Copper-Catalyzed radical/radical Csp3-H/P-H cross-Coupling: α-Phosphorylation of aryl ketone O-Acetyloximes

Article abstract of DOI:10.1002/anie.201501287

The selective radical/radical cross-coupling of two different organic radicals is a great challenge due to the inherent activity of radicals. In this paper, a copper-catalyzed radical/radical C_sp³-H/P-H cross-coupling has been developed. It provides a radical/radical cross-coupling in a selective manner. This work offers a simple way toward β-ketophosphonates by oxidative coupling of aryl ketone o-acetyloximes with phosphine oxides using CuCl as catalyst and PCy₃ as ligand in dioxane under N₂ atmosphere at 130 C for 5 h, and yields ranging from 47% to 86%. The preliminary mechanistic studies by electron paramagnetic resonance (EPR) showed that, 1) the reduction of ketone o-acetyloximes generates iminium radicals, which could isomerize to α-sp³-carbon radical species; 2)phosphorus radicals were generated from the oxidation of phosphine oxides. Various aryl ketone o-acetyloximes and phosphine oxides were suitable for this transformation.

Full text of DOI:10.1002/anie.201501287

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501287
Cross-Coupling Reactions
German Edition:
DOI: 10.1002/ange.201501287
À
À
Copper-Catalyzed Radical/Radical Csp3 H/P H Cross-Coupling:
a-Phosphorylation of Aryl Ketone O-Acetyloximes**
Jie Ke, Yuliang Tang, Hong Yi, Yali Li, Yongde Cheng, Chao Liu, and Aiwen Lei*
À
Abstract: The selective radical/radical cross-coupling of two
different organic radicals is a great challenge due to the
inherent activity of radicals. In this paper, a copper-catalyzed
C P bond construction by oxidative cross-coupling between
À
À
C H and P H bonds. Although some progress has been made
in this emerging field,[5] there still remains a great challenge in
oxidative Csp3 H/P H cross-coupling, especially the direct
[6]
À
À
À
À
radical/radical Csp3 H/P H cross-coupling has been devel-
oped. It provides a radical/radical cross-coupling in a selective
manner. This work offers a simple way toward b-ketophos-
phonates by oxidative coupling of aryl ketone o-acetyloximes
with phosphine oxides using CuCl as catalyst and PCy3 as
ligand in dioxane under N2 atmosphere at 1308C for 5 h, and
yields ranging from 47% to 86%. The preliminary mechanistic
studies by electron paramagnetic resonance (EPR) showed
that, 1) the reduction of ketone o-acetyloximes generates
iminium radicals, which could isomerize to a-sp3-carbon
radical species; 2) phosphorus radicals were generated from
the oxidation of phosphine oxides. Various aryl ketone o-
acetyloximes and phosphine oxides were suitable for this
transformation.
À
À
ketone a-Csp3 H/P H coupling. This may be due to the
nucleophilic addition of phosphorus to the carbonyl com-
pound.[7] Recently, radical processes have been receiving
special attention in the first-row transition-metal-catalyzed
and photocatalytic oxidative cross-coupling.[8] It is known that
the phosphorus radical could also be generated from the
oxidation of H-phosphonate.[5b,c,d,9] We wondered whether
a radical/radical cross-coupling phosphorylation strategy in
À
À
oxidative Csp3 H/P H coupling could be developed to allow
the Csp3 P bond formation with more alternatives.
À
It was widely believed that the direct coupling of two
radicals would represent a powerful approach for bond
formations.[10] However, most radicals are so reactive that it
is hard to achieve the selective cross-coupling of two different
radicals, which limits the application of this protocol in
organic synthesis. Usually, the selective radical/radical cross-
coupling is based on the Ingold–Fischer “persistent radical
effect”. Only the radical coupling between a persistent radical
and a transient radical would lead to a selective bond
formation.[11] In general terms, an sp3-carbon-centered radical
without steric hindrance and conjugation effect can be
regarded as a transient radical due to the short half-life.
Although a phosphorus radical generated from diaryl phos-
phine oxide exhibits large steric hindrance, it may be
considered as a persistent radical.[11a] If methods could be
developed to generate a-ketone carbon radicals and phos-
À
C
P bond formation is of great importance in organic
synthesis because phosphorus-containing compounds have
wide applications in organic chemistry,[1] medicinal chemis-
try,[2] and material chemistry.[3] Along with the development
of transition-metal-catalyzed oxidative cross-coupling reac-
tions,[4] more and more attention was paid to the studies of
[*] J. Ke, Y. Tang, H. Yi, Y. Cheng, C. Liu, Prof. A. Lei
College of Chemistry and Molecular Sciences
The Institute for Advanced Studies (IAS), Wuhan University
Wuhan, Hubei 430072 (P.R. China)
E-mail: aiwenlei@whu.edu.cn
À
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
phorus radicals from a-Csp3 H and H-phosphonate in the
À
same system, Csp3 P bond formation might be realized
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
730000 Lanzhou (P.R. China)
through selective radical/radical cross-coupling.
Reactions that use an internal oxidant are redox neutral,
thus, excess external oxidants could be avoided. Ketone
o-acetyloxime is a kind of internal oxidant, which can be
easily prepared by the reaction of ketone, hydroxylamine
hydrochloride, and acetic anhydride under mild conditions.[12]
Therefore, it has been widely used for the development of
Y. Li
Key Laboratory for Organic Electronics and Information Display and
Institute of Advanced Materials, Nanjing University of Posts and
Telecommunications
Nanjing, 210023 (P.R. China)
À
transition-metal-catalyzed a-Csp3 H bond activation reac-
[**] This work was supported by the 973 Program (2012CB725302,
2011CB808600), the National Natural Science Foundation of China
(21390400, 21272180, and 21302148), the Research Fund for the
Doctoral Program of Higher Education of China (20120141130002),
the Program for Changjiang Scholars and Innovative Research Team
in University (IRT1030), and the Ministry of Science and Technology
of China (2012YQ120060). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also acknowl-
edged. Particular thanks also go Prof. Longmin Wu for his guidance
in EPR experiments.
tions.[13] We proposed that the reduction of an aryl ketone
o-acetyloxime by CuI may afford an iminium radical inter-
mediate which could isomerize to an a-carbon radical species
(transient radical).[14] On the other hand, oxidation of
phosphine oxides by CuII may generate the phosphorus
radical (persistent radical). Subsequently, selective cross-
coupling of this two radicals can lead to the formation of b-
ketophosphonates (Schemes 1 and 3), which are valuable
commodity chemicals in organic chemistry, especially for the
construction of a,b-unsaturated carbonyl compounds through
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501287.
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Scheme 1. Proposed strategy for the cross-coupling of aryl ketone
o-acetyloximes with phosphine oxides.
the well-known Horner–Wadsworth–Emmons (HWE) reac-
tion.[1a,b]
Our initial efforts focused on the reaction of acetophe-
none oxime acetate 1a with diphenylphosphine oxide 2a
using CuCl as the catalyst precursor and PCy3 as the ligand.
To our delight, when the mixture in dioxane was heated at
1308C for 5 h, the desired product 4aa was detected by LC-
MS. It was hydrolyzed by diluted hydrochloric acid (HCl aq.)
to afford b-ketophosphonate 3aa in 48% yield (Scheme 2
Figure 1. The electron paramagnetic resonance (EPR) spectra (X band,
9.4 GHz, room temperature) of the reaction mixture of 1a, CuCl, and
PCy3 in dioxane at 1308C.
radical A (g = 2.0059, aN1 = 13.68 G, aH = 13.68 G, aN2
2.84 G). These results illustrated that aryl ketone o-acetyl-
oxime can oxidize CuI to CuII species, while it is reduced to an
iminium radical.
Further EPR experiments were performed to detect the
phosphorus radical intermediate with the addition of free
radical spin trapping agent MNP (2-methyl-2-nitrosopro-
pane). To our delight, when MNP was added to the
stoichiometric reaction of 1a, CuCl, PCy3, Ac2O, and 2a, an
EPR signal was identified (Figure 2). Data analysis suggest
that phosphorus radical generated and quickly trapped by
MNP to form the relatively stable radical B (aN = 10.54 G,
aP = 11.76 G).[15]
=
Scheme 2. Copper-catalyzed oxidative cross-coupling of 1a with 2a.
Conditions: 1) 1a (0.5 mmol), 2a (0.6 mmol), CuCl (0.1 mmol), PCy3
(0.1 mmol), dioxane (2.0 mL), 1308C, 5 h, under N2. 2) 1a (0.5 mmol),
2a (0.6 mmol), CuCl (0.1 mmol), PCy3 (0.1 mmol), Ac2O (0.5 mmol),
dioxane (2.0 mL), 1308C, 5 h, under N2.
(1)). As we know, most of the radical/radical cross-coupling
reactions are reversible. Converting 4aa to the more stable
compound may shift the equilibrium toward the final product.
Therefore, acetic anhydride (Ac2O) was chosen as an
additive. Indeed, in the presence of Ac2O, the yield of 3aa
increased to 74%. Without hydrolysis by aqueous HCl,
a diphenylphosphoryl enamine product 5aa was isolated in
71% yield, which may result from the reaction of 4aa with
Ac2O (Scheme 2 (2)). Finally, a control reaction demon-
strated that only 16% yield of the final product 3aa was
obtained in the absence of copper catalyst (for more details
see the Supporting Information (SI), Table S1).
On the basis of the above results and previous studies, we
proposed a radical/radical cross-coupling pathway for this
À
À
To confirm our hypothesis for this oxidative Csp3 H/P H
coupling reaction undergoing a radical/radical cross-coupling
process, a series of mechanistic studies by electron para-
magnetic resonance (EPR) spectroscopy was performed.
Firstly, the valence state of the copper species was determined
by EPR. An EPR signal of a CuII species was observed in the
stoichiometric reaction of 1a, CuCl, and PCy3 (Figure 1a).
When the free-radical spin-trapping agent DMPO (5,5-
dimethyl-1-pyrroline N-oxide) was added to the reaction,
a signal of the trapping radical was observed (Figure 1a, in the
box). Enlargement of this signal is shown in Figure 1b. Data
analysis suggests that a nitrogen radical is generated and
quickly trapped by DMPO to form the relatively stable
Figure 2. The electron paramagnetic resonance (EPR) spectra (X band,
9.4 GHz, room temperature) of the reaction mixture of 1a, CuCl, PCy3,
Ac2O, and 2a in dioxane at 1308C.
2
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Scheme 3. Putative mechanism.
copper-catalyzed
oxidative phosphorylation reaction
(Scheme 3). Firstly, reduction of 1a by CuI affords iminium
radical I, which may quickly isomerize to a-carbon radical II.
On the other hand, oxidation of diphenylphosphine oxide 2a
by CuII generates the phosphorus radical III. Next, selective
cross-coupling of the radical species II and III constructed
Scheme 4. Substrate scope for the copper-catalyzed oxidative phos-
À
a new C P bond to afford 4aa. This radical/radical cross-
phorylation of 2a with aryl ketone O-acetyloximes 1. Conditions:
1 (0.5 mmol), 2a (0.6 mmol), CuCl (0.1 mmol), PCy3 (0.1 mmol), Ac2O
(0.5 mmol), dioxane (2.0 mL), 1308C, 5 h, under N2. Yields are of
isolated products.
coupling may be a reversible reaction. A relatively stable
compound 5aa was generated by a substitution reaction of
4aa with Ac2O, which shifted the equilibrium toward the
desired reaction product. Final product 3aa was obtained by
hydrolysis of 5aa.
With these insights into the mechanism and the optimized
reaction conditions, we next explored the substrate scope of
this copper-catalyzed oxidative phosphorylation reaction.
Firstly, various aryl ketone o-acetyloximes 1 were coupled
with diphenylphosphine oxide 2a under the standard con-
ditions (Scheme 4). Aryl ketone o-acetyloximes with elec-
tron-rich substituents (p-Me, p-OMe) or electron-poor sub-
stituent (p-CF3), as well as the ortho-, meta-, and para-
substituted groups all gave the desired products in satisfactory
yields (3ba–3ca, 3 fa–3ha). Halogen substituents such as
bromine and chlorine were well tolerated, affording the
corresponding products in 63% and 73% yield, respectively
(3da–3ea). Naphthalen-2-yl ethanone oxime acetates is also
a suitable substrate for this reaction (3ia). It is noteworthy
that propiophenone, 1,2-diphenylethanone, and 3,4-dihydro-
naphthalen-1(2H)-one oxime acetates also gave good yields
of the desired b-ketophosphonates (3ja–3la).
We further examined the scope of phosphine oxides 2
using 1b as the coupling partner and the results are listed in
Scheme 5. Both electron-donating and electron-withdrawing
substituents on the aryl groups were well tolerated in this
reaction (3bb–3bd) and the o-methyl substituted substrate
afforded a higher yield of 75% (3be). In addition, substrates
bearing multiple substituents also worked well (3bf, 3bg) and
di-2-naphthylphosphine oxide could also deliver the desired
product 3bh with a good yield of 86%. Moreover, diethyl
phosphonate and ethyl phenylphosphinate could also afford
the corresponding b-ketophosphonates in moderate yields
(3bi, 3bj).
Scheme 5. Substrate scope for the copper-catalyzed oxidative phos-
phorylation of phosphine oxides 2 with 1b. Conditions: 1b (0.5 mmol),
2 (0.6 mmol), CuCl (0.1 mmol), PCy3 (0.1 mmol), Ac2O (0.5 mmol),
dioxane (2.0 mL), 1308C, 5 h, under N2. Yields are of isolated
products.
radical species (transient radical) and a phosphorus radical
species (persistent radical) were generated in the same system
by using an internal oxidant. The cross-coupling of the two
radical species is selective based on the “persistent radical
effect”. Various aryl ketone o-acetyloximes and phosphine
oxides were suitable for this transformation. The application
of this powerful strategy to other radical/radical cross-
coupling reactions with various persistent radicals and further
mechanistic investigations are underway in our laboratory.
In conclusion, we have disclosed a copper-catalyzed
radical/radical cross-coupling reaction. This transformation
À
offered a new protocol for Csp3 P bond formation by direct
À
À
oxidative Csp3 H/P H coupling. During the reaction, an a-Csp3
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Experimental Section
General procedure: a mixture of acetophenone oxime acetate 1a
(0.5 mmol), diphenylphosphine oxide 2a (0.6 mmol), CuCl
(0.1 mmol, 20 mol%), PCy3 (0.1 mmol, 20 mol%), and Ac2O
(0.5 mmol) in dioxane (2 mL) was stirred under N2 at 1308C for 5 h.
After completion of the reaction, as indicated by TCL, it was
quenched by diluted hydrochloride (4 mL, 2m). The mixture was
extracted with diethyl ether and the organic phase was washed with
aqueous K2CO3 and brine, and dried over Na2SO4. The pure product
was obtained by flash column chromatography on silica gel (ethyl
acetate). The desired product was isolated as a white solid in 74%
1
yield. H NMR (400 MHz, CDCl3): d = 8.02–7.94 (m, 2H), 7.86–7.75
(m, 4H), 7.56–7.36 (m, 9H), 4.15 ppm (d, J = 15.2 Hz, 2H); 13C NMR
(101 MHz, CDCl3): d = 193.0 (d, J = 5.7 Hz), 137.1, 133.8, 132.4 (d, J =
2.7 Hz), 132.1 (d, J = 103.7 Hz), 131.3 (d, J = 9.9 Hz), 129.4, 128.9,
128.8, 128.7, 43.5 ppm (d, J = 58.2 Hz); 31P NMR (162 MHz, CDCl3):
d = 27.18 ppm.
3
À
Keywords: C(sp ) P bonds · copper catalysis ·
oxidative coupling · radical/radical cross-coupling ·
b-ketophosphonates
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Received: February 9, 2015
Published online: && &&, &&&&
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Cross-Coupling Reactions
A copper-catalyzed radical/radical cross-
À
coupling reaction enables Csp3 P bond
À
À
J. Ke, Y. Tang, H. Yi, Y. Li, Y. Cheng, C. Liu,
formation by direct oxidative Csp3 H/P H
A. Lei*
&&&& — &&&&
coupling. During the reaction, an a-Csp3
radical species (transient radical) and
a phosphorus radical species (persistent
radical) were generated in the same
system by using an internal oxidant. The
cross-coupling of the two radical species
is selective based on the “persistent
radical effect”.
À
Copper-Catalyzed Radical/Radical Csp3
À
H/P H Cross-Coupling: a-
Phosphorylation of Aryl Ketone O-
Acetyloximes
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!