Pd(II)-Catalyzed Phosphorylation of Enamido C(sp2)–H Bonds: A General Route to β-Amido-vinylphosphonates

Article abstract of DOI:10.1002/cjoc.201800262

Organophosphorus compounds are essential structures in modern pharmaceutical, agrochemical, and material sciences. The development of new and efficient methods for the synthesis of C–P bonds has been an important focus of research. We herein report a Pd-catalyzed enamido C(sp²)–H phosphorylation for direct construction of C–P bonds under simple and convenient conditions without the need for additional ligands or directing groups. The present reaction can tolerate a wide range of functional groups, and furnish a variety of phosphorylation products including tetrasubstituted-vinyl β-aminophosphonates that are otherwise difficult to access. This protocol was also exemplified into the late-stage modification of bioactive natural products and was suitable for large-scale synthesis.

Full text of DOI:10.1002/cjoc.201800262

Pd(II)-Catalyzed Phosphorylation of Enamido C(sp2)‒H Bonds: A General
Route to β-Amido-Vinylphosphonates
Baokun Qiao,§ Hao-Qiang Cao,§ Yin-Jun Huang, Yue Zhang, Jing Nie, Fa-Guang Zhang,* Jun-An Ma*
ABSTRACT Organophosphorus compounds are essential
structures in modern pharmaceutical, agrochemical, and
material sciences. The development of new and efficient
methods for the synthesis of C–P bonds has been an
important focus of research. We herein report
a
Pd-catalyzed enamido C(sp2)–H phosphorylation for
direct construction of C–P bonds under simple and
convenient conditions without the need for additional
ligands or directing groups. The present reaction can
tolerate a wide range of functional groups, and furnish a
variety of phosphorylation products including
tetrasubstituted-vinyl β-aminophosphonates that are
otherwise difficult to access. This protocol was also
exemplified into the late-stage modification of bioactive
natural products and was suitable for large-scale
synthesis.
KEYWORDS C-H activation, phosphorylation, palladium catalysis, enamines, late-stage functionalization
enamido C(sp2)−H activation, and only one report by Loh and
Introduction
co-workers has described a palladium-catalyzed sulfonylation of
enamides for the generation of carbon–sulfur bonds (Scheme
1b).7t We surmised that transition-metal catalyzed C–H activation
/ C–P coupling reactions using enamides as substrates could
provide a direct and general method for the preparation of
β-amido-vinylphosphonates (β-AVPs).[8] Commonly used methods
for the synthesis of β-AVPs include the addition of α-methyl
phosphonate carbanions to nitriles,[9] the hydroamination of
Organophosphorous compounds have wide applications in
organic synthesis, agricultural chemistry, biomedicinal science,
and material industries.[1] As a result of their immense usefulness,
the construction of C−P bonds has captured the attention of
synthetic chemists over the past decades.[2] In this context, the
conventional
methods
involving
Michaelis-Arbuzov
rearrangement, Hirao cross-coupling, and hydrophosphinylation
reactions have been well established for making C−P bonds.[3]
Furthermore, many transformations have been successfully
applied to the synthesis of agrochemicals and compounds of
pharmaceutical significance. Despite these notable advances, the
development of new reactions for the construction of C−P
compounds is still highly desirable. Direct functionalization of C–H
bonds has emerged as an efficient and promising strategy for
rapid generation of valuable products from simple starting
materials.[4] Recently, several research groups have paid attention
to metal-catalyzed phosphorylation of aryl C(sp2)−H bonds as a
late-stage functionalization method for preparing aryl
phosphonates.[5] In sharp contrast, direct metal-catalyzed alkenyl
C(sp2)−H acꢀvaꢀon and phosphorylaꢀon remains largely
unexplored. Only one example by Murakami and co-workers has
addressed the Pd-catalyzed alkenyl C(sp2)−H phosphorylaꢀon by
the use of a pyridyl group as the directing group.[5c] This creates
alkynyl-phosphonates,[10]
the
hydrophosphonylation
of
ynamides,[11] and some addition-elimination transformations.[12]
However, harsh reaction conditions, limited functional group
tolerance, and narrow substrate scopes have restricted these
strategies. Therefore, the cross-coupling of enamido C(sp2)−H
bonds with P(O)–H reagents[13] is an unanswered challenge and
Scheme 1. Transition-metal Catalyzed Enamido C(sp2)–H Functionalization
the
interesting
challenge
of
developing
new
transition-metal-catalyzed phosphorylation processes to make
alkenyl C(sp2)−P bonds.
In recent years, enamides have been the subject of elegant
metal-catalyzed C–H bond functionalization reactions because
they allow the direct modification of given substrates without the
installation of an additional coordinating functional group
(directing group).[6] The transformation of enamido C(sp2)−H
bonds into carbon–carbon bonds has been widely studied by
using various C-coupling partners, including arylating, vinylating,
alkylating, and acylating reagents (Scheme 1a).[7a–s] In sharp
contrast, little progress has been made in the development of
carbon–heteroatom bond forming reactions via metal-catalyzed
yet a significant goal from the viewpoint of synthetic applications.
Herein,
we
report
such
with
a
facile
high
access
chemo-
to
and
β-amido-vinylphosphonates
a Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic
Sciences, and Tianjin Collaborative Innovation Center of Chemical Science &
Engineering, Tianjin University, Tianjin 300072, P. R. of China
E-mail: majun_an68@tju.edu.cn, zhangfg1987@tju.edu.cn
§These authors contributed equally to this work. Baokun Qiao joined Henan
University after receiving his Ph.D. in 2017.
This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201800262
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stereoselectivity via palladium-catalyzed phosphorylation of
enamido C(sp2)–H bonds (Scheme 1c). This cross-coupling
reaction can be conducted under mild conditions without the
need for additional ligands or directing groups. Furthermore, the
generality of this newly observed C(sp2)–H bond functionalization
was further demonstrated by phosphorylating α,β-disubstituted
14
15
16
Pd(OAc)2
PdCl2
Ag2O
Ag2O
Ag2O
Ag2O
Na2CO3
NaOAc
NaOAc
NaOAc
80
80
80
80
CH3CN
CH3CN
CH3CN
CH3CN
72
22
68
31
Pd(TFA)2
17 [Pd(PPh3)2Cl2]
a
and cyclic enamides to provide
a
wide range of
Reaction conditions: Enamide 1a (97 mg, 0.6 mmol), diisopropyl
tetrasubstituted-vinyl β-aminophosphonate derivatives that are
otherwise difficult to access.
phosphonate 2a (50.0 μL, 0.3 mmol), palladium salt (5 mol%), oxidant (0.6
mmol), and base (0.6 mmol) in solvent (4 mL) under the stated
temperature for 12 h. Although excess enamide is required for good
b
mono-phosphorylation, the unreacted equivalents could be recovered.
Results and Discussion
Initial Studies and Reaction Optimization Results.
Yield shown is the average of two runs based on the phosphonate
substrate. The ratio of stereoisomers (Z/E) was determined by 31P NMR
analysis of the crude reaction mixture.
To assess the feasibility of the outlined enamido C(sp2)–H
phosphorylation, we commenced our investigation with the
coupling of phenyl enamide 1a and diisopropyl phosphonate 2a
by using Pd(OAc)2 as a catalyst. After extensive screening of
various oxidants [such as Cu(OAc)2, Mn(OAc)3, AgOAc, and K2S2O8.
See the Supporting Information (SI)], it was found that only
AgOAc could deliver the desired phosphorylation product 3a in 20%
yield with high regioselectivity (Z/E: 7/1). On the basis of this
reactivity, we then proceeded to develop catalytic conditions for
this transformation (Table 1). Several other silver salts were
further examined (entries 1–4), and Ag2O was found to be the
best choice, improving the yield to 66% (entry 4). Exploration of
solvents revealed that besides acetonitrile, DMF (N,
N-dimethyl-formamide) also promoted this transformation,
whereas the use of chloroform, toluene, tert-amylalcohol, DME
Substrate
scope
for
palladium-catalyzed
direct
phosphorylation of enamides with H-phosphonates.
With these interesting results in hand, we examined the scope
of this catalytic phosphorylation using a broad array of enamides
and P(O)–H hydrogen phosphoryl compounds under the optimal
reaction conditions (Scheme 2). In most cases, both Z- and
E-isomers of the desired β-amido-vinylphosphonates could be
easily separated through flash column chromatography (FCC).
This Pd-catalyzed direct phosphorylation also took place
efficiently with dimethyl and diethyl phosphonates under our
standard reaction conditions to afford the corresponding
products 3b and 3c in high yields. In the case of aryl enamides,
the phosphorylation reaction tolerates various substitution
patterns and a range of different substituents on the aryl ring.
Alkyl, alkoxy-, halo-, and trifluoromethyl-substituted phenyl
enamides all undergo the desired reaction to give the
phosphorylated products 3d–r in 62–97% yields with good to high
stereoselectivities. Furthermore, the major isomer of 3j and the
minor isomer of 3k proved to be suitable crystallines, thus
allowing the determination of the stereochemistry of C=C double
bond to be (Z)-3j and (E)-3k by means of X-ray crystallographic
analysis (see the SI). 1-Naphthyl-, 2-naphthyl-, and
3-thiophenyl-substituted enamides were also found to be good
substrates, delivering the desired β-amido-vinylphosphonates
3s–u in 69–96% yields with good stereoselectivities. In addition,
several alkyl-substituted enamides were also prepared and
subjected to this cross-coupling process under the same
conditions. For example, tert-butyl-substituted enamide
(dimethoxyethane), or DMSO (dimethyl sulfoxide) led to
a
significantly lower yield (entries 5–10). The yield of (Z)-3a was
further improved to 88% when the reaction temperature was
increased from 60 to 80 °C (entry 11). In addition, a small amount
of (E)-3a could also be isolated in 8% yield. Several bases and
palladium species were also examined, but the transformation
works well only in the presence of NaOAc as base and Pd(OAc)2 as
a catalyst (entries 12–17 vs 11). It should be noted that this
reaction
is
also
excellently
chemoselective,
and
N-phosphorylation side-product was not observed under these
reaction conditions.
O
H
H
Pd(OAc)2 (5 mol%)
P(OiPr)2
O
H
P(OiPr)2
+
H
oxidant, base, solvent, T oC
Ph
N
H
Ph
N H
Ac
Ac
3a
2a
1a
underwent
a
clean conversion and the corresponding
Table 1 Optimization of Catalytic Conditionsa
β-amido-vinylphosphonate 3v was obtained in 85% yield with
excellent stereoselectivity. Cyclohexyl- and phenethyl-substituted
enamides furnished Z- and E-isomers of the phosphorylated
products 3w and 3x in total yields of 91% and 79%, respectively.
Encouraged by these results, we moved to examine the
phosphorylation of α,β-disubstituted enamides. As shown in
Scheme 3, when α,β-disubstituted (E)-enamide 4a was employed
under the current reaction conditions, not surprisingly, the
phosphorylation of enamido C(sp2)–H bond was observed to
produce the expected (Z)-amido-vinylphosphonate 5a in 59%
yield (Scheme 3a). In contrast, when α,β-disubstituted
(Z)-enamide 4a was exposed to the optimized conditions, (Z)-5a
was obtained in very low yield (Scheme 3b). Subsequently, a
series of α,β-disubstituted enamides were investigated and the
results are listed in Scheme 4. Three (E)-enamides 4b–d bearing
α-phenyl and β-alkyl substituents were readily transformed into
the corresponding (Z)-amido-vinyl-phosphonates 5b–d in 57–64%
yields. The (Z/E)-mixtures of dialkyl-substituted enamides 4e–g
were also subjected to this Pd-catalyzed phosphorylation process
entry Pd catalyst
oxidant
base
T (oC)
solvent yield (%)b
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOAc
AgNO3
Ag2CO3
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
60
60
60
60
60
60
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
20
28
15
66
15
14
3
4
5
6
toluene
7
60 tert-AmylOH 15
8
60
60
60
80
80
80
DME
DMSO
DMF
22
27
65
88
73
83
9
10
11
12
13
CH3CN
CH3CN
CH3CN
NaBF4
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Scheme 2 Pd-Catalyzed Direct Phosphorylation of Enamides a-c
a
Reaction conditions: Enamide 1 (0.6 mmol), phosphonate 2 (0.3 mmol), Pd(OAc)2 (3.4 mg, 5 mol%), Ag2O (137.2 mg, 0.6 mmol), and NaOAc (49.2 mg,
b
c
0.6 mmol) in CH3CN (4 mL) under the stated temperature for 12 h. Isolated yields based on the phosphonate substrates. The values in parentheses
were determined by 31P NMR analysis of the crude mixtures.
to afford the desired products 5e–g in good yields with
moderate to good stereoselectivities.
can be tolerated, and moderate to high yields were observed
for the products 7m–x. 1-Benzosuberone-derived cyclic
enamide was also compatible with the current reaction
conditions to give the functionalized product 7y in 83% yield.
1-Indanone-derived enamide was simultaneously oxidized and
Scheme 3 Pd-Catalyzed Phosphorylation of α,β-disubstituted (E) and
(Z)-Enamides 4a
Scheme 4 Pd-Catalyzed Phosphorylation of α,β-disubstituted Enamides
4b–g a
Further extension of our protocol to various cyclic
enamides 6 was also generally successful, and the results are
summarized
in
Scheme
5.
We
found
that
cyclohexanone-derived enamides readily participated in this
Pd-catalyzed phosphorylation to deliver the corresponding
β-amido-vinylphosphonates 7a–f in high yields. The
phosphorylation of cyclopentanone-derived enamide gave the
desired product 7g in relatively lower yield. Cycloheptanone-
and cyclooctanone-derivated enamides also furnished the
corresponding products 7h and 7i in 88% and 78% yields,
respectively. Several large-ring E-enamides were also viable
substrates, affording β-amido-vinylphosphonates 7j–l in good
yields. Subsequently, a series of cyclic enamides derived from
1-tetralones were tested. It appeared that electron-neutral,
-donating, and -withdrawing substituents on the phenyl ring
a
Reaction conditions: Enamide 4 (0.3 mmol), diisopropyl phosphonate
2 (50.0 μL, 0.3 mmol), Pd(OAc)2 (3.4 mg, 5 mol%), Ag2O (137.2 mg, 0.6
mmol), and NaOAc (49.2 mg, 0.6 mmol) in CH3CN (4 mL) under the
stated temperature for 12 h. Isolated yields based on the enamide
b
c
substrates. (Z/E)-isomers of 5e–g could not be isolated by the FCC,
and the values in parentheses were determined by 31P NMR analysis of
the isolated products.
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Scheme 5 Pd-Catalyzed Direct Phosphorylation of Cyclic Enamides 6 a, b
a Reaction conditions: Enamide 6 (0.3 mmol), phosphonate 2 (0.3 mmol), Pd(OAc)2 (3.4 mg, 5 mol%), Ag2O (137.2 mg, 0.6 mmol), and NaOAc (49.2 mg,
0.6 mmol) in CH3CN (4 mL) under the stated temperature for 12 h. b Isolated yields based on the enamide substrates. c The yield in parenthesis was based
on 1,3-indanedione-derived enamide.
Scheme 6 Scaled-up Version of Pd-Catalyzed Phosphorylation, and Synthesis of Prasterone- and Prasterone-based β-Amido-vinylphosphonates
phosphorylated to afford the product 7z in 31% yield,[14]
whereas the phosphorylation of 1,3-indanedione-derived
enamide furnished the same product 7z in good yield.
Additionally, four 4-chromanone-based cyclic enamides could
also undergo direct phosphorylation to give the corresponding
AVPs 7a’–d’ in 81–91% yields.
silver species could be recovered and recycled conveniently by
filtration and treatment with nitric acid and NaOH. The
regenerated Ag2O could still promote this phosphorylation in
comparable yield without loss of activity (see the SI). In
addition, the applicability of our protocol to the facile
modification of complex natural products is a highly desirable
feature, as analogues of bioactive molecules could be
constructed without the need for de novo synthesis. For
example, two enamides 8 and 9 derived from natural
pregnenolone and prasterone were subjected to the current
phosphorylation process to afford the corresponding products
10 and 11 in 69% and 59% yields, respectively (Scheme 6).
These syntheses exemplify the potential utility of the current
phosphorylation method for the rapid and efficient
construction of important β-amnio-phosphonate targets.[15]
Scaled-up version of Pd-catalyzed phosphorylation and
synthetic applicability.
To evaluate this catalytic system on a gram-scale, the
phosphorylation of enamides 1a, 4c, 6a, and 6m with
diisopropyl phosphonate 2a was repeated over one grams and
the reaction delivered the desired products 3a, 5c, 7a, and 7m
with results almost identical to that of the model reaction.
Although 2.0 equivalents of Ag2O was used in this
phosphorylation reaction, the excess Ag2O and the resulting
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Mechanistic discussion.
Conclusions
To cast some light on the mechanism, the kinetic isotope
effect (KIE)[16] and radical-trapping experiments were
conducted (Scheme 7). The significant kinetic isotope effect
was observed in the reaction of the deuterated and the
protonated enamides with diisopropyl phosphonate (Scheme
7a and 7b). These results show that the enamido C(sp2)−H
cleavage could occur during the rate-determining step. In
In summary, we have successfully developed a Pd-catalyzed
direct and efficient phosphorylation of enamido C(sp2)–H
bonds with P(O)–H reagents to access a wide range of
β-amido-vinylphosphonates without the need for additional
ligands or directing groups. This new cross-coupling reaction
displayed high functional-group tolerance and proved to be a
quite general methodology. Furthermore, this system was
found to be applicable to the late-stage modification of
bioactive natural products and was suitable for gram-scale
synthesis. The expansion of this strategy to other substrates
and further transformation of these compounds prepared here
into β-aminophosphonic acids are currently under way and will
be reported in due course.
addition,
when
1.5
equivalent
of
TEMPO
or
cyclohexa-1,4-diene was employed under the normal reaction
conditions, the desired product 3a was obtained in 35% and 58%
yields (Scheme 7c). Thus, this phosphorylation transformation
might not involve a radical process.
Scheme 7 Kinetic Isotope Effect and Radical-trapping Experiments
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
This work was supported financially by the National Natural
Science Foundation of China (No. 21472137, 21532008 and
21772142), and the National Basic Research Program of China
(973 Program: 2014CB745100)
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Figure
1
A
plausible mechanism for palladium-catalyzed
phosphonation of enamides.
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Entry for the Table of Contents
Page No.
Title Pd(II)-Catalyzed Phosphorylation of
Enamido C(sp2)‒H Bonds: A General Route
to β-Amido-Vinylphosphonates
Baokun Qiao,§ Hao-Qiang Cao,§ Yin-Jun
Huang, Yue Zhang, Jing Nie, Fa-Guang
Zhang,* Jun-An Ma*
Text for Table of Contents.
This article is protected by copyright. All rights reserved.