Route to α-Aryl Phosphonoacetates: Useful Synthetic Precursors in the Horner-Wadsworth-Emmons Olefination

Article abstract of DOI:10.1021/acs.joc.5b01887

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.

Full text of DOI:10.1021/acs.joc.5b01887

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Article
pubs.acs.org/joc
Route to α‑Aryl Phosphonoacetates: Useful Synthetic Precursors in
the Horner−Wadsworth−Emmons Olefination
Kelsey F. VanGelder, Melinda Wang, and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
*
S Supporting Information
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.
INTRODUCTION
Phosphonates are biologically ubiquitous compounds, with
applications in biology and medicine.
Scheme 2. Elaboration of Biologically Relevant Cinnamic
Acids Using α-Aryl Phosphonoacetates
■
1
−6
Several such
compounds are shown in Scheme 1. Phosphonates and the
Scheme 1. Examples of α-Aryl Phosphonoacetates
Primarily, these compounds are generated via the Michaelis−
Arbuzov reaction, which requires high temperatures and has
limited tolerance for sterically hindered substrates (Scheme
12
3
a). This method is also limited by the availability of the α-
Scheme 3. Literature Precedent To Form α-Arylated
Phosphonates
corresponding phosphonoacetamides can also be useful as
7
peptidomimetics. Phosphonoacetates are also useful synthetic
precursors, such as in Horner−Wadsworth−Emmons-type
8
olefinations. Incorporating α-substitution in a stereodefined
α,β-unsaturated ester has been a significant limitation to date
8
c,9
for this method. There are several valuable natural product
cores that can be elaborated using the described α-arylated
phosphonoacetates, especially the cinnamic acid core, shown in
8
c
Scheme 2. The 2-arylcinnamic acid derivatives have been
10
studied for their antimitotic activity, as well as their activity as
11
endothelin A receptor antagonists. Unfortunately, derivatiza-
tion has been limited due to an inability to broadly
8c
functionalize the α-arene.
Despite their clear utility, there are few reported methods to
Received: August 13, 2015
synthesize any variety of α-arylated phosphonoacetates.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01887
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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 corre-
sponding phosphonic acids, proceeds in poor yield, especially
Table 1. High-Throughput Screen Validation of Ligand and
Solvent
12a,b
for sterically hindered tertiary phosphonoacetates.
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.
An alternative bond disconnection to this structural class
utilizes an aryl halide and phosphonoacetate (Scheme 3b,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
product/ isolated yield
a
b
entry
ligand
BrettPhos
solvent
CPME
IS
(%)
1
3
1
2
3
4
5
2.004
2.013
2.031
2.435
1.940
84
83
78
75
74
amides. 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
SPhos
CPME
BrettPhos
BrettPhos
trifluorotoluene
toluene
1
4−17
(Scheme 3b).
Iodobenzene works well in this trans-
CataCXium
POMetB
toluene
formation, 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
6
CataCXium
POMetB
CPME
2.025
39
a
Reactions were conducted at 100 °C and 0.1 M in solvent, with 5 mol
of Pd (dba) , 20 mol % of ligand, 1.2 equiv f base, and 1.1 equiv of
bromobenzene. Product to internal standard ratio from HTE
18
recently published the α-arylation of benzyl phosphonates,
%
2
3
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
b
screening.
19
catalyst which are not productive reaction intermediates. In
this report, we describe the first intermolecular α-arylation of
phosphonoacetates with readily available aryl bromides and
chlorides (Scheme 3c).
Table 2. Ligand and Base Screening for the α-Arylation of
Triethyl Phosphonoacetate with Bromobenzene
RESULTS AND DISCUSSION
■
An initial survey of cross-coupling conditions from related
1
8,19
acidic substrates
failed to cause α-arylation of phospho-
noacetates. Thus, reaction conditions were investigated utilizing
20
high-throughput parallel microscale experimentation. Using
bromobenzene, 12 ligands and eight solvents were evaluated
using Pd (dba) as a palladium source and 1.2 equiv of K PO .
2
3
3
4
As shown in Table 1, 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.
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 2.
a
b
entry
ligand
base
product/IS
isolated yield (%)
1
2
3
4
BrettPhos
BrettPhos
SPhos
Cs
CO
2
2.716
2.361
3.149
3.325
80
75
74
70
3
K
PO
3
4
Cs
CO
2
3
SPhos
K PO
3 4
a
Reactions were conducted at 100 °C and 0.2 M in CPME, with 2.5
mol % of Pd (dba) , 10 mol % of ligand, 1.2 equiv of base, and 1.1
equiv of bromobenzene. Product to internal standard ratio from HTE
screening.
2
3
b
Overall, reactions using BrettPhos as the ligand had a cleaner
reaction profile, and Cs CO was the most effective base for the
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
4 and 5 can be synthesized via the Arbuzov reaction from
2
3
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 3, both aryl
bromides and aryl chlorides perform well at 2.5 mol % of
Pd (dba) . The reactivity of chlorobenzene dropped off at 1.25
2
3
mol % of Pd (dba) , but that of bromobenzene was well
2
3
maintained.
With these conditions in hand, the substrate scope of the
reaction was investigated, as shown in Schemes 4 and 5. Both
21
commercially available starting materials. Both aryl chlorides
B
DOI: 10.1021/acs.joc.5b01887
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The Journal of Organic Chemistry
Article
Table 3. Comparison of Chlorobenzene and Bromobenzene
at Lower Catalyst Loadings
Scheme 5. Substrate Scope of the α-Arylation of Triethyl
Phosphonoacetate with Aryl Chlorides
a
a
entry
Ar−X
Pd (dba) (mol %)
time (h)
isolated yield (%)
2
3
1
2
3
4
Ph−Br
Ph−Br
Ph−Cl
Ph−Cl
2.5
19
19
17
17
80
78
83
55
1.25
2.5
1.25
a
Reactions were conducted at 100 °C in CPME, in a 2:1 ligand:metal
ratio, with 1.2 equiv Cs CO , and 1.1 equiv aryl halide.
2
3
Scheme 4. Substrate Scope of the α-Arylation of Triethyl
a
Phosphonoacetate with Aryl Bromides
a
Reactions were conducted at 100 °C in CPME, with 1.25 mol % of
Pd (dba) , 5 mol % of BrettPhos, 1.2 equiv of Cs CO , and 1.1 equiv
2
3
2
3
b
of aryl chloride. Reactions were conducted at 100 °C in CPME, with
.5 mol % of Pd (dba) , 10 mol % of BrettPhos, 1.2 equiv of Cs CO ,
2
2
3
2
3
and 1.1 equiv of aryl chloride.
Scheme 6. Large Scale Cross-Coupling
a
Reactions were conducted at 100 °C in CPME with 1.25 mol % of
Pd (dba) , 5 mol % of BrettPhos, 1.2 equiv of Cs CO , and 1.1 equiv
of aryl bromide. Reactions were conducted at 100 °C in CPME with
2
3
2
3
b
2
.5 mol % of Pd (dba) , 10 mol % of BrettPhos, 1.2 equiv of Cs CO ,
2
3
2
3
and 1.1 equiv of aryl bromide.
Scheme 7. Proposed Mechanism for the α-Arylation of
Phosphonoacetates
and aryl bromides are well-tolerated for a diverse array of
functional groups.
We next set out to test the scalability of the reaction. As
shown in Scheme 6, on a 5.0 mmol scale, this previously
unreport α-arylated phosphonoacetate was able to be isolated
in 80% yield.
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 7. The different
chelation modes are shown in structures C, D, and E. As
proposed by Culkin and Hartwig, reductive elimination likely
1
occurs from the κ -C-bound structure (C), which is accessible
only in the presence of bulky ligands on the transition
1
3a,22
metal.
The increased stability of the chelated form D
presents the key challenge to this method, causing the reductive
elimination step to be comparatively slow.
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 8, a quaternary α-
arylated product, 5, could be achieved in an unoptimized 50%
yield.
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
C
DOI: 10.1021/acs.joc.5b01887
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The Journal of Organic Chemistry
Article
CDCl ) δ 19.10 (s); IR (neat) 3058, 2988, 2940, 1733, 1300, 1253,
Scheme 8. Unoptimized Conditions for the α-Arylation of
Phosphine Oxides to Form Quaternary Centers
3
−1
+
1
050, 1026 cm ; HRMS (ESI) calcd for C H O PNa [M + Na] m/
18 23 5
z = 373.1181, found 373.1189.
Ethyl 2-(Diethoxyphosphoryl)-2-(4-methoxyphenyl)acetate (Aryl
Bromide) (3c). 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
8
c,23
were in agreement with published literature values.
Ethyl 2-(Benzofuran-5-yl)-2-(diethoxyphosphoryl)acetate (Aryl
Bromide) (3d). The general method was followed with a reaction
time of 17 h. Purification by chromatography (60% EtOAc/hexanes)
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.
1
provided the title compound as a yellow oil (49 mg, 72%): H NMR
(
300.1 MHz, CDCl ) δ 7.81 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.49−
3
7
4
3
1
1
.42 (m, 2H), 6.77−6.76 (m, 1H), 4.34 (d, J
= 23.5 Hz, 1H),
EXPERIMENTAL SECTION
I. General Information. Unless otherwise noted, all reagents were
reagent grade and used without further purification. Cyclopentyl
H−P
■
.32−3.89 (m, 6H), 1.283 (t, J = 7.1 Hz, 3H), 1.276 (t, J = 7.1 Hz,
H), 1.19 (t, J = 7.1 Hz, 3H); 13C{ H} NMR (90.6 MHz, CDCl ) δ
1
3
68.2, 154.8, 145.7, 127.9, 126.1 (d, J = 6.3 Hz), 125.6 (d, J = 8.1 Hz),
22.6 (d, J = 6.7 Hz), 111.5, 106.9, 63.5 (d, J = 6.8 Hz), 63.3 (d, J = 7.1
methyl ether (CPME) and toluene were distilled over CaH and
2
stored under argon. Flash column chromatography was performed
using silica gel 60 (230−400). Analytical thin-layer chromatography
Hz), 62.0, 52.2 (d, J = 135.8 Hz), 16.5 (d, J = 5.8 Hz), 16.4 (d, J = 5.8
Hz), 14.2; 31P{ H} NMR (121.5 MHz, CDCl ) δ 18.04 (s); IR (neat)
1
(
TLC) was performed using 0.25 mm silica gel 254-F plates.
3
−1
2
985, 2930, 1733, 1468, 1446, 1256, 1050, 1026 cm ; HRMS (ESI)
Visualization was accomplished with UV light and/or potassium
permanganate stain. H NMR and C NMR spectra were recorded at
2
recorded at 25 °C on 300 or 360 MHz spectrometers and are proton
decoupled. Chemical shifts are reported relative to the solvent
+
1
13
calcd for C H O PNa [M + Na] m/z = 363.0973, found 363.0975.
16 21 6
31
Ethyl 2-(Diethoxyphosphoryl)-2-(3,5-dimethylphenyl)acetate
Aryl Bromide) (3f). The general method was followed with a reaction
5 °C on 300, 360, or 500 MHz spectrometers. P NMR spectra were
(
time of 23 h. Purification by chromatography (40% EtOAc/hexanes)
1
1
13
provided the title compound as a pale oil (56.3 mg, 86%): H NMR
resonance peak δ 7.27 (CDCl ) for H and δ 77.23 (CDCl ) for C.
3
3
For 1 F spectra, chemical shifts are reported relative to a capillary
9
(360 MHz, CDCl ) δ 7.12 (s, 2H), 6.94 (s, 1H), 4.30−3.97 (m, 7H),
3
31
2
.31 (s, 6H), 1.28 (t, J = 7.2 Hz, 6H), 1.22 (t, J = 7.0 Hz, 3H);
internal standard of δ −76.55 (trifluoroacetic acid). For P spectra,
chemical shifts are reported relative to a capillary internal standard δ 0
1
3
1
C{ H} NMR (90.6 MHz, CDCl ) δ 167.8, 138.0 (d, J = 1.8 Hz),
3
(
H PO ). Peaks are reported as follows: chemical shift, multiplicity (s
singlet, d = doublet, t = triplet, q = quartet, bs = broad singlet, m =
130.6 (d, J = 8.1 Hz), 129.6 (d, J = 3.6 Hz), 127.3 (d, J = 6.3 Hz), 63.3
(d, J = 7.2 Hz), 63.1 (d, J = 7.2 Hz), 61.7, 52.1 (d, J = 134.9 Hz), 21.3,
16.3 (d, J = 5.9 Hz), 16.2 (d, J = 5.9 Hz), 14.0; 31P{ H} NMR (145.8
3
4
=
1
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
MHz, CDCl ) δ 19.47 (s); IR (neat) 2985, 2928, 1735, 1602, 1256,
3
−1
+
1051, 1024, 733 cm ; HRMS (ESI) calcd for C H O P [M + H]
16
26
5
1
purity was determined by H NMR spectroscopy.
m/z = 329.1518, found 329.1516.
II. General Procedure for the Synthesis of α-Aryl Phospho-
Methyl 4-(1-(Diethoxyphosphoryl)-2-ethoxy-2-oxoethyl)-
benzoate (Aryl Bromide) (3g). The general method was followed
with a reaction time of 21 h. Purification by chromatography (50%
noacetates 3. In a glovebox, a flame-dried microwave vial containing
a magnetic stir bar was charged with Cs CO (78 mg, 0.24 mmol),
Pd (dba) (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
2
3
2
3
EtOAc/hexanes) provided the title compound as a pale yellow oil
1
(
41.6 mg, 58%): H NMR (360 MHz, CDCl ) δ 8.01 (d, J = 8.3 Hz,
3
2
4
7
H), 7.60 (dd, J = 8.6 Hz, 2.2 Hz, 2H), 4.31 (d, JH−P = 23.8 Hz, 1H),
.28−3.96 (m, 6H), 3.91 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.26 (t, J =
13
1
.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); C{ H} NMR (90.6 MHz,
CDCl ) δ 167.1 (d, J = 3.6 Hz), 166.7, 136.2, 136.1, 129.73, 129.66,
3
6
5
3.5 (d, J = 7.2 Hz), 63.3 (d, J = 7.2 Hz), 62.0, 52.4 (d, J = 133.1 Hz),
2.1, 16.3 (d, J = 4.8 Hz), 16.2 (d, J = 4.8 Hz), 14.0; P{ H} NMR
1
31
monitored by TLC, H, or P 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 H O and extracted with EtOAc (3
31
1
(
1
145.8 MHz, CDCl ) δ 18.44 (s); IR (neat) 2984, 2910, 1724, 1279,
257, 1021, 734 cm ; HRMS (ESI) calcd for C H O P [M + Na]
16 23 7
3
2
−1
+
×
15 mL). The combined organic layers were dried over MgSO and
4
m/z = 381.1079, found 381.1085
Ethyl 2-(Diethoxyphosphoryl)-2-(3-nitrophenyl)acetate (Aryl Bro-
mide) (3h). The general method was followed with a reaction time of
concentrated in vacuo. The resulting residue was purified by flash
column chromatography to afford the pure α-arylated phosphonoa-
cetates.
1
9 h. Purification by chromatography (60% EtOAc/hexanes) provided
Ethyl 2-(Diethoxyphosphoryl)-2-phenylacetate (Aryl Bromide)
the title compound as a pale oil (42.3 mg, 61%). All reported spectra
(
3a). The general method was followed with a reaction time of 19
2
4
were in agreement with published literature values: IR (neat) 2984,
h. Purification by chromatography (50% EtOAc/hexanes) provided
−1
2
940, 1735, 1532, 1025, 735 cm .
the title compound as a pale yellow oil (47 mg, 78%). All spectra were
in agreement with the published literature values.
Ethyl 2-(Diethoxyphosphoryl)-2-(naphthalen-2-yl)acetate (Aryl
Bromide) (3b). The general method was followed with a reaction
time of 17 h. Purification by chromatography (60% EtOAc/hexanes)
provided the title compound as a yellow solid (62 mg, 88%): mp 65−
6
3
4
3
8c,23
Ethyl 2-(Diethoxyphosphoryl)-2-(3-(trifluoromethyl)phenyl)-
acetate (Aryl Bromide) (3i). The general method was followed with
a reaction time of 19 h. Purification by chromatography (40% EtOAc/
1
hexanes) provided the title compound as a pale oil (48.5 mg, 66%): H
NMR (360 MHz, CDCl ) δ 7.78 (m, 1H), 7.75−7.73 (m, 1H), 7.59−
3
1
7.57 (m, 1H), 7.47 (dd, J = 7.8 Hz, 7.8 Hz, 1H), 4.32−4.00 (m, 6H),
7 °C; H NMR (360 MHz, CDCl ) δ 7.99 (m, 1H), 7.86−7.82 (m,
3
4
.30 (d, J
= 24.1 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2
H), 7.68 (ddd, J = 8.6 Hz, 1.6 Hz, 1.4 Hz, 1H), 7.50−7.47 (m, 2H),
.43 (d, J
H), 1.28 (t, J = 6.7 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); C{ H} NMR
H−P
13
1
Hz, 3H), 1.21 (t, J = 7.0 Hz, 3H); C{ H} NMR (125.8 MHz,
CDCl ) δ 167.3 (d, J = 5.0 Hz), 133.3 (d, J = 6.3 Hz), 132.4 (d, J = 8.8
= 23.4 Hz, 1H), 4.31−3.97 (m, 6H), 1.29 (t, J = 6.8 Hz,
H−P
13 1
3
(
125.7 MHz, CDCl ) δ 167.7 (d, J = 1.5 Hz), 133.2 (d, J = 1.5 Hz),
Hz), 131.0 (dq, J = 32.1 Hz, 1.9 Hz), 129.1 (d, J = 2.5 Hz), 126.8−
126.6 (m), 125.0−124.9 (m), 124.1 (q, JC−F = 272.1 Hz), 63.8 (d, J =
6.3 Hz), 63.5 (d, J = 7.5 Hz), 62.3, 52.2 (d, J = 134.6 Hz), 16.4 (d, J =
6.3 Hz), 16.3 (d, J = 6.3 Hz), 14.2; 31P{ H} NMR (145.8 MHz,
3
1
1
6
6
33.8, 128.81, 128.75, 128.5 (d, J = 5.3 Hz), 128.1 (d, J = 0.9 Hz),
28.0, 127.6, 127.3 (d, J = 5.0 Hz), 126.2 (d, J = 3.8 Hz), 63.4 (d, J =
.3 Hz), 63.1 (d, J = 7.5 Hz), 61.8, 52.4 (d, J = 134.6 Hz), 16.3 (d, J =
.3 Hz), 16.2 (d, J = 6.3 Hz), 14.1; 31P{ H} NMR (145.8 MHz,
1
1
CDCl ) δ 18.30 (s); IR (neat) 2987, 2938, 1736, 1330, 1026, 736
3
D
DOI: 10.1021/acs.joc.5b01887
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The Journal of Organic Chemistry
Article
−
1
+
= 5.7 Hz), 14.2; 31P{ H} NMR (145.8 MHz, CDCl ) δ 19.58 (s); IR
1
cm ; HRMS (ESI) calcd for C H F O P [M + H] m/z = 369.1079,
15
20
3
5
3
−1
found 369.1080.
(neat) 2981, 2934, 1733, 1024, 731 cm ; HRMS (ESI) calcd for
C H NO P [M + H] m/z = 440.1838, found 440.1823.
Large-Scale Reaction: Ethyl 2-(Diethoxyphosphoryl)-2-(3,5-
dimethylphenyl)acetate (Aryl Bromide) (3f). In a glovebox, a
flame-dried Schlenk flask containing a magnetic stir bar was charged
with Cs CO (1.95 g, 6.0 mmol), Pd (dba) (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
+
Ethyl 2-(Diethoxyphosphoryl)-2-phenylacetate (Aryl Chloride)
3k). In a glovebox, a flame-dried microwave vial containing a
magnetic stir bar was charged with Cs CO (78 mg, 0.24 mmol),
21
31
7
(
2
3
Pd (dba)3 (4.6 mg, 0.005 mmol), and BrettPhos (11.6 mg, 0.02
2
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
2
3
2
3
3
,5-dimethylbromobenzene (657 μL, 5.5 mmol) and triethyl
phosphonoacetate (1) (992 μL, 5.0 mmol). The flask was heated to
5 °C in an oil bath with vigorous stirring. Upon consumption of the
phosphonoacetate, as monitored by TLC, 1H, or 31P NMR, the
8
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
triethyl phosphonoacetate, as monitored by TLC, the reaction mixture
diluted with H O and extracted with EtOAc (3 × 15 mL). The
was allowed to cool to room temperature and then quenched with 25
2
combined organic layers were dried over MgSO and concentrated in
mL of 1.0 M HCl. This mixture was diluted with H O and extracted
4
2
vacuo. Purification by chromatography (50% EtOAc/hexanes)
with EtOAc (3 × 15 mL). The combined organic layers were dried
provided the title compound as a pale yellow oil (49.8 mg, 83%).
over MgSO and concentrated in vacuo. The resulting residue was
4
8
c,23
All spectra were in agreement with the published literature values.
purified by flash column chromatography (40% EtOAc/hexanes) to
provide the title compound as a pale oil (1.31g, 80%).
Ethyl 2-(Diethoxyphosphoryl)-2-(4-fluorophenyl)acetate (Aryl
Chloride) (3l). 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
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
2
6
2
5
31
1
ethoxydiphenylphosphane. 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
values:
P{ H} NMR (145.8 MHz, CDCl ) δ 18.85 (d, J = 12.6
3
−1
Hz); IR (neat) 2985, 2936, 1735, 1509, 1050, 1026, 735 cm ; HRMS
ESI) calcd for C H FO PNa [M + Na] m/z = 341.0930, found
14 20 5
+
(
341.0923.
Ethyl 2-(Diethoxyphosphoryl)-2-(4-(trifluoromethyl)phenyl)-
compound as a white powder (10.28 g, 38%, unoptimized): mp 146−
1
acetate (Aryl Chloride) (3m). The general method was followed
with a reaction time of 17 h. Purification by chromatography (60%
1
47 °C; H NMR (499.7 MHz, CDCl ) δ 7.92−7.84 (m, 4H), 7.65−
3
7
.60 (m, 2H), 7.56−7.52 (m, 4H), 5.70 (dd, JH−P = 8.0 Hz, JH−F = 47.0
EtOAc/hexanes) provided the title compound as a pale yellow oil
13
1
Hz, 1H), 4.91 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H); C{ H}
1
(
4
3
(
1
1
=
=
(
61.1 mg, 83%): H NMR (300 MHz, CDCl ) δ 7.68−7.60 (m, 4H),
3
NMR (125.7 MHz, CDCl ) δ 165.2 (d, J = 22.0 Hz), 133.3 (d, J = 2.8
3
.33−3.96 (m, 6H), 4.31 (d, J
H), 1.28 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); C{ H} NMR
= 23.7 Hz, 1H), 1.29 (t, J = 7.1 Hz,
H−P
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
13
1
125.8 MHz, CDCl ) δ 167.2 (d, J = 3.8 Hz), 135.4 (d, J = 8.8 Hz),
3
Hz), 128.9 (d, J = 14.8 Hz), 88.5 (dd, J
= 70.5 Hz, JC−F = 203.6
C−P
30.4 (dq, J = 32.7 Hz, JC−F = 2.5 Hz), 130.2 (d, J = 6.3 Hz), 125.6−
25.5 (m), 124.2 (q, JC−F = 272.5 Hz), 63.8 (d, J = 7.5 Hz), 63.5 (d, J
19
1
Hz), 62.6, 14.1; F{ H} NMR (282.4 MHz, CDCl ) δ −202.2 (d, J
3
F−P
=
59.3 Hz); 31P{ H} NMR (145.8 MHz, CDCl ) δ 26.3 (d, J = 57.7
1
6.3 Hz), 62.3, 52.3 (d, J = 133.3 Hz), 16.5 (d, J = 6.9 Hz), 16.4 (d, J
3
P−F
6.9 Hz), 14.2; 31P{ H} NMR (145.8 MHz, CDCl ) δ 18.03 (s); IR
1
−1
MHz); IR (neat) 3058, 2924, 1756, 1246, 1190, 1071, 698 cm ;
3
−1
+
neat) 2985, 2936, 1736, 1325, 1020, 736 cm ; HRMS (ESI) calcd
for C H F O P [M + H] m/z = 369.1079, found 369.1071.
HRMS (ESI) calcd for C16
H O FP [M + H] m/z = 307.0899, found
17 3
+
15
21
3
5
307.0902.
Ethyl 2-(4-(1H-Pyrrol-1-yl)phenyl)-2-(diethoxyphosphoryl)acetate
Ethyl 2-(Diphenylphosphoryl)-2-fluoro-2-phenylacetate (5). In a
glovebox, a flame-dried microwave vial containing a magnetic stir bar
(
Aryl Chloride) (3n). The general method was followed with a reaction
time of 19 h. Purification by chromatography (60% EtOAc/hexanes)
was charged with KHMDS (47.9 mg, 0.24 mmol), [Pd(allyl)Cl] (3.7
1
2
provided the title compound as a pale yellow oil (65.6 mg, 90%): H
mg, 0.01 mmol), XantPhos (5.8 mg, 0.01 mmol), and ethyl 2-
NMR (300.1 MHz, CDCl ) δ 7.59 (dd, J = 8.7 Hz, 2.3 Hz, 2H), 7.39
3
(diphenylphosphoryl)-2-fluoroacetate (4) (61.3 mg, 0.2 mmol). The
(
d, J = 8.3 Hz, 2H), 7.10 (dd, J = 2.2 Hz, 2.2 Hz, 2H), 6.35 (dd, J = 2.1
= 23.8 Hz, 1H),
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
Hz, 2.1 Hz, 2H), 4.34−3.96 (m, 6H), 4.27 (d, J
H−F
1
3
1
.304 (t, J = 7.1 Hz, 3H), 1.295 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz,
H); 1 C{ H} NMR (125.8 MHz, CDCl ) δ 167.5 (d, J = 3.8 Hz),
3
1
3
40.4, 130.8 (d, J = 6.3 Hz), 128.2 (d, J = 7.5 Hz), 120.3 (d, J = 2.5
Hz), 119.1, 110.6, 63.4 (d, J = 6.3 Hz), 63.2 (d, J = 6.3 Hz), 51.6 (d, J
=
133.3 Hz), 16.31 (d, J = 6.3 Hz), 16.26 (d, J = 6.3 Hz), 14.03;
diluted with H O and extracted with CH Cl (3 × 15 mL). The
2
2
2
3
1
1
P{ H} NMR (121.5 MHz, CDCl ) δ 18.79 (s); IR (neat) 3054,
combined organic layers were dried over MgSO and concentrated in
3
4
−1
2
984, 2930, 1733, 1521, 1265, 735 cm ; HRMS (ESI) calcd for
C H NO P [M + H] m/z = 366.1470, found 366.1472.
vacuo. The resulting residue was purified by flash column
+
1
8
25
5
chromatography (50% EtOAc/hexanes) to afford the title compound
1
tert-Butyl-5-(1-(Diethoxyphosphoryl)-2-ethoxy-2-oxoethyl)-1H-
indole-1-carboxylate (Aryl Chloride) (3o). The general method was
followed with a reaction time of 21 h. Purification by chromatography
as a pale yellow oil (38.3 mg, 50%): H NMR (500 MHz, CDCl ) δ
3
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,
(
40% EtOAc/hexanes) provided the title compound as a pale yellow
13
1
3
H); C{ H} NMR (125.8 MHz, CDCl ) δ 166.5 (dd, J = 4.6 Hz,
1
3
oil (85.6 mg, 97%): H NMR (500 MHz, CDCl ) δ 8.10 (d, J = 8.0
3
2
3.8 Hz), 133.0 (d, J = 2.8 Hz), 132.7 (d, J = 1.9 Hz), 132.6 (d, J = 2.1
Hz, 1H), 7.75 (dd, J = 2.0 Hz, 2.0 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H),
Hz), 132.4 (dd, J = 3.3 Hz, 8.8 Hz), 131.7 (d, J = 20.7 Hz), 131.1,
7
4
.44 (ddd, J = 8.6 Hz, 1.9 Hz, 1.9 Hz, 1H), 6.56 (d, J = 3.5 Hz, 1H),
.33 (d, JH−P = 23.0 Hz, 1H), 4.28−3.91 (m, 6H), 1.67 (s, 9H), 1.270
1
2
−
2
29.1, 129.0, 128.9 (d, J = 12.1 Hz), 128.3, 128.2, 128.1, 125.8 (dd, J =
19
1
.9 Hz, 10.2 Hz), 62.9, 13.9; F{ H} NMR (338.9 MHz, CDCl ) δ
(
t, J = 7.0 Hz, 3H), 1.268 (t, J = 7.0 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H);
3
169.4 (d, JF−P = 74.5 Hz); 31P{ H} NMR (145.8 MHz, CDCl ) δ
1
1
3
1
C{ H} NMR (125.8 MHz, CDCl ) δ 168.2 (d, J = 1.8 Hz), 149.8,
3
3
7.5 (d, JP−F = 74.4 MHz); IR (neat) 3057, 1750, 1591, 1265, 1246,
1
(
35.0, 130.9, 126.6, 125.9 (d, J = 4.3 Hz), 125.3 (d, J = 6.1 Hz), 122.3
d, J = 5.0 Hz), 115.3, 107.5, 84.0, 63.6 (d, J = 4.5 Hz), 63.2 (d, J = 4.5
Hz), 61.9, 52.2 (d, J = 97.8 Hz), 28.3, 16.52 (d, J = 5.7 Hz), 16.48 (d, J
−1
FPNa [M + Na]+
1206, 1116 cm ; HRMS (ESI) calcd for C22H O
20 3
m/z = 405.1032, found 405.1050.
E
DOI: 10.1021/acs.joc.5b01887
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
12) (a) Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01887.
■
4
15−430. (b) Demmer, C. S.; Krogsgaard-Larsen, N.; Bunch, L. Chem.
*
S
Rev. 2011, 111, 7981−8006. (c) Rajeshwaran, G. G.; Nandakumar, M.;
Sureshbabu, R.; Mohanakrishnan, A. K. Org. Lett. 2011, 13, 1270−
1
273.
Experimental procedures and tabulated results of high-
throughput experiments; H, C, F, and P NMR
spectra (PDF)
(13) Reviews of activated α-arylation: (a) Culkin, D. A.; Hartwig, J. F.
1
13
19
31
Acc. Chem. Res. 2003, 36, 234−245. (b) Bellina, F.; Rossi, R. Chem.
Rev. 2010, 110, 1082−1146. (c) Lloyd-Jones, G. C. Angew. Chem., Int.
Ed. 2002, 41, 953−956. (d) Johansson, C. C. C.; Colacot, T. J. Angew.
Chem., Int. Ed. 2010, 49, 676−707.
AUTHOR INFORMATION
(14) Buchwald, S. L.; Klapars, A.; Kwong, F. Y. Copper-catalyzed
■
formation of carbon−heteroatom and carbon−carbon bonds. Interna-
Corresponding Author
E-mail: marisa@sas.upenn.edu.
tional PatentWO 2004/013094 A2, 2004.
*
(
1
(
3
15) Minami, T.; Isonaka, T.; Okada, Y.; Ichikawa, J. J. Org. Chem.
993, 58, 7009−7015.
16) Rout, L.; Regati, S.; Zhao, C.-G. Adv. Synth. Catal. 2011, 353,
340−3346.
17) For an intramolecular cyclization to form oxindoles that was
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(
■
only successful with iodides and bromides (not chlorides), see:
Millemaggi, A.; Perry, A.; Whitwood, A. C.; Taylor, R. J. K. Eur. J. Org.
Chem. 2009, 18, 2947−2952.
We are grateful to the National Institutes of Health
(
(
GM087605) and the National Science Foundation
CHE1213230 and CHE1464778) for financial support of
(
18) Montel, S.; Raffier, L.; He, Y.; Walsh, P. J. Org. Lett. 2014, 16,
446−1449.
19) Metz, A. E.; Berritt, S.; Dreher, S. D.; Kozlowski, M. C. Org. Lett.
this research. The NSF provided funding for the High
Throughput Laboratory (GOALI CHE-0848460). Partial
instrumentation support was provided by the NIH for MS
1
(
2
012, 14, 760−763.
(
(
1S10RR023444), NMR (1S10RR022442), and HTE
S10OD011980). We thank Dr. Simon Berritt for his help
(20) Schmink, J. R.; Bellomo, A.; Berritt, S. Aldrichimica Acta 2013,
46, 71−80.
with the high-throughput experimentation. We thank Dr. Sonia
Montel and Dr. Patrick Walsh for helpful discussions.
(21) Based on the availability of the corresponding ethyl α-halo-α-
aryl acetate in the Sigma Aldrich and Fisher compound catalogs as of
the date of submission.
(
22) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
REFERENCES
■
5
2
(
816−5817. (b) Wolkowski, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed.
(
1) Weigele, M.; Jacobsen, V. A.; Macek, K.; Yang, M. G.; Kawahata,
002, 41, 4289−4291.
N. H.; Sundaramoorthi, R. Wang, Y.; Luke, G. P.; Metcalf, C. A.;
Shakespeare, W. C.; Sawyer, T. Novel Signal Transduction Inhibitors,
Compositions Containing Them. International Patent WO 99/24442,
23) Minami, T.; Isonaka, T.; Okada, Y.; Ichikawa, J. J. Org. Chem.
1
(
1
(
993, 58, 7009−7015.
24) Zhang, N.; Casida, J. E. Bioorg. Med. Chem. 2002, 10, 1281−
290.
25) Poon, J.-F.; Alao, J. P.; Sunnerhagen, P.; Diner
Chem. 2013, 11, 4526−4536.
26) Ethoxydiphenylphosphane was synthesized following the
1
(
999.
2) Close, J.; Grimm, J.; Heidebrecht, R. W.; Kattar, S.; Miller, T. A.;
́
, P. Org. Biomol.
Otte, K. M.; Peterson, S.; Siliphaivanh, P.; Tempest, P.; Wilson, K. J.;
Witter, D. J. The Phosphorus Derivatives as Histone Deacetylase
Inhibitors. International Patent WO 2008/010985 A2, 2008.
3) Hollis, L. S.; Miller, A. V.; Amundsen, A. R.; Schurig, J. E.; Stern,
E. W. J. Med. Chem. 1990, 33, 105−111.
4) Mao, J. C.-H.; Otis, E. R.; von Esch, A. M.; Herrin, T. R.;
Fairgrieve, J. S.; Shipkowitz, N. L.; Duff, R. G. Antimicrob. Agents
Chemother. 1985, 27, 197−202.
5) Eriksson, B.; Oberg, B.; Wahren, B. Biochim. Biophys. Acta, Gene
(
procedure outlined in the following reference and was used without
purification. Note: the product is air sensitive, so care was taken to
minimize atmospheric exposure. Germaund, L.; Brunel, S.; Chevalier,
Y.; Le Perchec, P. Bull. Soc. Chim. Fr. 1988, 4, 699−704.
(
(
(
Struct. Expression 1982, 696, 115−123.
(
6) Beers, S.; Malloy, E. A.; Schwender, C. Substituted Phosphonic
Acids and Derivatives Useful in Treating Bone Wasting Diseases. U.S.
Patent 5,508,273, 1996.
(
7) (a) Azema, L.; Baron, R.; Ladame, S. Curr. Enzyme Inhib. 2006, 2,
1−72. (b) Kudzin, Z. H.; Kudzin, M. H.; Drabowicz, J.; Stevens, C. V.
Curr. Org. Chem. 2011, 15, 2015−2071. (c) Engel, R. Chem. Rev. 1977,
7, 349−367.
8) (a) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87−99.
b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927.
c) Ianni, A.; Waldvogel, S. R. Synthesis 2006, 2006, 2103−2112.
9) (a) Patois, C.; Savignac, P.; About-Jaudet, E.; Collignon, N.
6
7
(
(
(
(
Organic Synthesis; John Wiley & Sons: New York, 1996; Collect. Vol.
IX, pp 88−91. (b) Mani, N. S.; Mapes, C. M.; Wu, J.; Deng, X.; Jones,
T. K. J. Org. Chem. 2006, 71, 5039−5042.
(
10) Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.;
McGown, A. T. J. Org. Chem. 2001, 66, 8135−8138.
(
11) (a) Astles, P. C.; Brown, T. J.; Halley, F.; Handscombe, C.;
Harris, N. V.; McCarthy, C.; McLay, I. M.; Lockey, P.; Majid, T.;
Porter, B.; Roach, A. G.; Smith, C.; Walsh, R. J. Med. Chem. 1998, 41,
2
745−2753. (b) Ohsumi, K.; Nakagawa, R.; Fukuda, Y.; Hatanaka, T.;
Morinaga, Y.; Nihei, Y.; Ohishi, K.; Suga, Y.; Akiyama, Y.; Tsuji, T. J.
Med. Chem. 1998, 41, 3022−3032.
F
DOI: 10.1021/acs.joc.5b01887
J. Org. Chem. XXXX, XXX, XXX−XXX