Use of polymer-supported dialkylphosphinobiphenyl ligands for palladium-catalyzed amination and Suzuki reactions

Article abstract of DOI:10.1021/jo010025w

The preparations of polymer-supported dialkylphosphinobiphenyl ligands (3) are reported. A palladium catalyst based on ligand 3a is active for amination and Suzuki reactions using unactivated aryl iodides, bromides, or chlorides. Filtration of the catalyst from the reaction mixtures allows for simplified product isolation via an aqueous workup. The resin-bound catalyst can be recycled without additional palladium in both the amination and Suzuki reactions.

Full text of DOI:10.1021/jo010025w

3820
J . Org. Chem. 2001, 66, 3820-3827
Use of P olym er -Su p p or ted Dia lk ylp h osp h in obip h en yl Liga n d s for
P a lla d iu m -Ca ta lyzed Am in a tion a n d Su zu k i Rea ction s
Cynthia A. Parrish and Stephen L. Buchwald*,†
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received J anuary 9, 2001
The preparations of polymer-supported dialkylphosphinobiphenyl ligands (3) are reported. A
palladium catalyst based on ligand 3a is active for amination and Suzuki reactions using unactivated
aryl iodides, bromides, or chlorides. Filtration of the catalyst from the reaction mixture allows for
simplified product isolation via an aqueous workup. The resin-bound catalyst can be recycled without
additional palladium in both the amination and Suzuki reactions.
In tr od u ction
scale due to their high cost and the difficulty in removal
of palladium and ligand. Various types of solid-supported
catalysts have been prepared.8-10 Polymer-supported
palladium catalysts have found applications in allylic
substitutions,11,12 hydrogenations,11b,13 polymerizations,14
enantioselective reactions,12,15 and cross-coupling
reactions.11d,16 Several reports have been published de-
scribing polymer-supported C-C bond-forming reactions
such as the Heck and Suzuki reactions.11e-g,14c,17,18 How-
ever, most of these examples utilize reactive and costly
aryl iodides or bromides as substrates. Initial findings
Palladium-catalyzed coupling reactions have become
a common method for the synthesis of aromatic amines
and biaryls.1,2 The introduction of dialkylphosphinobi-
phenyl ligands has enhanced the efficiency of various
C-C and C-N bond-forming reactions by providing
access to highly active palladium catalysts.3 These cata-
lysts allow for sterically congested Suzuki couplings,
room temperature cross-couplings of aryl bromides or
chlorides, and the use of low catalyst loading.4 Such
catalysts have also led to efficient systems for the cross-
coupling of various aryl bromides, chlorides, and triflates
with a variety of amines at room temperature or above.5
These dialkylphosphinobiphenyl ligands are now either
commercially available6 or readily prepared in a one-pot
procedure.7 To further expand the utility of these active
phosphine ligands, we considered solid-supported cata-
lysts, whereby the ease of product isolation, the purity
of the crude product, and the potential to recycle the
catalyst can be major advantages over homogeneous
systems.
(8) For reviews on functionalized polymers, see: (a) Shuttleworth,
S. J .; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217. (b) Shuttle-
worth, S. J .; Allin, S. M.; Wilson, R. D.; Nasturica, D. Synthesis 2000,
1035, and references therein.
(9) Kaldor, S. W.; Siegel, M. G. Curr. Opin. Chem. Biol. 1997, 1,
101.
(10) For a review on the use of soluble polymers, see: Toy, P. H.;
J anda, K. D. Acc. Chem. Res. 2000, 33, 546.
(11) (a) Trost, B. M.; Keinan, E. J . Am. Chem. Soc. 1978, 100, 7779.
(b) Bergbreiter, D. E.; Chen, B.; Lynch, T. J . J . Org. Chem. 1983, 48,
4179. (c) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett. 1997,
38, 3557. (d) Bergbreiter, D. E.; Liu, Y.-S. Tetrahedron Lett. 1997, 38,
7843. (e) Riegel, N.; Darcel, C.; Ste´phan, O.; J uge´, S. J . Organomet.
Chem. 1998, 567, 219. (f) Uozumi, Y.; Danjo, H.; Hayashi, T. J . Org.
Chem. 1999, 64, 3384. (g) Corte´s, J .; Moreno-Man˜as, M.; Pleixats, R.
Eur. J . Org. Chem. 2000, 239.
(12) (a) Uozumi, Y.; Danjo, H.; Hayashi, T. Tetrahedron Lett. 1998,
39, 8303. (b) Hallman, K.; Macedo, E.; Nordstro¨m, K.; Moberg, C.
Tetrahedron: Asymmetry 1999, 10, 4037.
(13) (a) Gilbertson, S. R.; Wang, X.; Hoge, G. S.; Klug, C. A.;
Schaefer, J . Organometallics 1996, 15, 4678. (b) Zecca, M.; Fisera, R.;
Palma, G.; Lora, S.; Hronec, M.; Kra´lik, M. Chem. Eur. J . 2000, 6,
1980.
Because of the need for more environmentally benign
chemistry and the desire to develop simplified protocols
for rapid screening methods, there is a demand for highly
active heterogeneous catalysts. Although increasingly
popular on a research scale, many palladium-catalyzed
processes have not found significant use on an industrial
† FAX: (617) 253-3297.
(14) (a) Nguyen, S. T.; Grubbs, R. H. J . Organomet. Chem. 1995,
497, 195. (b) Boussie, T. R.; Coutard, C.; Turner, H.; Murphy, V.;
Powers, T. S. Angew. Chem., Int. Ed. 1998, 37, 3272. (c) Buchmeiser,
M. R.; Wurst, K. J . Am. Chem. Soc. 1999, 121, 11101.
(1) For reviews on Pd-catalyzed amination, see: (a) Yang, B. H.;
Buchwald, S. L. J . Organomet. Chem. 1999, 576, 125. (b) Hartwig, J .
F. Angew. Chem., Int. Ed. 1998, 37, 2046. (c) Wolfe, J . P.; Wagaw, S.;
Marcoux, J .-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(2) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Dieder-
ich, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, Germany, 1998;
Chapter 2.
(3) (a) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722. (b) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413. (c) Fox, J . M.; Huang, X.; Chieffi, A.; Buchwald, S.
L. J . Am. Chem. Soc. 2000, 122, 1360.
(4) Wolfe, J . P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J . Am.
Chem. Soc. 1999, 121, 9550.
(5) Wolfe, J . P.; Tomori, H.; Sadighi, J . P.; Yin, J .; Buchwald, S. L.
J . Org. Chem. 2000, 65, 1158.
(6) 2-Dicyclohexylphosphinobiphenyl, 2-di-tert-butylphosphinobi-
phenyl, and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
are commercially available from Strem Chemicals, Inc.
(7) Tomori, H.; Fox, J . M.; Buchwald, S. L. J . Org. Chem. 2000, 65,
5334.
(15) (a) Fujii, A.; Sodeoka, M. Tetrahedron Lett. 1999, 40, 8011. (b)
Bao, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2000, 41, 131.
(16) Stille, J . K.; Su, H.; Hill, D. H.; Schneider, P.; Tanaka, M.;
Morrison, D. L.; Hegedus, L. S. Organometallics 1991, 10, 1993.
(17) Heck reactions: (a) Terasawa, M.; Kaneda, K.; Imanaka, T.;
Teranishi, S. J . Organomet. Chem. 1978, 162, 403. (b) Andersson, C.-
M.; Karabelas, K.; Hallberg, A. J . Org. Chem. 1985, 50, 3891. (c)
Zhuangyu, Z.; Yi, P.; Honwen, H.; Tsi-yu, K. Synthesis 1991, 539. (d)
Wang, P.-W.; Fox, M. A. J . Org. Chem. 1994, 59, 5358. (e) J ang, S.-B.
Tetrahedron Lett. 1997, 38, 4421. (f) Alper, H.; Arya, P.; Bourque, S.
C.; J efferson, G. R.; Manzer, L. E. Can. J . Chem. 2000, 78, 920, and
references therein. (g) Schwarz, J .; Bo¨hm, V. P. W.; Gardiner, M. G.;
Grosche, M.; Herrmann, W. A.; Hieringer, W.; Raudaschl-Sieber, G.
Chem. Eur. J . 2000, 6, 1773.
(18) Suzuki reactions: (a) J ang, S.-B. Tetrahedron Lett. 1997, 38,
1793. (b) Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287. (c)
Zhang, T. Y.; Allen, M. J . Tetrahedron Lett. 1999, 40, 5813.
10.1021/jo010025w CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

Polymer-Supported Dialkylphosphinobiphenyl Ligands
J . Org. Chem., Vol. 66, No. 11, 2001 3821
Sch em e 1
hydroxybiphenyl (2a ) in 84% crude yield. Care was taken
to avoid the presence of oxygen or basic conditions, both
of which seemed to facilitate oxidation of the ligand.
Deprotonation of the phenol with sodium hydride in N,N-
dimethylformamide followed by addition of the Merrifield
resin (1% cross-linked with divinylbenzene, 200-400
mesh size) afforded the resin-bound dicyclohexylphos-
phine ligand 3a with an average coupling efficiency of
80%.22 Once attached to the solid support, the ligand is
air stable. Ligands 2a and 2b could also be prepared in
a one-step procedure from dibenzofuran according to the
method of Heinicke and co-workers.23 The di-tert-bu-
tylphosphine ligand 3b could only be prepared using a
dilute solution of 2-di-tert-butylphosphino-2′-hydroxybi-
phenyl (2b) provided by this alternative method. How-
ever, subsequent reactions utilizing ligand 3b indicated
no advantage as compared to ligand 3a , and due to its
more difficult preparation, it was not pursued further.
The polymer-supported phosphine ligands 3 were char-
acterized by gel phase 31P NMR (Figure 1)24 and by
phosphorus elemental analysis.
Initial studies with polymer-supported dicyclohexyl-
phosphine ligand 3a revealed that premixing of the
catalyst system is essential for high catalytic activity.
Palladium-catalyzed amination and Suzuki reactions
were successful when resin 3a was allowed to stir and
swell in the presence of the palladium source in solvent
for 30-60 min prior to addition of the remaining reac-
tants. As visualized in Figure 2, the yellow color of the
palladium solution transferred to the polymer beads over
the course of 30 min, leaving the solution colorless, likely
an indication of the formation of a palladium-phosphine
complex. That such a complex is formed on the resin and
acts as a catalyst is further supported by the following
experiments. Removal of the solution from the resin (after
premixing with either Pd(OAc)2 or Pd2(dba)3) followed by
addition of fresh solvent and the remaining reactants to
the flask provided results similar to those when the
original solution was left untouched. Similarly, control
experiments performed with resin containing no phos-
phine (prepared from 2-hydroxybiphenyl and the Merri-
field resin in the same manner as ligands 3) led only to
trace amounts of product formation in the palladium-
catalyzed amination and Suzuki reactions.
by Buchmeiser and Wurst describe aryl chloride activa-
tion in the Heck reaction between chlorobenzene or
4-chloroacetophenone and styrene (89% and 96% conver-
sion, respectively) in the presence of tetrabutylammo-
nium bromide and a polymer-supported palladium cata-
lyst at high temperature (140 °C).14c,19 However, a general
and practical solid-supported palladium catalyst system
that can utilize readily available and inexpensive aryl
chlorides as substrates still remains a goal.20
As our group and others have shown that the use of
electron-rich phosphine ligands in palladium-catalyzed
C-C and C-N bond-forming reactions allows for an
increase in aryl halide substrate scope,21 we initiated a
program to develop heterogeneous catalysts based on the
incorporation of dialkylphosphinobiphenyl ligands into
polymer supports as leading to highly practical and
general catalysts. On the basis of our previous results
with the related homogeneous catalysts, we would also
expect such polymer-supported ligands to be air stable.
A few examples of polymer-bound electron-rich phos-
phines have been published; complexes of these ligands
catalyzed olefin metathesis,14a the Heck reaction of aryl
iodides,17d and the hydrogenation of enamides.13a Herein
we disclose the synthesis of polymer-supported dialkyl-
phosphinobiphenyl-based catalysts and their success in
the Suzuki and amination reactions of unactivated aryl
iodides, bromides, and chlorides.
Resu lts a n d Discu ssion
Use of the solid-supported electron-rich phosphine
ligand 3a led to an active catalyst system for the
palladium-catalyzed amination reaction.25 Under stan-
dard conditions using typically only 1.0 mol % of pal-
ladium, primary amines, secondary cyclic and acyclic
amines, and anilines were all coupled successfully with
various unactivated or deactivated aryl halides in very
good yields (Table 1). Furthermore, aryl chlorides could
now be successfully utilized as substrates (entries 5, 11-
13), something which had not previously been possible
with the other reported polymer-supported phosphine-
or carbene-based ligands for palladium-catalyzed aryl
halide activation.11d-f,17,18 In fact, similar reaction condi-
tions were used in these amination reactions with
Our initial work focused on the use of a short ether
linkage to attach the biphenylphosphine to the polymer
backbone. Polymer-bound dialkylphosphinobiphenyl ligand
3a was readily prepared utilizing recent methodology
described from these laboratories.7 The biphenyl frame-
work, 2-dicyclohexylphosphino-2′-methoxybiphenyl (1a ),
was synthesized by the reaction of 2-methoxyphenylmag-
nesium bromide with benzyne and subsequent addition
of chlorodicyclohexylphosphine in 48% overall yield
(Scheme 1). Deprotection of the aryl methyl ether with
boron tribromide then led to 2-dicyclohexylphosphino-2′-
(19) Two examples of ArCl activation (<40%) with heterogeneous
Pd catalysts have been published, see: (a) Reetz, M. T.; Lohmer, G.
Chem. Commun. 1996, 1921. (b) Djakovitch, L.; Heise, H.; Ko¨hler, K.
J . Organomet. Chem. 1999, 584, 16.
(20) The Suzuki reaction of aryl chlorides using Ni/C (5-10 mol %)
has been published. However, catalyst activation by added tri-
phenylphosphine (4 equiv) is required. Lipshutz, B. H.; Sclafani, J .
A.; Blomgren, P. A. Tetrahedron 2000, 56, 2139.
(22) Coupling efficiency is calculated as the weight gained by the
resin divided by the expected weight gain.
(23) Kadyrov, R.; Heinicke, J .; Kindermann, M. K.; Heller, D.;
Fischer, C.; Selke, R.; Fischer, A. K.; J ones, P. G. Chem. Ber. 1997,
130, 1663.
(21) For a discussion of this, see: (a) Buchwald, S. L.; Fox, J . M. In
The Strem Chemiker; Strem Chemicals, Inc.: Newburyport, MA, 2000;
Vol. XVIII, No. 1, and references therein. (b) Littke, A. F.; Dai, C.; Fu,
G. C. J . Am. Chem. Soc. 2000, 122, 4020, and references therein.
(24) (a) J ohnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253.
(b) Lorge´, F.; Wagner, A.; Mioskowski, C. J . Comb. Chem. 1999, 1, 25.
(25) An example of aryl bromide amination using
supported Pd catalyst has been published, see ref 14c.
a polymer-

3822 J . Org. Chem., Vol. 66, No. 11, 2001
Parrish and Buchwald
F igu r e 1. Gel phase 31P NMR (121 MHz, C6D6) spectrum of ligand 3a . Spectrum was processed with a line broadening of 10 Hz.
rahydrofuran solution. However, analysis of filtered
reaction mixtures by 31P NMR indicated that there was
in fact phosphine cleavage from the resin under these
reaction conditions in up to 20% in the presence of 2.0
mol % of palladium. Further experiments indicated that
no phosphine leaching was occurring when the reaction
conditions consisted of cesium carbonate as the base and
Pd2(dba)3 as the palladium source.
Using these modified Suzuki reaction conditions, aryl-
boronic acids were successfully cross-coupled with a
number of unactivated aryl halides with solid-supported
ligand 3a and no more than 1.0 mol % of palladium
(Table 2). Aryl iodides and bromides required even less
catalyst. Although aryl chlorides were successfully uti-
lized as starting materials, competitive hydrolytic de-
boronation of the arylboronic acid was observed.27 In-
creased amounts of boronic acid (1.5-3.0 equiv) were
often necessary to drive the reactions to completion. This
did not lead to increased byproduct formation; negligible
amounts of biaryl products were formed and the de-
boronation products were removed in vacuo. Once again,
the products were isolated in excellent yield upon filtra-
tion and aqueous workup and were determined to be of
>95% purity by standard analytical methods.26
The ability to successfully recycle a heterogeneous
catalyst system is of great importance. The catalyst
derived from ligand 3a and Pd(OAc)2 or Pd2(dba)3 can
be recycled in both the amination and Suzuki reactions
without addition of palladium (Table 3).28,29 Catalyst
activity and reaction rate were typically unaffected until
F igu r e 2. A visual description of the premixing protocol. Both
test tubes contain identical solutions of Pd(OAc)2 (15.0 µmol)
and ligand 3a (18.8 µmol, 200-400 mesh size) in THF (1.0
mL). The solution on the left has been standing for 5 min,
whereas the solution on the right has been stirring for 30 min.
comparable results for aryl iodides, bromides, or chlo-
rides. Furthermore, the lack of byproduct formation and
the use of a polymer-supported catalyst allowed for facile
product isolation. The resin was simply separated from
the reaction mixture by filtration, and the product was
isolated following an aqueous workup. As such, the
products were judged to be of >95% purity by standard
analytical methods.26 Filtered reaction mixtures were
also subjected to analysis by 31P NMR, whereby no
phosphorus peaks were detected.
Initial results demonstrated the use of palladium-
activated ligand 3a to be effective for the cross-coupling
of aryl bromides with arylboronic acids using potassium
fluoride or potassium phosphate as the base in a tet-
(27) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(28) Recycling experiments were conducted with a larger size (100-
200 mesh) resin, prepared as shown in Scheme 1, due to its greater
ease of use.
(29) The reaction mixture was diluted with ether and the resin was
filtered, washed with water, tert-butyl alcohol, and ether, and dried
in vacuo prior to the next reaction.
(26) In most cases, 1H NMR, GC, 13C NMR, FTIR, and EA data were
obtained.

Polymer-Supported Dialkylphosphinobiphenyl Ligands
J . Org. Chem., Vol. 66, No. 11, 2001 3823
Ta ble 1. Am in a tion Rea ction s Usin g Liga n d 3a a
a
Reaction conditions: 1.0 equiv of aryl halide, 1.3 equiv of amine, 1.5 equiv of NaOt-Bu, catalytic Pd(OAc)2, ligand 3a (1.3:1 L:Pd),
toluene (0.5 M solution), 80 °C, 15-20 h (reaction times have not been minimized). Yields (average of two or more experiments) represent
b
isolated yields of products estimated to be >95% pure as indicated by 1H NMR, GC, and EA. THF was used as the solvent at 65 °C.c The
d
reaction temperature was increased to 100 °C. A total of 3.0 equiv of amine was used. e The product was isolated from 3% of the diarylamine
byproduct by flash chromatography. f Pd2(dba)3 was used instead of Pd(OAc)2.
the fourth consecutive reaction. Although the reactions
became impractical due to extended reaction times, the
absence of byproducts would have allowed for additional
recycles. The use of the aqueous or alcoholic workup to
remove inorganic solids from the reaction mixture may
lead to modification of the palladium-phosphine complex
and catalyst deactivation.
aryl chloride substrates with a solid-supported catalyst
for amination or Suzuki reactions. The catalyst derived
from ligand 3a can also be recycled a limited number of
times without additional palladium for both the amina-
tion and Suzuki reactions. Efforts are currently underway
in our laboratories to develop other palladium-based
heterogeneous catalyst systems that maintain excellent
C-C and C-N bond-forming activity but demonstrate
improved recycling ability.
Con clu sion
In summary, we have ligated a dialkylphosphinobi-
phenyl ligand to a polymer support and have demon-
strated its utility in palladium-catalyzed cross-coupling
reactions. In combination with a palladium source, ligand
3a forms an active resin-bound catalyst for amination
and Suzuki reactions, allowing for simplified product
purification and a product devoid of phosphine contami-
nation. Reactions using the electron-rich phosphine
ligand 3a are the first successful examples of the use of
Exp er im en ta l Section
Gen er a l P r oced u r es. All reactions were carried out under
an argon atmosphere in oven-dried glassware. Toluene was
distilled under nitrogen from molten sodium. THF was dis-
tilled under argon from sodium benzophenone ketyl or pur-
chased anhydrous from Sigma-Aldrich Chemical Co. Dichlo-
romethane and N,N-dimethylformamide were purchased
anhydrous from Sigma-Aldrich. Copper(I) chloride, chlorodi-
cyclohexylphosphine, palladium acetate, and tris(dibenzyli-

3824 J . Org. Chem., Vol. 66, No. 11, 2001
Ta ble 2. Su zu k i Cr oss-Cou p lin g Rea ction s Usin g Liga n d 3a a
Parrish and Buchwald
a
Reaction conditions: 1.0 equiv of aryl halide, 1.2 equiv of boronic acid, 2.0 equiv of Cs2CO3, catalytic Pd2(dba)3, ligand 3a (1.3-1.5:1
L:Pd), THF (0.5 M solution), 65 °C, 17-21 h (reaction times have not been minimized). Yields (average of two or more experiments)
represent isolated yields of products estimated to be >95% pure as indicated by 1H NMR, GC, and EA. A total of 1.5 equiv of boronic
b
acid was used. c A total of 3.0 equiv of boronic acid was used. One of the two reaction mixtures proceeded to ∼98% conversion.
d
deneacetone)dipalladium(0) were purchased from Strem Chemi-
cals, Inc. Merrifield’s peptide resin (1% cross-linked with
divinylbenzene, 100-200 or 200-400 mesh) and 2-methoxy-
phenylmagnesium bromide were purchased from Sigma-Ald-
rich. Aryl halides were purchased from commercial sources
and were used as received. Amines were purchased from
commercial sources and were passed through a short column
of basic alumina prior to use. Boronic acids were purchased
from Sigma-Aldrich or Strem Chemicals. Sodium tert-butoxide
was purchased from Sigma-Aldrich; the bulk of this material
was stored under nitrogen in a Vacuum Atmospheres glovebox.
Small (1-2 g) portions were removed from the glovebox in
glass vials and stored in a desiccator for use up to 1 week.
Cesium carbonate was obtained from Chemetall Chemical
Products, Inc.; the bulk of this material was stored under
nitrogen in a glovebox. Portions (∼10 g) were removed from
the glovebox in glass vials and stored in a desiccator for
extended use. Standard elemental analyses were performed
by Atlantic Microlabs Inc., Norcross, GA, and phosphorus
elemental analyses were performed by E&R Microanalytical
Laboratory, Parsippany, NJ . The procedures described in this
section are representative, and thus yields may differ from
those given in Tables 1-3.
2-Dicycloh exylph osph in o-2′-m eth oxybiph en yl (1a). Tet-
rahydrofuran (45.0 mL) was added to a 500 mL flask charged
with magnesium (1.22 g, 50.0 mmol, 1.0 equiv). 2-Methoxy-
phenylmagnesium bromide (55 mL of a 1.0 M solution in THF,
55.0 mmol, 1.1 equiv) and 1,2-bromochlorobenzene (5.8 mL,
50.0 mmol, 1 equiv) were added sequentially to the reaction
mixture. A reflux condenser was fitted to the flask, and the
reaction mixture was heated at 60 °C. After 2.5 h, the mixture
was cooled to room temperature. Copper(I) chloride (5.94 g,
60.0 mmol, 1.2 equiv) and then chlorodicyclohexylphosphine
(12.3 mL, 55.0 mmol, 1.1 equiv) were added, and the reaction
mixture was stirred at room temperature. After 16 h, the
mixture was filtered and rinsed with hexanes (2 × 50 mL).
The solid was transferred to a 500 mL Erlenmeyer flask. Ether
(150 mL) and saturated aqueous ammonia solution (200 mL)
were added, and the mixture was stirred for 2 h. The mixture
was transferred to a separatory funnel with a saturated

Polymer-Supported Dialkylphosphinobiphenyl Ligands
J . Org. Chem., Vol. 66, No. 11, 2001 3825
Ta ble 3. Ca ta lyst Recyclin g Exp er im en tsa
a
Reaction conditions (Suzuki): 1.0 equiv of aryl bromide, 1.2 equiv of boronic acid, 2.0 equiv of Cs2CO3, stated amount of Pd2(dba)3,
ligand 3a (2.6 mol %), THF (0.5 M solution), 65 °C. The same resin was used for each entry. Reaction conditions (amination): 1.0 equiv
of aryl bromide, 1.3 equiv of amine, 1.5 equiv of NaOt-Bu, stated amount of Pd(OAc)2, ligand 3a (2.0 mol %), THF (0.5 M solution), 65 °C.
The same resin was used for each entry. Yields refer to isolated product estimated to be >95% pure as indicated by 1H NMR and GC (and
EA, first entry only).
aqueous ammonia solution (500 mL) and ether (200 mL). The
layers were separated, and the aqueous layer was further
extracted with ether (2 × 200 mL). The combined organic
2H), 7.10 (dd, 1H, J ) 7.8, 1.8 Hz), 7.00-6.95 (m, 2H), 5.14
(br s, 1H), 2.07 (m, 1H), 1.77-1.50 (m, 11H), 1.34-0.83 (m,
10H); 13C NMR (75 MHz, CDCl3) δ 151.6, 145.1 (d, J CP ) 30.8
Hz), 135.0 (d, J CP ) 19.7 Hz), 133.0 (d, J CP ) 2.6 Hz), 131.8
(d, J CP ) 1.9 Hz), 131.6 (d, J CP ) 6.0 Hz), 130.0 (d, J CP ) 6.2
Hz), 129.4, 129.2, 127.6, 120.4, 116.5, 35.2 (d, J CP ) 14.7 Hz),
32.4 (d, J CP ) 10.9 Hz), 30.6 (d, J CP ) 14.5 Hz), 30.0-29.6 (2
resonances), 28.6, 27.7-27.1 (5 resonances), 26.5; 31P NMR
(121 MHz, CDCl3) δ -8.7; IR (neat, cm-1) 3554, 3415 (br), 2924,
2849, 1446, 1182, 751. Anal. Calcd for C24H31OP: C, 78.64; H,
8.54. Found: C, 78.65; H, 8.45.
Resin -bou n d d icycloh exylp h osp h in obip h en yl 3a . A 25
mL Schlenk flask was charged with the Merrifield resin (608
mg of a 200-400 mesh resin containing 1.23 mmol/g Cl, 0.748
mmol, 1 equiv) and N,N-dimethylformamide (6.0 mL). The
mixture was degassed and was allowed to swell for 60 min.
Sodium hydride (50 mg of a 60% dispersion in mineral oil, 1.20
mmol, 1.6 equiv) was added to a 50 mL recovery flask
containing a degassed solution of 2-dicyclohexylphosphino-2′-
hydroxybiphenyl (2a ) (370 mg, 1.01 mmol, 1.4 equiv) and DMF
(4.5 mL); the reaction mixture was stirred at 25 °C for 15 min.
The phosphine solution was then transferred via cannula to
the Schlenk flask containing the resin. The recovery flask was
rinsed with DMF (1.0 mL), which was also transferred to the
reaction flask. The reaction mixture was degassed and was
purged with argon. The flask was placed on an orbital shaker
(400 rpm) at 25 °C for 23 h. The reaction mixture was
transferred to a sintered glass funnel with DMF (2 × 5 mL).
The resin was washed with the following (2 × 7 mL each):
water, 1 N aqueous hydrochloric acid solution, water, metha-
nol, dichloromethane, methanol, dichloromethane, and ether
(3 × 7 mL). The tan resin 3a was dried under vacuum to
constant weight (817 mg, 96%, coupling efficiency of 85%).22
When 100-200 mesh Merrifield resin was used, the average
coupling efficiency was higher (91%). Gel phase 31P NMR (121
MHz, C6D6) δ -10.6. Anal. Calcd for P (in duplicate): 2.33
(resin loading of 0.752 mmol/g phosphine).
Gen er a l P r oced u r e for Am in a tion Rea ction s. A solu-
tion of Pd(OAc)2 in toluene (1.00 mL of a 7.50 mM solution,
7.50 µmol, 1.00 mol %) was added to an oven-dried test tube
(16 × 100 mm) containing resin 3a (9.8 µmol, 1.3 mol %) and
sealed with a septum. The mixture was stirred at 25 °C for
30-75 min. Sodium tert-butoxide (108 mg, 1.12 mmol, 1.50
equiv) was then added to the flask, and the system was purged
with argon. Aryl halide (0.750 mmol, 1 equiv), amine (0.975
mmol, 1.30 equiv), and toluene (0.50 mL) were added sequen-
tially via syringe. The flask was placed into an 80 °C oil bath,
and the reaction mixture was stirred for 15-20 h. After
cooling, the mixture was diluted with ether (5 mL), filtered
through Celite, and rinsed with ether (2 × 5 mL). The
combined organic layers were transferred to a separatory
funnel and diluted with ether (50 mL). The organic layer was
layers were washed with
a saturated aqueous ammonia
solution (2 × 150 mL) and brine (150 mL), dried over sodium
sulfate, and concentrated in vacuo. Recrystallization of the
residue with hot methanol provided the title compound as a
1
white solid (9.09 g, 48%) in two crops. Mp: 120-122 °C; H
NMR (300 MHz, CDCl3) δ 7.57 (m, 1H), 7.42-7.33 (m, 3H),
7.23 (m, 1H), 7.10 (dd, 1H, J ) 7.3, 1.8 Hz), 6.98 (t, 1H, J )
7.4 Hz), 6.91 (d, 1H, J ) 8.2 Hz), 3.74 (s, 3H), 1.94 (m, 1H),
1.73-1.58 (m, 11H), 1.32-0.89 (m, 10H); 13C NMR (75 MHz,
THF-d8) δ 157.6 (d, J CP ) 1.0 Hz), 148.3 (d, J CP ) 32.0 Hz),
136.5 (d, J CP ) 21.2 Hz), 133.0 (d, J CP ) 3.4 Hz), 133.0 (d, J CP
) 6.6 Hz), 132.6 (d, J CP ) 2.6 Hz), 131.3 (d, J CP ) 5.9 Hz),
129.1, 128.8 (d, J CP ) 1.2 Hz), 127.1, 120.2, 110.9, 55.3, 36.3
(d, J CP ) 16.2 Hz), 35.0 (d, J CP ) 15.9 Hz), 31.9 (d, J CP ) 18.3
Hz), 31.4 (d, J CP ) 18.0 Hz), 30.9 (d, J CP ) 12.8 Hz), 30.0 (d,
J CP ) 6.9 Hz), 28.5-28.3 (4 resonances), 27.8, 27.6; 31P NMR
(121 MHz, CDCl3) δ -10.0; IR (neat, cm-1) 2924, 2849, 1496,
1446, 1246, 749. Anal. Calcd for C25H33OP: C, 78.90; H, 8.76.
Found: C, 78.62; H, 8.72.
2-Dicycloh exylp h osp h in o-2′-h yd r oxybip h en yl (2a ). A
50 mL Schlenk flask was charged sequentially with 2-dicy-
clohexylphosphino-2′-methoxybiphenyl (1a ) (1.20 g, 3.15 mmol,
1 equiv) and dichloromethane (9.0 mL). The solution was
cooled to -78 °C, and a solution of boron tribromide in
dichloromethane (6.95 mL of a 1.0 M solution, 6.94 mmol, 2.2
equiv) was added dropwise over 5 min. The reaction mixture
was stirred at -78 °C for 15 min, at which point the cooling
bath was removed and the reaction mixture was allowed to
warm to room temperature. After 16 h, the mixture was
quenched upon addition of saturated aqueous sodium bicar-
bonate solution (3 mL) and then transferred to a separatory
funnel containing water (130 mL). The pH of the aqueous layer
was adjusted to 7 with additional saturated aqueous sodium
bicarbonate solution. The mixture was diluted with ethyl
acetate (100 mL), and the layers were separated. The product
was extracted with ethyl acetate (2 × 100 mL). The combined
organic layers were then washed with brine (4 × 100 mL) until
the pH of the aqueous extract was ∼5. The organic layer was
washed once more with brine (100 mL), dried over sodium
sulfate, and concentrated in vacuo to afford the title compound
(980 mg, 84%). Occasionally the product is contaminated with
a boron complex (31P NMR (121 MHz, CDCl3) δ 34.4) and/or
the phosphine oxide (31P NMR (121 MHz, CDCl3) δ 52.4). The
former can be removed or converted to product by dissolving
the solid in ethyl acetate and further washing with brine until
the pH of the washes are neutral. The latter, if significant,
can be removed by flash chromatography through a short plug
1
of silica gel (5% EtOAc/hexanes). Mp: 131-134 °C; H NMR
(300 MHz, CDCl3) δ 7.60 (m, 1H), 7.44 (m, 2H), 7.33-7.26 (m,

3826 J . Org. Chem., Vol. 66, No. 11, 2001
Parrish and Buchwald
washed with a saturated aqueous bicarbonate solution (3 ×
50 mL), dried over sodium sulfate, and concentrated in vacuo
to provide analytically pure product.
N-Meth yl-N-(4-ter t-bu tylp h en yl)a n ilin e (Table 1, entries
1-2).5 Entry 1: the reaction was performed using 1-tert-butyl-
4-iodobenzene (135 µL), N-methylaniline (105 µL), and THF
in place of toluene at 65 °C to provide the product as a tan oil
(174 mg, 97%). Entry 2: the general procedure using 1-bromo-
4-tert-butylbenzene (130 µL) and N-methylaniline (105 µL)
afforded 172 mg (96%) of the title product.
N-Meth yl-N-p h en yl-p-tolu id in e (Table 1, entry 12).30 The
reaction was performed using 4-chlorotoluene (89 µL), N-
methylaniline (105 µL), and THF in place of toluene at 65 °C
to provide the product as a tan oil (131 mg, 89%).
N-(4-Meth ylp h en yl)m or p h olin e (Table 1, entry 13).30 The
general procedure using 4-chlorotoluene (89 µL) and morpho-
line (85 µL) afforded the title compound as a yellow solid (122
mg, 92%).
Gen er a l P r oced u r e for Su zu k i Rea ction s. THF (1.00
mL) was added to an oven-dried test tube (16 × 100 mm)
sealed with a septum containing resin 3a (5.2 µmol, 0.70 mol
%) and Pd2(dba)3 (1.7 mg, 1.9 µmol, 0.25 mol %). The mixture
was stirred at 25 °C for 30-75 min. Aryl halide (0.750 mmol,
1 equiv) was added via syringe. Cesium carbonate (489 mg,
1.50 mmol, 2.00 equiv) and boronic acid (0.900 mmol, 1.20
equiv) were added simultaneously to the flask, and the system
was purged with argon. THF (0.50 mL) was added via syringe.
The flask was placed into a 65 °C oil bath, and the reaction
mixture was stirred for 17-21 h. After cooling, the mixture
was diluted with ether (5 mL), filtered through Celite, and
rinsed with ether (2 × 5 mL). The combined organic layers
were transferred to a separatory funnel and diluted with ether
(50 mL). The organic layer was washed with a 1 N aqueous
sodium hydroxide solution (3 × 50 mL), dried over sodium
sulfate, and concentrated in vacuo to provide analytically pure
product.
3-Meth oxy-4′-m eth ylbip h en yl (Table 2, entry 1). The
general procedure was modified by adding a solution of Pd2-
(dba)3 in THF (1.0 mL of a 0.75 mM solution, 0.75 µmol, 0.10
mol %) to a test tube containing ligand 3a (2.2 µmol, 0.30 mol
%). The remainder of the procedure using 3-iodoanisole (99
µL) and p-tolylboronic acid (122 mg) provided the title com-
pound as a yellow oil (138 mg, 93%). 1H NMR (300 MHz,
CDCl3) δ 7.50 (d, 2H, J ) 8.0 Hz), 7.36 (t, 1H, J ) 7.8 Hz),
7.26 (d, 2H, J ) 7.7 Hz), 7.18 (d, 1H, J ) 7.7 Hz), 7.13 (t, 1H,
J ) 2.1 Hz), 6.89 (dd, 1H, J ) 8.2, 2.5 Hz), 3.88 (s, 3H), 2.42
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.9, 142.7, 138.2, 137.2,
129.8, 129.5, 127.1, 119.6, 112.8, 112.4, 55.4, 21.4; IR (neat,
cm-1) 3025, 2938, 1601, 1481, 1296, 1220, 1175, 1053, 1032,
867, 818, 777. Anal. Calcd for C14H14O: C, 84.80; H, 7.13.
Found: C, 84.57; H, 7.18.
N-Ben zyl-2,5-d im eth yla n ilin e (Table 1, entries 3-5).5
Entry 3: the general procedure using 2-iodo-p-xylene (105 µL)
and benzylamine (105 µL) gave 144 mg (91%) of the product
as a yellow oil. Entry 4: the general procedure was modified
by adding toluene (1.00 mL) to a test tube containing Pd(OAc)2
(3.4 mg, 15 µmol, 2.0 mol %) and ligand 3a (19 µmol, 2.5 mol
%) for the catalyst premix. The remainder of the procedure
using 2-bromo-p-xylene (105 µL) and benzylamine (105 µL) at
100 °C afforded 145 mg (92%) of the title compound. Entry 5:
the general procedure using 2-chloro-p-xylene (101 µL) and
benzylamine (105 µL) provided 151 mg (96%) of the product.
N-(3-Meth oxyp h en yl)-n -h exyla m in e (Table 1, entry 6).
The general procedure was performed using 3-iodoanisole (99
µL) and n-hexylamine (295 µL, 2.25 mmol, 3.00 equiv). The
residue was purified by flash chromatography (2% EtOAc/
hexanes) to afford the desired product as a pale yellow oil (130
mg, 84%) and the diarylation byproduct (8.2 mg, 3%). 1H NMR
(300 MHz, CDCl3) δ 7.08 (t, 1H, J ) 8.1 Hz), 6.25 (m, 2H),
6.17 (t, 1H, J ) 2.3 Hz), 3.79 (s, 3H), 3.64 (br s, 1H), 3.10 (t,
2H, J ) 6.9 Hz), 1.63 (m, 2H), 1.44-1.31 (m, 6H), 0.92 (t, 3H,
J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 160.8, 150.0, 129.9,
106.0, 102.2, 98.6, 55.2, 44.1, 31.9, 29.7, 27.1, 22.9, 14.3; IR
(neat, cm-1) 3405, 2926, 2854, 1613, 1510, 1460, 1210, 1160,
1046, 826, 753. Anal. Calcd for C13H21NO: C, 75.31; H, 10.23.
Found: C, 75.59; H, 10.25.
N-(4-ter t-Bu tylp h en yl)m or p h olin e (Table 1, entry 7).5
The general procedure using 1-bromo-4-tert-butylbenzene (130
µL) and morpholine (85 µL) provided 146 mg (89%) of the title
compound as an ivory solid.
N,N-Dibu tyl-3,5-d im eth yla n ilin e (Table 1, entry 8). The
general procedure using 5-bromo-m-xylene (102 µL) and dibu-
tylamine (165 µL) gave 139 mg (79%) of the title compound as
a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.31 (s, 1H), 6.29 (s,
2H), 3.25 (t, 4H, J ) 7.6 Hz), 2.28 (s, 6H), 1.57 (m, 4H), 1.36
(m, 4H), 0.97 (t, 6H, J ) 7.3 Hz); 13C NMR (75 MHz, CDCl3)
δ 148.4, 138.7, 117.3, 109.8, 51.0, 29.8, 22.2, 20.7, 14.3; IR
(neat, cm-1) 2957, 2867, 1599, 1485, 1366, 1194, 814. Anal.
Calcd for C16H27N: C, 82.33; H, 11.68. Found: C, 82.07; H,
11.49.
4-ter t-Bu tyl-2′-m eth ylbip h en yl (Table 2, entry 2).4 The
general procedure was modified by adding a solution of Pd2-
(dba)3 in THF (1.5 mL of a 0.75 mM solution, 1.1 µmol, 0.15
mol %) to a test tube containing ligand 3a (3.4 µmol, 0.45 mol
%). The remainder of the procedure using 1-tert-butyl-4-
iodobenzene (135 µL), o-tolylboronic acid (122 mg), and no
additional THF gave the title compound as a yellow oil (164
mg, 98%).
4-ter t-Bu tylbip h en yl (Table 2, entry 3).4 The general
procedure using 1-bromo-4-tert-butylbenzene (130 µL) and
phenylboronic acid (110 mg) afforded the title compound as a
yellow solid (155 mg, 98%).
N-(4-Meth oxyp h en yl)m or p h olin e (Table 1, entry 9).30
The general procedure using 4-bromoanisole (94 µL) and
morpholine (85 µL) afforded the title compound as a tan solid
(125 mg, 86%).
2,6-Dim eth ylbip h en yl (Table 2, entry 4).4 The general
procedure using 2-bromo-m-xylene (100 µL) and phenylboronic
acid (110 mg) provided the title compound as a pale yellow oil
(124 mg, 91%).
N-(2,5-Dim eth ylp h en yl)-m -tolu id in e (Table 1, entries
10-11). Entry 10: the general procedure was modified by
adding toluene (1.00 mL) to a test tube containing Pd2(dba)3
(3.4 mg, 3.8 µmol, 0.50 mol %) and ligand 3a (9.8 µmol, 1.3
mol %). The remainder of the procedure using 2-bromo-p-
xylene (105 µL) and m-toluidine (105 µL) at 100 °C provided
the product as a tan oil (157 mg, 99%). Entry 11: the general
procedure was modified by adding toluene (1.00 mL) to a test
tube containing Pd2(dba)3 (5.2 mg, 5.6 µmol, 0.75 mol %) and
ligand 3a (14 µmol, 1.9 mol %). The remainder of the procedure
using 2-chloro-p-xylene (101 µL) and m-toluidine (105 µL) at
100 °C gave the title compound in 98% (156 mg). 1H NMR (300
MHz, CDCl3) δ 7.19-7.08 (m, 3H), 6.80-6.73 (m, 4H), 5.32
(br s, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.23 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 144.1, 141.1, 139.2, 136.5, 130.8, 129.2, 125.3,
122.8, 121.3, 119.7, 118.2, 114.6, 21.8, 21.4, 17.7; IR (neat,
cm-1) 3388, 2920, 1604, 1577, 1476, 1310, 1170, 1000, 771.
Anal. Calcd for C15H17N: C, 85.25; H, 8.13. Found: C, 85.28;
H, 8.30.
2,5-Dim eth yl-2′-m eth ylbip h en yl (Table 2, entries 5 and
8).4 Entry 5: the general procedure using 2-bromo-p-xylene
(105 µL) and o-tolylboronic acid (153 mg, 1.12 mmol, 1.50
equiv) gave the product as a yellow oil (146 mg, 99%). Entry
8: the general procedure using 2-chloro-p-xylene (101 µL),
o-tolylboronic acid (306 mg, 2.25 mmol, 3.00 equiv), Pd2(dba)3
(3.4 mg, 3.8 µmol, 0.50 mol %), and ligand 3a (9.75 µmol, 1.30
mol %) provided the title compound (146 mg, 99%).
3-(1,3-Dioxola n e)-2′-m eth oxybip h en yl (Table 2, entry
6).4 The general procedure using 2-(3-bromophenyl)-1,3-diox-
olane (115 µL), 2-methoxyphenylboronic acid (137 mg), Pd2-
(dba)3 (2.4 mg, 2.6 µmol, 0.35 mol %), and ligand 3a (7.50 µmol,
1.00 mol %) afforded the product as a viscous oil (175 mg, 91%).
3-Ca r bom eth oxy-4′-m eth ylbip h en yl (Table 2, entry 7).
The general procedure using methyl 3-chlorobenzoate (105 µL)
and p-tolylboronic acid (152 mg, 1.12 mmol, 1.50 equiv)
1
provided the product as a yellow oil (154 mg, 91%). H NMR
(30) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1996, 61, 1133.
(300 MHz, CDCl3) δ 8.27 (t, 1H, J ) 1.7 Hz), 8.00 (dt, 1H, J )

Polymer-Supported Dialkylphosphinobiphenyl Ligands
J . Org. Chem., Vol. 66, No. 11, 2001 3827
7.7, 1.7 Hz), 7.78 (ddd, 1H, J ) 7.7, 1.9, 1.2 Hz), 7.55-7.48
with ether (10 mL) and filtered through the side arm with a
positive argon pressure. The resin was further washed with
ether (2 × 7 mL) and filtered, and the combined organic
washes were subjected to the workup procedures described
above for product isolation. The resin was rinsed with water
(2 × 7 mL), tert-butyl alcohol (2 × 7 mL), and ether (3 × 7
mL) and was dried in vacuo in the reaction flask for at least
3 h. Subsequent reactions were initiated by adding solvent
(1.50 mL) via syringe to the reaction flask containing the used
resin. The mixture was stirred at 25 °C for 30-75 min. The
rest of the experiment was set up as stated in the previous
procedures after the premixing protocol.
(m, 3H), 7.28 (d, 2H, J ) 6.6 Hz), 3.96 (s, 3H), 2.42 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 167.1, 141.4, 137.6, 137.2, 131.3,
130.6, 129.7, 128.8, 128.1, 128.0, 127.0, 52.3, 21.3; IR (neat,
cm-1) 3016, 2950, 1724, 1440, 1307, 1246, 1111, 811, 756. Anal.
Calcd for C15H14O2: C, 79.61; H, 6.25. Found: C, 79.85; H,
6.36.
2,5-Dim eth yl-2′-m eth oxybip h en yl (Table 2, entry 9). The
general procedure using 2-chloro-p-xylene (101 µL), 2-meth-
oxyphenylboronic acid (342 mg, 2.25 mmol, 3.00 equiv), Pd2-
(dba)3 (3.4 mg, 3.8 µmol, 0.50 mol %), and ligand 3a (9.75 µmol,
1.30 mol %) afforded the product as a tan oil (144 mg, 91%).
1H NMR (300 MHz, CDCl3) δ 7.35 (ddd, 1H, J ) 8.2, 7.4, 1.9
Hz), 7.15 (dd, 2H, J ) 7.3, 1.8 Hz), 7.08 (d, 1H, J ) 7.8 Hz),
7.04-6.95 (m, 3H), 3.78 (s, 3H), 2.36 (s, 3H), 2.11 (s, 3H); 13
C
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 46059 and 58160) for financial
support. Additional unrestricted funds from Pfizer and
Merck are also greatly appreciated. C.A.P. is a trainee
of the National Cancer Institute (Grant CA09112), to
whom we are indebted. We would also like to thank Dr.
J ohn P. Wolfe for first preparing ligand 2a .
NMR (75 MHz, CDCl3) δ 156.6, 138.5, 134.8, 133.8, 131.1,
131.0, 130.7, 129.5, 128.6, 128.2, 120.5, 110.6, 55.5, 21.2, 19.7;
IR (neat, cm-1) 3000, 2922, 1595, 1579, 1488, 1457, 1431, 1236,
1114, 1026, 751. Anal. Calcd for C15H16O: C, 84.85; H, 7.61.
Found: C, 84.76; H, 7.67.
Gen er a l Recyclin g P r oced u r es. Reactions were per-
formed as above except on a 1.00 mmol scale (0.500 M solution)
and in a 10 mL side arm flask fitted with an 18 mm diameter
sintered glass filter disk. After cooling, the mixture was diluted
J O010025W