Silver-Catalyzed Oxidative C(sp3)?P Bond Formation through C?C and P?H Bond Cleavage

Article abstract of DOI:10.1002/anie.201704910

The silver-catalyzed oxidative C(sp³)?H/P?H cross-coupling of 1,3-dicarbonyl compounds with H-phosphonates, followed by a chemo- and regioselective C(sp³)?C(CO) bond-cleavage step, provided heavily functionalized β-ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional-group tolerance, and exclusive selectivity.

Full text of DOI:10.1002/anie.201704910

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Accepted Article
Title: Silver-catalyzed Oxidative C(sp3)-P Bond Formation via C-C and
P-H Bond Cleavages
Authors: Lili Li, Wenbin Huang, Lijin Chen, Jiaxing Dong, Xuebing Ma,
and Yungui Peng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704910
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Silver-catalyzed Oxidative C(sp3)–P Bond Formation via C–C and
P–H Bond Cleavages
Lili Li, Wenbin Huang, Lijin Chen, Jiaxing Dong*, Xuebing Ma* and Yungui Peng*
Abstract: A new reaction has been developed for the silver-
catalyzed oxidative C(sp3)–H/P–H cross-coupling of 1,3-dicabonyl
compounds with H-phosphonates, followed by a chemo- and
regioselective C(sp3)–C(CO) bond cleavage step to provide heavily
functionalized β-ketophosphonates. This novel method exhibits a
wide substrate scope, high functional group tolerance and exclusive
selectivity, as well as being a readily available reaction system.
C
arbon-carbon bonds are the most ubiquitous and
fundamental chemical bonds in organic compounds. Compared
with transition-metal-catalyzed carbon-carbon bond forming
reactions, reactions for the selective cleavage of C–C bonds,
especially single bonds, and subsequent formation of new C–X
bonds, remains a major challenge to organic synthesis. The
difficulties associated with this area have been attributed to two
major hurdles, namely (1) the chemo- and regioselective
cleavage of a specific C–C single bond in a compound
containing many similar chemical bonds; and (2) the
[1]
thermodynamic stability of the C–C σ-bond.
1,3-Dicarbonyl
Scheme 1. Representative C–X bond reconstructions via C–C bond cleavage
of 1,3-dicarbonyl compounds.
moieties can be found in a wide range of natural products,
pharmaceuticals and functional materials, and can also be used
as versatile building blocks in organic synthesis. Recently,
several elegant examples of transition-metal-catalyzed C–C
bond cleavage and C–X bond reconstruction of 1,3-dicarbonyl
compounds have been reported.[2] In 2010, Lei and co-workers
reported their seminal work on the formation of α-aryl ketones
via the copper-catalyzed cleavage of the C–C σ-bond of a 1,3-
diketone, followed by the formation of a new C–C bond with an
aryl halide (Scheme1, a).[2a] More recently, Jiao’s group
uncovered a copper-catalyzed oxidative esterification reaction,
which underwent sequential C–C bond breaking and C–O bond
reconstruction reactions (Scheme1, b).[2d] Almost simultaneously,
Bolm’s group reported a copper-catalyzed C–S bond forming
reaction, which proceeded via C–C and S–S σ-bond cleavages
involving 1,3-dicarbonyl and disulfide substrates (Scheme1, c).[2e]
These pioneering reports have demonstrated that the formation
of C–X bonds via the transition-metal-catalyzed selective
cleavage of the C–C bond of a 1,3-dicarbonyl compound
represents a powerful method for target-oriented synthesis of
organic molecules. However, despite considerable progress, this
area of research is still in its infancy. Reports describing the
routine use of this strategy are seldom, and the choice of
transition-metal catalyst is limited to copper salts.
On the other hand, silver catalysts have attracted more and
more attentions due to their excellent reactivity and impressive
selectivity in a variety of organic transformations during the past
[3]
few decades.
Particularly, silver-triggered radical-type
reactions, including oxidation, addition, coupling and cyclization
have sprung up rapidly, and become the cutting-edge research
area in organic chemistry in recent years. [4] However, to the best
of our knowledge, no example has been described in literature
of silver-catalyzed carbon–heteroatom bond formation via C–C
bond activation reaction. Herein, we wish to disclose the
development of a novel silver-catalyzed tandem transformation
involving an oxidative C(sp3)–P bond formation,[5] followed by
the selective C(sp3)–C(CO) bond cleavage of a 1,3-dicarbonyl
compound with a H-phosphonate. This reaction provided facile
access to
a
series of
heavily
functionalized
β-
ketophosphonates,[6] which are omnipresent in a wide range of
biologically active molecules, natural products and functional
materials. Compounds of this type are also widely employed as
synthetic intermediates and metal ligands [7] (Scheme1, d).
Our study commenced with the reaction of diethyl
phosphonate (1a) with acetylacetone (2a) [ Eq (1); also see the
Supporting Information, Table S1). After judicious evaluation of
the reaction parameters, we found that the desired product 3aa
could be obtained in high yield (76%) when 20 mol% AgOAc
was used as a catalyst in combination with 2.0 equivalents of
K2S2O8 as an oxidant in a 1:1 (v/v) mixture of DMF and H2O at
85 °C over a period of 24 h (Table S1, entry 1). A series of
control experiments demonstrated that silver catalysts were
indispensable to the success of this transformation (Table S1,
entries 2 and 16). Several other silver catalysts were also tested,
including AgNO3 and Ag2SO4, but both performed poorly (Table
S1, entries 3 and 4), whereas palladium and copper (I) salts
[]
L. Li, W. Huang, L. Chen, Prof. Dr. J. Dong, Prof. Dr. X. Ma and
Prof. Dr. Y. Peng
School of Chemistry and Chemical Engineering
Southwest University
2 Tiansheng Road, Beibei, Chongqing 400715 (PR China)
E-mail: jiaxingdong@swu.edu.cn;
zcj123@swu.edu.cn;
pyg@swu.edu.cn.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
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C(sp3)–H phosphonation products. In contrast, previously
reported phosphonation reactions usually occur at the aromatic
[9]
ring in the presence of silver
catalysts. [10]
or some other transition-metal
failed to afford any of the desired product (Table S1, entry 2).
The choice of oxidant was also found to be critical to the
outcome of this transformation (Table S1, entries 5, 6 and 17).
For example, some of the most commonly used oxidants in
transition-metal-catalyzed reactions, such as Cu(OAc)2, tert-
butyl peroxide (DTBP), phenyliodine diacetate (PIDA) and oxone,
were determined to be completely ineffective for this reaction
(Table S1, entry 5). Interestingly, the use of 2.0 equivalents of
AgOAc as a dual catalyst and terminal oxidant also afforded the
desired product 3aa in a comparable yield (72%, Table S1, entry
7). It is noteworthy that this reaction also proceeded smoothly in
water (Table S1, entry 8), while other mixed-solvents diminished
the reaction efficiency to some extent (Table S1, entries 9-11).
Increasing or decreasing the temperature of the reaction led to a
decrease in the yield (Table S1, entries 12 and 13). Similar small
reductions in the yield were also observed when the reaction
was conducted under an atmosphere of air or oxygen (Table S1,
entries 14 and 15). Decreasing the catalyst loading to 10 mol%
resulted in a slight loss in yield (68%, Table S1, entry 18).
With the optimized conditions in hand, we proceeded to
investigate the scope of the 1,3-dicarbnyl compounds (Scheme
2). Pleasingly, our newly developed catalytic system facilitated
the phosphonation/C–C bond activation reactions of a wide
range of 1,3-dicarbonyl compounds with diethyl phosphonate
(1a), provided facile access to a series of β-ketophosphonates
3aa–3aaa in moderate to good yields. Importantly, this
transformation was also amenable to β-ketoamides and β-
ketoesters, where the C–C bond cleavage occurred exclusively
at the amide or ester side of the substrate to afford the desired
product 3aa in good yield (Scheme 2, 3aa, for β-ketoesters, R3 =
OEt or OBn; for β-ketoamides,[8] R3 = NMe2 or NEt2). These
Scheme 2. Scope of 1,3-dicarbonyl compounds. For reaction conditions, see
TableS1, entry 1. [a] DME:H2O (1:1, 1.0 mL). [b] 1a (0.75 mmol, 3 equiv.), 2
(0.25 mmol).
reactions proceeded in a different manner to those reported in
[2c, 2e]
the literatures,
where the C–C bond cleavages usually
occur at the ketone side. For unsymmetrical diketones, the C–C
bond cleavage proceeded selectively at the less sterically
hindered methyl ketone side (Scheme 2, 3af–3ai, 3ak–3aaa).
Notably, despite considerable steric hindrance, the reaction still
proceeded as anticipated when the R2 position was substituted
with an alkyl group (Scheme 2, 3ai, 3aj). In addition to aliphatic
1,3-diketones, this reaction was successfully applied to aryl-
substituted diketones bearing an electron-donating (Scheme 2,
3ao–3as) or electron-withdrawing group (Scheme 2, 3at–3aaa).
The positioning of the substituents on the aromatic ring (i.e.,
ortho-, meta- or para-positions) had very little effect on the
outcome of the reaction (Scheme 2, 3ao–3aq). This
transformation also tolerated ester, nitrile, trifluoromethyl,
chlorine and bromine groups, all of which are useful for further
synthetic transformations. Moreover, heteroaryl-substituted
diketones, such as 2-thiophenyl, 2-benzofuranyl and 4-pyridyl
1,3-diketones, could also participate in the tandem reactions,
albeit in moderate yields (Scheme 2, 3al–3an). It is noteworthy
that the current catalytic system also exhibited a high level of
chemoselectivity. The H-phosphonates reacted with aryl-
substituted diketones specifically at the α-position of their two
carbonyl groups, without forming any other aromatic C(sp2)–H or
Scheme 3. Scope of H-phosphonates.
Next, we evaluated the scope of the H-phosphonates
(Scheme 3). Gratifyingly, in addition to diethyl phosphonate (1a),
we found that various H-phosphonates 1b-1g were amenable to
this
transformation,
affording
the
corresponding
β-
ketophosphonates 3ba-3ga in good to excellent yields. It is
noteworthy that ethyl phenylphosphinate 1g also reacted as
anticipated to give the desired product 3ga in 90% yield.
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As shown in Eq.(2), the gram-scale reaction of 1f with 2a,
which was conducted using wet solvent without taking any
precaution to exclude air or moisture (open-flask), afforded the
desired product 3fa in 77% isolated yield. This reaction
highlights the practical utility and robust nature of this
transformation.
bond cleavage was more likely to occur at the more electron-
deficient carbonyl center [Eq. (6)]. Taken together, these results
convinced us that the nucleophilic attack of H2O at the carbonyl
group of the intermediate would lead to the cleavage of the
C(sp3)–C(CO) bond, leading to the formation of the target
molecule along with the carboxylic acid byproduct. However, we
found that this nucleophilic attack did not take place in the
reaction of 1a with the cyclic 1,3-diketone 2ac, probably due to
the pronounced steric hindrance of the carbonyl center in
compound 5 [Eq. (7)].
Figure 1. Distribution of substrate 1a (square), intermediate 4 (dot) and
product 3aa (triangle) with reaction time for the model reaction of 1a with 2a
under the standard conditions (See SI for details).
To develop some insights into the mechanism of this
reaction, we conducted a series of control experiments. When
the model reaction of 1a with 2a was conducted in anhydrous
DMF, we only observed the formation of trace amounts of the
target molecule 3aa, whereas the direct phosphonation product
4 was obtained in 46% yield [Eq.(3)]. Furthermore, isolated 4
could be readily converted to the final product 3aa under the
standard conditions in high yield [Eq.(4)]. Based on these
[2a, 2e]
observations and previous reports,
we envisioned that the
reaction of 1a with 2a probably proceeded via an oxidative
C(sp3)–H/P–H cross-coupling and a tandem C(sp3)–C(CO) bond
cleavage reaction to provide the desired product 3aa. To prove
our hypothesis, we monitored changes in the levels of the
different components of the reaction mixture over time (Figure 1).
Not surprisingly, during the first few minutes, the amount of 4
increased steadily, whereas the desired product 3aa remained
at a low concentration. However, as the reaction proceeded, the
amount of 3aa gradually increased, whereas the amount of 4
decreased. These results clearly confirmed our hypothesis that
compound 4 was a key intermediate for product 3aa.
To further clarify the decarbonylated product in the C(sp3)–
C(CO) bond cleavage step, the in-situ NMR study of the crude
reaction mixture in Eq. (5) was conducted. After comparison with
an authentic sample of HOAc, we confirmed that acetic acid was
being formed as a byproduct (see SI for NMR spectra).
Furthermore, the intramolecular competitive reaction of
unsymmetrical diketone 2ab with 1a demonstrated that the C–C
Scheme 4. Trapping and detecting the intermediate.
Although we successfully identified the C(sp3)–C(CO) bond
cleavage step, more efforts are still required to better
understand the mechanism of the oxidative C(sp3)–H/P–H cross-
coupling step. The addition of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) completely inhibited the reaction [Eq.(8)],
indicating that this transformation may proceed via a radical
pathway. Moreover, HRMS analysis of the crude mixture
resulting from the reaction of 1c and 2k revealed the formation
of the adduct 6 (Scheme 4), suggesting that the radical species
7, probably generated by the radical addition of 1c’ to 2k’, was
the key intermediate in the oxidative C(sp3)–H/P–H cross-
coupling step.
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Based on the results described above and literature
precedents
developed catalytic system also promoted the oxidative cross-
coupling reactions of H-phosphonates and simple aliphatic
ketones. Preliminary mechanistic studies revealed that a radical
pathway and a nucleophilic attack process may be involved in
the C(sp3)–P bond formation and C(sp3)–C(CO) bond cleavage
steps, respectively. This new method provides an alternative
approach to β-ketophosphonate scaffolds and has several key
advantages, including (1) simple and readily available catalyst
system; (2) base-, ligand- and additive-free; (3) wide substrate
scope and good functional group tolerance; and (4) exclusive
chemo- and regioselectivity. Further studies aimed at exploring
the application of this strategy to other systems are currently
underway in our laboratory.
[2f,
9], a tentative mechanism was proposed in
Scheme 5. Diethyl phosphonate (1a) was oxidized by AgI salt to
generate the corresponding P-centered radical A and Ag0, which
would be reoxidized to AgI by a persulfate anion.[11] The radical
addition of intermediate A to enolate 2a’ gave intermediate B, [12]
which would be oxidized to intermediate 4.[13] Subsequently, the
C–C bond cleavage reaction took place immediately after the
nucleophilic attack of H2O to the more electron-deficient
carbonyl group to deliver enolate D, along with the acetic acid as
a byproduct. Finally, enolate D rapidly tautomerized to form the
more stable product 3aa.
Acknowledgements
This work was supported by grants from the National NSF of
China (Nos 21502155) and the Fundamental Research Funds
for the Central Universities (SWU114077 and XDJK2015C103).
Conflict of interest
The authors declare no conflict of interest.
Keywords: cross-coupling • C(sp3)–P bond formation • C–C
bond cleavage • 1,3-dicarbonyl compounds • silver
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Scheme 5. Plausible mechanism.
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Scheme 6. Silver-catalyzed direct oxidative cross-coupling reactions of H-
phosphonates and simple ketones. For details, see supporting information.
It is noteworthy that our newly developed catalytic system
could also be applied to the direct C–H/P–H cross-coupling of H-
phosphonates and simple aliphatic ketones. We have provided a
few representative examples of this reaction in Scheme 6, and
detailed results of this transformation will be published in due
course.
In summary, we have reported for the first time a silver-
catalyzed C(sp3)–P bond forming reaction consisting of an
oxidative C(sp3)–H/P–H cross-coupling and a tandem C(sp3)–
C(CO) bond cleavage reaction, affording a wide range of
functionalized β-ketophosphonates. This reaction was also
found to be amenable to β-ketoamides and β-ketoesters, where
the C–C bond cleavage reaction occurred specifically at the
ester or amide side of the substrate. Notably, this newly
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10.1002/anie.201704910
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COMMUNICATION
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[5]
Quite recently, an elegant review on silver-based radical reactions was
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believed to be oxidized to Ag(II) by potassium peroxodisulfate. And
then, the Ag(II) deprived an electron from 1a or 2a to give the
corresponding radical species and regenerate the Ag(I). However, in
the current reaction system, the catalytic cycle of Ag(I)/Ag(0) seemed
more reasonable, because stoichiometric AgOAc could also promote
the reaction smoothly in the absence of K2S2O8 (Table S1, entry 7), and
when the reaction was finished, elemental silver particles were always
found at the bottom of the Schlenk test tube (See Figure S1 and S2).
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[8]
[9]
When acetoacetamide and N-methyl acetoacetylamide were used as
substrates, we only obtained the C(sp3)–H phosphonation products 9
and 10 in 60% and 48% yields, respectively; and the C–C bond
cleavage step didn’t occur in these two cases (for details, see SI).
For selected examples, see: a) F. Effenberger, H. Kottmann,
Tetrahedron 1985, 41, 4171–4182; b) C.-B. Xiang, Y.-J. Bian, X.-R.
Mao, Z.-Z. Huang, J. Org. Chem. 2012, 77, 7706-7710; c) X. Mao, X.
Ma, S. Zhang, H. Hu, C. Zhu, Y. Cheng, Eur. J. Org. Chem. 2013,
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10.1002/anie.201704910
Angewandte Chemie International Edition
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Tandem transformation
A novel silver-catalyzed
Lili Li, Wenbin Huang, Lijin Chen,
Jiaxing Dong*, Xuebing Ma*,
Yungui Peng*
transformation involving oxidative
C(sp3)–H/P–H cross-coupling of
1,3-dicabonyl compounds with H-
phosphonates and tandem
exclusive C(sp3)–C(CO) bond
cleavage has been realized to give
heavily functionalized β-
Page No. – Page No.
Silver-catalyzed Oxidative
C(sp3)–P Bond Formation via C–
C and P–H Bond Cleavages
ketophosphonate scaffolds.
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