Kelsey F VanGelder1, Melinda Wang1, Marisa C Kozlowski1. 1. Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6323, United States.
Abstract
A versatile and general catalytic strategy has been developed for the α-arylation of phosphonoacetates utilizing parallel microscale experimentation. These α-substituted phosphonoacetates are widely useful, notably as substrates in the Horner-Wadsworth-Emmons-type olefinations. However, the current routes to these products involve harsh conditions, limiting the variety of functionality. The reported method can be used with a variety of aryl chlorides and aryl bromides, including several heterocyclic examples.
A versatile and general catalytic strategy has been developed for the α-arylation of phosphonoacetates utilizing parallel microscale experimentation. These α-substituted phosphonoacetates are widely useful, notably as substrates in the Horner-Wadsworth-Emmons-type olefinations. However, the current routes to these products involve harsh conditions, limiting the variety of functionality. The reported method can be used with a variety of aryl chlorides and aryl bromides, including several heterocyclic examples.
Phosphonates are biologically ubiquitous
compounds, with applications
in biology and medicine.[1−6] Several such compounds are shown in Scheme . Phosphonates and the corresponding phosphonoacetamides
can also be useful as peptidomimetics.[7] Phosphonoacetates are also useful synthetic precursors, such as
in Horner–Wadsworth–Emmons-type olefinations.[8] Incorporating α-substitution in a stereodefined
α,β-unsaturated ester has been a significant limitation
to date for this method.[8c,9] There are several valuable
natural product cores that can be elaborated using the described α-arylated
phosphonoacetates, especially the cinnamic acid core, shown in Scheme .[8c] The 2-arylcinnamic acid derivatives have been studied for
their antimitotic activity,[10] as well as
their activity as endothelin A receptor antagonists.[11] Unfortunately, derivatization has been limited due to an
inability to broadly functionalize the α-arene.[8c]
Scheme 1
Examples of α-Aryl Phosphonoacetates
Scheme 2
Elaboration of Biologically Relevant
Cinnamic Acids Using α-Aryl
Phosphonoacetates
Despite their clear utility, there are few reported methods
to
synthesize any variety of α-arylated phosphonoacetates. Primarily,
these compounds are generated via the Michaelis–Arbuzov reaction,
which requires high temperatures and has limited tolerance for sterically
hindered substrates (Scheme a).[12] This method is also limited
by the availability of the α-halo-α-aryl acetate starting
materials, and the electrophilic functional group tolerance is particularly
limited. This approach has been the primary route to elaborated cinnamic
acids. The analogous Michaelis–Becker reaction, which uses
the corresponding phosphonic acids, proceeds in poor yield, especially
for sterically hindered tertiary phosphonoacetates.[12a,12b] In addition, strong bases are required to deprotonate the phosphonic
acids, which are incompatible with many desirable functional groups.
The starting phosphonic acids are also not readily available, which
further limits the utility of the method.
Scheme 3
Literature Precedent
To Form α-Arylated Phosphonates
An alternative bond disconnection to this structural class
utilizes
an aryl halide and phosphonoacetate (Scheme b,c). There is extensive literature precedent
for the α-arylation of acidic substrates to form tertiary centers,
using activating functional groups such as esters, ketones, nitro
groups, and amides.[13] However, in the literature
to date, only the α-arylation of phosphonoacetates using aryl
iodides has been reported, and the substrate scope was not thoroughly
explored (Scheme b).[14−17] Iodobenzene works well in this transformation, but aryl bromides
do not couple effectively under the reaction conditions. Since fewer
aryl iodides are available relative to the bromo and chloro arenes,
we targeted this transformation for study. Notably, Walsh and co-workers
recently published the α-arylation of benzyl phosphonates,[18] but we have found that the addition of an acetate
coordinating group greatly alters the optimal reaction conditions;
such acidic substrates readily form stable chelated adducts with the
metal catalyst which are not productive reaction intermediates.[19] In this report, we describe the first intermolecular
α-arylation of phosphonoacetates with readily available aryl
bromides and chlorides (Scheme c).
Results and Discussion
An initial survey of cross-coupling
conditions from related acidic
substrates[18,19] failed to cause α-arylation
of phosphonoacetates. Thus, reaction conditions were investigated
utilizing high-throughput parallel microscale experimentation.[20] Using bromobenzene, 12 ligands and eight solvents
were evaluated using Pd2(dba)3 as a palladium
source and 1.2 equiv of K3PO4. As shown in Table , cyclopentyl methyl
ether (CPME) was quickly identified as the best solvent for this arylation,
and both BrettPhos and SPhos afforded the product in good isolated
yield upon 0.2 mmol scale validation of the microscale leads.
Table 1
High-Throughput Screen Validation
of Ligand and Solvent
entrya
ligand
solvent
product/ISb
isolated yield (%)
1
BrettPhos
CPME
2.004
84
2
SPhos
CPME
2.013
83
3
BrettPhos
trifluorotoluene
2.031
78
4
BrettPhos
toluene
2.435
75
5
CataCXium POMetB
toluene
1.940
74
6
CataCXium POMetB
CPME
2.025
39
Reactions were conducted at 100
°C and 0.1 M in solvent, with 5 mol % of Pd2(dba)3, 20 mol % of ligand, 1.2 equiv f base, and 1.1 equiv of bromobenzene.
Product to internal standard
ratio
from HTE screening.
Reactions were conducted at 100
°C and 0.1 M in solvent, with 5 mol % of Pd2(dba)3, 20 mol % of ligand, 1.2 equiv f base, and 1.1 equiv of bromobenzene.Product to internal standard
ratio
from HTE screening.Most
reactions still had trace starting material remaining at the
end of the reaction time. Therefore, different bases were investigated
with the goal of increasing conversion. With CPME as a solvent, 12
different bases and the top two ligands were again assessed via parallel
microscale experimentation. The top results of that screen were validated
on a 0.2 mmol scale and are shown in Table .
Table 2
Ligand and Base Screening
for the
α-Arylation of Triethyl Phosphonoacetate with Bromobenzene
entrya
ligand
base
product/ISb
isolated yield (%)
1
BrettPhos
Cs2CO3
2.716
80
2
BrettPhos
K3PO4
2.361
75
3
SPhos
Cs2CO3
3.149
74
4
SPhos
K3PO4
3.325
70
Reactions were conducted at 100
°C and 0.2 M in CPME, with 2.5 mol % of Pd2(dba)3, 10 mol % of ligand, 1.2 equiv of base, and 1.1 equiv of
bromobenzene.
Product to
internal standard ratio
from HTE screening.
Reactions were conducted at 100
°C and 0.2 M in CPME, with 2.5 mol % of Pd2(dba)3, 10 mol % of ligand, 1.2 equiv of base, and 1.1 equiv of
bromobenzene.Product to
internal standard ratio
from HTE screening.Overall,
reactions using BrettPhos as the ligand had a cleaner
reaction profile, and Cs2CO3 was the most effective
base for the transformation. A further concentration study showed
that moving from 0.1 to 0.2 M caused an 11% improvement in the isolated
yield of the arylated product 3a. Proceeding at a 0.2
M reaction concentration, the reactivity of aryl bromides was compared
to aryl chlorides. As shown in Table , both aryl bromides and aryl chlorides perform well
at 2.5 mol % of Pd2(dba)3. The reactivity of
chlorobenzene dropped off at 1.25 mol % of Pd2(dba)3, but that of bromobenzene was well maintained.
Table 3
Comparison of Chlorobenzene and Bromobenzene
at Lower Catalyst Loadings
entrya
Ar–X
Pd2(dba)3 (mol %)
time (h)
isolated yield
(%)
1
Ph–Br
2.5
19
80
2
Ph–Br
1.25
19
78
3
Ph–Cl
2.5
17
83
4
Ph–Cl
1.25
17
55
Reactions were conducted at 100
°C in CPME, in a 2:1 ligand:metal ratio, with 1.2 equiv Cs2CO3, and 1.1 equiv aryl halide.
Reactions were conducted at 100
°C in CPME, in a 2:1 ligand:metal ratio, with 1.2 equiv Cs2CO3, and 1.1 equiv aryl halide.With these conditions in hand, the
substrate scope of the reaction
was investigated, as shown in Schemes and 5. Both electron-poor and
electron-rich substrates are well-tolerated, as are several heterocyclic
substrates. Nitrogenous heterocycles (3j,n–o,q–r) generally
did not perform well in the reaction unless the nitrogen basicity
was moderated, as with substrates 3n and 3o. Aryl halides with ortho-substituents did not perform
well in the coupling (3e); presumably, the steric bulk
of the ortho-group upon coordination to the palladium
center hinders transmetalation or reductive elimination. Notably,
substrates with electrophilic functional groups (3g)
are coupled in high yield. This arylated product was previously unattainable
via reported methods. Additionally, only 3a, 3k, and 3l in Schemes and 5 can be synthesized via
the Arbuzov reaction from commercially available starting materials.[21] Both aryl chlorides and aryl bromides are well-tolerated
for a diverse array of functional groups.
Scheme 4
Substrate Scope of
the α-Arylation of Triethyl Phosphonoacetate
with Aryl Bromides
Reactions were conducted at 100
°C in CPME with 1.25 mol % of Pd2(dba)3, 5 mol % of BrettPhos, 1.2 equiv of Cs2CO3, and 1.1 equiv of aryl bromide.
Reactions were conducted at 100 °C in CPME with 2.5 mol %
of Pd2(dba)3, 10 mol % of BrettPhos, 1.2 equiv
of Cs2CO3, and 1.1 equiv of aryl bromide.
Scheme 5
Substrate Scope of the α-Arylation of Triethyl
Phosphonoacetate
with Aryl Chlorides
Reactions were conducted at 100
°C in CPME, with 1.25 mol % of Pd2(dba)3, 5 mol % of BrettPhos, 1.2 equiv of Cs2CO3, and 1.1 equiv of aryl chloride.
Reactions were conducted at 100 °C in CPME, with 2.5 mol %
of Pd2(dba)3, 10 mol % of BrettPhos, 1.2 equiv
of Cs2CO3, and 1.1 equiv of aryl chloride.
Substrate Scope of
the α-Arylation of Triethyl Phosphonoacetate
with Aryl Bromides
Reactions were conducted at 100
°C in CPME with 1.25 mol % of Pd2(dba)3, 5 mol % of BrettPhos, 1.2 equiv of Cs2CO3, and 1.1 equiv of aryl bromide.Reactions were conducted at 100 °C in CPME with 2.5 mol %
of Pd2(dba)3, 10 mol % of BrettPhos, 1.2 equiv
of Cs2CO3, and 1.1 equiv of aryl bromide.
Substrate Scope of the α-Arylation of Triethyl
Phosphonoacetate
with Aryl Chlorides
Reactions were conducted at 100
°C in CPME, with 1.25 mol % of Pd2(dba)3, 5 mol % of BrettPhos, 1.2 equiv of Cs2CO3, and 1.1 equiv of aryl chloride.Reactions were conducted at 100 °C in CPME, with 2.5 mol %
of Pd2(dba)3, 10 mol % of BrettPhos, 1.2 equiv
of Cs2CO3, and 1.1 equiv of aryl chloride.We next set out to test the scalability of the
reaction. As shown
in Scheme , on a 5.0
mmol scale, this previously unreport α-arylated phosphonoacetate
was able to be isolated in 80% yield.
Scheme 6
Large Scale Cross-Coupling
We propose a mechanism for
this transformation similar to those
proposed for the α-arylations of other enolic substrates. In
this case, however, the palladium can chelate to the phosphonate or
the ester, as shown in Scheme . The different chelation modes are shown in structures C, D, and E. As proposed by Culkin
and Hartwig, reductive elimination likely occurs from the κ1-C-bound structure (C), which is accessible only
in the presence of bulky ligands on the transition metal.[13a,22] The increased stability of the chelated form D presents
the key challenge to this method, causing the reductive elimination
step to be comparatively slow.
Scheme 7
Proposed Mechanism for the α-Arylation
of Phosphonoacetates
We have also begun to investigate whether this reaction
can be
applied to quaternary centers, a much more challenging C–C
bond construction. As shown in Scheme , a quaternary α-arylated product, 5, could be achieved in an unoptimized 50% yield.
Scheme 8
Unoptimized Conditions
for the α-Arylation of Phosphine Oxides
to Form Quaternary Centers
In conclusion, a robust method for the α-arylation
of phosphonoacetates
has been developed. The method provides an efficient route to complex
arylated products that are not otherwise accessible. This process
can be utilized for a variety of functionalized aryl bromides and
aryl chlorides to afford these highly useful compounds in good to
excellent yields.
Experimental Section
General Information
Unless otherwise
noted, all reagents were reagent grade and used without further purification.
Cyclopentyl methyl ether (CPME) and toluene were distilled over CaH2 and stored under argon. Flash column chromatography was performed
using silica gel 60 (230–400). Analytical thin-layer chromatography
(TLC) was performed using 0.25 mm silica gel 254-F plates. Visualization
was accomplished with UV light and/or potassium permanganate stain. 1H NMR and 13C NMR spectra were recorded at 25 °C
on 300, 360, or 500 MHz spectrometers. 31P NMR spectra
were recorded at 25 °C on 300 or 360 MHz spectrometers and are
proton decoupled. Chemical shifts are reported relative to the solvent
resonance peak δ 7.27 (CDCl3) for 1H and
δ 77.23 (CDCl3) for 13C. For 19F spectra, chemical shifts are reported relative to a capillary internal
standard of δ −76.55 (trifluoroacetic acid). For 31P spectra, chemical shifts are reported relative to a capillary
internal standard δ 0 (H3PO4). Peaks are
reported as follows: chemical shift, multiplicity (s = singlet, d
= doublet, t = triplet, q = quartet, bs = broad singlet, m = multiplet),
coupling constants, and number of protons. High-resolution mass spectra
were obtained using a TOF mass analyzer in ESI ionization mode. All
yields refer to isolated yields, and product purity was determined
by 1H NMR spectroscopy.
General
Procedure for the Synthesis of α-Aryl
Phosphonoacetates 3
In a glovebox, a flame-dried
microwave vial containing a magnetic stir bar was charged with Cs2CO3 (78 mg, 0.24 mmol), Pd2(dba)3 (2.3 mg, 0.0025 mmol), BrettPhos (5.8 mg, 0.01 mmol), and
the aryl halide (2) (if a solid) (0.22 mmol). The vial
was capped and brought out of the glovebox. CPME was added via syringe,
followed by the aryl halide (2) (if a liquid) (0.22 mmol)
and triethyl phosphonoacetate (1) (40 μL, 0.20
mmol). The vial was sparged with dry argon and then heated to 100
°C in an oil bath with vigorous stirring. Upon consumption of
the triethyl phosphonoacetate, as monitored by TLC, 1H,
or 31P NMR, the reaction mixture was allowed to cool to
room temperature and then quenched with 1.0 mL of 1.0 M HCl. This
mixture was diluted with H2O and extracted with EtOAc (3
× 15 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified
by flash column chromatography to afford the pure α-arylated
phosphonoacetates.
The general method was followed with a
reaction time of 19 h. Purification by chromatography (50% EtOAc/hexanes)
provided the title compound as a pale yellow oil (47 mg, 78%). All
spectra were in agreement with the published literature values.[8c,23]
The general method was followed
with a reaction time of 18 h. Purification by chromatography (60%
EtOAc/hexanes) provided the title compound as a yellow oil (46 mg,
70%). All spectra were in agreement with published literature values.[8c,23]
The general method was followed
with a reaction time of 19 h. Purification by chromatography (60%
EtOAc/hexanes) provided the title compound as a pale oil (42.3 mg,
61%). All reported spectra were in agreement with published literature
values:[24] IR (neat) 2984, 2940, 1735, 1532,
1025, 735 cm–1.
In a glovebox, a flame-dried microwave
vial containing a magnetic stir bar was charged with Cs2CO3 (78 mg, 0.24 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol), and BrettPhos (11.6 mg, 0.02 mmol). The vial
was capped and brought out of the glovebox. CPME was added via syringe
followed by chlorobenzene (2k) (22 μL, 0.22 mmol)
and triethyl phosphonoacetate (1) (40 μL, 0.20
mmol). The vial was sparged with dry argon and then heated to 100
°C in an oil bath with vigorous stirring. Upon consumption of
the triethyl phosphonoacetate, as monitored by TLC, 1H,
or 31P NMR, the reaction mixture was allowed to cool to
room temperature and then quenched with 1.0 mL of 1.0 M HCl. The resultant
mixture was diluted with H2O and extracted with EtOAc (3
× 15 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by chromatography
(50% EtOAc/hexanes) provided the title compound as a pale yellow oil
(49.8 mg, 83%). All spectra were in agreement with the published literature
values.[8c,23]
The general method was followed
with a reaction time of 18 h. Purification by chromatography (60%
EtOAc/hexanes) provided the title compound as a pale yellow oil (50.1
mg, 79%). All reported spectra were in agreement with the published
literature values:[25]31P{1H} NMR (145.8 MHz, CDCl3) δ 18.85 (d, J = 12.6 Hz); IR (neat) 2985, 2936, 1735, 1509, 1050, 1026,
735 cm–1; HRMS (ESI) calcd for C14H20FO5PNa [M + Na]+m/z = 341.0930, found 341.0923.
In a glovebox, a flame-dried
Schlenk flask containing a magnetic stir bar was charged with Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (57.2 mg, 0.0625 mmol), and BrettPhos (134.2 mg, 0.25 mmol.
The flask was sealed and brought out of the glovebox. CPME (25 mL)
was added, followed by 3,5-dimethylbromobenzene (657 μL, 5.5
mmol) and triethyl phosphonoacetate (1) (992 μL,
5.0 mmol). The flask was heated to 85 °C in an oil bath with
vigorous stirring. Upon consumption of the triethyl phosphonoacetate,
as monitored by TLC, the reaction mixture was allowed to cool to room
temperature and then quenched with 25 mL of 1.0 M HCl. This mixture
was diluted with H2O and extracted with EtOAc (3 ×
15 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by
flash column chromatography (40% EtOAc/hexanes) to provide the title
compound as a pale oil (1.31g, 80%).
Ethyl 2-(Diphenylphosphoryl)-2-fluoroacetate
(4)
Under an argon atmosphere, a round-bottom
flask containing
a magnetic stir bar and equipped with a reflux condenser was charged
with ethoxydiphenylphosphane.[26] Ethyl 2-bromo-2-fluoroacetate
was charged, and the reaction was heated to reflux. After 4.5 h, the
reaction was cooled. The resulting residue was purified by flash column
chromatography (50% EtOAc/hexanes) to afford the title compound as
a white powder (10.28 g, 38%, unoptimized): mp 146–147 °C; 1H NMR (499.7 MHz, CDCl3) δ 7.92–7.84
(m, 4H), 7.65–7.60 (m, 2H), 7.56–7.52 (m, 4H), 5.70
(dd, JH–P = 8.0 Hz, JH–F = 47.0
Hz, 1H), 4.91 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125.7
MHz, CDCl3) δ 165.2 (d, J = 22.0
Hz), 133.3 (d, J = 2.8 Hz), 133.1 (d, J = 2.9 Hz), 132.1 (d, J = 2.0 Hz), 132.04 (d, J = 2.9 Hz), 131.96 (d, J = 2.9 Hz), 131.88
(d, J = 1.8 Hz), 129.0 (d, J = 14.8
Hz), 128.9 (d, J = 14.8 Hz), 88.5 (dd, JC–P = 70.5 Hz, JC–F = 203.6 Hz), 62.6, 14.1; 19F{1H} NMR (282.4 MHz, CDCl3) δ
−202.2 (d, JF–P = 59.3 Hz); 31P{1H} NMR (145.8 MHz, CDCl3) δ 26.3 (d, JP–F = 57.7 MHz); IR (neat) 3058, 2924,
1756, 1246, 1190, 1071, 698 cm–1; HRMS (ESI) calcd
for C16H17O3FP [M + H]+m/z = 307.0899, found 307.0902.
In a glovebox, a flame-dried microwave vial containing
a magnetic stir bar was charged with KHMDS (47.9 mg, 0.24 mmol), [Pd(allyl)Cl]2 (3.7 mg, 0.01 mmol), XantPhos (5.8 mg, 0.01 mmol), and ethyl
2-(diphenylphosphoryl)-2-fluoroacetate (4) (61.3 mg,
0.2 mmol). The vial was capped and brought out of the glovebox. Toluene
was added via syringe followed by iodobenzene (0.6 mmol). The vial
was then heated to 110 °C in an oil bath with vigorous stirring.
After 16 h, the reaction mixture was allowed to cool to room temperature
and then quenched with 1.0 mL of pH = 7 phosphate buffer. This mixture
was diluted with H2O and extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The resulting residue
was purified by flash column chromatography (50% EtOAc/hexanes) to
afford the title compound as a pale yellow oil (38.3 mg, 50%): 1H NMR (500 MHz, CDCl3) δ 8.14–8.1
(m, 2H), 7.7–7.63 (m, 3H), 7.59–7.56 (m, 2H), 7.50–7.46
(m, 3H), 7.37–7.3 (m, 5H), 4.1 (q, J = 7.0
Hz, 2H), 1.0 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125.8 MHz, CDCl3) δ 166.5 (dd, J = 4.6 Hz, 23.8 Hz), 133.0 (d, J = 2.8
Hz), 132.7 (d, J = 1.9 Hz), 132.6 (d, J = 2.1 Hz), 132.4 (dd, J = 3.3 Hz, 8.8 Hz), 131.7
(d, J = 20.7 Hz), 131.1, 129.1, 129.0, 128.9 (d, J = 12.1 Hz), 128.3, 128.2, 128.1, 125.8 (dd, J = 2.9 Hz, 10.2 Hz), 62.9, 13.9; 19F{1H} NMR
(338.9 MHz, CDCl3) δ −169.4 (d, JF–P = 74.5 Hz); 31P{1H} NMR
(145.8 MHz, CDCl3) δ 27.5 (d, JP–F = 74.4 MHz); IR (neat) 3057, 1750, 1591, 1265, 1246,
1206, 1116 cm–1; HRMS (ESI) calcd for C22H20O3FPNa [M + Na]+m/z = 405.1032, found 405.1050.
Authors: J C Mao; E R Otis; A M von Esch; T R Herrin; J S Fairgrieve; N L Shipkowitz; R G Duff Journal: Antimicrob Agents Chemother Date: 1985-02 Impact factor: 5.191
Authors: P C Astles; T J Brown; F Halley; C M Handscombe; N V Harris; C McCarthy; I M McLay; P Lockey; T Majid; B Porter; A G Roach; C Smith; R Walsh Journal: J Med Chem Date: 1998-07-16 Impact factor: 7.446
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8