Synthesis of 4-sulfonatobenzylphosphines and their application in aqueous-phase palladium-catalyzed cross-coupling

Article abstract of DOI:10.1016/j.jorganchem.2014.11.011

Aqueous-biphasic catalysis offers the potential for safer and more environmentally sustainable synthetic processes. In addition, hydrophilic supporting ligands allow homogeneous catalysts to be readily separated from organic products and potentially reused. The synthesis of two new water-soluble ligand precursors, di-tert-butyl(4-sulfonatobenzyl)phosphonium and di-1-adamantyl(4-sulfonatobenzyl)phosphonium, are reported. The air-stable, zwitterionic phosphonium salts were prepared by the reaction of dialkylphosphines with ethyl 4-bromomethylbenzenesulfonate, which results in a one-pot alkylation followed by deprotection of the ethyl sulfonate. This methodology provides an operationally simpler route to sulfonated benzylphosphines than electrophilic sulfonation. The new phosphine ligands were applied to aqueous-phase Suzuki and Sonogashira couplings of aryl bromides.

Full text of DOI:10.1016/j.jorganchem.2014.11.011

Journal of Organometallic Chemistry 777 (2015) 16e24
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis of 4-sulfonatobenzylphosphines and their application in
aqueous-phase palladium-catalyzed cross-coupling
Jane N. Moore, Nicholas M. Laskay, Kevin S. Duque, Steven P. Kelley, Robin D. Rogers,
Kevin H. Shaughnessy*
Department of Chemistry, The University of Alabama, Box 870336, Tuscaloosa, AL 35487-0336, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Aqueous-biphasic catalysis offers the potential for safer and more environmentally sustainable synthetic
processes. In addition, hydrophilic supporting ligands allow homogeneous catalysts to be readily sepa-
rated from organic products and potentially reused. The synthesis of two new water-soluble ligand
precursors, di-tert-butyl(4-sulfonatobenzyl)phosphonium and di-1-adamantyl(4-sulfonatobenzyl)phos-
phonium, are reported. The air-stable, zwitterionic phosphonium salts were prepared by the reaction of
dialkylphosphines with ethyl 4-bromomethylbenzenesulfonate, which results in a one-pot alkylation
followed by deprotection of the ethyl sulfonate. This methodology provides an operationally simpler
route to sulfonated benzylphosphines than electrophilic sulfonation. The new phosphine ligands were
applied to aqueous-phase Suzuki and Sonogashira couplings of aryl bromides.
Received 4 October 2014
Received in revised form
5 November 2014
Accepted 6 November 2014
Available online 25 November 2014
Keywords:
Cross-coupling
Palladium
© 2014 Elsevier B.V. All rights reserved.
Phosphine
Aqueous-phase reaction
Catalysis
Introduction
[10]. Common features among these ligands are large steric de-
mands and strong
s-electron donating ability. These properties
Water has received significant attention as a reaction medium in
metal-catalyzed reactions because of its numerous attractive
properties compared to traditional organic solvents [1e4]. Water is
nonflammable, nontoxic, renewable, and widely available. Water
has also been considered as an environmentally friendly solvent
due these many beneficial properties. Reactions run in water are
not inherently environmentally friendly, however; as aqueous
waste streams with organic contaminants represent their own
disposal challenges. For metal-catalyzed reactions, water offers the
potential to easily separate hydrophilic precious metal catalysts
from organic product streams for potential reuse. Finally, water has
been shown to promote organic reactions of hydrophobic sub-
strates in many reactions [5].
Palladium-catalyzed cross-coupling reactions have become
widely used tools for construction of carbonecarbon and carbon-
heteroatom bonds [6,7]. Significant research effort has identified
several highly effective classes of ligands, such as sterically
demanding trialkylphosphines (Pt-Bu3, Ad2PBu) [8], dialkylbiar-
ylphosphines (X-phos) [9], and N-heterocylic carbenes (IMes, IPr)
favor low-coordination, electron-rich active species that are highly
active towards oxidative addition [11]. The steric bulk can also favor
challenging reductive eliminations [12,13].
The use of water-soluble phosphine ligands in palladium-
catalyzed cross-coupling reactions dates to Casalnuovo's pioneer-
ing report of the use of Pd(TPPMS)3 (TPPMS ¼ sodium diphenyl(3-
sulfonato)phenylphosphine) for Suzuki, Heck, and Sonogashira
couplings of aryl halides in water/organic solvent mixtures [14].
Since that initial report, numerous examples of hydrophilic ligands
have been disclosed to provide effective cross-coupling catalysts
[2,15]. Early hydrophilic ligands, such as TPPTS (Fig. 1) [16], were
based on modified triphenylphosphine scaffolds. Catalysts derived
from these ligands showed modest activity and were limited to aryl
iodides or in some cases aryl bromides at elevated temperatures
(>100 ꢀC). Our group reported the first examples of hydrophilic,
sterically demanding trialkylphosphine ligands for cross-coupling
reactions [17,18]. Since these initial reports, we and others have
developed hydrophilic phosphines [19e25] and N-heterocyclic
carbene precursors [26,27] that provide high activity catalysts
capable of coupling aryl bromides and chlorides under mild con-
ditions (Fig. 1).
In designing more effective water-soluble phosphine ligands,
we were interested in exploring alkylaryl substituents, such as
* Corresponding author. Tel.: þ1 205 348 4435; fax: þ1 205 348 9104.
E-mail address: kshaughn@ua.edu (K.H. Shaughnessy).
http://dx.doi.org/10.1016/j.jorganchem.2014.11.011
0022-328X/© 2014 Elsevier B.V. All rights reserved.

J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
17
Scheme 1. Retrosynthetic plan to synthesis sulfonated benzylphosphines.
white precipitates (1aec, Eq. (1)). Treatment of phosphonium salt
1a with concentrated sulfuric acid gave no appreciable sulfonation.
Use of 20% fuming sulfuric acid resulted in sulfonation of the aro-
matic ring predominately at the para-position to give 2a (Eq. (2)).
Neutralization of the reaction mixture afforded desired 2a along
with the corresponding oxide (3a) and other unknown phosphorus
containing byproducts. In order to better control the pH during
neutralization, 5 equivalents of KH2PO4 were added after comple-
tion of the sulfonation reaction followed by careful neutralization
to pH 7 with 10% aqueous NaOH. The product was extracted into
methanol to give 2a with no oxide (3a) contamination. The product
was contaminated with a significant amount of phosphate salts
that could not be effectively separated, however. Use of Herrmann's
[32] isolation protocol allowed sulfonated phosphine 2a to be iso-
lated as a pure material, but in low yield (17%). Spectroscopic
characterization showed that material was exclusively the para-
sulfonated isomer. Further attempts to improve the yields from
sulfonation reactions were unsuccessful.
Fig. 1. Examples of water-soluble ligands previously reported.
benzyl or phenethyl. We envisioned that these substituents would
be an easily introduced group that would provide the potential for
incorporation of hydrophilic substituents through well-established
arene functionalization chemistry. Electrophilic sulfonation of
benzylphosphines have been previously reported, for example
[28,29]. In addition, we hypothesized that the nearby aromatic
substituent could provide additional stabilization of the palladium
center. This hemilabile coordination is thought to play a key role in
the success of the 2-biarylphosphine class of ligands (Fig. 2) [30,31].
Herein,
we
report
a
novel
synthesis
of
4-
(1)
sulfonatobenzylphosphines and their application in aqueous-
phase Suzuki and Sonogashira coupling reactions.
Results and discussion
Synthesis of sulfonated benzylphosphines
Synthesis of the sulfonated benzylphosphines was originally
envisioned to involve electrophilic sulfonation of readily available
dialkylbenzylphosphonium salts (Scheme 1). Sulfonation of tri-
benzylphosphine is reported to give the trisulfonated phosphine in
good yield as a mixture of ortho and para isomers, with the all para-
isomer being the major product [28]. Small amounts of phosphine
(2)
With the sulfonation reaction requiring tedious separation and
providing poor yields, alternative routes to the desired sulfonated
benzylphosphines were explored. Since oxidation of the phos-
phorus center during workup was a major challenge with 1a, we
considered an alternative synthetic strategy in which the sulfonate
would be installed on the benzyl group prior to alkylation of the
phosphorus center (Scheme 2). This approach would require syn-
thesis of a 4-bromomethylbenzene sulfonic acid equivalent. The
synthesis of sodium 4-bromomethylbenzenesulfonate has been
previously reported in three steps starting from N,N-dime-
thylbenzylamine [33]. As an alternative, we envisioned that radical
oxide byproducts were also observed. Homologous tri(u-phenyl-
alkyl)phosphines were less prone to competitive oxidation than
tribenzylphosphine. The typical sulfonation conditions are strongly
oxidizing due to the presence of SO3. Under the highly acidic re-
action conditions, the basic trialkylphosphine is protonated and
protected from oxidation. During neutralization with base, it is
critical to control the pH in order to consume the remaining SO3
prior to deprotonation of the phosphorus center in order to avoid
oxidation of phosphorus.
Reaction of dialkylphosphines with benzyl bromide in toluene
produced the respective dialkylbenzylphosphonium bromides as
Fig. 2. Potential coordination of pendant aryl groups.
Scheme 2. Revised approach to sulfonated benzylphosphines.

18
J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
bromination of readily available p-toluenesulfonic acid (p-TSA)
derivatives would be a more efficient strategy.
clohexylphosphine gave no conversion to the desired product
(2c).
The direct bromination of p-toluenesulfonic acid (p-TSA) was
explored initially. Treatment of p-TSA with NBS in the presence of
either AIBN or benzoyl peroxide in refluxing chloroform gave no
bromination. A small amount of brominated product (14%) was
obtained by treatment of p-TSA with bromine in refluxing chloro-
form while being irradiated with a sun lamp. Although radical
bromination of p-TSA proved difficult, tosylate esters have been
reported to undergo benzylic bromination in good yields [34]. Re-
action of ethyl tosylate with NBS in the presence of benzoyl
peroxide in refluxing benzene gave approximately 60% conversion
to ethyl 4-(bromomethyl)benzenesulfonate (4, Eq. (3)). Due to
difficulty in separating the brominated product 4 from ethyl tosy-
late, the isolated yield of pure material was only 35%. Subsequently
it was found that 4 containing up to 25% of ethyl tosylate could be
used in the ligand synthesis without negative effects.
(4)
X-ray quality crystals of 2a and 2b were grown from saturated
solutions in ethanol with a small amount of water. Phosphonium 2a
crystallized as a monohydrate (Fig. 3). The molecules packed as
hydrogen bonded dimers with interactions between the sulfonate
oxygen of one molecule with the phosphonium hydrogen of a
second (see Supporting information). The steric bulk at the phos-
phorus center results in a large P1eC7eC4 angle (116.0(2)ꢀ). The
diadamantyl analog (2b) crystallized without co-crystallization of
water or solvent molecules (Fig. 4). The molecules organize into
infinite hydrogen bonded zigzags along the a axis through head-to-
tail P1eH/O3 hydrogen bonds (see Supporting information). The
(3)
adamantyl substituents result in
a larger P1eC7eC4 angle
(119.6(3)ꢀ) than is seen in 2a.
Sulfonated benzyl bromide 4 was reacted with one equivalent
of either di-tert-butylphosphine or di-1-adamantylphosphine in
toluene under nitrogen (Eq. (4)). The product precipitated from
the reaction mixture and was recovered by filtration. Fortu-
itously, the bromide liberated during the substitution step dis-
placed the sulfonate from the ethyl protecting group. As a result,
the reaction directly afforded di-tert-butyl(4-sulfonatobenzyl)
phosphonium (2a) and di-1-adamantyl(4-sulfonatobenzyl)
phosphonium (2b), respectively. Both 2a and 2b were obtained
in 38% yield after recrystallization from ethanol. Attempts to
prepare dicyclohexyl(4-sulfonatobenzyl)phosphonium from dicy
Free 5a was prepared by deprotonation with sodium carbonate
to provide a crystalline solid that slowly oxidized over a period of 2
weeks when exposed to air in the solid state. Phosphine 5a was
complexed to palladium(II) dichloride in anhydrous acetonitrile to
yield a moss green precipitate with a 31P NMR shift at 43 ppm (Eq.
(5)). Virtual coupling of the tert-butyl protons in the 1H NMR
spectrum of 6a indicated that the complex was a trans-diphosphine
complex. Recrystallization from water/ethanol gave glassy yellow
crystals. Attempts to obtain X-ray quality crystals were unsuc-
cessful. The complex was analyzed by high resolution ESI-MS to
confirm the structure of 6a as Pd(5a)2Cl2.
(5)
Catalytic application of 2a and 2b
Suzuki coupling
With ligands 2a and 2b prepared, their application in promoting
palladium-catalyzed cross-coupling in aqueous solvents was
explored. The performance of ligands 2a and 2b was compared
with the DTBPPS ligand previously reported by our group [20].
Palladium acetate (2 mol %) was chosen as the palladium source
and sodium carbonate as the base. Initial studies were carried out in
1:1 water/acetonitrile. In contrast to the DTBPPS ligand, which
Fig. 3. Thermal ellipsoid plot of di-tert-butyl(4-sulfonatobenzyl)phosphonium (2a) at
50% probability level. Carbon-bound hydrogen atoms have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): P1eC7, 1.808(3); P1eC8, 1.844(3); P1eC12,
1.850(3); C7eP1eC8, 112.8(1); C7eP1eC12, 108.2(1); C8eP1eC12, 117.2(1);
P1eC7eC4, 116.0(2); C3eC4eC7eP1, 70.3(3); H1PeP1eC7eC4, 62(1).

J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
19
Aryl chlorides could not be effectively coupled using catalysts
derived from 2a or 2b. Coupling of 4-chloroanisole with phenyl-
boronic acid at 80 ꢀC using 4 mol % Pd/ligand gave modest yields of
coupled products. The diadamantyl ligand 2b gave a 49% yield,
whereas the tert-butyl ligand 2a gave only 19% conversion to
product (entry 10). The use of water/THF as the solvent gave lower
yields in couplings of sterically unhindered aryl bromides (entries
1, 2, and 4). In contrast, the yields were significantly higher with
ortho-substituted aryl bromides (entries 5 and 6).
The use of water/THF (1:1) and water alone as solvents were
further explored in comparison to the water/acetonitrile solvent
system at both 50 ꢀC and room temperature (Table 2). Both
water alone and water/THF proved to be effective solvents for
this reaction. An interesting effect was observed as the steric
hindrance of the aryl bromide substrate was altered. With un-
hindered aryl bromides, water/THF gave comparable (entry 3) or
lower yields (entries 1 and 2) at room temperature than water/
acetonitrile. In contrast, aryl bromides with one or two ortho-
substituents gave increased yields in water/THF compared to
water/acetonitrile at room temperature (entries 4e6). This effect
appears to be due to steric hindrance at the reaction site rather
than due to a hydrophobic effect. For example, THF/water gave
lower yields than water/acetonitrile with 4-bromoanisole, but a
higher yield with 2-bromoanisole. At 50 ꢀC, the difference in
performance was generally smaller. In the case of bromomesi-
tylene, a significant improvement in yield was seen in water/THF
compared to water/acetonitrile. Water alone generally gave
higher yields than those obtained with the mixed solvent sys-
tems. The one exception to this trend was bromomesitylene,
where the yield in water was between those obtained with
water/THF and water/acetonitrile. The nature of this size
dependent solvent effect is unclear.
Fig. 4. Thermal ellipsoid plot of di-1-adamantyl(4-sulfonatobenzyl)phosphonium (2b)
at 50% probability level. Carbon-bound hydrogen atoms have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): P1eC7, 1.809(4); P1eC8, 1.829(4); P1eC18,
1.827(4); C7eP1eC8, 108.8(2); C7eP1eC18, 107.5(2); C8eP1eC18, 120.3(2);
P1eC7eC4, 119.6(3); C3eC4eC7eP1, 48.7(5); H1AeP1eC7eC4, 34(1).
generally gives good yields for couplings at room temperature,
optimal yields with 2a and 2b were obtained at 50 ꢀC in most cases.
Under these conditions, good yields were achieved for a variety
of aryl bromide and arylboronic acid substrates (Table 1). Electron-
deficient (entry 1) and electron-rich (entry 2) aryl bromides gave
good yields when coupled with phenylboronic acid. In most cases
2b gave somewhat higher yields than 2a under the same condi-
tions. Isolated yields obtained with catalysts derived from 2a and
2b at 50 ꢀC were comparable to those obtained with DTBPPS at
room temperature. In the case of 4-bromotoluene, a good yield was
achieved at room temperature using 2a, whereas 2b required 50 ꢀC
for optimal yields. Lower yields were obtained with sterically
demanding bromomesitylene and 2-bromotoluene substrates
(entries 5 and 6). Sterically hindered 2-tolylboronic acid and 1-
naphthylboronic acid gave good yields of coupled product with 4-
bromoanisole, however. The challenging heterocyclic substrate 3-
bromobenzothiophene gave 72% and 76% yields when coupled
with 4-methoxyphenylboronic acid using ligands 2a and 2b,
respectively (entry 9).
Ligands 2a and 2b provide catalysts that are effective at lower
temperature and with lower catalyst loading than are achieved
with hydrophilic triarylphosphines, such as TPPTS [35]. The cat-
alysts derived from 2a and 2b show comparable activities to
those derived from DTBPPS [20] or t-Bu-Amphos [17] previously
reported by our group for aryl bromides. The DTBPPS catalyst
affords better activity towards aryl chlorides, however. The
Table 1
Suzuki coupling of aryl bromides using 2a and 2ba.
Entry
ArX
ArB(OH)2
Solventb
% Yieldc
2a
2b
96
92
97
DTBPPS
99d
1
2
4-NCC6H4Br
4-MeC6H4Br
PhB(OH)2
PhB(OH)2
MeCN/H2O
THF/H2O
MeCN/H2O
THF/H2O
89
74
94e
80e
90
98d
92e
3
4
4-t-BuC6H4Br
4-MeOC6H4Br
PhB(OH)2
PhB(OH)2
MeCN/H2O
MeCN/H2O
THF/H2O
91
100
92
94d
75e
70
87
5
6
2,4,6-Me3C6H2Br
2-MeC6H4Br
PhB(OH)2
MeCN/H2O
THF/H2O
MeCN/H2O
THF/H2O
56f
83
80
76
2,4-F2C6H3B(OH)2
63f
79
77
89
7
8
9
10
4-MeOC6H4Br
4-MeOC6H4Br
3-Br-benzothiophene
4-MeOC6H4Cl
2-MeC6H4B(OH)2
1-naphthylB(OH)2
4-MeOC6H4B(OH)2
PhB(OH)2
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
87
100
72f
19f,g
97
76
49f,g
a
Reaction conditions: aryl bromide (1 equiv), arylboronic acid (1.2 equiv), Pd(OAc)2 (2 mol %), ligand (2 mol %), sodium carbonate (1.1 equiv), solvent, at 50 ꢀC for 2a and 2b
or room temperature for DTBPPS under N2 for 24 h. Reaction time not optimized.
b
(1:1) solvent ratio.
Isolated yield.
Literature results [20].
Reaction performed at room temperature.
Yield determined by gas chromatography.
Reaction performed with 4 mol % Pd(OAc)2/ligand at 80 ꢀC.
c
d
e
f
g

20
J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
Table 2
Suzuki coupling of aryl bromides using 2a aqueous mediaa.
Entry
ArBr
Ligand
Yield (%) at 23 ꢀCb
MeCN/H2O
Yield (%) at 50 ꢀCb
MeCN/H2O
THF/H2O
H2O
THF/H2O
H2O
1
2
4-MeC6H4Br
2a
DTBPPS
2a
DTBPPS
2a
2a
DTBPPS
2a
DTBPPS
2a
94
85
92
71
80
(88)
(85)
80
78
75
100
95
98
99
96
92
95
(90)
89
(62)
75
87
nd
96
nd
(100)
96
91
(88)
(89)
86
(96)
(97)
97
86
73
76
83
(95)
(94)
(100)
(97)
97
98
94
97
(92)
70
(95)
(90)
(97)
(86)
(80)
75
(64)
56
64
4-MeOC6H4Br
3
4
3,5-Me2C6H3Br
2-MeC6H4Br
5
6
2-MeOC6H4Br
Br-mesitylene
76
(91)
(57)
(88)
(75)
(79)
DTBPPS
64
89
(76)
a
Reaction conditions: aryl bromide (1 equiv), arylboronic acid (1.2 equiv), Pd(OAc)2 (2 mol %), ligand (2 mol %), sodium carbonate (1.1 equiv), under N2 for 24 h. Reaction
time not optimized.
b
Average isolated yield from at least two trials. Values in parentheses determined by GC analysis.
cataCXium FSulf water-soluble ligand developed by the Plenio
group are more effective in the coupling of heteroaryl halides
than 2a and 2b [36].
Using the optimized conditions, a variety of aryl bromides
were coupled with phenylacetylene to obtain moderate to
excellent yields of coupled product using 2a and 2b as
ligands (Table 4). With 4-bromoanisole, the 2a-derived catalyst
gave a higher yield than was achieved with 2b (entry 1) as was
seen in Table 3. With the more reactive 1-bromo-4-
trifluoromethylbenzene, high yields (87 and 89%, respectively)
were achieved with both ligands (entry 2). The moderately hin-
dered 2-bromotoluene substrate gave good yields with both li-
gands, but the more hindered bromomesitylene gave lowered
yields, although 2a gave a more effective catalyst than 2b.
Excellent yields of coupled product were obtained using both
ligands with 2-bromopyridine (entry 6). The more electron-rich
thiophene substrates gave lower yields, however. A low yield
was obtained with both ligands using 2-bromothiophene,
whereas good yields were obtained with 3-bromothiophene. In
Sonogashira coupling
Conditions for the Sonogashira coupling using ligands 2a and 2b
were optimized for the model coupling of 4-bromoanisole and
phenylacetylene (Table 3). The conditions previously reported for
the DTBPPS ligand, with Pd(OAc)2 as the palladium source and
CsOH as the base [20], were found to be ineffective in the coupling
of 4-bromoanisole with phenylacetylene at 80 ꢀC (entry 1). Using
PdCl2(CH3CN)2 as the palladium source (1 mol %) with a 2:1 L/Pd
ratio and potassium carbonate as the base afforded a 65% yield of
coupled products (entry 2). Increasing the L/Pd ratio to 3:1 gave a
small improvement in yield to 69% (entry 3). Increasing the palla-
dium loading to 2 mol % did not improve the yield (entry 4). Use of
KOH as base gave a slightly lower yield than was achieved with
potassium carbonate (entry 5). Replacing acetonitrile with dioxane
in the solvent mixture decreased the yield to 57% (entry 6). Using
Pd2(dba)3 gave a slight increase in yield compared to PdCl2(MeCN)2
(72%, entry 7). Given the lower cost of PdCl2(MeCN)2 compared to
Pd2(dba)3, PdCl2(MeCN)2 was chosen as the preferred palladium
source going forward. Unlike the Suzuki coupling, 2b gave a
significantly lower yield in the Sonogashira coupling than 2a (entry
8). Decreasing the temperature from 80 ꢀC resulted in lower yields
of product (entries 9 and 10).
Table 4
Substrate scope for the Sonogashira coupling of aryl bromides with phenyl-
acetylenea.
Entry
1
ArBr
L
Yield (%)b
Table 3
Optimization of Sonogashira coupling with 2aa.
4-MeOC6H4Br
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
69
43
87
89
78
73
51
33
79
69
86
86
36
28
65
73
Entry
Pd
Pd/L (mol %)
Base
Yieldb (%)
2
3
4
5
6
7
8
4-CF3C6H4Br
1
2
3
4
5
6
7
8
9
Pd(OAc)2
2/3.75
CsOH
K2CO3
K2CO3
K2CO3
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0
64
69
68
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
Pd2(dba)3
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
1/2
1.25/3.75
2/6
1.25/3.75
1.25/3.75
1.25/3.75
1.25/3.75
1.25/3.75
1.25/3.75
2-MeC6H4Br
2,4,6-Me3C6H2Br
1-Br-Naphth
65
57c
72
49d
59e
49f
2-Br-pyridine
2-Br-thiophene
3-Br-thiophene
10
a
4-Bromoanisole (1 equiv), phenylacetylene (1.1 equiv), Pd source, 2a base
(1.1 equiv) in 1:1 water/acetonitrile at 80 ꢀC.
b
Yields determined by gas chromatography.
Water/dioxane used as solvent.
c
a
Reaction conditions: aryl bromide (1 equiv), arylboronic acid (1.2 equiv),
PdCl2(MeCN)2 (1.25 mol %), ligand (3.75 mol %), potassium carbonate (1.1 equiv),
under N2 for 2 h. Reaction time not optimized.
d
2b used as ligand.
e
50 ꢀC.
f
b
23 ꢀC.
Isolated yield.

J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
21
Table 6
this case, 2b gave a slightly higher yield than that obtained with
2a. In general, the two ligands gave yields that were not signifi-
cantly different, although the 2b-derived catalyst gave lower
yields in most cases. It appears that the 2b-derived catalyst is less
active towards electron-rich aryl halides than the 2a system. The
2b complex is also more sensitive to steric bulk than the 2a
derived catalyst. This steric sensitivity is in line with the larger
steric strain at phosphorus for 2b suggested by the X-ray struc-
tural data.
Comparison of water-soluble palladium sources for the Sonogashira coupling of 3-
bromobenzothiophene with phenylacetylene.
The coupling of aliphatic alkynes was also attempted (Table 5).
Using the optimized conditions identified for phenylacetylene
resulted in low yields with aliphatic alkynes. Switching the base to
N-methyldicyclohexylamine afforded moderate yields for the
coupling of 4-bromoanisole with 1-hexyne and 5-hexynenitrile. 2-
Bromotoluene produced low yields when coupled with 1-hexyne.
Modest yields of product were obtained in the coupling of 4-
bromoanisole and propargyl alcohol.
The use of a water-soluble palladium source was considered as a
means of more quickly generating the active catalyst species in
aqueous solvents. Several different palladium sources were
compared for the Sonogashira coupling of 3-bromobenzothiophene
and phenylacetylene, including complex 6a (Table 6). Sodium tet-
rachloropalladate gave slightly lower yields of coupled products
compared to PdCl2(MeCN)2 in both water/acetonitrile and water
alone (entries 1e4). Notably, the yield was higher in water alone
compared with water/acetonitrile with both palladium sources.
The results with palladium nitrate in water/acetonitrile were
comparable to those achieved with both PdCl2(MeCN)2 and
Na2PdCl4. In water alone, palladium nitrate was much less effective,
however. The preformed Pd(II) complex 6a was also a competent
precatalyst, although it afforded a lower yield than the catalyst
generated in situ from PdCl2(MeCN)2 and 2a. In the absence of 2a,
no conversion occurred (entry 9).
The use of Na2PdCl4 as precatalyst with both water/acetonitrile
and water alone as well as PdCl2(MeCN)2 in water was explored in
the coupling of a range of aromatic and heteroaromatic aryl bro-
mides with phenylacetylene (Table 7). The results with Na2PdCl4 in
water/acetonitrile were similar to those obtained with
PdCl2(MeCN)2 in the same solvent (Table 4). Both precatalysts gave
lower yields for reactions carried out in water without a cosolvent
in most cases. The lower yields are likely due to poor interaction
between the hydrophobic organic substrates and the water-soluble
catalyst system and base. The lone exception to this trend was 3-
Entry
Pd source
Solvent
Yield (%)a
1
2
3
4
5
6
7
8
9
PdCl2(MeCN)2
PdCl2(MeCN)2
Na2PdCl4
Na2PdCl4
Pd(NO3)2
Pd(NO3)2
6a
H2O/MeCNb
H2O
59
67
52
63
54
48
54
52
0
H2O/MeCNb
H2O
H2O/MeCNb
H2O
H2O/MeCNb
H2O
6a
c
PdCl2(MeCN)2
H2O
a
Isolated yields.
1:1 water/acetonitrile.
No 2a used.
b
c
bromobenzothiophene, which gave a higher yield in water than
in water/acetonitrile.
Buchwald has reported that propiolic acid, a challenging Sono-
gashira substrate, worked well in the copper-free Sonogashira
coupling of aryl bromides at elevated temperatures using a sulfo-
nated variant of X-phos (Eq. (6)) [19]. This led us to attempt the
Sonogashira coupling of 4-bromoanisole with propiolic acid using
the optimized conditions for PdCl2(CH3CN)2 and 2a. None of the
expected Sonogashira product 7 could be isolated, however. A 56%
yield of the decarboxylative diarylated product 8, based on pro-
piolic acid, was produced instead (Eq. (7)). Decarboxylative diary-
lation of propiolic acid has been previously reported by the Lee
[37,38] and Gooßen [39] groups, including examples using
aqueous solvent [40]. In these reports, the decarboxylative coupling
is generally slower than the initial arylation of the terminal alkyne
carbon, which allows unsymmetrical products to be generated [37].
In our case, the diarylated product was formed without any
Table 7
Aqueous condition comparison for the Sonogashira coupling of aryl bromides.
Table 5
The Sonogashira coupling of aryl bromides with aliphatic alkynesa.
Entry ArBr
Ligand Isolated yield (%)
Na2PdCl4
Na2PdCl4 PdCl2(MeCN)2
H2O/MeCN H2O
H2O
Entry
1
ArBr
R
L
Yield (%)
1
2
3
4
5
6
4-MeOC6H4Br
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
74
42
82
73
85
81
35
26
70
66
52
36
54
43
75
23
56
76
13
26
55
56
63
38
52
37
81
28
61
76
20
26
54
49
67
56
4-MeOC6H4Br
n-Bu
2a
2b
2a
2b
2a
2b
2a
2b
57
46
78
72
2-MeC6H4Br
2
3
4
4-MeOC6H4Br
2-MeC6H4Br
4-MeOC6H4Br
(CH2)5CN
n-Bu
2-Br-pyridine
2-Br-thiophene
3-Br-thiophene
25
30a
47b,c
30c
CH2OH
a
Product isolated with inseparable minor impurities.
CuI (1 mol %) added.
2.2 equiv of base.
3-Br-benzothiophene 2a
b
c
2b

22
J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
evidence of the propiolic acid product (7) being formed despite
having only one equivalent of aryl bromide present.
varying amounts did not significantly affect the yield with the
higher aryl bromide to propiolic acid ratio (entries 5e6).
Conclusions
A novel approach to the synthesis of sulfonated benzylphos-
phine ligands is reported that involves the one pot alkylation of
secondary phosphines and concomitant deprotection of a protected
sulfonate ester to afford zwitterionic phosphonium sulfonate salts.
This methodology overcomes the challenges of electrophilic sul-
fonation of oxidatively sensitive trialkylphosphines. The resulting
hydrophilic ligands provide effective catalysts for the Suzuki and
Sonogashira coupling of aryl bromides in water or water/organic
solvent systems.
(6)
Experimental
General experimental methods
Diadamantylphosphine [41] and ethyl 4-(bromomethyl)benze-
nesulfonate [34] were prepared according to a literature procedure.
Toluene was refluxed from molten sodium prior to use. DI water,
THF, and acetonitrile were deoxygenated by sparging with N2 for
15 min prior to use. All other compounds were obtained commer-
cially and used as received. NMR spectral data were obtained on
Brüker 360 and 500 MHz spectrometers. 1H and 13C NMR spectra
are referenced to the NMR solvent peaks or internal TMS. 31P NMR
spectra were externally referenced to 85% H3PO4. HRMS were ob-
tained on a Waters Autospec NT magnetic sector mass spectrom-
eter using EI ionization and operating in the positive ion mode. ESI-
HRMS on compounds 2a, 2b, and 6 were obtained at the LSU Mass
Spectrometry Facility on an Agilent 6210 ESI-TOF instrument
operating in positive ion mode. Elemental analysis was performed
by Atlantic Microlab, Inc.
(7)
Conditions for this reaction were further explored in an effort to
form either the 3-arylpropiolic acid 7 or dicarboxylated product 8
in high yield (Table 8). Use of CuI as a cocalyst with a 1:1.1 ratio of 4-
bromoanisole and propiolic acid gave an improved yield (67%,
based on propiolic acid) of 8 with no evidence of cross-coupled
product 7 (entry 2). Using 2 equiv of aryl bromide to optimize the
yield of 8 resulted in the yield decreasing to 31% (entry 4). This
corresponds to approximately the same level of conversion relative
to propiolic acid as entries 1 and 2, suggesting that catalyst deac-
tivation may be limiting conversion in this reaction. Adding CuI in
General procedure for synthesis of dialkyl(4-sulfonatobenzyl)
phosphonium (2aec)
Dialkylphosphine and ethyl 4-sulfonatobenzyl bromide
(1.25 equiv) were dissolved in anhydrous toluene and left to reflux
under nitrogen atmosphere overnight. The resulting cream-colored
precipitate was recovered by filtration. The crude product was
recrystallized from ethanol with a small amount of water to afford
the desired product as white crystals.
Table 8
Decarboxylative Sonogashira diarylation of propiolic acid with 4-bromoanisole.
Di-tert-butyl(4-sulfonatobenzyl)phosphonium (2a)
Di-tert-butylphosphine (0.75 mL, 4.00 mmol) and 4 (1.40 g,
5.00 mmol) in toluene (10 mL) were reacted according to the
general procedure. The crude product was recrystallized to yield
0.50 g (38%) of 2a contaminated with a small amount of the
phosphine oxide (3a). 1H NMR (500 MHz, MeOH-d4):
d 7.80 (d,
J ¼ 8.4 Hz, 2H), 7.50 (d, J ¼ 7.9 Hz, 2H), 4.02 (d, J ¼ 13.7 Hz, 2H), 1.50
(d, J ¼ 16.5 Hz, 18H). 13C NMR (126 MHz, MeOH-d4): d 145.2, 133.6
(d, JPeC ¼ 8.7 Hz), 129.5 (d, JPeC ¼ 6.2 Hz), 126.8, 33.2 (d,
JPeC ¼ 33.8 Hz), 26.3, 20.4 (d, JPeC ¼ 39.3 Hz). 31P NMR (203 MHz,
Entry
ArBr:PA
CuI (mol %)
Yield (%)a
MeOH-d4):
d
47.3 (t, JPeD ¼ 65.3 Hz); (203 MHz, DMSO-d6):
d 46.3 (d,
1
2
3
4
5
6
1:1
1:1
1:1
2:1
2:1
2:1
0
1
0
0
1
2.8
56
JPeH ¼ 458.7 Hz). HR-ESI-MS m/z calcd for C15H26O3SP, 317.1340
[M þ H]þ; found, 317.1341.
67
28b,c
31
Di-1-adamantyl(4-sulfonatobenzyl)phosphonium (2b)
32
38c
Di-1-adamantylphosphine (3.89 g, 12.9 mmol) and 4 (4.49 g,
16.1 mmol) were reacted according to the general procedure in
toluene (25 mL). The crude product was recrystallized to yield
a
Average isolated yield from two trials.
Reaction performed at 50 ꢀC.
Yield determined by GC.
b
c

J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
23
2.32 g (38%) of 2b. 1H NMR (500 MHz, DMSO-d6):
d
7.61 (d,
J ¼ 6.0 Hz, 18H). 31P NMR (203 MHz, D2O):
d
45.5 (s). HR-ESI-MS
J ¼ 7.9 Hz, 2H), 7.37 (d, J ¼ 7.7 Hz, 2H), 6.09 (d, JPeH ¼ 469.2 Hz, 1H),
(cation) m/z calcd for
C
30H49P2S2O6Cl2PdNa2 ([M
þ
H]þ)
4.00 (brs, 2H), 2.12e1.67 (m, 30H). 13C NMR (126 MHz, MeOH-d4):
853.0653, found 853.0646.
d
144.9, 130.3 (d, JPeC ¼ 5.0 Hz), 129.5 (d, JPeC ¼ 6.0 Hz), 126.7, 38.0
(d, JPeC ¼ 33.2 Hz), 37.6 (d, JPeC ¼ 2.7 Hz), 36.1 (d, JPeC ¼ 20.3 Hz),
General procedure for Suzuki coupling with ligands 2a and 2b
35.1, 27.7 (d, JPeC ¼ 9.2 Hz). 31P NMR (203 MHz, DMSO-d6):
d 36.9 (d,
JPeH ¼ 476.0 Hz). HR-ESI-MS m/z calcd for C27H38O3SP, 473.2279
In a nitrogen filled glove box, Pd(OAc)2 (4.5 mg, 0.020 mmol),
water-soluble phosphine (2a, 2b, or DTBPPS, 0.0200 mmol), sodium
carbonate (116 mg, 1.10 mmol), arylboronic acid (1.10 mmol) were
measured into a 1 dram vial containing a small stir bar. The vial was
sealed with a screw cap and septum and removed from the glo-
vebox before adding the aryl halide (1.00 mmol) and deoxygenated
solvent (2 mL). The reaction vial was stirred at room temperature or
placed in a preheated oil bath until reaction completion as deter-
mined by gas chromatography was achieved. Upon completion, the
reaction mixture was taken into ethyl acetate and washed three
times with brine solution, dried with anhydrous magnesium sul-
fate, and filtered. The excess organic solvent was removed under
reduced pressure, and the crude residues were evaporated onto
silica gel from methylene chloride. Once dry, the silica gel mixture
was used in column chromatography to isolate the desired product.
[M þ H]þ; found, 473.2277.
X-ray crystallography
X-ray crystallographic data collection was performed using a
Brüker diffractometer using MoK
a radiation with a Platform 3-
circle goniometer and an Apex 2 CCD area detector. For structures
obtained below ambient temperature, crystals were cooled under a
cold nitrogen stream using an N-Helix cryostat. A hemisphere of
data was collected for each crystal using a strategy of omega scans
with 0.5ꢀ frame widths. Unit cell determination, data integration,
absorption correction, and scaling were performed using the Apex2
software suite from Brüker [42]. Space group determination,
structure solution, refinement, and generation of ORTEP diagrams
were done using the SHELXTL software package [43].
X-ray quality crystals of 2b were obtained by slow diffusion of
ethanol into a concentrated aqueous solution of 2b. Crystal data for
General procedure for Sonogashira coupling of phenylacetylene
2a:
C
15H27O4PS; 334.39; 296(2) K; monoclinic;
P
2(1)/c;
In a nitrogen filled glovebox, the PdCl2(CH3CN)2 (3.3 mg,
0.013 mmol), 2a (11.8 mg, 0.0375 mmol) or 2b (17.7 mg,
0.0375 mmol), and potassium carbonate (151.8 mg, 1.10 mmol)
were measured into a 1 dram vial containing a small stir bar. The
vial was sealed with a screw cap and septum and removed from the
glovebox before adding the aryl halide (1.00 mmol), aryl acetylene
(1.10 mmol) and 1:1 water/acetonitrile (2 mL). The reaction vial was
placed in a preheated oil bath at 80 ꢀC and stirred until reaction
completion was observed by gas chromatography (2e12 h). Upon
completion, the reaction mixture was taken into diethyl ether,
washed with brine solution, dried with anhydrous magnesium
sulfate, and filtered. The excess organic solvent was removed under
reduced pressure and the crude residues were taken into methy-
lene chloride and evaporated onto silica gel under reduced pres-
sure. Once dry, the silica gel mixture was used in column
chromatography.
a
¼
14.719(2) Å,
b
¼
9.5904(14) Å,
c
¼
13.9718(17) Å,
b ¼ 117.091(4)ꢀ; 20,456 reflections; 3571 independent reflections;
[Rint
¼
0.0920]; final
R
indices [I
>
2s
(I)]: R1
¼
0.0453,
wR2 ¼ 0.1012; R indices (all data): R1 ¼ 0.0877, wR2 ¼ 0.1193.
X-ray quality crystals of 2b were obtained by slow diffusion of
ethanol into a concentrated aqueous solution of 2b. Available
crystals for 2b were small and weakly scattering so extended
exposure times (60 s per 0.5ꢀ frame) were used to get solvable data.
Crystal data for 2b: C27H37O3PS; 472.59; 173(2) K; orthorhombic; P
2(1) 2(1) 2(1); a ¼ 8.016(4) Å, b ¼ 13.974(8) Å, c ¼ 20.656(12) Å;
21,803 reflections; 4704 independent reflections; [Rint ¼ 0.1827];
final R indices [I > 2
wR2 ¼ 0.0999.
s(I)]: R1 ¼ 0.0548, wR2 ¼ 0.0810; R1 ¼ 0.1325,
Sodium di-tert-butyl(4-sulfonatobenzyl)phosphine (5a)
2a (500 mg, 1.58 mmol) and sodium carbonate (850 mg,
7.91 mmol) were placed in a two-neck round bottom flask under
nitrogen. Degassed methanol was added to the mixture, and the
reaction was allowed to stir at room temperature for 24 h. The
solution was then filtered by cannula through an air-free glass frit
containing Celite into a two-neck round bottom flask, where the
solvent was removed under high vacuum to yield a white solid that
was modestly sensitive to oxidation in air. This material was then
used directly to generate the palladium complex. 1H NMR
General procedure for Sonogashira coupling of alkylacetylenes
In
a nitrogen filled glove box, PdCl2(CH3CN)2 (3.25 mg,
0.010025 mmol) and 2a (11.8 mg, 0.0375 mmol) or 2b (17.7 mg,
0.0375 mmol) were measured into a 1 dram vial containing a small
stir bar. The vial was sealed with a screw cap and septum and
removed from the glovebox before adding Cy2NMe (235
mL,
1.10 mmol), aryl halide (1.00 mmol), alkyl acetylene (1.10 mmol),
and 1:1 water/acetonitrile (2 mL). The reaction vial was placed in a
preheated oil bath at 80 ꢀC and stirred until it reached completion
as determined by gas chromatography (2e12 h). Upon completion,
the reaction mixture was taken into diethyl ether, washed with
brine solution, dried with anhydrous magnesium sulfate, and
filtered. The excess organic solvent was removed under reduced
pressure, and the crude residues were taken into methylene chlo-
ride and evaporated onto silica gel under reduced pressure. Once
dry, the silica gel mixture was used in column chromatography.
(500 MHz, DMSO-d6):
d
7.46 (d, J ¼ 8.1 Hz, 2H), 7.25 (d, J ¼ 8.2 Hz,
2H), 2.83 (d, J ¼ 2.8 Hz, 2H), 1.08 (d, J ¼ 10.8 Hz, 18H). 31P NMR
(203 MHz, DMSO-d6):
d 35.1 (s).
Disodium [palladium bis(di-tert-butyl[4-sulfonatobenzyl]
phosphine) dichloride] (6a)
Ligand 5a (500 mg, 1.48 mmol) was placed into a reflux setup
under nitrogen atmosphere with palladium dichloride (133 mg,
0.74 mmol) and anhydrous acetonitrile (15 mL). The mixture was
allowed to reflux overnight to yield a moss green powder (235 mg)
that was precipitated using cold diethyl ether. Recrystallization by
slow diffusion using ethanol and water yielded a small amount of a
Acknowledgment
We thank the National Science Foundation (CHE-1058984) for
financial support of this work and Johnson-Matthey for donation of
palladium compounds.
glassy yellow solid. 1H NMR (500 MHz, DMSO-d6):
J ¼ 7.5 Hz, 2H), 7.51 (d, J ¼ 7.4 Hz, 2H), 3.67 (bs, 2H), 1.48 (brt,
d 8.00 (d,

24
J.N. Moore et al. / Journal of Organometallic Chemistry 777 (2015) 16e24
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Appendix A. Supplementary material
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CCDC 1023221; CCDC 1023222 for 2a and 2b contain the sup-
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obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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€
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Supplementary data related to this article can be found at http://
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