Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates

Article abstract of DOI:10.1002/anie.201802082

A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional-group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive P^V species (phosphoryl pyridin-1-ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf₂O/pyridine.

Full text of DOI:10.1002/anie.201802082

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Accepted Article
Title: Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the
Synthesis of Mixed Phosphonates
Authors: Hai Huang, Johanna Denne, Chou-Hsun Yang, Haobin Wang,
and Jun Yong Kang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802082
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10.1002/anie.201802082
Angewandte Chemie International Edition
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Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for
the Synthesis of Mixed Phosphonates
Hai Huang,[a] Johanna Denne,[b] Chou-Hsun Yang,[b] Haobin Wang,[b] and Jun Yong Kang*[a]
phosphonochloridates. In 2014, Feringa and co-workers[12]
Abstract: The direct functionalization strategy of inertial dialkyl
disclosed an efficient copper-catalyzed direct arylation of
phosphonates with hydroxy compounds to afford diverse mixed
dialkylphosphonates with diaryliodonium salts for the synthesis of
phosphonates with good yields and functional group tolerance has
mixed alkyl aryl phosphonates, which requires elevated reaction
been developed. Mechanistic investigations of both NMR studies and
temperature and extra steps to prepare diaryliodonium salts
DFT studies support that an unprecedented highly reactive P(V)
(Scheme 1, b). Therefore, a direct aryloxylation/alkyloxylation of
species (phosphoryl pyridin-1-ium salt), a key intermediate for this
new synthetic transformation, is generated in situ from dialkyl
phosphonate in the presence of Tf2O/pyridine.
dialkylphosphonates in one-pot using phenols/alcohols under
mild reaction conditions is an ideal and step-economic strategy to
generate mixed phosphonates. However, there are several
challenges:
(1)
as
compared
to
the
reactive
phosphonochloridates, P(O)-H,[13] and P(O)-OH compounds,[14]
the phosphonate moieties are chemically inert; (2) For the mixed
phosphonate synthesis, the reactivity and chemoselectivity must
be carefully controlled to prevent dual substitution of the twin
alkoxy groups.
Organophosphonate compounds are ubiquitous structural motifs
widely present in pharmaceuticals,[1] agrochemicals,[2] and ligand
scaffolds[3], highlighting the significance of these structures.
Among them, mixed alkyl aryl phosphonates have attracted
significant attention in nucleoside phosphonate prodrugs[4] and in
coordination chemistry for the study of biological system A (Figure
1).[5] Mixed phosphonates show a wide range of biological
activities such as phosphonate prodrugs of butyrophilin ligand B[6]
and antibacterial reagent C.[7] They are also used as γ-glutamyl
transpeptidase inhibitors D[8] and esterase inhibitors E.[9]
Moreover, due to their unique structural properties of
a
hydrolysable P–O bond, mixed phosphonate units have been
utilized as fluorogenic analogues to study biological
mechanisms.[10]
Scheme 1. Synthetic routes toward mixed phosphonates
Figure 1. Examples of pharmaceutically-relevant mixed alkyl aryl phosphonates
Triflic anhydride (Tf2O)-mediated activation of carbonyl
compounds such as ketones, aldehydes, and amides as well as
sulfoxides has emerged as a powerful synthetic tool in organic
synthesis.[15] Similarly, the activation of phosphorus compounds
with P=O bond, especially phosphine oxides, was also achieved
by Tf2O.[16] Recently, Miura and co-workers[17] reported an elegant
strategy for the activation of H-phosphine oxides. An electrophilic
Current synthetic approaches toward mixed alkyl aryl
phosphonates predominantly rely on stepwise processes
involving substitution reaction of pre-generated alkyl
11]
phosphonochloridates with arenols (Scheme 1, a).[6,
These
methods employ hazardous and toxic reagents such as
phosphorus chloride and oxalyl chloride to generate the
phosphorus species (P-species) generated from
a diaryl
phosphine oxide and Tf2O reacts with an alkyne to form a reactive
phosphirenium cation, which undergoes arylative ring-opening
reaction to afford phosphinative cyclization product. (Scheme 1,
c). Despite the demonstration of electrophilic P-species from the
secondary arylphosphine oxides and Tf2O at elevated
temperature,[17-18] the activation of dialkylphosphonates with Tf2O
at room temperature to generate electrophilic P-species remains
undeveloped. Hence, we hypothesized that the terminal oxygen
P(V)=O of dialkylphosphonates 1 could be activated by Tf2O to
afford a phosphonium intermediate I (Scheme 1, d),[19] which is
then converted to TfO-substituted phosphonate intermediate II via
[a]
[b]
Dr. H. Huang, Prof. Dr. J. Y. Kang
Department of Chemistry and Biochemistry
University of Nevada Las Vegas
4505 South Maryland Parkway, Las Vegas, Nevada, 89154-4003,
United States
E-mail: junyong.kang@unlv.edu
J. Denne, Dr. C. Yang, Prof. Dr. H. Wang
Department of Chemistry
University of Colorado Denver
Denver, Colorfado 80217-3364, United States
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201802082
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COMMUNICATION
nucleophilic substitution reaction.[20] Finally, we envisioned that
the phosphonate intermediate II in presence of pyridine could be
effects of the phenyl substituents on the phosphonates have
significant influence on the product yield: for example, an
transformed to
a
highly reactive pyridinium phosphonate
electron-deficient phosphonate 1o with
a
p-nitro phenyl
intermediate III.[21] With this idea in mind, we explored the
substituent provided the product 3o in 28% yield (Scheme 2). This
reaction shows broad compatibility with a diverse array of
substrates bearing halide, allylic, vinyl, alkyne, and diene groups
(Scheme 2, 3p-3v). A heteroaromatic phosphonate was also
efficiently transformed to the desired mixed phosphonate 3w in
83% yield. Importantly, the synthesis of O-ethyl O-, S-diphenyl
phosphorothioate 3x known as a classical antibacterial agent[7]
was demonstrated by this system with 81% yield.
development of new electrophilic P-species using the chemically
inert dialkylphosphonates for
phosphonates. Herein, we describe metal-free, chloride reagent-
free, and Tf2O-mediated activation of phosphonates for the
a facile synthesis of mixed
synthesis
of
mixed
phosphonates
via
direct
aryloxylation/alkyloxylation strategies.
Optimization of the reaction conditions was carried out with
diethyl benzylphosphonate 1a and phenol 2a (see the Supporting
Information for the initial works). Initially, we studied pre-activation
time for the generation of the intermediate III shown in Scheme 1
(d), and we found that a pre-reaction time of 10 min prior to the
addition of 2a to a mixture of 1a and Tf2O/pyridine is required for
high yields (Table 1, entry 1). Screening of other bases did not
improve the product yield but a phenyl triflate byproduct was
formed (See SI for details). In contrast, there was no target
product without bases (Table 1, entry 2). Among the screened
solvents, DCM is superior to other solvents (Table 1, entries 3-8).
Further optimization revealed that the highest yield of 3a (99%
yield by NMR) could be achieved with an excess of Tf2O (1.5
equiv), pyridine (2.0 equiv), and phenol 2a (2.5 equiv) (Table 1,
entry 9, See SI for details).
We next investigated the scope of phenol derivatives. The
reaction tolerates both electron-donating groups (Me, MeO) and
electron-deficient substituents (Br, I, NO2, CF3) on the phenyl ring,
providing the desired products in high yields (Scheme 2, 4a-4h).
Ortho-, para-substituted dichlorophenol was a suitable substrate
for this transformation to afford 4i in 77% yield. In contrast, having
bulky groups on 2-, 6-positions on phenols significantly reduced
the product yields (Scheme 2, 4k-4l). To our delight, as compared
to our initial experimental results with no pre-activation process
(see Table S1 in SI), polycyclic aromatic alcohols such as 1-
naphthol, 2-naphthol, and quinolin-6-ol proved to be suitable
substrates under our optimized reaction conditions, affording the
mixed phosphonates 4n-4p in 70-87% yields. In addition, this
method tolerates a wide range of functional groups (e.g., ester,
carbonate, allyl, azo and acrylate) on the phenol (Scheme 2, 4q-
4u). Especially, the reaction of 1a with cholesterol-derived phenol
proceeded efficiently to give 4v as a phosphonylated cholesteryl
Table 1. Optimization of reaction conditions[a]
ester derivative bearing
a
biologically important mixed
phosphonate scaffold in 84% yield (Scheme 2, 4v).
With a demonstration of aryloxylation of phosphonates with
various phenol derivatives, we next explored the reactivity of
aliphatic alcohols under the same reaction conditions (Scheme 2).
We found that various alcohols such as 1º alcohols and 2ºalcohol
were all efficiently coupled with dialkylphosphonates to provide
mixed phosphonates 5a-5h in moderate to high yields.
entry
base
pyridine
–
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
solvent
DCM
DCM
CHCl3
DCE
Et2O
toluene
THF
CH3CN
DCM
X:Y:Z
yield (%)[b]
85
1
2
3
4
5
6
7
8
9
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
2.0:2.0:2.0
1.5:2.0:2.5
NR
37
49
46
36
NR
Next, we investigated late-stage phosphonylation of various
natural products to demonstrate functionalization of bioactive
small molecules (Scheme 2). This phosphonylation reaction of
natural compounds such as coumarin 2af, ferulate 2ag and
estradiol 2ah exhibited good functional group tolerance (e.g. ester,
acrylate, ether, and hydroxyl group) and provided the
corresponding products in moderate to high yields (Scheme 2, 6a-
6c). It is worth mentioning that this protocol shows an excellent
chemoselectivity with estradiol 2ah bearing both aryl alcohol and
aliphatic alcohol, providing only 6c with 41% yield. In addition,
sesamol 2ai afforded the corresponding mixed phosphonate 6d
in excellent yield (90% yield). An enol nucleophile of maltol was
also a suitable coupling partner for this transformation to furnish
the desired mixed phosphonate 6e in 51% yield. Finally, we
subjected an aliphatic alcohol-containing natural product
cholesterol 2ak to our standard reaction conditions, and we
isolated the target mixed phosphonate product 6f[22] with 81%
yield.
trace
99(92)[c]
[a] Reaction conditions: 1a (0.2 mmol), Tf2O (X equiv), base (Y equiv) in solvent
(1.0 mL) for 10 min, then PhOH (Z equiv) for 30 min. [b] Yield was determined
by 1H NMR on the crude reaction mixture using 1,3,5-trimethylbenzene as an
internal standard. [c] Isolated yield.
With the optimized reaction conditions in hand, the scope of the
reaction was explored with diverse dialkyl phosphonates 1,
demonstrating efficient substrates to form mixed alkyl aryl
phosphonates 3a-3x (Scheme 2). Different substituents on the
benzyl group were well tolerated (86-94% yields) (Scheme 2, 3a-
3g). Phosphonates with aliphatic substituents 1h-1j are also
suitable substrates for this reaction to provide alkyl-substituted
mixed phosphonates 3h-3j in 85-90% yields. In addition, phenyl
phosphonates 1k-1n with different alkoxy substituents MeO, EtO,
i-PrO and n-BuO were examined, and they afforded the
corresponding mixed phosphonates 3k-3n in 81-93% yields. In
line with our hypothesis of favoring electron-rich substituents on
the phosphonate motif for the activation with Tf2O, the electronic
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10.1002/anie.201802082
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COMMUNICATION
Scheme 2. The reaction scope. For the standard reaction conditions, see supporting information. Isolated yields are given.
a) direct meta-C–H functionalization
R2
Ph
To demonstrate the potential application of this synthetic
protocol to pharmaceuticals and organic synthesis, we performed
a larger-scale reaction of 1l (1.07 g, 5.0 mmol) with 2a, which
afforded the target mixed phosphonate 3l (1.26 g) in 96% yield
along with 52% recovery of the phenol 2a (See SI for details). 2-
Hydroxybenzonitrile 2al was also a suitable substrate and
generated a functionalized phosphonate 7a (87% yield), which is
a key precursor for meta-C–H activation of the benzene ring to
give multi-substituted benzene compounds 7aa (Scheme 3, a).[11c,
23] Next, we applied our aryloxylation protocol for the synthesis of
a key intermediate of butyrophilin ligand prodrug 7bb reported by
the Wiemer group. Our transformation achieved one step
synthesis of 7b from 1x and 2o and enables higher yield (84%) in
short reaction time (40 min) (Scheme 3, b).[6] Finally, a mixed
phosphonate 7c, a key intermediate of polymer immobilized
enzyme inhibitors 7cc, was also successfully synthesized in 87%
yield from 1y and 2f (Scheme 3, c).[24]
O
P
OEt
O
OEt
Tf2O (1.5 equiv)
Pyridine (2.0 equiv)
2-NCC6H4OH
ref. 11c
P
2al
O
OEt
DCM, rt, 10 min DCM, rt, 30 min
7a, 91%
7aa
1a
R1
O
N
b) synthesis of butyrophilin ligand prodrug
O
ONa
OMe
P
P
conditions
as above
1-Naphthol
O
P
OMe
ref. 6
O
2o
O
OH
DCM, rt, 30 min
OMe
7bb
7b, 84%
1x
c) synthesis of enzyme inhibitors
O
O
O
O
P
OEt
OEt
conditions
as above
4-NO2C6H4OH
*
O
P
P
O
ref. 24
NO2
2f
O
OEt
1y
O
DCM, rt, 30 min
7c, 87%
7cc
R
NO2
Scheme 3. Larger-scale reaction and synthesis of key mixed phosphonates as
versatile building blocks
Based on the experimental data and density functional theory
(DFT) calculations (See SI for details), a plausible mechanism is
proposed in Scheme 4. The terminal oxygen of the phosphonate
1a attacks the Tf2O via TS1 to furnish
a phosphonium
intermediate I. Next, TfO-substituted phosphonate II and ethyl
triflate byproduct are generated via SN1-type mechanism from the
intermediate I.[12, 25] Then, the pyridine nucleophile attacks the
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10.1002/anie.201802082
Angewandte Chemie International Edition
COMMUNICATION
intermediate II to form a highly reactive electrophilic phosphorus
species of phosphoryl pyridin-1-ium III.[26] Finally, this
intermediate III is transformed to the mixed phosphonate 3a by
substitution reaction with phenol 2a through the TS2.[21b, 21c, 27]
Foundation CHE-1361150. The computational work uses
resources of the National Energy Research Scientific Computing
Center, which is supported by the Office of Science of the U.S.
Department of Energy under Contract No. DE-AC02-05CH11231.
TfOEt
OTf
Keywords: Aryloxylation • Alkyloxylation • Phosphonates •
‡
pyridine
O
S
O
S
P
OTf
P
OTf
F3
C
CF3
O
Bn
O
O
Phosphoryl pyridin-1-ium • DFT study
O
O
Bn
O
O
II
O
O
-14.1
[-16.5]
I
Ph
P
N
-2.8
[-18.7]
[1]
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OTf
O
TS1
2.9
[-11.5]
P
O
III
-8.9
[-21.8]
Bn
O
TS1
O
P
[2]
Bn
O
O
+
a]
Tf2O
[3]
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PhOH
2a
1a
0.0[
‡
[-15.2][b]
Tf
O
H
O
P
O
P
O
O
Ph
Ph
O
N
O
[5]
3a
-33.8
[-42.7]
TS2
-10.6
[-36.5]
N
OTf
H
Scheme 4. Proposed mechanistic pathway. Theoretical investigations on the
reaction pathways for the formation of 3a. Free energy (ΔG) and enthalpy
corrections (ΔH) of key intermediates and transition states are obtained at the
DFT-M062X/6-31G*//MP2/6-311++G**//PCM(DCM) level of theory; [a] ΔG
(298K, in kcal/mol); [b] ΔH (298K, in kcal/mol).
[6]
[7]
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In summary, we have developed a mild, efficient, direct
aryloxylation/alkyloxylation of dialkyl phosphonates for the
synthesis of mixed phosphonates. This synthetic transformation
enabled the synthesis of a wide range of functional mixed
phosphonates without the use of metal or chloride reagents. In
this chemistry, we have demonstrated that a phosphoryl pyridin-
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1-ium,
a
highly electrophilic P-species of powerful
phosphonylation reagent for the synthesis of mixed
phosphonates, can be generated from dialkyl phosphonates with
Tf2O/pyridine. The synthetic utility of this transformation was
demonstrated by the synthesis of key intermediates of bioactive
compounds (butyrophilin ligand prodrug and enzyme inhibitors)
and the late-stage phosphonylation of natural compounds.
[11]
[12]
[13]
[14]
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Experimental Section
Ethyl phenyl benzylphosphonate (3a): To
a
solution of diethyl
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30.
benzylphosphonate 1a (45.4 mg, 0.2 mmol), Tf2O (50.5 μL, 0.3 mmol) in DCM
(1.0 mL) was added pyridine (32 μL, 0.4 mmol) in a 2-dram vial with a PTFE
cap. After stirring for 10 min, phenol 2a (46.5 mg, 0.5 mmol) was added to the
reaction mixture. After stirring for another 30 min at room temperature, the
resulting mixture was concentrated to give the crude product which was then
purified by column chromatography on silica gel to afford ethyl phenyl
benzylphosphonate (3a): 50.8 mg, 92%; as a colorless oil.
[16]
Acknowledgements
[17]
[18]
This work was supported by University of Nevada Las Vegas.
Maciej Kukula at SCAAC is acknowledged for mass spectra data.
The authors thank Prof. Rich G. Carter (OSU) for helpful
discussion. The reviewers are thanked for helpful commentary.
H.W. acknowledges the support from the National Science
[19]
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2015, 137, 9375.
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COMMUNICATION
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O
OPh
Ph
P
O
N
TS2'
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10.1002/anie.201802082
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hai Huang, Johanna Denne, Chou-Hsun
Yang, Haobin Wang, Jun Yong Kang*
Page No. – Page No.
Direct Aryloxylation/Alkyloxylation of
Dialkyl
Phosphonates
for
the
Synthesis of Mixed Phosphonates
We expanded the applicability of Tf2O to phosphorus chemistry for generating
electrophilic P-species and developed a novel metal-free activation strategy of
stable dialkyl phosphonates for the synthesis of diverse mixed phosphonates.
This article is protected by copyright. All rights reserved.