Base-Promoted Direct Oxyphosphorylation of Alkynes with H-Phosphine Oxides in the Presence of Water

Article abstract of DOI:10.1055/s-0036-1591562

We have developed a simple method for the oxyphosphorylation of arylalkynes to give β-keto phosphine oxides without the assistance of any transition metal. An inorganic base promoted the oxyphosphorylation and water played a synergistic role in the formation of various β-keto phosphine oxides. The reaction showed a wide structural scope and broad functional-group tolerance, and it proceeded under mild reaction conditions. This method solved the problem of metal dependence in the oxyphosphorylation of alkynes, providing a potential application in organic chemistry. Control experiments revealed the mechanism of the oxyphosphorylation and the synergistic role played by water in the radical process.

Full text of DOI:10.1055/s-0036-1591562

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
Synlett
W. Zhong et al.
Letter
Base-Promoted Direct Oxyphosphorylation of Alkynes with
H-Phosphine Oxides in the Presence of Water
Wenwu Zhong
O
O
Tao Tan
O
R2
R3
metal-free
,O2
P
Lei Shi*
R1
H
P
R3
R2
R1
LiOH, DMF–H2O
Xue Zeng*
1
2
3
Chongqing Medical and Pharmaceutical College, Chongqing
Engineering Technology Research Center of Pharmaceutical
Preparation, Chongqing 401331, P. R. of China
shilei1987081706@126.com
* metal-free, synergy of H2O
* R = halo, alkyl, aryl, heterocycle, –CN, –CF3, and so on;
R2 = alkoxy, aryl; R3 = alkoxy, aryl
* 23 examples, yield = 43–88%
1
xuezengcqyz@163.com
Received: 03.02.2018
Accepted after revision: 14.03.2018
Published online: 13.04.2018
activities that render them interesting for their potential
2
applications in various fields such as medicinal chemistry,
3
1c
DOI: 10.1055/s-0036-1591562; Art ID: st-2018-u0073-l
organic chemistry, or agrochemicals. Among the various
organophosphorus compounds, β-keto phosphine oxides
and β-keto phosphonates have recently attracted consider-
able attention because they are extremely versatile inter-
mediates in organic chemistry.4 β-Keto phosphine oxides
and β-keto phosphonates, in addition to exhibiting various
Abstract We have developed a simple method for the oxyphosphory-
lation of arylalkynes to give β-keto phosphine oxides without the assis-
tance of any transition metal. An inorganic base promoted the oxy-
phosphorylation and water played a synergistic role in the formation of
various β-keto phosphine oxides. The reaction showed a wide structural
scope and broad functional-group tolerance, and it proceeded under
mild reaction conditions. This method solved the problem of metal de-
pendence in the oxyphosphorylation of alkynes, providing a potential
application in organic chemistry. Control experiments revealed the
mechanism of the oxyphosphorylation and the synergistic role played
by water in the radical process.
5
biological activities and metal-complexing abilities, can
also can serve as useful precursors for the construction of
α,β-unsaturated compounds through the Horner–Wad-
6
sworth–Emmons reaction or in the synthesis of chiral β-
amino or β-hydroxy phosphonic acids.7
Generally, β-keto phosphine oxides are synthesized by
Key words alkynes, arylphosphorylalkanones, keto phosphine oxides,
oxyphosphorylation, aralkynes
8
the classical Arbuzov reaction or by acylation of alkylphos-
9
phonates with carboxylic acid derivatives (Scheme 1). Sev-
eral reports of new methods for synthesizing β-keto phos-
phine oxides have recently been published;10 these mainly
involve the oxyphosphorylation of alkynes or arylalkynoic
Organic phosphorus compounds are of widespread in-
terest in synthetic chemistry and medicinal chemistry.1
Many phosphorus derivatives have remarkable biological
acids,1
0a,10b,11
the hydration of alkynylphosphonates, de-
12
Traditional synthetic methods
Recently developed methods
O
O
Arbuzov reaction
Noble metal
H2O
R1
P(OR)3
X
R2
R2
P
R1
O
P
O
R1
R1
R2
R2
R2
or
O
R1
O
LDA, T< 0 °C
Metal catalysis
O
P
P
R1
R1
R2
O2
R1
O
H
This work
O
O
R2
R3
O
Metal-free ,O2
LiOH, DMF–H O
P
R1
H
P
R3
R2
R1
2
Scheme 1 Comparison of previous methods with the present protocol
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
Synlett
W. Zhong et al.
Letter
carboxylation or deesterification and coupling,10c,10d,13 or a
domino Knoevenagel/decarboxylation/oxyphosphorylation
Table 1 Optimization of the Reaction Parametersa
14
O
O
reaction. For example, in 2011, Wei and Ji reported the
Ph
Ph
O
10a
base, solvent
P
oxyphosphorylation of alkenes with dioxygen. A series of
simple and efficient copper-catalyzed one-pot methods for
the construction of β-keto phosphine oxides through aero-
bic oxidative coupling of various ketones or imines with
H
P
Ph
temp.
Ph
1a
2a
3a
b
15
Entry
Base
KOH
Temp (°C)
Solvent
Yield (%)
P(O)–H compounds were later developed. For example, Lei
and co-workers reported a copper-catalyzed radical α-
phosphorylation of aryl ketone O-acetyloximes to give good
yields of the corresponding β-keto phosphine oxides.1
Peng and co-workers developed a silver-catalyzed oxidative
cross-coupling of 1,3-dicarbonyl compounds with H-phos-
phonates to give β-keto phosphonates.15a Subsequently, Ji’s
group investigated the one-pot direct oxyphosphorylation
1
2
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
r.t.
40
60
70
80
THF
THF
35
41
45
12
14
16
10
15
28
17
23
58
46
53
60
66
75
81
77
70
38
63
85
80
72
NaOH
LiOH
5e
3
THF
4
Cs
CO
Na CO
2
CO
3
THF
5
K
2
3
THF
6
2
3
THF
1
5b,15c,16
of enamides or ketones.
Notably, Zhao and co-work-
7
Et
3
N
THF
ers developed an acetonitrile-dependent oxyphosphoryla-
tion to give β-keto phosphine oxides through the reaction
of α,β-alkenylcarboxylic acids or alkenes with H-phospho-
8
DIPEA
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
THF
9
DCE
toluene
nates. Similar research was also reported by Gu and Cai.18
17
10
11
However, almost all of these methods have limitations
such as a low atom economy, inaccessible starting materi-
als, complex procedures, relatively harsh reaction condi-
tions, or dependency on metals. In particular, the oxyphos-
phorylation of alkynes involves major challenges because of
its dependence on transition metals. Therefore, it was still
highly desirable to develop a simple, efficient, and mild
method for the oxyphosphorylation of alkynes. Although
some known methods do not require harsh reaction condi-
tions, the use of transition-metal catalysts is necessary in
these cases. Fortunately, in 2016 Cai and co-workers devel-
oped a metal-free oxyphosphorylation of aryl alkynes by
CH
DMF
DMSO
2
Cl
2
12
13
14
15
16
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
O
O–DMF (1:1)
O–DMF (1:2)
O–DMF (1:4)
O–DMF (1:8)
O–DMF (1:10)
O–DMF (1:12)
O–DMF (1:8)
17
18
19
20
19
21
22
23
using rhodamine B as a photocatalyst. A plausible free-
radical mechanism was proposed in their work.
2O–DMF (1:8)
We surmised that the P-centered radicals generated un-
der alkaline conditions might engage in oxidative couplings
with arylalkynes to form the corresponding β-keto phos-
phine oxides. We therefore examined a metal-free base-
promoted oxyphosphorylation of alkynes with H-phospho-
nates under an oxygen atmosphere (Scheme 1). As com-
pared with previous methods, our method has the promi-
nent advantage of being more convenient and more eco-
nomical. Inexpensive metals can be used instead of more-
expensive metal catalysts, and the reaction has a wide
scope; these properties meet the requirements of green
chemistry.
In our initial study, we examined the optimal experi-
mental conditions by using the model reaction of ethynyl-
benzene (1a) with diphenylphosphine oxide (2a) under an
oxygen atmosphere (Table 1). First, various alkalis were in-
vestigated in the presence of THF at 50 °C for three hours
2
H O–DMF (1:8)
24
H
H
2
2
O–DMF (1:8)
O–DMF (1:8)
25
a
Conditions: 1a (0.25 mmol), 2a (0.5 mmol), base (0.05 mmol), solvent
2.25 mL), O (balloon), 2–6 h.
Isolated yield.
(
2
b
ethanone (3a), except for LiOH, which gave 3a in 45% yield
(entry 3).
As the next optimization step, the effects of various sol-
vents on the model reaction were studied (entries 9–14).
The solvent system had a marked effect on the efficiency of
the reaction. Astonishingly, the reactions in H O and in
DMF afforded similar yields of 3a (53% and 58%, respective-
ly; entries 12 and 14). We surmised that a mixture of H O
2
2
and DMF might enhance the efficiency of this reaction, and
we examined the effects of various mixtures of DMF and
H O. Interestingly, the addition of H O to DMF markedly in-
(Table 1, entries 1–8). Unfortunately, most alkalis did
not give a high yield of 2-(diphenylphosphoryl)-1-phenyl-
2
2
creased the yield of 3a (entries 15–20), and a 1:8 v/v mix-
ture provided an optimal yield from the reaction (entry 18).
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W. Zhong et al.
Letter
With these optimized conditions, we finally examined the
effects of various reaction temperatures (entries 21–25).
The reaction efficiency was slightly affected by the tem-
perature, and 60 °C was found to be the optimal tempera-
ture for this model reaction (entry 23).
With the optimal conditions in hand, we examined the
substrate scope of the oxyphosphorylation (Scheme 2).
Most substituent groups were well tolerated, and excellent
yields were obtained from the oxyphosphorylation reac-
tion. The oxyphosphorylation of aralkynes was slightly in-
fluenced by the electronic properties of substituents on the
aryl group (3a–k). Electron-rich aralkynes were more suit-
able substrates for this protocol (3e and 3f). Steric effects of
substituents attached to the benzene ring had little effect
on the efficiency of the reaction (3e, 3f, and 3l–o), but
bulky groups in the 2-position of benzene ring slightly de-
creased the efficiency of the transformation as a result of
steric hindrance (3m and 3o). Interestingly, a heteroaro-
matic alkyne gave the desired β-keto phosphine oxide 3r in
65% yield. A polysubstituted alkyne was also a suitable sub-
strate, giving the corresponding product 3p in 81% yield.
The scope of the oxyphosphorylation was also evaluated
for various H-phosphine oxides. As seen from Scheme 2, in
addition to diphenylphosphine oxide, ethyl(phenyl)phos-
phine oxide, diethylphosphine oxide, dibutylphosphine ox-
ide, diisopropylphosphine oxide, bis(4-chlorophenyl)phos-
phine oxide, and di(4-tolyl)phosphine oxide were all suit-
able substrates for this reaction, generating the
corresponding products 3s–w in moderate to good yields.
The wide substitute scope of both the arylalkyne and phos-
phonate partners illustrates the potential of this reaction as
an efficient route to various β-keto phosphine oxides.
O
O
P
O
R2
R3
2
0 mol% LiOH, O2, 60 °C
R2
R1
H
P
R3
R1
H2O–DMF 1:8
1
2
3
O
O
P
O
O
P
O
O
O
O
P
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
P
F
Cl
Br
3
3
a, 85%
3b, 73%
3c, 77%
3d, 79%
O
O
O
O
O
O
P
O
O
Ph
Ph
Ph
Ph
Ph
Ph
P
P
P
Ph
Ph
H3CO
F3CO
O
e, 84%
3f, 88%
3g, 76%
3h, 83%
O
O
O
O
O
O
O
O
P
Ph
Ph
Ph
Ph
P
P
P
Ph
Ph
Ph
Ph
NC
F3C
Ph
3
i, 73%
3j, 76%
3k, 71%
3l, 80%
O
O
P
O
O
P
O
O
O
O
P
Ph
Ph
Ph
Ph
Ph
Ph
H3CO
P
Ph
Ph
OCH3
3
m, 74%
3n, 85%
3o, 75%
3p, 81%
O
O
P
O
O
P
O
O
P
O
O
P
O
Ph
Ph
O
Ph
Ph
O
Ph
S
3
q, 68%
3r, 65%
3s, 69%
3t, 52%
Cl
O
O
O
O
P
O
O
P
O
O
P
Cl
3
u, 43%
3v, 75%
3w, 79%
Scheme 2 Screening of the substrate scope. Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), LiOH (0.05 mmol), 1:8 H O–DMF (2.25 mL), O (bal-
2
2
loon), 60 °C, 3 h. Isolated yields are reported.
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W. Zhong et al.
Letter
Because previous reports on the mechanism of the oxy-
In conclusion, a new metal-free base-promoted oxy-
phosphorylation of alkynes with H-phosphonates was de-
veloped. These reactions proceeded smoothly without the
11b–d,19
phosphorylation of alkynes
have mainly proposed
free-radical processes, we performed several control exper-
iments to further identify the mechanism (Scheme 3). First,
the oxyphosphorylation reaction was carried out in the
presence of 2,2,6,6-tetramethyl-1-piperidin-1-oxyl (TEMPO),
a well-known radical scavenger. The model reaction was
completely inhibited, suggesting that a radical process
might be involved, in agreement with the previous re-
a) Evidence in support of a radical pathway:
O
O
P
Ph
Ph
O
LiOH, TEMPO
H
P
Ph
Ph
O2, 60 °C
1a
2a
3a
3a
16
ports. When the reaction was conducted under nitrogen,
none of the desired product 3a was obtained, indicating
that this protocol requires the presence of oxygen. Subse-
quently, the role of LiOH was investigated. As shown in
Scheme 3(c), product 3a was obtained in an extremely low
yield under base-free conditions, whereas the addition of
b) N2 atmosphere:
O
O
P
Ph
Ph
O
LiOH, N2
H
P
Ph
Ph
60 °C
1a
2a
c) Role of LiOH:
O
O
P
2
0 mol% of LiOH to this system markedly enhanced the
Ph
Ph
O
2
H O–DMF 1:8
yield of 3a. Finally, when the reaction was investigated un-
der anhydrous conditions, β-keto phosphine oxide 3a was
H
P
Ph
Ph
base-free , O2, 60 °C
20
1a
2a
3a, 8%
obtained in 66% yield [Scheme 3(d)]. When H O was add-
2
ed to the system, the yield of 3a markedly increased
O
O
P
Ph
Ph
O
[
Scheme 3(c)]. These results indicated that the oxygen of
H2O–DMF 1:8
H
P
Ph
the carbonyl group comes from molecular oxygen, that
LiOH, O2, 60 °C
Ph
LiOH promotes the oxyphosphorylation, and that H O plays
1a
2a
3a, 85%
2
a synergistic role in the formation of the various β-keto
phosphine oxides.
d) Role of H2O:
O
O
P
Ph
Ph
O
dry DMF
To further investigate the reaction pathway, isotope-la-
beling experiments were carried (Scheme 4). Initially, when
H
P
Ph
LiOH, O2, 60 °C
Ph
1
8
the model reaction was performed in the presence of O ,
1a
2a
3a, 66%
2
18
the O-labeled product 3a′ was obtained as the major
Scheme 3 Control experiments. (a) Radical-capture experiment with
TEMPO under the standard conditions. (b) The experiment was con-
ducted under nitrogen with the standard conditions. (c) The experiment
was conducted under base-free conditions and under the standard con-
ditions, respectively. (d) The experiment was conducted in the presence
of 4 Å MS and in the absence of water.
product. Amazingly, when the reaction was performed
18
in the presence of H O under the same conditions, the
2
1
8
O-isotope-labeled 3a′ was not detected by mass spec-
18
trometry, whereas O-labeled diphenylphosphinic acid
was obtained as a byproduct. These results provided addi-
tional confirmation that the oxygen of the carbonyl group
came from molecular oxygen and that H O plays a synergis-
a) 18O2 Isotope labeling experiment
2
tic role in the formation of the β-keto phosphine oxides,
rather than acting as a reactant in the system.
On the basis of these control experiments and previous
18O
16O
O
P
O
P
18
1a
Ph
Ph
Ph
Ph
reports, we tentatively proposed the plausible reaction
pathway for the oxyphosphorylation shown in Scheme 5.
First, the diphenylphosphine oxide cation radical 5 is
formed from 2a by a single-electron transfer with dioxygen,
with simultaneous generation of a superoxide radical an-
ion. Next, the proton from 5 is abstracted by the base to
give the diphenyl P-centered radical 6. Addition of this radi-
cal to ethynylbenzene in situ generates the C-centered radi-
cal 7. A superoxide radical anion then abstracts a proton
H2O–DMF 1:8
LiOH, 18O2, 60 °C
O
3
a', major, 60%
3a, minor, 18%
H
P
Ph
Ph
2a
b) H218O Isotope labeling experiment
O
O
P
from the H O-containing solvent to generate a hydroperox-
1a
H218O–DMF 1:8
Ph
Ph
O
P
O
2
Ph
Ph
Ph
Ph
P
yl radical. The H O might play a synergistic role in the for-
H18
H16
O
2
O
LiOH, O2, 60 °C
O
mation of this hydroperoxyl radical. Intermediate 7 then re-
acts with the hydroperoxyl radical to form hydroperoxide
3
a, 82%
H
P
Ph
byproducts
Ph
8
. Subsequent reduction of 8 by intermediate 5 generates
2a
the enol 10. Simultaneously, byproduct 9 is formed. Finally,
product 3a is obtained through a rapid tautomerization.
Scheme 4 Isotope-labeling experiment under the standard conditions
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Synlett
W. Zhong et al.
Letter
O2/H2O
O
P
5
6
base+H+
Ph
Ph
H
2
O
HO
Ph
a
O
O
8
P
O
OH
Ph
P
Ph
Ph
Ph
7
OH
P
OH
5
Ph
4
reduction
OH
P
O2
1
a
O
Ph
O2
Ph
9
radical addition
O
O
OH
O
base
OH
O
P
P
P
Ph
Ph
P
Ph
Ph
Ph
Ph
Ph
Ph
5
base+H+
6
10
3a
Scheme 5 Plausible mechanism for the oxyphosphorylation reaction
assistance of any transition metal through a radical process,
and they provided a wide range of β-keto phosphine oxides
in moderate to good yields. This protocol is metal-free, eco-
nomic, and operationally simple. The results showed that
inorganic base can promote the oxyphosphorylation and
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New Technology Extension Program of Chongqing Municipal Educa-
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Acknowledgment
We sincerely thank Chongqing Medical and Pharmaceutical College
and Chongqing Engineering Technology Research Center of Pharma-
ceutical Preparation for providing experimental conditions.
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https://doi.org/10.1055/s-0036-1591562.
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

F
Synlett
W. Zhong et al.
Letter
(
11) (a) Gutierrez, V.; Mascaró, E.; Alonso, F.; Moglie, Y.; Radivoy, G.
(17) Chen, X.; Chen, X.; Li, X.; Qu, C.; Qu, L.; Bi, W.; Sun, K.; Zhao, Y.
Tetrahedron 2017, 73, 2439.
(18) Gu, J.; Cai, C. Org. Biomol. Chem. 2017, 15, 4226.
(19) Bu, M.-j.; Lu, G.-p.; Cai, C. Catal. Sci. Technol. 2016, 6, 413.
(20) β-Keto Phosphonate Derivatives 3a–w; General Procedure
A round-bottomed flask was charged with the appropriate
alkyne 1 (0.25 mmol), H-phosphonate 2 (0.5 mmol), LiOH (0.05
RSC Adv. 2015, 5, 65739. (b) Zhou, M.; Chen, M.; Zhou, Y.; Yang,
K.; Su, J.; Du, J.; Song, Q. Org. Lett. 2015, 17, 1786. (c) Peng, P.;
Lu, Q.; Peng, L.; Liu, C.; Wang, G.; Lei, A. Chem. Commun. 2016,
5
2, 12338. (d) Zhong, W.-W.; Zhang, Q.; Li, M.-S.; Hu, D.-Y.;
Cheng, M.; Du, F.-T.; Ji, J.-X.; Wei, W. Synth. Commun. 2016, 46,
377.
1
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12) (a) Xie, L.; Yuan, R.; Wang, R.; Peng, Z.; Xiang, J.; He, W. Eur. J.
Org. Chem. 2014, 2014, 2668. (b) Xiang, J.; Yi, N.; Wang, R.; Lu, L.;
Zou, H.; Pan, Y.; He, W. Tetrahedron 2015, 71, 694.
mmol), DMF (2 mL), and H O (0.25 mL), and the mixture was
stirred at 60 °C for 3 h under O2 (balloon). When the reaction
2
was complete, it was quenched with aq NaHCO (20 mL) and the
3
(
13) Zhou, Y.; Zhou, M.; Chen, M.; Su, J.; Du, J.; Song, Q. RSC Adv.
mixture was extracted with EtOAc (3 × 10 mL). The combined
organic layers were washed with sat. brine (×2) then dried
2015, 5, 103977.
(
(
14) Zhou, M.; Zhou, Y.; Song, Q. Chem. Eur. J. 2015, 21, 10654.
15) (a) Li, L.; Huang, W.; Chen, L.; Dong, J.; Ma, X.; Peng, Y. Angew.
Chem. Int. Ed. 2017, 56, 10539. (b) Liang, W.; Zhang, Z.; Yi, D.; Fu,
Q.; Chen, S.; Yang, L.; Du, F.; Ji, J.; Wei, W. Chin. J. Chem. 2017, 35,
(MgSO ), filtered, and concentrated in vacuum. The crude
4
product was purified by chromatography [silica gel, CH Cl –
2
2
MeOH (30:1 to 50:1)].
2-(Diphenylphosphoryl)-1-phenylethanone (3a)
1
378. (c) Zhang, Z.; Yi, D.; Fu, Q.; Liang, W.; Chen, S.-Y.; Yang, L.;
Du, F.-T.; Ji, J.-X.; Wei, W. Tetrahedron Lett. 2017, 58, 2417.
d) Zhou, P.; Hu, B.; Li, L.; Rao, K.; Yang, J.; Yu, F. J. Org. Chem.
017, 82, 13268. (e) Ke, J.; Tang, Y.; Yi, H.; Li, Y.; Cheng, Y.; Liu,
White solid; yield: 68 mg (85%); mp 139.5–140.4 °C. 1H NMR
(400 MHz, CDCl ): δ = 4.14 (d, J = 15.4 Hz, 2 H), 7.38–7.53 (m, 9
3
13
(
2
H), 7.78–7.83 (m, 4 H), 7.96–7.98 (m, 2 H). C NMR (101 MHz,
CDCl ): δ = 193.03 (d, J = 5.7 Hz), 137.13, 133.83, 132.52 (d, J =
3
C.; Lei, A. Angew. Chem. Int. Ed. 2015, 54, 6604.
16) Fu, Q.; Yi, D.; Zhang, Z.; Liang, W.; Chen, S.; Yang, L.; Zhang, Q.;
Ji, J.; Wei, W. Org. Chem. Front. 2017, 4, 1385.
2.8 Hz), 131.67 (d, J = 103.9 Hz), 131.32 (d, J = 9.7 Hz), 129.45,
(
128.85 (d, J = 12.3 Hz), 128.75, 43.52 (d, J = 58.2 Hz). 31P NMR
+
(162 MHz, CDCl ): δ = 27.16. HRMS (ESI): m/z [M + Na] calcd
3
for C20H17NaO P : 343.0858; found: 343.0861.
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F