β-Ketophosphonate formation via aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonates

Article abstract of DOI:10.1021/acs.orglett.5b00574

A synergistic Cu/Fe-catalyzed aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonate is disclosed. The useful β-ketophosphonate products were obtained in good yields under oxygen atmosphere in a novel way. This reaction exhibits a wide substrate scope, and the mechanistic experiments indicate that a radical mechanism forms both C-P and C=O bonds simultaneously. This mechanism contrasts existing aerobic difunctionalization of alkynes.

Full text of DOI:10.1021/acs.orglett.5b00574

Letter
pubs.acs.org/OrgLett
β‑Ketophosphonate Formation via Aerobic Oxyphosphorylation
of Alkynes or Alkynyl Carboxylic Acids with H‑Phosphonates
Mingxin Zhou,†,∥ Ming Chen,‡,∥ Yao Zhou,§ Kai Yang,† Jihu Su,‡ Jiangfeng Du,‡ and Qiuling Song*,†
†Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei Blvd,
Xiamen, Fujian 361021, P. R. China
‡Hefei National Laboratory for Physical Sciences at Microscale, Department of Modern Physics, University of Science and
Technology of China, Hefei, Anhui 230026, P. R. China
§College of Materials Science & Engineering, Huaqiao University, 668 Jimei Blvd, Xiamen, Fujian 361021, P. R. China
S
* Supporting Information
ABSTRACT: A synergistic Cu/Fe-catalyzed aerobic oxy-
phosphorylation of alkynes or alkynyl carboxylic acids with
H-phosphonate is disclosed. The useful β-ketophosphonate
products were obtained in good yields under oxygen atmo-
sphere in a novel way. This reaction exhibits a wide substrate
scope, and the mechanistic experiments indicate that a radical
mechanism forms both C−P and CO bonds simultaneously.
This mechanism contrasts existing aerobic difunctionalization of alkynes.
Scheme 1. Transition-Metal-Catalyzed Reaction between
Alkynes or Alkynyl Carboxylic Acids and H-Phosphonates
ecause carbonyl-containing organic compounds play a
Btremendously important role in synthetic chemistry, efficient
construction of carbonyl-containing compounds remains a long-
standing goal in organic chemistry. Dioxygen is an ideal oxidant to
access these compounds owing to its abundance, inexpensiveness,
and environmentally benign feature.1,2 Terminal alkynes have also
been extensively used in numerous transition-metal-catalyzed
transformations during the past decade. In spite of their ubiquity
in these processes, the C−C triple bond generally remains intact
during aerobic transformations.3−7 For these reasons, creating
CO bonds from C−C triple bonds using dioxygen as both the
oxidant and oxygen source has motivated organic chemists and
becomes a promising field in modern syntheticchemistry. Despite
these efforts, there are only a few examples reported to date.8−10
The limited nature of these examples underscore that the
development of efficient and practical methods that produce
carbonyl compounds via difunctionalization of alkynes under
dioxygen atmosphere remain an urgent and a tremendous
challenge for modern synthetic chemistry.
β-Ketophosphonates are an extremely useful class of carbonyl-
and phosphorus-containing organic compounds. In addition to
possessing interesting bioactivities, they are key intermediates
in the well-known Horner−Wadsworth−Emmons (HWE) re-
action to construct α,β-unsaturated carbonyl compounds11−13
as well as versatile precursors for various synthetically useful
transformations.14−18 Great efforts have been devoted to
constructing β-ketophosphonate scaffolds, including the acyla-
tion of alkylphosphonates under basic conditions,19,20 the
hydration of alkynylphosphonates,21 Arbuzov reaction,22 or the
oxyphosphorylation of alkenes.23 Because of the importance of
phosphorus-containing compounds in organic synthesis, biology,
and material sciences,24−26 developing transition-metal-
catalyzed cross coupling between terminal alkynes and
H-phosphonates has been pursued. Despite these advances,
in most cases only alkenylphosphonates (Scheme 1a)27 or
alkynylphosphonates (Scheme 1b)5 can be formed. Using
alkynyl carboxylic acids as a common practical surrogate for
terminal alkynes has attracted significant attention recently and is
widely used in transition-metal-catalyzed coupling reactions to
generate new C−C, C−N, C−S, or C−P bonds.28−36 For the
C−P bond formation, however, once again only alkenylphosph-
onates (Scheme 1a)34 or alkynylphosphonates (Scheme 1b)29,35
were obtained. During the preparation and submission of this
manuscript, Zhao and co-workers reported an elegant synthesis
of β-ketophosphonates directly from alkynes and dialkyl
H-phosphonates in the presence of AgNO3/CuSO4 and
K2S2O8 (Scheme 1c).37 Herein, we disclose a Cu/Fe-co-
catalyzed reaction that constructs β-ketophosphonates from
alkynes or propiolate acids and H-phosphonates using O2 as the
Received: February 25, 2015
© XXXX American Chemical Society
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terminal oxidant. Compared to Zhao’s method, our reaction
employs a more environmentally benign catalytic system (Fe/Cu)
with simple operation and exhibits a wider substrate scope and
both terminal alkynes and alkynyl carboxylic acids feasible under
the standard conditions. Simultaneously, molecular oxygen itself
servesas theonlyterminal oxidant and enablesthis transformation.
Our mechanistic studies suggest that oxygen in the carbonyl group
of β-ketophosphonate originates from both molecular oxygen and
water, which is in contrast to precedent difunctionalization of
alkynes.
Scheme 2. Oxophosphorylation of Terminal Alkynes with
H-Phosphonates under Dioxygen Atmosphere
a
To determine if the oxyphosphorylation of alkynes was
feasible, we commenced our study with phenylacetylene (1a)
and H-diethyl phosphonate (2a) as a model reaction (Table 1).
a
Table 1. Optimization of the Reaction Parameters
a
Reaction conditions: phenylacetylene 1a (0.5 mmol), H-phosphonate
2a (2.0 mmol), CuOTf (5 mol %), FeCl3 (10 mol %) in DMSO
(0.5 M), Et3N (0.5 mmol), O2 (balloon), 24 h, all isolated yields.
Using the optimal conditions, the substrate scope was
investigated (Scheme 2). To our delight, our oxyphosphorylation
transforms a range of alkynes and H-phosphonates into
β-ketophosphonates. Arylacetylenes possessing either electron-
donating or electron-withdrawing substituents were well
tolerated in this transformation, affording the desired products
in moderate to good yields (3ba−ra in Scheme 2). In addition
to alkyl and alkoxy groups, halo- and even cyano-substituted
arylacetylenes were compatible with the standard conditions.
The latter groups can be used to further elaborate the
β-ketophosphonate product. Polycyclic and heteroaromatic
substituted acetylenes could also be transformed into the
corresponding β-ketophosphonates in good to moderate yields.
Our oxyphosphorylation reaction tolerates both aliphatic
acetylene and internal alkyne substrates (3ua−va), albeit with
diminished yields. The constraint of our transformation was
revealed in diphenylacetylene (1w), which produced no product.
The scope of our oxyphosphorylation was also surveyed by
varying the identity of the H-phosphonate. In addition to diethyl
phosphonate (2a), we found that dimethyl (2b), diisopropyl
(2c), di-n-butyl (2d), and dibenzyl phosphates (2e) could be
used in this oxidative transformation to generate the cor-
responding β-ketophosphonates 3aa−ae in good yields (Scheme 2).
Most remarkably, both diphenylphosphine oxide (2f) and ethyl
phenylphosphinate (2g) were applicable under the standard
conditions as well and produced the desired products 3af and 3ag in
reasonable yields. The wide scope of both the acetylene and phos-
phonate partners illustrates the potential of our reaction to efficiently
assemble a broad range of functionalized β-ketophosphonates.
Because alkynyl carboxylic acids have no unpleasant smell, are
solids, and are easy to handle and store, they have attracted
attention in the synthetic community in recent years as terminal
acetylene equivalents. To determine if our transformation would
be applicable to this class of substrates, phenylpropiolic acid
was submitted to the reaction conditions, and to our delight,
β-ketophosphonate 3aa was obtained in 72% yield upon isolation.
Further screening suggests that amount of H-phosphonate could
be reduced to 3 equivalents and the reaction temperature and
a
Reaction conditions: phenylacetylene 1a (0.5 mmol), H-diethyl
phosphonate 2a (2.0 mmol), Cu catalyst and Fe co-catalyst in DMSO
(0.5 M), Et3N (0.5 mmol), O2 (balloon), 24 h. GC yield. Isolated
yield in parentheses. The reaction was conducted under air. The
reaction was performed under N2 atmosphere.
b
c
d
e
First, we examined if a metal-free oxidative process was possible
by using only a base following the report by Lei and co-workers.9
Unfortunately, no desired products were ever isolated even after
extensive screening (for details, see the Supporting Information
(SI)). A series of transition-metal salts were then screened, and
we were delighted to find that when 10 mol % of CuOTf was
used together with 5 mol % of FeCl3, the desired product
β-ketophosphonate was formed in 28% isolated yield (Table 1,
entry 1). Among the other iron salts screened, we found that only
FeBr3 and FeCl3 produced product. Changing the oxidation state
or the counterion of the iron salt resulted in only trace amounts
of the β-ketophosphonate (Table 1, entries 1−3, and Table S2,
SI). Solvent and base screenings (Table S3, SI) indicated that
DMSO and triethylamine are the best choices, while other
solvents and bases were all less effective in this transformation.
Catalyst and co-catalyst loading screenings suggested that 5 mol
% of CuOTf and 10 mol % of FeCl3 gave the best yield of desired
product (Table 1, entry 8). When temperature was increased
to 70 °C, 76% (GC yield) of desired product 3aa was obtained
with 70% isolated yield. Lowering the temperature or changing
the identity of the copper salt had a detrimental effect on the
reaction conversion (Table S2, entries 13−23). Control
experiments revealed that CuOTf, FeCl3, and Et3N are required
for our oxyphosphorylation: very little of 3aa was obtained in
their absence (Table 1, entries 4 and 5). Further, when O2 was
replaced by air or N2, only trace amounts of 3aa were formed
(Table 1, entries 10 and 11) to suggest that O2 is also an essential
prerequisite for this reaction.
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time could be reduced to 60 °C and 8 h (Table S6, entry 9, SI).
We interpret these results to imply that alkynyl carboxylic acids are
more reactive than alkynes in our oxyphosphorylation reaction.
Various alkynyl carboxylic acids and H-phosphonates were
investigated to explore the scope of the reaction (Scheme 3).
Scheme 3. Oxophosphorylation of Alkynyl Carboxylic Acids
a
with H-Phosphonates under Dioxygen Atmosphere
Subsequently, the pivotal nature of dioxygen to our trans-
formation was investigated (eq 4). We anticipated that using
18O2 might enable us to gain insight into the origin of the oxygen
of carbonyl group in the β-ketophosphonate. Irrespective of
whether phenylacetylene or phenylpropiolic acid was used, this
isotope-labeling experiment produced the β-ketophosphonate 3aa
where ca. 84% of the 18O-label was incorporated into the carbonyl.
To determine if incorporation of the label occurred from
exchange with water, unlabeled β-ketophosphonate 3aa was
exposed to 18O-labeled water (H218O), and 48% of 18O-3aa
product was detected in the reaction mixture (eq 5), which was
consistent to the previous report.23 Further, when the reaction
was conducted in the presence of 5.0 equiv of H218O under O2,
63% of 18O-3aa and 37% of unlabeled products were detected
with alkyne 1a. In contrast, when alkynyl carboxylic acid 4a was
exposed to 5 equiv of 18O-labeled water, only 10% of the label
was incorporated into 3aa (eq 6, HRMS spectra in the SI).
a
Reaction conditions: phenylacetylene 1a (0.5 mmol), H-phosphonate
2a (1.5 mmol), CuOTf (5 mol %), FeCl3 (10 mol %) in DMSO
(0.5 M), Et3N (0.5 mmol), O2 (balloon), 8 h, all isolated yields.
The scope of our transformation mirrored our previous results:
a range of electron-releasing and electron-withdrawing aryl- and
heteroaryl substituents were tolerated on the propiolic acid
component. Similarly, the identity of the H-phosphonate could
be changed without attenuating the yield of the oxyphosphoryla-
tion reaction. Once again, the transformation underscored the
fact that both diphenylphosphine oxide (2f) and ethyl phenyl-
phosphinate (2g) were well tolerable and the desired products
3af and 3ag were obtained in good yields.
When 5 equiv of unlabeled water was added to the reaction
mixture in the presence of 18O2, the amount of the label in the
β-ketophosphonate product was reduced (eq 7).
In order to elucidate the reaction mechanism, radical trapping
experiments were performed (eq 1). First, 2,2,6,6-tetramethyl-1-
In order to better understand the mechanism, EPR (electron
paramagnetic resonance) experiments were conducted with
phenylacetylene (1a) and H-phosphonate 2a under various
reaction conditions with the addition of free-radical spin-trapping
agent DMPO (5,5-dimethyl-1-pyrroline N-oxide) (see the SI).
These experiments unambiguously show that FeCl3 is vital for the
formation of phosphonyl radical39 (Figure S15b-d) and phenyl-
acetylene (1a) is both the substrate and trap for this radical in the
subsequent reaction under O2 atmosphere (Figure S15d). Peroxide
species was always detected along with sulfinyl radical but with a
rather weak EPR signal intensity. Further EPR experiments
revealed that the formation of these two radicals was enhanced
by CuOTf (Figures S6−S8,S11, SI) irrespective of whether an
O2 atmosphere was present. In sum, these experiments suggest
that a portion of peroxide species was generated from water (Figure
S11, SI), which coincides with the 18O-labeled experiments.
On the basis of these results and previous reports,23 a tenta-
tive mechanism for our oxyphosphorylation was constructed
piperidinyloxy (TEMPO) was added along with phenylacetylene
or phenylpropiolic acid and H-phosphonate under the standard
conditions, and inhibition of the reaction was observed. When
BHT was employed as the radical scavenger, β-ketophosphonate
was produced in 20% yield in GC (eq 1). We interpret these
results as evidence that our transformation occurs through a
radical mechanism.
Next, diethyl (phenylethynyl)phosphonate (5) and
(E)-diethyl styrylphosphonate (6) were prepared according to
the literature,5,38 and both of them were exposed to the standard
conditions. Not surprisingly, no desired β-ketophosphonate 3aa
was obtained (eqs 2 and 3). Thus, coupling with H-phosphonate
followed by a Wacker oxidation process was excluded from our
transformation as a plausible mechanism.
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Scheme 4. Plausible Reaction Mechanism of
Oxyphosphorylation
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AUTHOR INFORMATION
Corresponding Author
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*Fax: 86-592-6162990. E-mail: qsong@hqu.edu.cn.
Author Contributions
∥M.Z. and M.C. contributed equally to this work.
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Science
Foundation of China (21202049), the Recruitment Program of
Global Experts (1000 Talents Plan) and Fujian Hundred Talents
Plan, National Key Basic Research Program of China (Grant No.
2013CB921800), the “Strategic Priority Research Program (B)”
of the CAS (Grant No. XDB01030400), and the Program for
Innovative Research Team of Huaqiao University.
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Org. Lett. XXXX, XXX, XXX−XXX