31.5, 29.2, 26.2, 25.5, 21.5, 16.2 (d, JC−P = 6.5 Hz), 13.8;
NMR (162 MHz, CDCl
P
) δ 20.3; IR (neat): 2982, 1715, 1686, 1572,
3
−1
+
1246, 1045, 982 cm ; HRMS (ESI): m/z [M + H] calcd for
P: 433.2138, found: 433.2125.
(S)-4-(2-(Diethoxyphosphoryl)acetyl)phenyl 2-((tert-
butoxycarbonyl)amino)-3-phenylpropanoate (3xa). Colorless oil;
C H O
24 34 5
1
yield: 44% (114 mg). H NMR (400 MHz, CDCl ) δ 8.03 (d, J = 8.8
3
Hz, 2H), 7.36−7.29 (m, 3H), 7.23 (d, J = 6.4 Hz, 2H), 7.09 (d, J = 8.8
Hz, 2H), 5.08 (d, J = 8.0 Hz, 1H), 4.83−4.78 (m, 1H), 4.17−4.10 (m,
4H), 3.60 (d, JH−P = 22.8 Hz, 2H), 3.22 (d, J = 6.0 Hz, 2H), 1.44 (s,
13
1
9H), 1.28 (t, J = 6.8 Hz, 6H); C{ H} NMR (100 MHz, CDCl ) δ
3
190.6 (d, JC−P = 6.6 Hz), 170.1, 155.1, 154.4, 135.5, 134.2, 130.7,
129.3, 128.8, 127.4, 121.5, 80.3, 62.7 (d, JC−P = 6.6 Hz), 54.7, 38.5 (d,
31
J
C−P = 128.3 Hz), 38.2, 28.2, 16.2 (d, JC−P = 6.5 Hz); P NMR (162
MHz, CDCl ) δ 19.7; IR (neat): 2988, 1765, 1683, 1570, 1242, 1050,
3
−1
+
987 cm ; HRMS (ESI): m/z [M + H] calcd for C26H35NO P:
8
520.2095, found: 520.2103.
1
1f
Dimethyl (2-Oxo-2-phenylethyl)phosphonate (3ab). Yellow oil;
1
yield: 50% (57 mg). H NMR (400 MHz, CDCl ) δ 8.00 (dd, J = 1.2
3
MHz, CDCl ) δ 190.7 (d, J = 6.5 Hz), 139.2, 132.4, 129.4, 117.7,
Hz, 8.4 Hz, 2H), 7.61−7.57 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 3.77 (d,
3
C−P
1
3
1
1
=
16.7, 62.8 (d, J
= 6.5 Hz), 38.9 (d, JC−P = 127.6 Hz), 16.1 (d, JC−P
J
= 11.2 Hz, 6H), 3.64 (d, J
= 22.8 Hz, 2H); C{ H} NMR
= 6.6 Hz), 136.3, 133.8, 128.9,
C−P
H−P
H−P
6.6 Hz); 31P NMR (162 MHz, CDCl ) δ 18.6.
(100 MHz, CDCl ) δ 191.7 (d, J
128.7, 53.1 (d, JC−P = 6.6 Hz), 37.4 (d, JC−P = 131.3 Hz); P NMR
3
3 C−P
3
1
Diethyl (2-(Naphthalen-2-yl)-2-oxoethyl)phosphonate (3sa). Yel-
1
low oil; yield: 50% (76 mg). H NMR (400 MHz, CDCl ) δ 8.54 (s,
(162 MHz, CDCl ) δ 22.9.
3
3
E
DOI: 10.1021/acs.joc.5b00408
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1g
Diisopropyl (2-Oxo-2-phenylethyl)phosphonate (3ac).
Yellow
20130161120035), China Postdoctoral Science Foundation
(no. 2013M540625), Hunan Provincial Natural Science
Foundation of China (no. 14JJ7028), Department of Science
and Technology Foundation of Changsha (no. k1403243-31),
and the Fundamental Research Funds for the Central
Universities (Hunan University).
1
oil; yield: 58% (82 mg). H NMR (400 MHz, CDCl ) δ 7.99 (d, J =
3
7
.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.74−
.66 (m, 2H), 3.57 (d, J = 22.8 Hz, 2H), 1.26−1.23 (m, 12H);
4
H−P
1
3
1
C{ H} NMR (100 MHz, CDCl ) δ 192.0 (d, J
= 6.5 Hz), 136.6,
3
C−P
1
2
33.4, 129.1, 128.4, 71.4 (d, JC−P = 6.5 Hz), 39.6 (d, JC−P = 129.8 Hz),
3.9 (d, JC−P = 3.6 Hz), 23.7 (d, JC−P = 5.1 Hz); 31P NMR (162 MHz,
CDCl ) δ 17.7.
3
1
1g
Dibutyl (2-Oxo-2-phenylethyl)phosphonate (3ad). Yellow oil;
yield: 62% (96 mg). H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 8.4
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(
(
m, 4H), 3.60 (d, J
m, 4H), 0.84 (t, J = 7.2 Hz, 6H); C{ H} NMR (100 MHz, CDCl )
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13 1
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5
(
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=
6
.6 Hz), 38.2 (d, JC−P = 128.3 Hz), 32.2 (d, JC−P = 6.5 Hz), 18.5, 13.4;
P NMR (162 MHz, CDCl ) δ 19.8.
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3
1
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3
1
1a
1
yield: 54% (102 mg). H NMR (400 MHz, CDCl ) δ 7.87 (m, 2H),
7
3
.47 (m, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24−7.19 (m, 10H), 5.03−
.91 (m, 4H), 3.58 (d, J
= 22.4 Hz, 2H); 1 C{ H} NMR (100
3 1
4
H−P
MHz, CDCl ) δ 191.5 (d, J
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3
C−P
Bac
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(
d, J = 5.8 Hz), 133.5, 128.9, 128.5, 128.4, 128.3, 127.9, 67.9 (d, J
=
C−P
.6 Hz), 38.5 (d, JC−P = 130.5 Hz); 3 P NMR (162 MHz, CDCl ) δ
1
6
2
3
(
1.2.
1
1a
40, 102. (e) Liu, C.; Liu, D.; Lei, A. Acc. Chem. Res. 2014, 47, 3459.
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2
-(Diphenylphosphoryl)-1-phenylethanone (3af).
Yellow oil;
1
yield: 32% (51 mg). H NMR (400 MHz, CDCl ) δ 7.97 (d, J = 7.6
Hz, 2H), 7.82−7.77 (m, 4H), 7.54−7.49 (m, 3H), 7.47−7.38 (m, 6H),
4
1
1
4
2
3
2
014, 2032. (b) Singh, A. K.; Chawla, R.; Yadav, L. D. S. Tetrahedron
= 15.6 Hz, 2H); 1 C{ H} NMR (100 MHz, CDCl ) δ
3
1
Lett. 2014, 55, 4742. (c) Wei, W.; Liu, C.; Yang, D.; Wen, J.; You, J.;
Suo, Y.; Wang, H. Chem. Commun. 2013, 49, 10239. (d) Zhang, F.;
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(e) Singh, A. K.; Chawla, R.; Keshari, T.; Yadav, V. K.; Yadav, L. D. S.
Org. Biomol. Chem. 2014, 12, 8550.
.14 (d, J
H
−
P
3
92.7 (d, JC−P = 5.8 Hz), 136.8, 133.5, 132.3, 132.1 (d, JC−P = 2.1 Hz),
31.2, 131.0 (d, JC−P = 10.2 Hz), 129.1, 128.6, 128.5, 128.4 (d, J
=
C−P
.4 Hz), 43.1 (d, JC−P = 64.2 Hz); 3 P NMR (162 MHz, CDCl ) δ
1
3
7.2.
(
(
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(
EtO) P(O)H (69 mg, 0.5 mmol) was added to a mixture of
2
Soc. 2013, 135, 11481.
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3
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3
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purified by flash column chromatography (Al O , neutral) to give the
2
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2
2
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product 5a.
Diethyl (2,2,6,6-Tetramethylpiperidin-1-yl) phosphate (5a). Yel-
low oil; yield: 13% (19 mg). H NMR (400 MHz, CDCl ) δ 4.09−
1
3
3
6
5
.93 (m, 4H), 1.59−1.54 (m, 6H), 1.42 (s, 12H), 1.29 (t, J = 7.0 Hz,
H); 13C{ H} NMR (100 MHz, CDCl ) δ 61.2 (d, J
1
= 5.1 Hz),
C−P
= 8.8 Hz), 31.3, 16.5, 16.2 (d,
(i) Huang, W.; Xiang, J.; He, W. Chem. Lett. 2014, 43, 893. (j) Xie, L.;
3
5.5 (d, JC−P = 3.7 Hz), 41.6 (d, J
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Lu, L.; Zou, H.; Pan, Y.; He, W. Tetrahedron 2015, 71, 694.
C−P
31
JC−P = 7.2 Hz); P NMR (162 MHz, CDCl ) δ 10.0; HRMS (EI): m/
z [M] calcd for C H NO P: 293.1756, found: 293.1751.
3
+
13
28
4
(
9) (a) Kondoh, A.; Yorimitsu, H.; Oshima, K. Chem.Asian J. 2010,
ASSOCIATED CONTENT
Supporting Information
Results of mechanistic studies, H NMR, C{ H} NMR, and
P NMR spectra of compounds 3aa−3af, 5a. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.joc.5b00408.
■
5
, 398. (b) Mikołajczyk, M.; Zurawinski, R.; Kiełbasinski, P.
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*
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1
13
1
3
1
AUTHOR INFORMATION
Corresponding Author
E-mail: wmhe@hnu.edu.cn.
Notes
■
*
Hansmann, M. M.; Pflas
013, 355, 2037. (j) Chav
Pizzano, A. Adv. Synth. Catal. 2011, 353, 2775.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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This work was supported by the National Natural Science
Foundation of China (no. 21302048), Specialized Research
Fund for the Doctoral Program of Higher Education (no.
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