Palladium-catalyzed C-C coupling under thermomorphic conditions

Article abstract of DOI:10.1021/ja001708g

Liquid-liquid biphasic systems that exhibit an increase in phase miscibility at elevated temperature together with soluble polymer-bound catalysts that have a strong phase preference at ambient temperature are described. In such systems, product isolation and catalyst recovery are effected by a liquid/liquid separation. This report describes the use of such thermomorphic catalyst recovery systems for palladium-catalyzed carbon-carbon bond forming reactions. Poly(N-isopropylacrylamide) (PNIPAM)-bound phosphine ligands with a Pd(0) catalyst used previously in allylic substitution chemistry are efficient catalysts in Heck, Suzuki, and sp-sp² cross-coupling reactions. Air-stable tridentate SCS-Pd(II) catalysts bound to PNIPAM or poly(ethylene glycol) (PEG) are also described. A particular advantage of these SCS catalysts is that no precautions against adventitious catalyst oxidation need be taken with the polymer-bound SCS-PdCl catalysts, thus avoiding time-consuming solvent purification and degassing protocols.

Full text of DOI:10.1021/ja001708g

9058
J. Am. Chem. Soc. 2000, 122, 9058-9064
Articles
Palladium-Catalyzed C-C Coupling under Thermomorphic
Conditions
David E. Bergbreiter,* Philip L. Osburn, Allan Wilson, and Erin M. Sink
Contribution from the Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
ReceiVed May 17, 2000
Abstract: Liquid-liquid biphasic systems that exhibit an increase in phase miscibility at elevated temperature
together with soluble polymer-bound catalysts that have a strong phase preference at ambient temperature are
described. In such systems, product isolation and catalyst recovery are effected by a liquid/liquid separation.
This report describes the use of such thermomorphic catalyst recovery systems for palladium-catalyzed carbon-
carbon bond forming reactions. Poly(N-isopropylacrylamide) (PNIPAM)-bound phosphine ligands with a Pd(0)
catalyst used previously in allylic substitution chemistry are efficient catalysts in Heck, Suzuki, and sp-sp2
cross-coupling reactions. Air-stable tridentate SCS-Pd(II) catalysts bound to PNIPAM or poly(ethylene glycol)
(PEG) are also described. A particular advantage of these SCS catalysts is that no precautions against adventitious
catalyst oxidation need be taken with the polymer-bound SCS-PdCl catalysts, thus avoiding time-consuming
solvent purification and degassing protocols.
Introduction
biphasic catalysissfluorous biphasic chemistry and thermo-
morphic chemistryshave been highlighted as new options for
facile product isolation and catalyst separation and reuse where
polymer supports can be useful.8 These schemes provide many
of the same features of aqueous biphasic catalysis but should
be more accommodating for typical organic substrates that may
not be soluble in water. This report details the use of the latter
of these strategies in the development of recoverable catalysts
for Pd-catalyzed C-C bond formation.
Fluorous biphasic catalysis was first introduced by Horva´th
and Ra´bai9 and further elaborated by Curran, Gladysz, Leitner,
and van Koten among others.10-14 The success of this chemistry
has increased interest in biphasic systems that can combine the
activity of homogeneous catalysis with the simplicity of product
isolation seen in a biphasic system. Some recent work with
fluorinated catalysts has also focused on the use of supercritical
CO2 as a solvent, expanding the library of potential substrates
and useful reactions that may be conducted.15-17
The use of polymer supports in catalysis has traditionally
relied on a solid-liquid separation to achieve catalyst recovery
and product isolation. Such chemistry typically uses cross-linked
polymer supports (e.g., a Merrifield or Wang resin) or soluble
polymer supports that may be either precipitated from solution1-3
or isolated via membrane filtration.4 Catalyst recovery in such
systems depends on a filtration process (a solid/liquid separation
or permselective membrane). Liquid-liquid separations that are
more often used in ordinary organic purification procedures are
less often used in polymer-supported chemistry. Nonetheless,
liquid/liquid biphasic systems are known to be useful in
catalysis. Three examples include phase transfer catalysis,5 the
Shell Higher Olefin Process (SHOP) for the production of
R-olefins from ethylene,6 and the Rhoˆne-Poulenc process for
the hydroformylation of propylene.7 In the first of these
examples, the reagent resides in the polar aqueous phase. In
the second example, a nonpolar product phase separates from
a polar catalyst-containing phase. In the third case, the catalyst
resides in the polar aqueous phase. Biphasic catalysis schemes
such as these enable catalyst recovery and product isolation
through a liquid/liquid separation. Two new strategies for
(8) Baker, R. T.; Tumas, W. Science 1999, 284, 1477.
(9) Horva´th, I. T.; Ra´bai, J. Science 1994, 266, 72.
(10) (a) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Curran, D. P. Tetrahedron
2000, 56, 351. (b) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.; Curran, D. P.
Tetrahedron Lett. 2000, 41, 57. (c) Wipf, P.; Curran, D. P. Science 1997,
275, 823.
(1) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724.
(2) Bergbreiter, D. E.; Zhang, L.; Mariagnanam, V. M. J. Am. Chem.
Soc. 1993, 115, 9295.
(11) (a) Juliette, J. J. J.; Rutherford, D.; Horva´th, I. T.; Gladysz, J. A. J.
Am. Chem. Soc. 1999, 121, 2696. (b) Dinh, L. V.; Gladysz, J. A. Tetrahedron
Lett. 1999, 40, 8995. (c) Klose, A.; Gladysz, J. A. Tetrahedron: Asymmetry
1999, 10, 2665.
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Kling, R.; Sinou, D.; Pozzi, G.; Choplin, A.; Quignard, F.; Busch, S.; Kainz,
S.; Koch, D.; Leitner, W. Tetrahedron Lett. 1998, 39, 9439.
(13) (a) Richter, B.; Spek, A. L.; van Koten, G.; Deelman, B.-J. J. Am.
Chem. Soc. 2000, 122, 3945. (b) Kleijn, H.; Rijnberg, E.; Jastrzebski, J. T.
B. H.; van Koten, G. Org. Lett. 1999, 1, 853.
(3) Bergbreiter, D. E.; Liu, Y.-S. Tetrahedron Lett. 1997, 38, 7843.
(4) Cornils, B.; Herrmann, W. A. Applied Homogeneous Catalysis with
Organometallic Compounds; VCH: Weinheim, 1996; Vol. 2.
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1999, 28, 37. (b) Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. ReV.
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10.1021/ja001708g CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/09/2000

Pd-Catalyzed C-C Coupling underThermomorphic Conditions
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9059
Figure 1. Schematic representation of thermomorphic catalysis.
Selective solubility of the polymer support under biphasic conditions
ensures quantitative catalyst recovery.
Figure 2. Synthesis of a PNIPAM-bound phosphine and subsequent
conversion to (PNIPAM-PPh2)4Pd(0), 2.
The idea that polymer supports can serve as phase traffic
control agents is the essence of the original Merrifield approach
for peptide synthesis. This same idea underlies all our work
with soluble polymers.18 We have shown that fluorinated
polymers are generic supports for fluorous reagents and
catalysts, that amphiphilic polymers serve as water-soluble
supports at the right pH, and that polymers with temperature-
dependent solubility are useful in both water and aqueous
systems.19,20
Heck and Suzuki couplings, other polymers, and other solvent
systems. These reactions employ either a poly(N-isopropylacryl-
amide) (PNIPAM)-bound phosphine ligand or a polymer-
supported tridentate SCS-Pd catalyst. The use of the latter
catalyst represents a significant simplification of reaction
protocol. The work described here also shows that complete
miscibility of the phases is not required and in some cases may
even impede reactions.
The biphasic catalyst recovery scheme we termed thermo-
morphic catalysis (Figure 1) can also use a soluble polymer to
facilitate catalyst recovery and separation from products.21 The
separation in these systems relies on two ideas. The first is that
many binary and ternary solvent systems exhibit a reversible
increase in miscibility with increasing temperature. For example,
in some systems an originally biphasic mixture becomes
miscible and monophasic with mild heating. Such systems have
precedence in organometallic chemistry22 and were also de-
scribed in the original fluorous paper by Horva´th and Ra´bai.9
There are also ample precedents for these systems in the
literature.23 The second idea is that a soluble polymer should
have a strong phase preference for one phase under biphasic
conditions. This leads to a general way to separate a product
from a homogeneous catalyst and to recover the catalyst by a
simple liquid/liquid-phase separation followed by solvent
removal to isolate the product. A preliminary report demon-
strated these concepts with Rh(I)-catalyzed hydrogenation and
Pd(0)-catalyzed allylic substitution reactions. This paper extends
this thermomorphic catalysis to include two important pal-
ladium-catalyzed carbon-carbon bond forming reactions, the
Results and Discussion
Pd(0)-Catalyzed Reactions Using PNIPAM-PPh2 under
Thermomorphic Conditions. Our initial efforts were focused
on the straightforward extension of the Pd(0)-catalyzed reactions
previously described21 to include the carbon-carbon bond-
forming processes shown in eq 1. The PNIPAM-bound phos-
phine 1 (Figure 2) was prepared using reported chemistry20d
and was then converted to the Pd(0) catalyst 2 via a ligand
exchange reaction with a palladium precatalyst, Pd(0)(dba)2.
Using 2 mol % (PNIPAM-PPh2)4Pd(0) and triethylamine
(TEA) as the base, iodobenzene was treated with either tert-
butyl acrylate (Heck reaction), phenylboronic acid (Suzuki
reaction), or phenylacetylene. In addition to the Pd(0) catalyst,
5 mol % CuI cocatalyst was used in the cross-coupling reaction.
These reactions were conducted in the same heptane/90%
aqueous EtOH thermomorphic system used previously. GC
analysis showed that these reactions were complete within 48
h at 70 °C. After each reaction, the system was allowed to cool
to room temperature, inducing phase separation. Removal of
(15) Klement, I.; Lu¨tjens, H.; Knochel, P. Angew. Chem., Int. Ed. 1997,
36, 1454.
(16) (a) Carter, C. A. G.; Baker, R. T.; Tumas, W.; Nolan, S. P Chem.
Commun. 2000, 5, 347. (b) Pesiri, D. R.; Morita, D. K.; Walker, T.; Tumas,
W. Organometallics 1999, 18, 4916. (c) Jacobson, G. B.; Lee, C. T.;
Johnston, K. P.; Tumas, W. J. Am. Chem. Soc. 1999, 121, 11902.
(17) (a) Carson, T.; Lizotte, J.; Desimone, J. M. Macromolecules 2000,
33, 1917. (b) Shiho, H.; Desimone, J. M. Macromolecules 2000, 33, 1565.
(c) Shiho, H.; Desimone, J. M. J. Polym. Sci., Part A: Polym. Chem. 2000,
38, 1146.
(18) Bergbreiter, D. E. Catal. Today 1998, 42, 389.
(19) (a) Bergbreiter, D. E.; Franchina, J. G.; Koshti, N.; Frels, J.;
Williams, L.; Case, B. L. Comb. Chem. High Throughput Screening 2000,
3, 153. (b) Bergbreiter, D. E.; Franchina, J. G.; Case, B. L. Org. Lett. 2000,
2, 393. (c) Bergbreiter, D. E.; Koshti, N.; Franchina, J. G.; Frels, J. D.
Angew. Chem., Int. Ed. Engl. 2000, 39, 1040. (d) Bergbreiter, D. E.;
Franchina, J. G. Chem. Commun. 1997, 1531.
(20) (a) Bergbreiter, D. E.; Case, B. L.; Liu, Y.-S.; Caraway, J. W.
Macromolecules 1998, 31, 6053. (b) Case, B. L.; Franchina, J. G.; Liu,
Y.-S.; Bergbreiter, D. E. Chem. Ind. 1998, 75, 403. (c) Bergbreiter, D. E.;
Liu, Y.-S. Tetrahedron Lett. 1997, 38, 3703. (d) Bergbreiter, D. E.; Liu,
Y.-S. Tetrahedron Lett. 1997, 38, 7843. (e) Bergbreiter, D. E.; Weatherford,
D. A. J. Org. Chem. 1989, 54, 2726.
1
the heptane phase and solvent evaporation furnished the H
NMR pure products 3-5. Catalyst recycling was achieved for
3 and 4 by adding a fresh heptane solution of the reactants and
reheating the system to 70 °C for an additional 48 h. The isolated
yields increased each cycle, becoming virtually quantitative in
the third cycle. Table 1 summarizes these results.
In the course of studying these reactions, it was found that
styrene reacted with iodobenzene only slowly in the heptane-
aqueous ethanol mixture. Careful repetition of this experiment
indicated that adventitious catalyst oxidation was not the
problem in this case. The problem instead is that the monophasic
(21) Bergbreiter, D. E.; Liu, Y.-S.; Osburn, P. L. J. Am. Chem. Soc.
1998, 120, 4250.
(22) Bianchini, C.; Frediani, P.; Sernau, V. Organometallics 1995, 14,
5458.
(23) Francis, A. W. Critical Solution Temperatures; American Chemical
Society: Washington, 1961.

9060 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bergbreiter et al.
Table 1. Thermomorphic C-C Coupling Reactions Catalyzed by
(PNIPAM-PPh2)4Pd(0) (2)a
Figure 3. The PNIPAM-bound Methyl Red dye used in preliminary
thermomorphic distribution experiments. The synthesis of PNIPAM-
MR has been previously reported.20a
a All reactions were run in 1:1 (v/v) 90% EtOH/C7 with PhI at 75
°C using 2 mol % catalyst and TEA as the base and all yields are for
product isolated from the heptane phase unless otherwise noted. b 5
mol % CuI was added and recycling experiments were not run for this
reaction. c This reaction was run in 1:1 (v/v) DMA/C7 at 90 °C. d GC
yields.
Figure 4. The poly(ethylene glycol)-supported SCS-PdCl catalyst used
in initial thermomorphic C-C coupling reactions. The synthesis of 8
has been previously reported.25
solvent mixture is a poor solvent. Using 2 mol % (PPh3)4Pd(0)
with TEA as the base at 75 °C, it was found that the reaction
is approximately four times faster in a polar aprotic solvent such
as N,N-dimethylformamide (DMF) or N,N-dimethylacetamide
(DMA) than in solvents such as aqueous ethanol or aqueous
ethanol/heptane mixtures at 90 °C. This finding was consistent
with previous work on solvent effects in the Heck and related
reactions24 and suggested that better rates would be obtained
using 2 in a thermomorphic system with DMF or DMA as one
of the solvent components.
The use of an air-stable SCS-Pd(II) catalyst instead of 2 would
simplify the reaction protocol involved in thermomorphic
catalysis. Thermomorphic catalyst recovery and recycling of
these SCS-Pd(II) catalysts would also avoid the need for large
amounts of a poor solvent to precipitate the polymer-bound
catalyst after each cycle. To study the feasibility of PEG-bound
catalyst recovery under thermomorphic conditions, we modified
commercially available monomethoxy PEG so that it contained
a terminally bound methyl red dye (PEG-MR). This derivative
of commercially available PEG contained a significant low
molecular weight, heptane-soluble fraction based on the col-
oration of the upper heptane phase that was seen after several
heating-cooling cycles. However, this heptane-soluble fraction
of commercially available PEG could be removed simply via
continuous liquid-liquid extraction of a 50:50 EtOH/H2O
solution of this polymer with heptane. Repeating the synthesis
of PEG-MR with the extracted PEG and subjecting it to the
same dye distribution experiment furnished qualitative evidence
for its recovery under thermomorphic conditions; no color was
observed in the upper phase of a 90% EtOH/C7 system even
after several heating-cooling cycles.
The synthesis of PEG-bound SCS-Pd catalyst 8 (Figure 4)
has been previously reported25 and was repeated using an
extracted PEG substrate to furnish a catalyst that we could
quantitatively recover under thermomorphic conditions. How-
ever, solvent effects similar to those observed with 2 precluded
the use of 8 for Heck catalysis in 90% EtOH/C7. Moreover,
when 8 was dissolved in pure DMA, addition of heptane resulted
in a system that was monophasic at room temperature. Poly-
(ethylene glycol) evidently lowers the critical solution temper-
ature (CST) of this system from 65 to e25 °C. However,
addition of 10% H2O (v/v) to the DMA phase (i.e., using 90%
aqueous DMA) does produce a biphasic system at 25 °C. While
this 90% aqueous DMA/C7 system did not completely misci-
bilize at any temperature below 100 °C, a significant change in
relative phase volume was observed for a 1:2 (v/v) 90% DMA/
C7 mixture at 95 °C.
DMA and heptane are immiscible at room temperature and
are miscible in all proportions above 65 °C.23 To study the
potential utility of a DMA/heptane system for thermomorphic
catalysis, we first synthesized a PNIPAM-bound methyl red dye
7 (Figure 3). Using this polymer-bound dye, we observed that
the polymer was evenly distributed throughout the system under
monophasic conditions and resided only in the DMA phase at
room temperature. A 1:1 (v/v) mixture of these solvents is
therefore exactly analogous to the 90% EtOH/C7 thermomorphic
system. We then used 2 mol % of 2 to catalyze the reaction
between iodobenzene and styrene in DMA/heptane. Under these
conditions, we observed complete conversion to 6 after 48 h at
90 °C. Recycling of this reaction was also successful; each of
3 cycles achieved complete conversion as shown in Table 1.
Pd(II)-Catalyzed Reactions Using PNIPAM-SCS-PdCl
under Thermomorphic Conditions. Although the recycling
experiments described above using 2 were successful, this
phosphine-ligated Pd(0) catalyst is air-sensitive. Care must be
taken to avoid a steady deactivation of the catalyst via
adventitious oxidation during recycling.20e This is a practical
limitation for catalyst recycling that could be avoided by the
use of a more stable tridentate sulfur-carbon-sulfur (SCS)
Pd(II) catalyst.25 Such palladacycles are thermally and oxida-
tively robust. At 120 °C in DMF solution, they catalyze the
Heck reaction between a number of aryl iodides and acceptor
alkenes in air; these catalysts can also readily be bound to poly-
(ethylene glycol) (PEG). Such PEG-bound SCS catalysts could
be recovered by solvent precipitation.
(24) (a) Zhao, F.; Shirai, M.; Arai, M. J. Mol. Catal. A: Chem. 2000,
154, 39. (b) Zhao, F. Y.; Bhanage, B. M.; Shirai, M.; Arai, M. J. Mol.
Catal. A: Chem. 1999, 142, 383.
(25) (a) Bergbreiter, D. E.; Osburn, P. L.; Liu, Y.-S. J. Am. Chem. Soc.
1999, 121, 9531. (b) Gruber, A. S.; Zim, D.; Ebeling, G.; Monteiro, A. L.;
Dupont, J. Org. Lett. 2000, 2, 1287. (c) Dupont, J.; Beydon, N.; Pfeffer,
M. J. Chem. Soc., Dalton Trans. 1989, 1715. (d) Spencer, J.; Pfeffer, M.;
Kyritsakas, N.; Fischer, J. Organometallics 1995, 14, 2214. (e) Zim, D.;
Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L. Org. Lett. 2000, 2,
2881.
Thus, 0.2 mol % of 8 readily catalyzed the Heck coupling of
various aryl iodides and acceptor alkenes in 1:2 (v/v) 90%
DMA/C7 at 95 °C with TEA as the base. Reactions with tert-
butyl acrylate were complete within 10 h; those with styrene
were complete within 20 h. All of the reactions with 8 were
run in an air atmosphere without any precautions against catalyst
oxidation. No catalyst degradation or decrease in rate was

Pd-Catalyzed C-C Coupling underThermomorphic Conditions
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9061
Table 2. Thermomorphic Heck Coupling Reactions Catalyzed by
PEG-SCS-PdCl (8)a
thermomorphic systems were of interest to us. Our success in
using the PNIPAM-supported catalyst 2 in the nonaqueous
DMA/C7 system prompted us to investigate the use of PNIPAM
as a support for SCS-Pd catalysts as well.
The synthesis of a PNIPAM-SCS-PdCl catalyst is depicted
in Figure 5. Synthesis of 3,5-bis(phenylthiomethyl)aniline has
been previously described.25 Coupling of this material to N-Boc-
6-aminocaproic acid was accomplished using 1,1′-carbonyldi-
imidazole (CDI) and 4-(N,N-dimethylamino)pyridine (DMAP)
as acylation catalysts. Subsequent deprotection of 11 yielded
the amine-terminated SCS ligand 12. Immobilization of this
ligand was then achieved by allowing a 10:1 copolymer of
N-isopropylacrylamide (NIPAM) and N-acryloxysuccinimide
(NASI) to react with 0.8 equiv of 12. The remaining active ester
groups were then quenched with NH3 in MeOH to yield a
terpolymer having a 50:1:4 ratio of N-isopropylacrylamide,
acrylamide, and tethered SCS ligand groups (13). Our prior work
has shown that substituting another amine for the NH3 (or by
changing the isopropyl group of the NIPAM) allows us to tune
polymer solubility. The 1H NMR and 13C NMR of this material
were completely analogous to those for the low molecular
weight ligand 12. Palladation of 13 was then achieved using
Pd(PhCN)2Cl2 in refluxing CH3CN to yield the PNIPAM-bound
SCS-Pd(II) catalyst 14. While the 1H NMR spectrum of 14 was
indeed analogous to that for the low molecular weight coun-
terpart, its 13C NMR spectrum was more informative; it clearly
showed a peak at δ 149.73 representing the C-Pd bond of the
SCS catalyst moiety. Figure 6 shows a selected region of the
13C NMR spectra for 13 and 14.
a All reactions were run in 1:2 (v/v) 90% aqueous DMA/C7 at 95
°C using 0.2 mol % 8 and TEA as the base in an air atmosphere.
Reactions with tert-butyl acrylate were complete within 10 h; those
with styrene were complete within 20 h. All yields are for product
isolated from the heptane phase.
observed over the three cycles for each reaction. Simply
removing the upper heptane phase after reaction and evaporating
the solvent achieved product isolation. Adding a fresh heptane
solution of the reactants and reheating the system for the
required time effected catalyst recycling. After drying under
vacuum, all the isolated products were pure single isomers by
1H NMR and 13C NMR spectroscopy. As noted for previous
reactions, isolated yields improved with each cycle, generally
becoming quantitative by the third cycle. Table 2 summarizes
these results. An advantage of this air-stable catalyst is the
simplicity of the reaction setup. Since all manipulations could
be performed in an air atmosphere, the setup time for each
reaction was just a few minutes. Conversely, reactions with the
air-sensitive catalyst 2 generally required significant time for
setup using standard Schlenk techniques.
The results using 8 show that the polymer support can affect
thermomorphic behavior. As described above, 8 induced room
temperature miscibility of a DMA/C7 system; addition of water
as a cosolvent was used to induce formation of a biphase. While
catalyst recycling with 8 was successful in the resulting ternary
solvent mixture, other polymer supports whose structure would
be more tunable and that could be used in nonaqueous
While methyl red analogues of 14 were soluble in DMA/C7,
the Pd(II)-SCS-catalyst 14 precipitated from a 1:1 DMA/C7
system on heating. The precipitated polymeric catalyst 14 was
not active. The polymeric catalyst 14 redissolved in the DMA
phase on cooling and we concluded that the problem was due
to the insolubility of the catalyst-containing polymer and not
catalyst degradation. Evidently the SCS-PdCl catalyst moiety
significantly alters the solubility of the PNIPAM polymer
support in the heated homogeneous mixture of pure DMA and
heptane even though the catalyst loading is only 7%. Fortunately,
Figure 5. Synthesis of the air-stable PNIPAM-bound SCS-Pd(II) catalyst, 14.

9062 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bergbreiter et al.
Figure 6. Selected region of the 13C NMRs of PNIPAM-SCS, 13, and PNIPAM-SCS-PdCl, 14. Both of these spectra are analogous to those for
low molecular weight analogues.25
the use of DMA containing 10% water (v/v) in place of pure
DMA (i.e., using 90% aq. DMA) prevented this polymer
precipitation. Subsequent catalytic reactions with 14 were
therefore conducted in solvent mixtures composed of 90%
aqueous DMA and heptane.
tions. The use of a thermomorphic solvent system in conjunction
with a selectively soluble polymer support like PEG or PNIPAM
allowed for facile product isolation and catalyst recycling. While
effective catalyst recycling was achieved with the phosphine-
ligated Pd(0) catalyst 2, use of an air-stable tridentate SCS-
Pd(II) catalyst greatly simplified reaction protocol. Initial work
with the PEG-supported catalyst 8 was frustrated by the presence
of a significant heptane-soluble fraction in the commercially
available polymer and the induced miscibilization of DMA and
heptane in the presence of PEG. Successful thermomorphic
catalysis was, however, achieved by extractive purification of
the PEG support and through the use of water as a cosolvent
for the reactions. In fact, the use of a 90% DMA/C7 system
demonstrated that complete miscibility of the two phases is not
a requirement for acceptable reaction rates. Changing to a
PNIPAM-supported catalyst resulted in a different solubility
problem; 14 precipitated from DMA/C7 under monophasic
conditions, effectively halting reaction. However, this was also
overcome by employing a 90% DMA/C7 thermomorphic system
and subsequent Heck and Suzuki reactions proceeded with
quantitative catalyst recycling. These results serve not only to
expand the repertoire of useful reactions that may be conducted
under thermomorphic conditions but also begin to demonstrate
the flexibility of this catalyst recovery technique. Further
refinement of these systems via alternative polymer supports
and solvent systems should lead to a nonaqueous thermomorphic
catalyst system as well as access to a wider variety of substrates
and increased early cycle yields and we are currently working
toward these goals.
Catalytic experiments using 0.2 mol % of 14 for the Heck
coupling of various aryl iodides and acceptor alkenes in 1:2
(v/v) 90% aqueous DMA/C7 at 95 °C using TEA as the base
were carried out at reaction times that were comparable to those
used with 8 (10-20 h). Thermomorphic reactions with 14
displayed no sensitivity to oxygen; no catalyst degradation was
observed, even after five cycles (Table 3, first entry). Product
isolation and catalyst recycling were as efficient as with 8. All
the isolated products were pure single isomers by 1H NMR and
13C NMR spectroscopy, except for 15 and 16, which were
mixtures of isomers. Table 3 summarizes these results.
The PNIPAM-supported SCS-Pd complex 14 also catalyzed
Suzuki coupling reactions. For example, reaction of various aryl
iodides with phenylboronic acid under identical conditions (0.2
mol % of 14, TEA, 95 °C) yielded biphenyls 4, 19, and 20. All
of these reactions achieved complete conversion within 20 h.
A significant feature of the results illustrated in Table 4 is that
the isolated yields of the biphenyl products in this DMA/C7
system were lower in the first few cycles because of dissolution
of the product in the polar DMA phase. High isolated yields
were, however, reached within four or five cycles.
Conclusions
In summary, palladium-catalyzed carbon-carbon bond-
forming reactions were successful under thermomorphic condi-

Pd-Catalyzed C-C Coupling underThermomorphic Conditions
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9063
Table 3. Thermomorphic Heck Coupling Reactions Catalyzed by PNIPAM-SCS-PdCl (14)a
a All reactions were run in 1:2 (v/v) 90% aqueous DMA/C7 at 95 °C using 0.2 mol % 14 and TEA as the base in an air atmosphere. All reactions
were complete in under 10 h, except those involving styrene; these required up to 20 h for completion. All yields are for product isolated from the
1
heptane phase. All products were the trans isomer, except 15 (a 3:1:1 mixture of Z, E, and internal isomers by H NMR) and 16 (a 2:1 mixture of
1
Z and E isomers by H NMR). b Five cycles were run for this reaction; the 5th cycle isolated yield was also quantitative.
Table 4. Thermomorphic Suzuki Coupling Reactions Catalyzed by PNIPAM-SCS-PdCl (14)a
a All reactions were run in 1:2 (v/v) 90% aqueous DMA/C7 at 95 °C using 0.2 mol % 14 and TEA as the base in an air atmosphere. All reactions
were complete within 20 h. All yields are for product isolated from the heptane phase.
h. After reaction, the CHCl3 solution was washed with 10 M NaOH (2
× 15 mL), 5% HOAc (2 × 15 mL), and brine (1 × 20 mL). The organic
phase was then dried over MgSO4 and filtered, and the solvent was
removed under reduced pressure. The residue was then purified by
column chromatography (silica gel, 1:1 hexane/EtOAc) to yield 0.717
g (89%) of 11 as a white solid material after drying under vacuum:
1H NMR (CDCl3) δ 1.34 (m, 2 H), 1.41 (s, 9 H), 1.60-1.71 (m, 4 H),
2.27 (t, 2 H), 3.07 (br q, 2 H), 4.00 (s, 4 H), 4.63 (br s, 1 H), 6.93 (s,
1 H), 7.10-7.23 (m, 10 H), 7.41 (s, 2 H), 7.73 (s, 1 H).
Synthesis of N-3,5-Bis(phenylthiomethyl)phenyl-6-aminocapro-
amide (12). To a solution of 11 (0.940 g, 1.67 mmol) in 20 mL of
CHCl3 was added trifluoroacetic acid (0.32 mL, 4.18 mmol). The
resulting homogeneous solution was heated to reflux for 20 h. After
this time, TLC (silica gel, 1:1 hexane/EtOAc) showed complete
deprotection of 11. Amberlyst-15 (8.0 g), cleaned according to a
reported procedure,26 was added to the reaction solution and the resultant
mixture shaken at ambient temperature for 16 h. The mixture was then
filtered and the Amberlyst-15 washed with 35 mL each of hexane, THF,
and MeOH. The resin was then added to a 4.0 M solution of NH3 in
MeOH. This heterogeneous mixture was then shaken at room temper-
Experimental Section
General. All reagents and solvents were obtained from commercial
sources and were generally used without further purification. However,
the commercially available monomethoxy PEG (Mn ) 5000) contained
a significant low molecular weight, heptane-soluble fraction, which was
removed before use by continuous liquid-liquid extraction of a 50%
aqueous ethanol solution of the polymer with heptane. Gas chromato-
graphic analyses were performed on a Shimadzu instrument equipped
with a 15-m SPB-5 (poly(5%-diphenyl-95%-dimethylsiloxane)) normal
1
phase fused silica capillary column (0.53 ID). H NMR spectra were
recorded on Varian VXR-300 or Unity p300 spectrometers at 300 MHz.
Chemical shifts are reported in ppm with either tetramethylsilane (TMS,
0.0 ppm) or hexamethyldisiloxane (HMDS, 0.055 ppm) as internal
standards. 13C NMR spectra were recorded at 75 MHz with CDCl3 or
DMSO-d6 as the internal reference. The syntheses of 2,21 8,25 and 3,5-
bis(phenylthiomethyl)aniline25 have been reported previously.
Synthesis of N-3,5-Bis(phenylthiomethyl)phenyl-(N′-boc-6-
amino)caproamide (11). To a solution of 3,5-bis(phenylthiomethyl)-
aniline (0.501 g, 1.43 mmol) and N-Boc-6-aminocaproic acid (0.529
g, 2.29 mmol) in 30 mL of CHCl3 was added 1,1′-carbonyldiimidazole
(0.373 g, 2.30 mmol) and 4-(N,N-dimethylamino)pyridine (0.176 g,
1.44 mmol). The resulting homogeneous solution was refluxed for 30
(26) Liu, Y.-S.; Zhao, C. X.; Bergbreiter, D. E.; Romo, D. J. Org. Chem.
1998, 63, 3471.

9064 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bergbreiter et al.
ature for 6 h. After this time the mixture was then filtered and the
solvent removed from the filtrate under reduced pressure. The resulting
residue was dried under vacuum to yield 0.61 g (80%) of pure 12 as
a pale yellow oil: 1H NMR (CDCl3) δ 1.30-1.51 (m, 4 H), 1.67 (m,
2 H), 2.30 (m, 4 H), 2.69 (m, 2 H), 4.01 (s, 4 H), 6.95 (s, 1 H), 7.10-
7.31 (m, 10 H), 7.41 (s, 2 H), 7.69 (s, 1 H).
reheating the system. Three cycles were run for each reaction except
the cross-coupling. Occasionally, after the three cycles some accumula-
tion of a black precipitate, presumably Pd metal, was observed. The
products 3-5 are all known compounds.
General Procedure for Thermomorphic Catalysis with 8 and 14.
A solution of either 8 or 14 (0.01 mmol of Pd; corresponding to 56
mg of 8 or 21 mg of 14) in 5 mL of 90% aqueous DMA was prepared
in a 30 mL screw-cap vial and a Teflon stirbar was added. Then, a
solution of the aryl iodide (5 mmol), acceptor (6 mmol), and
triethylamine (7.5 mmol) in 10 mL of heptane was added to the first
solution and the tube sealed with the screw cap. For the Suzuki coupling
reactions, phenylboronic acid (6 mmol) was first dissolved in the 90%
DMA phase due to its low solubility in heptane. The tube was heated
to 95 °C in an oil bath and the stirred reaction monitored by TLC (silica
gel, heptane). After reaction, the system was cooled to ambient
temperature, the upper heptane phase was removed by pipet, and the
solvent was removed under reduced pressure. Drying of the remaining
residue under vacuum provided the pure coupling products 3-4, 6,
9-10, and 15-20. Catalyst recycling was effected by adding a fresh
heptane solution of the reactants (plus a fresh portion of phenylboronic
acid to the DMA phase for the Suzuki reactions), resealing the system,
and reheating to 95 °C. At least three cycles were run for all reactions.
No catalyst decomposition or rate decrease was observed, even after
five cycles. All of the products are known compounds and were isolated
as pure single isomers, except 15 and 16, which were isolated as
mixtures of 3:1:1 Z/E/internal and 2:1 Z/E isomers (based on 1H NMR
spectroscopy), respectively. Selected spectral data are given below:
Synthesis of 50:1:4 P(NIPAM-AM-SCS) (13). To a solution of
10:1 P(NIPAM-NASI) (351 mg, 0.270 mmol; prepared according to a
published procedure)20a in 20 mL of 9:1 THF/MeOH was added 12
(100 mg, 0.216 mmol) and triethylamine (0.102 mL, 0.732 mmol). The
resulting solution was stirred at ambient temperature for 12 h. Then,
10 mL of 4 M NH3 in MeOH was added and the solution stirred for an
additional 4 h at ambient temperature. The solvent was then removed
from the reaction solution under reduced pressure. The residue was
redissolved in 10 mL of THF and poured into 100 mL of hexanes,
precipitating 13 as a white powder. This material was filtered, washed
with further portions of hexanes, and dried under vacuum to yield 320
mg (91%) of 13: 1H NMR (DMSO-d6) δ 0.95-1.20 (br, 60 H), 1.21-
1.40 (br, 20 H), 1.80-2.10 (br, 10 H), 3.82 (br s, 10 H), 4.13 (br s, 3.2
H), 7.12 (br s, 0.8 H), 7.17-7.22 (br m, 8 H), 7.51 (br s, 1.6 H); 13C
NMR (DMSO-d6) δ 22.29 (br), 25.13, 27.89, 29.01, 30.03, 36.70 (br),
50.09, 60.18 (br), 118.11, 125.78, 128.05, 128.94, 136.25, 137.90,
139.58, 173.22 (br).
Palladation of 50:1:4 P(NIPAM-AM-SCS) (14). A solution of 13
(1.06 g, 0.548 mmol SCS ligand) in 8 mL of DMF was prepared in a
three-necked flask fitted with a condenser. The system was sealed and
the air removed with a vacuum pump and then replaced with dry N2.
The flask was purged with N2 for 30 min and then Pd(PhCN)2Cl2
(209.34 mg, 0.548 mmol) was added rapidly and the system resealed.
The resulting dark red homogeneous solution was stirred at room
temperature for 1 h and then refluxed for 14 h. After the reaction, the
solution was filtered while hot to remove any insoluble material. The
filtrate was then poured into 35 mL of diethyl ether, precipitating a
yellow solid material. This solid was isolated by filtration and
redissolved in 10 mL of THF. This THF solution was then poured into
50 mL of hexanes, again yielding a yellow precipitate. This precipitate
was filtered again, washed with further portions of hexanes, and dried
under vacuum to yield 1.01 g (95%) of the catalyst 14: 1H NMR
(DMSO-d6) δ 0.96-1.12 (br s, 60 H), 1.16-1.38 (br m, 20 H), 1.80-
2.10 (br, 10 H), 3.80 (br s, 10 H), 4.71 (br s, 3.2 H), 7.41 (br s, 1.7 H),
7.39 (br m, 4.8 H), 7.78 (br m, 3.2 H); 13C NMR (DMSO-d6) δ 22.23
(br), 24.89, 26.03, 28.51, 36.29, 38.19 (br), 41.63 (br), 49.99, 66.92,
113.20, 129.39, 129.50, 130.67, 132.25, 149.73 (C-Pd), 162.25, 173.30
(br).
General Procedure for Thermomorphic Catalysis with 2. A
solution of the aryl iodide (5 mmol), alkene (6 mmol), and triethylamine
(7.5 mmol) in 20 mL of heptane was prepared and the flask sealed.
The air in the flask was removed by vacuum pump and replaced with
dry N2. The solution was allowed to purge with N2 for 15 min. Three
pump-purge cycles were performed. This solution was then added via
forced siphon through a cannula to a previously prepared, N2 flushed
(three pump-purge cycles) solution of 2 (0.1 mmol Pd; 0.25 mmol
CuI was also added for the cross-coupling) in 20 mL of either 90%
EtOH or N,N-dimethylacetamide. The resulting biphasic system was
heated to either 75 or 90 °C, with stirring, to induce miscibilization.
The reactions were monitored by gas chromatography and were
generally complete within 48 h. After the system was cooled to ambient
temperature to induce phase separation, the upper heptane phase was
removed by forced siphon through a cannula into a N2-flushed receiving
flask. Removal of the solvent followed by drying of the residue under
vacuum furnished the pure coupling products 3-5. Catalyst recycling
was effected by adding a fresh heptane solution of the reactants and
1
4-Methyl-tert-butyl cinnamate (17): H NMR (CDCl3) δ 1.50 (s,
9 H), 2.34 (s, 3 H), 6.29 (d, 1 H), 7.17 (d, 2 H), 7.39 (d, 2 H), 7.55 (d,
1 H); 13C NMR (CDCl3) δ 21.56, 28.35, 80.40, 119.20, 128.08, 129.71,
132.03, 140.43, 143.68, 166.61.
â-(p-Tolyl)styrene (18): 1H NMR (CDCl3) δ 2.38 (s, 3 H), 7.05
(s, 2 H), 7.17 (d, 2 H), 7.23 (d, 1 H), 7.37-7.42 (m, 4 H), 7.46 (d, 2
H); 13C NMR (CDCl3) δ 21.44, 113.82, 126.59, 127.58, 127.86, 128.30,
128.47, 128.81, 129.04, 129.58, 134.71, 137.68
â-(1-Naphthyl)-tert-butyl acrylate (9): 1H NMR (CDCl3) δ 1.90
(s, 9 H), 6.43 (d, 1 H), 7.42-7.50 (m, 3 H), 7.74 (d, 1 H), 7.84 (d, 2
H), 8.20 (d, 1 H), 8.43 (d, 1 H); 13C NMR (CDCl3) δ 28.51, 80.85,
123.06, 123.68, 125.14, 125.71, 126.41, 127.00, 128.95, 130.48, 131.66,
132.22, 133.91, 140.81, 166.48.
â-(1-Naphthyl)styrene (10): 1H NMR (CDCl3) δ 7.19 (d, 1 H),
7.32 (m, 2 H), 7.42 (t, 2 H), 7.55 (m, 2 H), 7.62 (d, 2 H), 7.80 (q, 2
H), 7.91 (m, 2 H), 8.23 (d, 1 H); 13C NMR (CDCl3) δ 123.93, 124.07,
126.03, 126.17, 126.43, 127.02, 128.03, 128.12, 128.29, 128.37, 128.95,
129.08, 132.05, 134.05, 135.27, 137.89.
Biphenyl (4): 1H NMR (CDCl3) δ 7.36 (t, 1 H), 7.43 (t, 2 H), 7.59
(d, 2 H); 13C NMR (CDCl3) δ 127.35, 127.43, 128.94, 141.40.
4-Phenyltoluene (19): 1H NMR (CDCl3) δ 2.39 (s, 3 H), 7.22 (m,
3 H), 7.40 (d, 2 H), 7.48 (d, 2 H), 7.58 (d, 2 H); 13C NMR (CDCl3) δ
21.27, 126.99, 127.16, 128.90, 129.65, 136.86, 138.50, 141.34.
1-Phenylnaphthalene (20): 1H NMR (CDCl3) δ 7.37 (m, 5 H),
7.42 (m, 4 H), 7.78 (d, 1 H), 7.82 (d, 2 H); 13C NMR (CDCl3) δ 125.73,
126.12, 126.38, 127.29, 127.58, 127.99, 128.62, 128.89, 129.31, 130.43,
132.46, 134.14, 137.76, 140.59.
Acknowledgment. Support of this work by the National
Science Foundation (CHE-9707710) and the Robert A. Welch
Foundation is gratefully acknowledged. P.L.O. also thanks the
National Science Foundation for support from a Graduate
Research Fellowship Award.
JA001708G