Water-soluble palladacycles as precursors to highly recyclable catalysts for the Suzuki coupling of aryl bromides in aqueous solvents

Article abstract of DOI:10.1021/om050940y

A family of water-soluble palladacycles was prepared from benzylamine or benzaldehyde imine ligands bearing hydrophilic functional groups. The palladacycles derived from N,N-dimethyl-p-hydroxybenzylamine (7) and sodium 4-(N-benzylideneamino)benzenesulfonate (10) gave active catalysts for the Suzuki coupling of aryl bromides and activated aryl chlorides in combination with (2-di-tert-butylphosphinoethyl)trimethylammonium chloride (t-Bu-Amphos). The catalyst derived from 10/t-Bu-Amphos could be used for 12 reaction cycles in the Suzuki coupling of 4-bromotoluene at 80°C before a significant loss of catalyst activity was observed.

Full text of DOI:10.1021/om050940y

Organometallics 2006, 25, 4105-4112
4105
Water-Soluble Palladacycles as Precursors to Highly Recyclable
Catalysts for the Suzuki Coupling of Aryl Bromides in Aqueous
Solvents
Rongcai Huang and Kevin H. Shaughnessy*
Department of Chemistry and Center for Green Manufacturing, The UniVersity of Alabama,
Box 870336, Tuscaloosa, Alabama 35487-0336
ReceiVed NoVember 1, 2005
A family of water-soluble palladacycles was prepared from benzylamine or benzaldehyde imine ligands
bearing hydrophilic functional groups. The palladacycles derived from N,N-dimethyl-p-hydroxybenzy-
lamine (7) and sodium 4-(N-benzylideneamino)benzenesulfonate (10) gave active catalysts for the Suzuki
coupling of aryl bromides and activated aryl chlorides in combination with (2-di-tert-butylphosphinoethyl)-
trimethylammonium chloride (t-Bu-Amphos). The catalyst derived from 10/t-Bu-Amphos could be used
for 12 reaction cycles in the Suzuki coupling of 4-bromotoluene at 80 °C before a significant loss of
catalyst activity was observed.
Introduction
Water has attracted attention as a potential replacement for
organic solvents due to its low cost, nonflammability, low
toxicity, and the fact that it is a renewable resource.1 In addition,
the use of water in combination with hydrophilic homogeneous
metal catalysts offers the potential to easily separate and recycle
the metal catalyst from organic product streams. Removal of
metal impurities from homogeneous catalysts is a challenging
issue, particularly in the manufacturing of pharmaceuticals,
where residual metal levels must be in the ppm range.2
Recyclable catalyst systems allow catalyst loadings that are high
enough to provide desirable reaction rates, while lowering the
cost of catalyst per unit product. Since Casalnuovo’s3 initial
report of palladium-catalyzed cross-coupling reactions in aque-
ous solvents catalyzed by TPPMS/Pd(OAc)2, there has been a
great deal of effort devoted to identifying active, hydrophilic
palladium catalysts for a range of cross-coupling reactions.4-7
Much of this work has focused on the development of water-
soluble analogues of phosphines, particularly derivatives of
triphenylphosphine.
catalyst systems have shown that palladacycles with a variety
of supporting ligands are decomposed under typical palladium-
catalyzed cross-coupling conditions.11-19 In the absence of other
supporting ligands, palladium clusters are formed that likely
are the true active species. In the presence of phosphine ligands,
Pd(0)-phosphine complexes can form. The lability of palla-
dacycle complexes has made identifying recyclable palladacycle
catalyst systems challenging. Attempts to attach palladacycles
to solid supports have given mixed results, since the supported
palladacycle can decompose to give soluble catalyst species that
are lost when the solid support is recovered.12,15 Bergbreiter
has reported soluble polymer-supported SCS-pincer complexes
that are recyclable catalysts for Heck and Suzuki couplings,20,21
but recent results show that the pincer complex acts as a slow
Since Beller and Herrmann’s8 initial report on the use of a
palladacycle precatalyst derived from (o-tol)3P and Pd(OAc)2,
there has been a growing interest in the use of palladacycles as
catalyst precursors.9,10 Mechanistic studies on palladacyclic
* Corresponding author. Phone: 205-348-4435. Fax: 205-348-4435.
E-mail: kshaughn@bama.ua.edu.
(11) Bergbreiter, D. E.; Osburn, P. L.; Frels, J. D. AdV. Synth. Catal.
2005, 347, 172-184.
(1) Sheldon, R. A. Green Chem. 2005, 7, 267-278.
(2) Garrett, C. E.; Prasad, K. AdV. Synth. Catal. 2004, 346, 889-900.
(3) Casalnuovo, A. L.; Calabrese, J. C. J. Am. Chem. Soc. 1990, 112,
4324-4330.
(4) Geneˆt, J. P.; Savignac, M. J. Organomet. Chem. 1999, 576, 305-
317.
(5) Beletskaya, I. P.; Cheprakov, A. V. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed., John Wiley & Sons:
New York, 2002; Vol. 2, pp 2957-3006.
(6) Shaughnessy, K. H.; DeVasher, R. B. Curr. Org. Chem. 2005, 9,
585-604.
(7) Shaughnessy, K. H. Eur. J. Org. Chem. 2006, 1827-1835.
(8) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossmer, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
(9) Bedford, R. B. Chem. Commun. 2003, 1787-1796.
(10) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet. Chem. 2004,
689, 4055-4082.
(12) Bedford, R.; Cazin, C. S. J.; Hursthouse, M. B.; Light, M. E.; Pike,
K. J.; Wimperis, S. J. Organomet. Chem. 2001, 633, 173-181.
(13) Bedford, R. B.; Welch, S. L. Chem. Commun. 2001, 129-130.
(14) Louie, J.; Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1996, 35,
2359-2367.
(15) Nowotny, M.; Hanefeld, U.; van Koningsveld, H.; Maschmeyer, T.
Chem. Commun. 2000, 1877-1878.
(16) Chen, C.-L.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organometallics
2005, 24, 1075-1081.
(17) Rocaboy, C.; Gladysz, J. A. New J. Chem. 2003, 27, 39-49.
(18) Consorti, C. S.; Flores, F. R.; Dupont, J. J. Am. Chem. Soc. 2005,
127, 12054-12065.
(19) Sommer, W. J.; Yu, K.; Sears, J. S.; Ji, Y.; Zheng, X.; Davis, R. J.;
Sherrill, C. D.; Jones, C. W.; Weck, M. Organometallics 2005, 24, 4351-
4361.
(20) Bergbreiter, D. E.; Osburn, P. L.; Liu, Y.-S. J. Am. Chem. Soc.
1999, 121, 9531-9538.
10.1021/om050940y CCC: $33.50 © 2006 American Chemical Society
Publication on Web 07/19/2006

4106 Organometallics, Vol. 25, No. 17, 2006
Huang and Shaughnessy
release source of a soluble catalytically active species.11 In
addition to catalyst leaching, most supported palladacyclic
systems are limited to reactive aryl iodide substrates, while
showing little activity toward aryl bromides or chlorides. An
exception is a recent report of a silica-supported oxime
palladacycle that was an effective and recyclable catalyst for
Suzuki couplings of activated aryl chlorides.22
The use of a hydrophilic palladacycle precursor in an aqueous-
biphasic solvent system would be an alternate way to obtain a
recyclable catalyst system. There are relatively few examples
of hydrophilic palladacyclic precatalysts, however. An SCS-
pincer complex functionalized with poly(ethylene glycol) arms
was shown to be an effective catalyst for the Heck coupling of
aryl iodides in an aqueous/organic biphase.21 Ryabov23 reported
the first example of a water-soluble Schiff base palladacycle,
which was applied as a catalyst for ester hydrolysis. Simple
oxime-derived palladacycles were shown to be active precata-
lysts for the Suzuki and Heck couplings of aryl bromides and
chlorides.24-26 High turnover numbers (TONs) were achieved
in the Suzuki coupling of activated aryl bromides (105) and
activated aryl chlorides (103), but the recyclability of these
catalyst systems was not explored. A hydrophobic palladacycle
derived from a sterically demanding Schiff base was shown to
give high activity for Suzuki couplings of deactivated aryl
bromides in refluxing water.27 The hydrophobic nature of this
palladacycle would presumably not allow the catalyst to be
retained in the aqueous phase.
Figure 1. Hydrophilic benzylamine ligands.
Figure 2. Hydrophilic imine ligands.
Scheme 1. Synthesis of Hydrophilic Palladacycles
Bedford has shown that simple alkylphosphines, such as
tricyclohexylphosphine (Cy3P), in combination with pallada-
cycles can give highly active catalysts for cross-coupling
reactions of aryl bromides and chlorides.28-31 Our group has
been exploring the utility of bulky, hydrophilic alkylphosphines
in palladium-catalyzed cross-coupling reactions. We have shown
that t-Bu-Amphos and t-Bu-Pip-phos give catalysts with good
activity for the Suzuki, Heck, and Sonogashira coupling of aryl
bromides under mild conditions.32,33 The t-Bu-Amphos/Pd-
(OAc)2 catalyst system could be completely restrained in the
aqueous phase and showed modest recyclability. The catalyst
system begins to lose activity after three reaction cycles,
presumably due to catalyst deactivation. Therefore, we were
interested to see if the combination of a water-soluble alkyl-
phosphine and a palladacycle precursor would show improved
activity and stability in aqueous-phase cross-coupling reactions.
Herein we report the synthesis of a family of novel water-soluble
palladacycles and their ability to act as recyclable precatalysts
for the Suzuki coupling of aryl bromides.
Results
Ligand Synthesis. Hydrophilic amine- and imine-based
palladacycle precursor ligands were synthesized that incorpo-
rated hydroxyl, carboxylate, or sulfonate substituents. p-Hy-
droxybenzylamine 1 (Figure 1) was prepared by reductive
amination of p-hydroxybenzaldehyde with dimethylamine. A
sulfonate-functionalized benzylamine (2) was similarly prepared
starting from the commercially available 2-formylbenzene-
sulfonate. A disulfonated benzylamine ligand was prepared by
dialkylation of benzylamine with 1,3-propane sultone to give
3. Sequential reductive amination of p-aminobenzoic acid with
benzaldehyde and then formaldehyde gave carboxylate-substi-
tuted benzylamine 4.
Schiff base ligands were prepared by the condensation of
hydrophilic aniline derivatives with benzaldehyde or acetophe-
none. Condensation of the sodium salt of sulfanilic acid with
benzaldehyde gave the sulfonated Schiff base 6 (Figure 2). Imine
ligand 6 could not be prepared directly from the condensation
of acetophenone and p-benzoic acid. Instead, acetophenone and
p-aminobenzoic acid were condensed in the presence of cyanide
to give an R-cyanobenzylamine that was decomposed to the
desired imine with base.
(21) Bergbreiter, D. E.; Osburn, P. L.; Wilson, A.; Sink, E. M. J. Am.
Chem. Soc. 2000, 122, 9058-9064.
(22) Baleiza˜o, C.; Corma, A.; Garc´ıa, H.; Leyva, A. J. Org. Chem. 2004,
69, 439-446.
(23) Bezsoudnova, E. Y.; Ryabov, A. D. J. Organomet. Chem. 2001,
622, 38-42.
(24) Botella, L.; Na´jera, C. Angew. Chem., Int. Ed. 2002, 41, 179-181.
(25) Botella, L.; Na´jera, C. J. Organomet. Chem. 2002, 663, 46-57.
(26) Botella, L.; Na´jera, C. Tetrahedron Lett. 2004, 45, 1833-1836.
(27) Chen, C.-L.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Tetrahedron Lett.
2005, 46, 521-523.
(28) Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Angew. Chem.,
Int. Ed. 2002, 41, 4120-4122.
(29) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton,
P. N.; Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987-
999.
(30) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Hursthouse,
M. B.; Scordia, V. J. M. Dalton Trans. 2003, 3350-3356.
(31) Bedford, R. B.; Cazin, C. S. J.; Hursthouse, M. B.; Light, M. E.;
Scordia, V. J. M. Dalton Trans. 2004, 3864-3868.
(32) Shaughnessy, K. H.; Booth, R. S. Org. Lett. 2001, 3, 2757-2759.
(33) DeVasher, R. B.; Moore, L. R.; Shaughnessy, K. H. J. Org. Chem.
2004, 69, 7919-7927.
Palladacycle Synthesis. The palladacycles were prepared by
stirring a mixture of the appropriate ligand precursor with PdCl2
and sodium acetate in methanol to give the desired chloride-
bridged palladacycle dimers (Scheme 1). p-Hydroxybenzylamine
1 gave palladacycle 7 in 81% yield as a yellow solid. The neutral
form of the palladacycle was insoluble in water, but was soluble

Water-Soluble Palladacycles
Organometallics, Vol. 25, No. 17, 2006 4107
Table 1. Suzuki Coupling of 4-Bromoanisole Using 7 as a
Precatalysta
entry
ligand
mol % 7
yield (%)b
1
2
none
DCPES
2
2
23
37
3
4
5
6
7
8
9
10
t-Bu-Pip-phos
t-Bu-Pip-phos
t-Bu-Amphos
t-Bu-Amphos
t-Bu-Amphos
Cy-Pip-phos
Cy-Pip-phos
Cy-Pip-phos
2
1
2
99
56
>99
99
99
90
63
63
The catalyst derived from t-Bu-Amphos and palladacycle 7
showed good activity for the cross-coupling of a deactivated
aryl bromide (4-bromoanisole) and phenylboronic acid at low
catalyst loadings (Figure 3). Yields g 90% were obtained with
palladium loadings as low as 0.04 mol % (2300 mol/mol Pd)
for coupling reactions carried out in water at 80 °C for 4 h.
When the catalyst loading was decreased below 0.02 mol %,
the yield dropped slightly to 86% (4300 mol/mol Pd). With 0.01
mol % Pd, a 68% yield (6800 mol/mol Pd) was obtained after
4 h, but only a trace (2%) of product was formed when the
catalyst loading was decreased to 0.002 mol % Pd. If this
reaction was allowed to proceed for 48 h at 80 °C, the yield
was increased to 66% (33 000 mol/mol Pd).
The ability of the other palladacycles to give effective
precatalysts with t-Bu-Amphos was explored in the coupling
of 4-bromotoluene and phenylboronic acid. The catalyst derived
from palladacycle 8 and t-Bu-Amphos gave a modest yield of
the coupled product, while palladacycle 9 in combination with
t-Bu-Amphos gave an inactive catalyst (Table 2). Longer
reaction times did not significantly improve the yield of the
product in either case. The sulfonated imine palladacycle 10
gave an efficient catalyst in combination with t-Bu-Amphos,
however. The coupling reaction using the 10/t-Bu-Amphos
system was repeated in the presence of mercury to determine
whether the active species was homogeneous or heterogeneous.35
Mercury had no significant effect (entry 4) on the yield of
coupled product, which suggests that the active catalyst is a
homogeneous species.
Catalyst Scope. With palladacycles 7 and 10 being identified
as effective precatalysts for model Suzuki coupling reactions,
the scope of these catalyst systems was explored with a range
of aryl halides and arylboronic acids. Palladacycles 7 and 10
both gave excellent yields for electron-deficient, -neutral, and
-rich aryl bromide substrates (Table 3). Both hydrophobic and
hydrophilic aryl bromides could be coupled in excellent yield
using water as the solvent. Catalysts derived from both
palladacycle precursors gave lower yields when the aryl bromide
contained an ortho-methyl substituent. The catalyst derived from
palladacycle 10 appeared to be more strongly affected by steric
bulk, as it gave lower yields with 2-bromotoluene and 2-bromo-
m-xylene than 7. In both cases, the yields were lower than those
obtained at room temperature with a catalyst derived from t-Bu-
Amphos/Pd(OAc)2.32 Catalysts derived from both 7 and 10 gave
modest yields with 4-chlorobenzonitrile. The catalyst derived
from 10 required higher temperature (100 °C) to match the yield
obtained at 80 °C with precatalyst 7 (higher temperature did
not improve the yield with 7). At 80 °C, the catalyst derived
from 7 gave no cross-coupled product with a 4-chlorotoluene.
At 120 °C a low yield of the coupling product could be obtained
after 4 h.
1
1c
2
1
1c
a 4-Bromoanisole (0.2 mmol), PhB(OH)2 (0.3 mmol), Na2CO3 (0.4
mmol), 7 (2-4 µmol of Pd), ligand (1:1 L:Pd), 1:1 H2O/CH3CN (1.5 mL),
50 °C, 2 h. b GC yield determined by comparison to an internal standard
(mesitylene) using response factors determined with authentic materials.
c Water (1.5 mL) used as the solvent.
in basic water, acetonitrile, DMSO, and hot methanol. Sul-
fonated palladacycles 8-10 were prepared from ligands 2, 3,
and 5 in the same way in 54, 75, and 52% yield, respectively.
Complex 8 was soluble in water and methanol, while pallada-
cycles 9 and 10 were soluble in water, but insoluble in methanol.
When carboxylate-functionalized ligands 4 and 6 were reacted
with PdCl2, a black precipitate was obtained. This material could
not be characterized due to its insolubility in all solvents tested
(water, methanol, acetonitrile, methylene chloride, DMSO).
Elemental analysis of this material showed that both palladium
and the carboxylate ligand were present in approximately
equimolar amounts. We believe that ligands 4 and 6 act as
bridging ligands through coordination to the imine and the
carboxylate group. The resulting network likely also entrains
some palladium black, accounting for its color. In contrast, the
more weakly coordinating sulfonate anion does not strongly
coordinate to palladium, allowing the simple palladacycle dimers
to be isolated.
Catalytic Activity of 7-10. The ability of palladacycle 7 to
give an active catalyst for the Suzuki coupling of a deactivated
aryl bromide was explored alone and in combination with a
variety of water-soluble alkylphosphines (eq 1, Table 1).
Hydroxybenzylamine palladacycle 7 gave only a modest yield
in the Suzuki coupling of 4-bromoanisole at 50 °C. Catalysts
derived from a combination of hydrophilic alkylphosphines (1:1
L:Pd) and 7 gave improved yields of the coupling product. t-Bu-
Pip-phos, t-Bu-Amphos, and Cy-Pip-phos all gave effective
catalysts (>90% yield) in combination with 7 (2 mol % Pd,
entries 3, 5, and 8), while DCPES gave a much less effective
catalyst (entry 2). When the catalyst loading was decreased to
1 mol % Pd, the yields dropped significantly for both the t-Bu-
Pip-phos and Cy-Pip-phos systems, while the t-Bu-Amphos/7
catalyst system again gave a quantitative yield of the coupling
product (entries 4, 6, and 9). The t-Bu-Amphos/7 system also
gave a quantitative yield of 4-methoxybiphenyl when the
reaction was carried out in water. The observed order of
reactivity for these ligands was different than that seen when
Pd(OAc)2 was used as the precursor. In the case of reactions
catalyzed by the alkylphosphine ligands and Pd(OAc)2, the order
of activity is t-Bu-Amphos ≈ t-Bu-Pip-phos > Cy-Pip-phos,
which follows the steric demand for these ligands.34 Using 7 as
the catalyst precursor, t-Bu-Amphos still gave the most active
catalyst, but there was little difference between Cy-Pip-phos
and t-Bu-Pip-phos.
Precatalysts 7 and 10 both gave good yields in the cross-
coupling of 4-bromotoluene and substituted arylboronic acids
(Table 4). The presence of electron-donating or -withdrawing
groups on the arylboronic acid did not significantly affect the
cross-coupling yield. The yields obtained with the two palla-
dacycles were generally the same, with the exception of
(34) DeVasher, R. B.; Spruell, J. M.; Dixon, D. A.; Broker, G. A.; Griffin,
S. T.; Rogers, R. D.; Shaughnessy, K. H. Organometallics 2005, 24, 962-
971.
(35) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198,
317-341.

4108 Organometallics, Vol. 25, No. 17, 2006
Huang and Shaughnessy
Table 3. Coupling of Aryl Halides with Phenylboronic Acid
Catalyzed by 7 or 10/t-Bu-Amphosa
Figure 3. Yield of 4-methoxybiphenyl as a function of catalyst
loading (t-Bu-Amphos/7, 1:1, H2O, 80 °C, 4 h).
Table 2. Suzuki Coupling Using Palladacycle/t-Bu-Amphos
Catalyst Systemsa
entry
palladacycle
yield (%)b
1
2
3
4
8
9
10
10
60
10
>99c
97d
a 4-Bromotoluene (0.2 mmol), PhB(OH)2 (0.3 mmol), Na2CO3 (0.4
mmol), 8-10 (2 µmol Pd), t-Bu-Amphos (2 µmol), H2O (1.5 mL), 80 °C,
4 h. b GC yield determined by comparison to an internal standard (mesi-
tylene) using response factors determined with authentic materials. c 1 h.
d Reaction run in the presence of mercury (7 mmol).
4-methoxyphenylboronic acid, where palladacycle 10 gave a
higher yield (90% compared with 79%). The incorporation of
an ortho-methyl substituent on the aryl boronic acid did not
affect the yield of coupled product with either palladacycle. This
result is in contrast to the lowered yields seen when an ortho-
methyl substituent was present on the aryl halide.
a ArX (1 mmol), PhB(OH)2 (1.5 mmol), Na2CO3 (2 mmol), 7 or 10 (0.01
mmol), t-Bu-Amphos (0.02 mmol), H2O (5 mL), 80 °C, 4 h, unless noted
otherwise. b Average isolated yield of two runs. c 100 °C. d 120 °C.
Catalyst Recycling. The potential recyclability of the cata-
lysts derived from t-Bu-Amphos and palladacycles 7 and 10
was explored in the model cross-coupling of 4-bromotoluene
and phenylboronic acid. The reaction was carried out in water
at 80 °C for 1 h. After cooling to room temperature, the organic
products were extracted with deoxygenated ethyl acetate and
the yield was determined by GC. The aqueous phase was then
transferred to a new reaction vessel containing fresh reagents.
This process was repeated until the yield began to decrease
significantly. We have previously reported that Pd(OAc)2/t-Bu-
Amphos can be used for three reaction cycles in the Suzuki
coupling at room temperature before yields begin to decrease.33
To provide a direct comparison with the palladacycle catalyst
precursors, the recycling experiment was repeated at 80 °C. At
80 °C, the Pd(OAc)2/t-Bu-Amphos system actually gave slightly
poorer results, with catalyst activity degrading significantly in
the fourth cycle (Table 5). The catalyst derived from pallada-
cycle 7 was somewhat more efficient than that derived from
Pd(OAc)2, giving four cycles of quantitative yield before the
efficiency of the catalyst began to degrade. Palladacycle 10 gave
a highly recyclable catalyst. This catalyst system gave a
quantitative yield of product for 11 catalyst cycles. The yield
was 85% in the 12th cycle and then 50% in the 13th.
Significantly, the reaction time was kept at 1 h throughout this
study; thus there was no apparent loss of catalyst efficiency
until the 12th cycle.
Table 4. Coupling of 4-Bromotoleuene with Arylboronic
Acids Catalyzed by 7 or 10/t-Bu-Amphosa
a ArX (1 mmol), PhB(OH)2 (1.5 mmol), Na2CO3 (2 mmol), 7 or 10 (0.01
mmol), t-Bu-Amphos (0.02 mmol), H2O (5 mL), 80 °C, 4 h, unless noted
otherwise. b Average isolated yield of two runs.
cycle to allow these salts to settle out. The aqueous supernatant
was then removed and transferred to a new reaction vial for
the subsequent cycles. Significantly, the efficiency of the catalyst
solution was not adversely affected by this additional manipula-
tion. An additional three cycles of quantitative yields were
achieved after decantation of the catalyst solution from the
precipitated salts. The fact that the precipitated solids could be
As the coupling reaction was repeated using the same aqueous
solution, inorganic salts began to precipitate from the reaction
mixture. In the recycling study with palladacycle 10, the aqueous
catalyst solution was allowed to stand overnight after the eighth

Water-Soluble Palladacycles
Organometallics, Vol. 25, No. 17, 2006 4109
Table 5. Recycling of Catalysts Derived from Pd(OAc)2, 7,
palladacycle was intact. Minor peaks corresponding to the free
benzylamine ligand were observed. Heating complexes 8 and
9 under similar conditions for 2 h did not result in the
precipitation of Pd black. The 1H NMR spectrum of complex 8
after heating in basic solution showed two broad sets of
resonances in an approximately 2:1 ratio. Both sets of peaks
were similar to the spectrum of 8 in neutral D2O. The two peaks
may represent cis and trans isomers of the Pd-cyclic dimer or
possibly hydroxide or carbonate analogues of 8. No evidence
of free 2 was observed. A 1H NMR spectrum of 9 in basic water
showed no evidence of decomposition of the palladacycle.
Palladacycle 10 proved to be much more labile. When a basic
solution of sulfonated imine palladacycle 10 was heated at 80
°C for 2 h, a large amount of palladium black precipitated from
the reaction mixture (eq 3). The 1H NMR spectrum after heating
showed that the palladacycle had been completely decomposed.
The major species in solution was the intact imine ligand 5.
Thus under these conditions, the complex appears to have
decomposed by clean decomplexation of the palladacycle ligand.
or 10/t-Bu-Amphosa
reaction yield by cycleb,c
Pd source
1
2
3
4
5
6-11d 12
13
Pd(OAc)2 >99%
89%
86%
31%
7
>99% >99% >99% >99%
66%
10
>99% >99% >99% >99% >99% >99% 85% 50%
a 4-Bromotoluene (0.2 mmol), PhB(OH)2 (0.22 mmol), Na2CO3 (0.4
mmol), Pd(OAc)2, 7, or 10 (4 µmol of Pd), t-Bu-Amphos (4 µmol), H2O
(1.5 mL), 80 °C, 1 h. b GC yield of product extracted with ethyl acetate.
c Cycles 2-13 used the aqueous solution remaining after the previous cycle.
d After cycle 8, the reaction was allowed to stand overnight. The catalyst
solution was removed from the precipitated salts and used for cycles 9-13.
discarded without adversely affecting the catalyst activity
indicates that the catalytically active species remains dissolved
or suspended in water at room temperature after standing
overnight.
Palladacycle Coordination Chemistry and Stability. The
palladacycle dimers could be split with t-Bu-Amphos to give
monomeric phosphine adducts (eq 2). Reaction of palladacycle
7 with t-Bu-Amphos in methanol gave two resonances in the
31P NMR spectrum at 53.0 and 50.7 ppm in a ratio of 1:2.5.
The presence of two peaks may represent formation of cis and
trans isomers of the phosphine adduct, 11a and 11b. Phosphine
adduct 11 was isolated in low yield (36%) by precipitation with
ether from a concentrated methanol solution as a single isomer
as determined by 31P NMR spectroscopy (53 ppm). The
palladium-bound carbon of the N-C ligand appeared as a broad
singlet, so it was not possible to determine which isomer was
isolated. Attempts to grow X-ray-quality crystals of this complex
The stability of the palladacycles under the catalytic condi-
tions was also explored. Palladacycles 7-10 were stirred in the
presence of sodium carbonate (20 equiv), phenylboronic acid
(10 equiv), and t-Bu-Amphos (2 equiv, L:Pd ) 1:1) at room
1
temperature for 6 h and then analyzed by H and 31P NMR
spectroscopy. In each case, the 31P NMR spectrum showed a
singlet at 53.7 ppm, which we have previously assigned as (t-
Bu-Amphos)2Pd(0),34 as the only phosphorus-containing species.
1
were unsuccessful. H and 13C NMR spectra were consistent
with the 1:1 phosphine adduct. t-Bu-Amphos adducts of 8-10
were prepared and characterized by 31P NMR spectroscopy.
Phosphine adduct 14 derived from palladacycle 10 also gave
two 31P NMR resonances at 41.6 and 39.9 ppm (4:1 ratio),
suggesting the formation of isomers with the phosphine cis and
trans to the imine nitrogen. Benzylamine palladacycles 8 and
9 both gave a single sharp peak in their 31P NMR spectra (52.7
and 52.9 ppm, respectively), indicating that only one isomer
(12a or 12b and 13a or 13b) was formed in each case.
1
The presence of an AXX′ virtual triplet at 1.3 ppm in the H
NMR spectrum in each case further confirmed the formation
of (t-Bu-Amphos)2Pd(0). Due to overlap from phenylboronic
acid, it was not possible to determine the fate of the displaced
nitrogen ligands. On the basis of results with similar systems
by Bedford,29,36 it is likely that the palladacycle reacted with
phenylboronic acid to give the 2-phenyl analogue of the nitrogen
ligand (eq 4).
Discussion
Palladacycle complexes 7 and 10 were effective catalyst
precursors for Suzuki couplings of aryl bromides in the presence
of t-Bu-Amphos. The 10/t-Bu-Amphos was a particularly
effective and stable catalyst system that can be recycled 11 times
before losing activity. Studies in model systems showed that
palladacycle 10 was completely decomposed to imine 5 and
palladium metal in 2 h at 80 °C. In the presence of the reducing
conditions of the catalytic system (t-Bu-Amphos, base, and
phenylboronic acid), palladacycles 7-10 were converted to (t-
Bu-Amphos)2Pd(0) as the only phosphorus-containing species
at room temperature. Displacement of the ligand likely occurs
by aryl transfer from boron to palladium followed by reductive
elimination to give the 2-aryl analogue of the nitrogen ligand
Although palladacycles are often described as thermally
stable, there are many examples of palladacycles that decompose
under mild conditions.15,16 In fact, this decomposition is often
thought to be the key step in the formation of the catalytically
activespeciesincross-couplingreactionscatalyzedbypalladacycles.9,11-14
The stability of the hydrophilic palladacycles was explored by
heating them in aqueous base. Hydroxy-functionalized palla-
dacycle 7 was dissolved in aqueous (D2O) sodium carbonate
and heated to 80 °C for 2 h. Some precipitation of palladium
1
black was observed during this time. The H NMR spectrum
(36) Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse, M.
of the mixture after heating showed that the majority of the
B. Dalton Trans. 2003, 4164-4174.

4110 Organometallics, Vol. 25, No. 17, 2006
Huang and Shaughnessy
(eq 4). These results seem to suggest that the palladacycle serves
only as a source of palladium and that (t-Bu-Amphos)2Pd(0) is
the catalytically active species. We have previously identified
this species as being the resting state in the Pd(OAc)2/t-Bu-
Amphos catalyst system.34
ligand continues to exert an influence after decomposition of
the palladacycle precursor. For example, the increased sensitivity
of catalysts derived from 7 and 10 to steric bulk in the aryl
halide compared to Pd(OAc)2 suggests that the active species
in the palladacycle-derived catalyst systems are more sterically
hindered than that derived from Pd(OAc)2. Similarly, the
longevity of the catalyst derived from palladacycle 10 suggests
that the displaced imine ligand is able to stabilize the catalyti-
cally active species. These results seem to suggest that the
nitrogen ligands continue to interact with the palladium center
after being displaced by the phosphine ligand. The nature of
this interaction, if present, is unclear at this time. Additional
work to understand the role of these nitrogen ligands on the
catalyst system are currently ongoing.
For some palladacyclic catalyst systems, it has been proposed
that the catalytically active species are palladium colloids.
Although we observed a t-Bu-Amphos complex under catalyti-
cally relevant conditions, it is still conceivable that a colloidal
species is the true catalyst. Two pieces of evidence point to a
homogeneous catalyst. First, removal of the aqueous supernatant
from precipitated materials after standing overnight did not result
in a loss of catalytic activity during the catalyst recycling study.
This result shows that the catalytically active species remains
dissolved, or suspended, after the solution is allowed to stand
overnight. Second, the addition of mercury did not inhibit the
Suzuki coupling reaction. If the active catalyst species were
heterogeneous palladium particles, these would be expect to be
amalgamated by the mercury, lowering catalyst activity.35
Therefore, we believe that (t-Bu-Amphos)2Pd(0), formed from
the palladacycle precursor, acts as a catalyst precursor or resting
state for a homogeneous, phosphine-stabilized active species.
Conclusions
Hydrophilic palladacycles 7 and 10 gave active catalysts for
the Suzuki coupling of aryl bromides in combination with t-Bu-
Amphos. The 7/t-Bu-Amphos systems gave high yields for the
coupling of a deactivated aryl bromide (4-bromoanisole) at 80
°C after 4 h with catalyst loadings as low as 0.02 mol % Pd.
The catalyst derived from 10/t-Bu-Amphos proved to be highly
recyclable. A total of 12 reaction cycles (80 °C, 1 h) with yields
>86% were obtained with an average yield of 98% for the 12
reaction cycles. This degree of recyclability is one of the highest
that we have been able to find in the literature for a Suzuki
coupling of an aryl bromide using a homogeneous, hydrophilic
catalyst system. Differences in catalyst stability and efficiency
as a function of catalyst precursor suggest that the palladacycle
ligands continue to play a role after decomplexation. Further
studies will attempt to address how the structure of the
palladacycle precursor affects the activity of the resulting catalyst
system.
Although Pd(OAc)2 and palladacycles 7-10 all appeared to
give (t-Bu-Amphos)2Pd(0) under the reaction conditions, the
palladium sources gave very different results in the catalytic
reaction. The catalyst derived from Pd(OAc)2 was highly active
at room temperature, while catalysts derived from 7 and 10
required temperatures of at least 50 °C to achieve reasonable
reaction rates. The higher temperature may represent a slower
formation of the (t-Bu-Amphos)2Pd(0) species, from the pal-
ladacycle precursors. Palladacycle precursors 8 and 9 gave
inactive catalysts, although both precursors give (t-Bu-
Amphos)2Pd(0) under the same conditions as 7 and 10.
Palladacycles 8 and 9 appeared to be more stable when heated
in aqueous base, so their low activity may be due to a slower
formation of (t-Bu-Amphos)2Pd(0). It should be noted that both
8 and 9 in combination with t-Bu-Amphos gave complete
conversion to (t-Bu-Amphos)2Pd(0) on the same time scale as
the reactions in Table 2, however.
Experimental Section
Nitrogen-Based Palladacycle Ligands. Ligands 1,37 3,38 4,39
5,40 and 641,42 were prepared by modifications of literature
procedures. Synthetic details for these compounds as well as ligand
2 are included in the Supporting Information.
Among the precursors that gave active catalysts systemss
Pd(OAc)2, 7, and 10sthere were differences in catalytic
efficiency, despite the apparent formation of identical catalyst
species. The recycling study (Table 5) shows a significant
difference in catalyst lifetime for the various precursors. While
the catalyst derived from Pd(OAc)2 loses activity after only three
cycles, the catalyst derived from 7 remains active for four cycles,
while 10 gives a catalyst that retained activity for 11 cycles.
One could imagine that this difference was due to the pallada-
cycles acting as slow release sources of active palladium species.
Our results show that 10 is more labile than 7 and is completely
decomposed in 2 h at 80 °C. Thus it seems unlikely that a
significant amount of 10 survives the first 1 h reaction cycle.
More subtle effects were seen with different aryl halide
substrates. Catalysts derived from Pd(OAc)2 were unaffected
by the presence of one, or even two, ortho-substituents on the
aryl halide.33 In contrast, catalysts derived from palladacycles
7 and 10 gave lower yields with 2-bromotoluene and 2-bromo-
m-xylene than with sterically unhindered substrates. Of these,
10 consistently gave lower yields than 7.
Synthesis of Palladacycle 7. The palladacycles were prepared
by a modification of the procedure reported by Cope.43 PdCl2
(0.1773 g, 1.0 mmol) was added to the solution of 1 (150 mg, 1.0
mmol) and sodium acetate (82 mg, 1.0 mmol) in methanol (5 mL).
The resulting heterogeneous mixture was stirred at room temper-
ature overnight. All of the palladium chloride was dissolved and
replaced with a yellow precipitate. The precipitate was filtered off,
washed with methanol (2 × 10 mL), and dried in vacuo to give 7
as a yellow solid (246 mg, 84%). Recrystallization from methanol
1
gave an analytically pure sample of 7. H NMR (CD3CN, 360
MHz): δ 6.99-6.31 (m, 8H), 3.85 (brs, 4H), 2.76 (brs, 12H). 13
C
NMR (DMSO-d6, 90.6 MHz): δ 154.0, 150.7, 138.3, 122.3, 119.7,
111.7, 72.1, 51.0. Anal. Calcd for C18H24Cl2N2O2Pd2: C, 37.01;
H, 4.14; N, 4.80. Found: C, 36.56; H, 3.99; N, 4.53.
(37) Bhattacharyya, S. Synth. Comm. 2000, 30, 2001-2008.
(38) Mizoguchi, M., U.S. Patent, 5,792,619, 1998; Chem. Abstr. 129:
92568.
(39) Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709-711.
(40) Reinehr, D.; Metzger, G.; Guesta, F.; Planchenault, D.; Signoret,
E., European Patent, EP 957,085, 1999; Chem. Abstr. 131:352569.
(41) Shukla, H. K.; Astik, R. R.; Thaker, K. A. J. Indian Chem. Soc.
1981, 58, 1182.
(42) Landor, S. R.; Sonola, O. O.; Tatchell, A. R. Bull. Chem. Soc. Jpn.
1984, 57, 1658-1661.
(43) Cope, A. C.; Friedrich, E. C. J. Am. Chem. Soc. 1968, 90, 909-
913.
Thus although each of the palladacycle catalyst precursors
appear to form the same Pd(0) complex, it is clear that the
identity of the palladacycle precursor affects both the activity
and lifetime of the catalyst formed in combination with t-Bu-
Amphos. These results suggest that the displaced palladacycle

Water-Soluble Palladacycles
Organometallics, Vol. 25, No. 17, 2006 4111
Palladacycle 8. To the solution of 2 (237 mg, 1.00 mmol) and
sodium acetate (82 mg, 1.0 mmol) in methanol (20 mL) was added
palladium chloride (177.3 mg, 1.00 mmol). The resulting mixture
was stirred overnight at room temperature until the palladium
chloride dissolved to give a wine-colored solution. The solvent was
removed under reduced pressure. The residue was taken up in a
hot methanol and water mixture (10 mL of methanol and 2 mL of
water). Acetone (5 mL) was added, and the flask was placed in a
freezer overnight. The mixture was filtered and the precipitate was
(D2O, 360 MHz): δ 7.10 (d, J ) 8.32 Hz, 1H), 6.90 (s, 1H), 6.62
(d, J ) 7.77 Hz, 1H), 4.01 (s, 2H), 3.26-3.06 (m, 2H), 2.86 (s,
9H), 2.53 (s, 6H), 2.48-2.36 (m, 2H), 1.52 (d, JP-H ) 13.87, 18H).
13C NMR (D2O, 90.6 MHz): δ 155.8, 141.4, 140.1, 125.5, 124.3
(br), 112.2, 73.8 (brs), 65.2 (brs), 53.4 (brs), 38.1 (d, JC-P ) 16.79
Hz), 31.04 (d, JC-P ) 4.58 Hz), 30.96 (d, JC-P ) 4.58 Hz). 31P
NMR (D2O, 202.5 MHz): δ 53.6 (s).
General Procedure for Ligand Screening Trials. Under
nitrogen, a vial was charged with an appropriate amount of
palladacycle, ligand, sodium carbonate (42.4 mg, 0.4 mmol), and
phenylboronic acid (36.6 mg, 0.3 mmol). To this was added
deoxygenated 1:1 H2O/CH3CN (1.5 mL). 4-Bromoanisole (25 µL,
0.2 mmol) and an internal standard, mesitylene (22 µL), were added
via syringe. The reactions were run at the desired temperature.
Aliquots were removed at a regular interval from the organic layer
and analyzed by GC. In the case of water (1.5 mL) as the solvent,
the reaction was run at the desired time and was then allowed to
cool to room temperature. Ethyl acetate (1 mL) and mesitylene were
added to the reaction mixture. Yields were calculated using response
factors determined with authentic samples of 4-bromoanisole and
4-methoxybiphenyl.
1
dried in vacuo to give a yellow powder (186 mg, 53%). H NMR
(D2O, 360 MHz): δ 7.55 (d, J ) 8.09 Hz, 2H), 7.46 (d, J ) 7.35
Hz, 2H), 7.08 (vt, J ) 8.09 Hz, 2H), 4.35 (s, 4H), 2.82 (s, 12H).
13C NMR (D2O, 90.6 MHz): δ 145.3, 143.8, 138.2, 126.1, 123.9,
72.3, 52.9. One of the aromatic peaks was not observed. Anal. Calcd
for C18H22Cl2N2Na2O6Pd2S2: C, 28.59; H, 2.93; N, 3.70. Found:
C, 28.74; H, 2.82; N, 3.93.
Palladacycle 9. PdCl2 (124 mg, 0.70 mmol) was added to a
solution of 3 (280 mg, 0.70 mmol) and sodium acetate (57.4 mg,
0.70 mmol) in methanol (12 mL). The mixture was stirred at room
temperature overnight. The resulting mixture was then filtered and
washed with methanol (2 × 10 mL). The product was dried in vacuo
to give a yellow powder (281 mg, 75%). 1H NMR (D2O, 360
MHz): δ 7.20-6.85 (m, 8H), 4.15 (s, 4H), 3.13-2.96 (m, 12H),
2.92-2.75 (m, 4H), 2.75-2.76 (m, 8H). 13C NMR (D2O, 90.6
MHz): δ 150.1, 141.3, 134.0, 126.8, 126.4, 123.2, 67.8, 61.1, 49.2,
23.9. Anal. Calcd for C26H36Cl2N2Na4O12Pd2S4‚2H2O: C, 28.17;
H, 3.64; N, 2.53. Found: C, 28.23; H, 3.54; N, 2.46.
General Procedure for Low Catalyst Loading Trials. Stock
solutions were prepared by dissolving the appropriate amount of
palladacycle 7 in deoxygenated acetonitrile to give solutions that
were 3.5 × 10-2 to 3.5 × 10-4 M in Pd. An appropriate amount of
t-Bu-Amphos was dissolved in deoxygenated water to give solutions
that were 7.5 × 10-2 to 7.5 × 10-4 M in P. Under nitrogen, a vial
was charged with sodium carbonate (42.4 mg, 0.4 mmol) and
phenylboronic acid (36.6 mg, 0.3 mmol). To this were added
deoxygenated water (1.5 mL) and 4-bromoanisole (25 µL, 0.2
mmol). The catalyst and ligand solutions were added via syringe.
The reaction was allowed to stand for 4 h at 80 °C. The reaction
then was allowed to cool to room temperature, and ethyl acetate (1
mL) was added. Aliquots were removed from the organic layer
and analyzed by GC. Yields were calculated using response factors
determined with authentic samples of 4-bromoanisole and 4-meth-
oxybiphenyl.
Palladacycle 10. PdCl2 (0.1773 g, 1.0 mmol) was added to the
solution of Schiff base 5 (0.28 g, 1.00 mmol) and sodium acetate
(0.08 g, 1.00 mmol) in methanol (25 mL). The resulting hetero-
geneous mixture was stirred at room temperature for 24 h. The
reaction was filtered to give a black solid, which was taken up in
DMSO (5 mL) and filtered through Celite to remove precipitated
Pd(0). Diethyl ether (60 mL) was added slowly to the filtrate to
form two layers. After standing for 24 h, the mixture was filtered.
1
The product was recovered as a yellow solid (0.2205 g, 52%). H
NMR (D2O, 360 MHz): δ 9.06 (d, J ) 7.40 Hz, 4H), 8.36 (s, 2H),
8.05 (d, J ) 8.01 Hz, 4H), 7.89-7.70 (m, 5H), 7.69-7.50 (m,
3H). 13C NMR (DMSO-d6, 90.6 MHz): δ 172.8, 150.6, 147.9,
133.9, 132.1, 131.6, 128.6, 126.6, 126.3, 123.4, 112.2. Anal. Calcd
for C26H18Cl2N2Na2O6Pd2S2: C, 36.81; H, 2.14; N, 3.30. Found:
C, 37.44; H, 2.64; N, 3.51.
General Procedure for Catalyst Recycling Trials. Under
nitrogen, a vial was charged with Pd(OAc)2, 7, or 10 (1 mol%),
t-Bu-Amphos (5.4 mg, 2 mmol %), sodium carbonate (42.4 mg,
0.4 mmol), and phenylboronic acid (27 mg, 0.22 mmol). To this
mixture was added deoxygenated water (1.5 mL). 4-Bromotoluene
was added via syringe (25 µL, 0.2 mmol). The reactions were run
at 80 °C for 1 h. After the reaction mixture was cooled to room
temperature, deoxygenated ethyl acetate (1 mL) was added and
stirred for 1 min. The upper layer was separated via cannula, and
mesitylene (15 µL) as internal standard was added to this layer.
Aliquots were removed from the organic layer and analyzed by
GC. The aqueous layer was transferred via cannula to a vial that
was charged with phenylboronic acid (27 mg, 0.22 mmol) and
sodium carbonate (21 mg, 0.2 mmol). 4-Bromotoluene (25 µL, 0.2
mmol) was added via syringe for the subsequent cycle.
Stability of Palladacycle (10). Palladacycle 10 (5.8 mg) and
sodium carbonate (21 mg) were added to an NMR tube in a drybox.
The NMR tube was sealed and moved from the drybox. After D2O
was added (0.5 mL), the NMR tube was placed in an 80 °C oil
bath. 1H NMR data were obtained at regular intervals. The 1H NMR
spectrum showed that palladacycle 10 decomposed to 5 in 2 h under
basic conditions. 1H NMR (D2O, 360 MHz): δ 9.97(s, 1H), 7.99-
(d, J ) 8.02 Hz, 2H), 7.79-7.68 (m, 1H), 7.67-7.50 (m, 4H),
6.88 (d, J ) 8.62 Hz, 2H).
Reaction of Palladacycles with t-Bu-Amphos. Palladacycle
dimer (0.01 mmol, 0.02 mmol in Pd) and t-Bu-Amphos (5.4 mg,
0.02 mmol) were taken up in an NMR tube in a drybox. The NMR
tube was then sealed and charged with deoxygenated water (0.5
mL). In the case of palladacycle 7, the mixture was heated at 80
°C for several minutes to give a clear yellow solution. The formation
of palladacycle phosphine adducts was monitored by 31P NMR
spectroscopy: 11, 53.0 and 50.7 ppm (1:2.5); 12, 52.7 ppm; 13,
52.9 ppm; 14, 41.6 and 39.9 ppm (4:1).
General Procedure for the Preparatory Scale Suzuki Cou-
pling Reaction of Water-Insoluble Aryl Halides and Arylboronic
Acids. In a drybox, a round-bottom flask was charged with
palladacycle dimer (0.01 mmol), t-Bu-Amphos (5.4 mg, 0.02
mmol), sodium carbonate (212 mg, 2.00 mmol), and arylboronic
acid (1.5 mmol). The flask was sealed and removed from the
drybox. Deoxygenated water (5 mL) and aryl halide (1.0 mmol)
were added via syringe, and the reaction was stirred at 80 °C for
4 h unless noted. After the reaction was allowed to cool to room
temperature, saturated sodium bicarbonate (20 mL) was added to
the reaction mixture. The resulting mixture was extracted with ether
(3 × 30 mL). The combined ether extracts were dried (MgSO4),
and the solvent was removed under reduced pressure. The crude
material was flash chromatographed on a short silica gel column.
Palladacycle Phosphine Adduct (11). Palladacycle 7 (29.2 mg,
0.05 mmol) and t-Bu-Amphos (26.7 mg, 0.10 mmol) were taken
up in deoxygenated methanol (3 mL). The mixture was refluxed
20 min. Methanol was evaporated in vacuo. The residue was
dissolved in a minimum amount of methanol and precipitated with
ether (10 mL) to give a pale yellow solid (20 mg, 36%). 1H NMR

4112 Organometallics, Vol. 25, No. 17, 2006
Huang and Shaughnessy
palladacycle complexes, and cross-coupled products. This informa-
tion is available via the Web at http://pubs.acs.org.
Acknowledgment. Financial support for this work was
provided by the National Science Foundation (CHE-0124255)
Supporting Information Available: Syntheses for ligands 1-6
and palladacycles 7-14 and characterization of the ligands,
OM050940Y