A preparatively convenient ligand-free catalytic PEG 2000 suzuki-miyaura coupling

Article abstract of DOI:10.1021/jo802277z

A ligand-free Suzuki-Miyaura reaction for the cross-coupling of aryl and heteroaryl bromides with aryl and heteroarylboronic acids has been developed utilizing catalytic polyethylene glycol 2000 (PEG 2000). This preparatively convenient system afforded the corresponding cross-coupled products in good to excellent isolated yields after a simple aqueous workup. Transmission electron microscopy (TEM) analysis of the Pd-PEG 2000 catalyst system revealed in situ-generated palladium nanoparticles after only 1 min of reaction.

Full text of DOI:10.1021/jo802277z

Phase-transfer complex (PTC) mediated Suzuki-Miyaura
cross-coupling reactions have recently become an area of
interest.9 Used as solvents, the polyethylene glycol (PEG) PTCs
promote ligand-free Suzuki-Miyaura reactions through reduc-
tion of Pd(II) to Pd(0),10,11 obviating the need for phosphine
reducing agents.12 Preparative use of the current methods,
however, is highly impractical due to the polar nature of PEG.
The high viscosity of the reaction mixture renders reaction
stirring and monitoring extremely difficult. More importantly,
it is prohibitively difficult to isolate all but the most simple biaryl
cross-coupled products from the PEG solvent by the standard
diethyl ether extraction.10d,11a,b,12 Thus, a catalytic PEG cross-
coupling protocol would minimize these difficulties, while
retaining the beneficial metal stabilizing and solubilizing at-
tributes of the PEGs. We report herein a practical ligand-free
Suzuki-Miyaura cross-coupling protocol employing 1 mol %
of Pd(OAc)2 and 10 mol % of PEG 2000.
A Preparatively Convenient Ligand-Free
Catalytic PEG 2000 Suzuki-Miyaura Coupling
Thomas M. Razler,*,† Yi Hsiao,† Feng Qian,‡ Ruiling Fu,‡
Rana Kashif Khan,†,§ and Wendel Doubleday†
The Department of Process Research and DeVelopment and
the Department of Biopharmaceutics Research and
DeVelopment, Bristol-Myers Squibb, One Squibb DriVe,
New Brunswick, New Jersey 08903
thomas.razler@bms.com
ReceiVed October 10, 2008
We began our investigation by screening the activity of a
variety of PTCs under ligand-free reaction conditions (Table
1). To evaluate the relative activity of each PTC, a 1:1 mixture
of 4-bromotoluene 1 and 4-methoxyphenylboronic acid 2 with
1 mol % of Pd(OAc)2 was reacted for 12 h. In the absence of
a PTC, K2CO3 afforded 23% conversion to the cross-coupled
product 3 (entry 1). In comparison to the other phase transfer
complexes, the higher molecular weight PEG-based PTCs
showed improved conversion. Specifically, PEG 2000-K2CO3
and PEG 2000-Cs2CO3 both delivered 42% conversion while
PEG 12000-Cs2CO3 and PEG 20000-K2CO3 furnished 3 with
46% and 43% conversion, respectively. With these observations,
we chose the PEG 2000-K2CO3 catalyst system due to its lower
molecular weight, low cost, and ease of product isolation relative
to the higher order PEG systems.13
A ligand-free Suzuki-Miyaura reaction for the cross-
coupling of aryl and heteroaryl bromides with aryl and
heteroarylboronic acids has been developed utilizing catalytic
polyethylene glycol 2000 (PEG 2000). This preparatively
convenient system afforded the corresponding cross-coupled
products in good to excellent isolated yields after a simple
aqueous workup. Transmission electron microscopy (TEM)
analysis of the Pd-PEG 2000 catalyst system revealed in situ-
generated palladium nanoparticles after only 1 min of
reaction.
In an attempt to boost reaction conversion, lithium halides14
(LiCl, LiBr, and LiI), solvent, and boronic acid stoichiometry
were evaluated with the PEG 2000-K2CO3 catalyst system. LiBr
afforded no change in conversion (ca. 42%) while LiCl and LiI
delivered much lower yields of 3. Acetonitrile, methanol, and
ethanol offered no advantage over tetrahydrofuran, however, a
more concentrated THF and H2O reaction solution offered a
substantial boost in reaction conversion (entries 15 and 16).
Increasing the boronic acid stoichiometry to 1.3 equiv in
conjunction with 1 mol % of Pd(OAc)2, 10 mol % of PEG 2000,
2 equiv of K2CO3, and a 1:1 ratio of THF and H2O at reflux
delivered the highest conversion to cross-coupled product 3
(entry 16). Upon reaction completion, dilution with ethyl acetate
The palladium-catalyzed Suzuki-Miyaura cross-coupling
reaction has emerged as an extremely powerful synthetic tool
in a broad range of disciplines, ranging from the synthesis of
novel materials to industrial manufacturing of pharmaceuticals.1,2
Significant research has been devoted toward the identification
of environmentally friendly cross-coupling protocols. Specifi-
cally, low palladium loadings,3 phosphine-free catalyst systems,3-7
and microwave irradiation8 protocols in water have all been
demonstrated to actively promote the Suzuki-Miyaura reaction.
(8) (a) Blettner, C. G.; Ko¨nig, W. A.; Stenzel, W.; Schotten, T. J. Org. Chem.
1999, 64, 3885. (b) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973. (c)
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68, 888.
(9) Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org. Lett. 2008, 10, 1333.
(10) (a) Li, J. H.; Hu, X. C.; Liang, Y.; Xie, Y. X. Tetrahedron 2006, 62,
31. (b) Corma, A.; Garcia´, A.; Leyva, A. J. Catal. 2006, 240, 87. (c) Li, J.-H.;
Liu, W.-J.; Xie, Y.-X. J. Org. Chem. 2005, 70, 5409. (d) Liu, L.; Zhang, Y.;
Wang, Y. J. Org. Chem. 2005, 70, 6122.
(11) For the cross-coupling of aryl chlorides in PEG 400 solvent under oxygen
or air, see: (a) Han, W.; Liu, C.; Jin, Z.-L. Org. Lett. 2007, 9, 4005. (b) Han,
W.; Liu, C.; Jin, Z. AdV. Synth. Catal. 2008, 350, 501.
(12) Luo, C.; Zhang, Y.; Wang, Y. J. Mol. Catal. A: Chem. 2005, 229, 7.
(13) PEG 2000 powder is commercially available from Alfa Aesar at $78.00/
kg.
* To whom correspondence should be addressed.
† Department of Process Research and Development.
‡ Department of Biopharmaceutics Research and Development.
§ Bristol-Myers Squibb 2007 Summer Intern.
(1) (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: New York, 2004; Chapter 2. (b) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (c) Nakamura, I.; Yamamoto, Y.
Chem. ReV. 2004, 104, 2127.
(2) Rouhi, A. M. Chem. Eng. News 2004, 82, 49.
(3) Liu, L.; Zhang, Y.; Xin, B. J. Org. Chem. 2006, 71, 3994.
(4) Goodson, F. E.; Wallow, T. I.; Novak, B. M. Org. Synth. 1998, 75, 61.
(5) Lu, F.; Ruiz, J.; Astruc, D. Tetrahedron Lett. 2004, 45, 9443.
(6) Korolev, D. N.; Bumagin, N. A. Tetrahedron Lett. 2005, 46, 5751.
(7) LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett.
2001, 3, 1555.
(14) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron 2000,
56, 2139.
10.1021/jo802277z CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1381–1384 1381

TABLE 1. Evaluation of Phase Transfer Complexes (PTCs) in the
TABLE 2. Substrate Scope of Aryl and Heteroaryl Bromide 4 in
the Reaction with 4-Methoxyphenylboronic Acid 2
Ligand-Free Suzuki-Miyaura Reactiona
entry
PTC
base
solvent
additive conv, %
1
K2CO3
K2CO3
K2CO3
K2CO3
THF/H2O
THF/H2O
THF/H2O
THF/H2O
23
2.5
9.4
18
33
39
37
42
42
46
43
29
34
31
2b
3c
4d
5
OABCDBr
BCDBr
ANCDCl
Bu4NI
NaHCO3 THF/H2O
6
7
8
9
18-c-6
K2CO3
Cs2CO3
K2CO3
Cs2CO3
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
ACN/H2O
MeOH/H2O
EtOH/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
PEG 600
PEG 2000
PEG 2000
10
11
15e
16
17
12
13
14
15f
16g
PEG 12000 Cs2CO3
PEG 20000 K2CO3
PEG 2000
PEG 2000
PEG 2000
PEG 2000
PEG 2000
PEG 2000
PEG 2000
PEG 2000
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
LiCl
LiBr
LiI
25
43
14
88
98
a Conditions: 4-bromotoluene 1 (1.0 mmol), 4-methoxyphenylboronic acid 2
(1.0 mmol), Pd(OAc)2 (0.01 mmol), PTC (0.1 mmol), base (2.0 mmol), solvent
(5.0 mL), H2O (5.0 mL), reflux, 12 h. b O-Allyl-N-benzylcinchonidinium
bromide (OABCDBr). c N-Benzylcinchonidinium bromide (BCDBr). d N-(9-
Anthracenylmethyl)cinchonidinium chloride (ANCDCl). e Acetonitrile
(ACN). f 4-Bromotoluene (1.0 mmol), 4-methoxyphenylboronic acid (1.2
mmol), THF (1.6 mL), H2O (1.6 mL). g 4-Bromotoluene (1.0 mmol), 4-methoxy-
phenylboronic acid (1.3 mmol), THF (1.6 mL), H2O (1.6 mL).
a General reaction conditions: aryl and heteroaryl bromide 4 (1.0
mmol), 4-methoxyphenylboronic acid 2 (1.3 mmol), Pd(OAc)2 (0.01
mmol), PEG 2000 powder (0.1 mmol), K2CO3 (2.0 mmol), THF (1.6
mL), H2O (1.6 mL), reflux. b Isolated yields. c 5-Bromoindole and 2
were recovered in 29% and 15% yield, respectively.
followed by an aqueous brine wash enabled the efficient
extraction of the product with no observable loss to the aqueous
and PEG 2000 layers. Zhang10d and Liu11a,b have reported that
oxygen can promote PEG-mediated Suzuki-Miyaura cross-
coupling of simple aryl chlorides and bromides, respectively.
In contrast, our reaction conducted open to the air resulted in
the formation of homodimerization byproducts derived from the
arylboronic acid in up to 12% yield. Presumably, air oxidation
of Pd(0) to Pd(II) induces this dimerization pathway, which was
not observed in the previous reports.15 An inert atmosphere of
nitrogen completely suppressed the boronic acid dimerization
and delivered the cross-coupled products in high yield.
Heteroaryl halides have rarely been employed in ligand-free
Suzuki-Miyaura cross-coupling protocols.17 Typically, high
catalyst loading (5 mol %) is required to overcome catalyst
deactivation through heteroatom coordination.18 With the 1 mol
% of Pd(OAc)2 and catalytic PEG 2000 conditions, pyridine,
pyrimidine, and pyrazole substrates all afforded their cross-
coupled products in high isolated yields (entries 10 to 12).
Modest conversion with 5-bromoindole, however, furnished 5l
in 41% isolated yield, presumably due to palladium coordination
by the indole nitrogen.
In a similar fashion, the steric and electronic tolerance of the
aryl and heteroarylboronic acid fragments were evaluated against
4-bromoanisole 6 (Table 3). Both electron-rich and electron-
deficient arylboronic acids performed well under the reaction
conditions (entries 1 to 7). Of note, Boc-protected 4-aminophe-
nylboronic acid (entry 4) furnished 5p in 79% isolated yield as
well as 15% yield of the des-Boc product. Presumably, des-
Boc 5p arises from basic hydrolysis of 5p, not from the starting
boronic acid, as 4-aminophenylboronic acid was not observed
With conditions in hand, we explored the electronic and steric
effects of various substituents in the cross-coupling of aryl and
heteroaryl bromide coupling partner 4 with 4-methoxyphenyl-
boronic acid 2 (Table 2). Aryl bromides with diverse electron-
donating and electron-withdrawing substituents delivered the
cross-coupled products in high yields (entries 1 to 9). Of note,
3-bromothioanisole (entry 6), a potentially difficult substrate due
to palladium coordination, furnished the cross-coupled product
5e in 97% yield.16 The sterically demanding 2,6-tolylbromide
(entry 3), however, proved to be a difficult substrate. After
extended reaction times, product 5b was isolated in modest 22%
yield with 61% and 53% recovery of the starting aryl bromide
and boronic acid, respectively.
(17) Conlon, D. A.; Pipik, B.; Ferdinand, S.; LeBlond, C. R.; Sowa, J. R.,
Jr.; Izzo, B.; Collins, P.; Ho, G.-J.; Williams, J. M.; Shi, Y.-J.; Sun, Y. AdV.
Synth. Catal. 2003, 345, 931.
(18) Thompson, A. E.; Hughes, G.; Batsanov, A. S.; Bryce, M. R.; Parry,
P. R.; Tarbit, B. J. Org. Chem. 2005, 70, 388.
(15) Miller, W. D.; Fray, A. H.; Quatroche, J. T.; Sturgill, C. D. Org. Proc.
Res. DeV. 2007, 11, 359.
(16) Chauhan, B. P. S.; Rathore, J. S.; Bandoo, T. J. Am. Chem. Soc. 2004,
126, 8493.
1382 J. Org. Chem. Vol. 74, No. 3, 2009

TABLE 3. Substrate Scope of Aryl and Heteroarylboronic Acids 7
in the Reaction with 4-Bromoanisole 6
5-indoleboronic acid (entry 12), only 21% of the des-Boc
product was isolated with recovery of both the starting halide
and boronic acid.
Suzuki-Miyaura protocols employing a PEG solvent system
have been shown to form palladium nanoparticles possessing
high catalytic activity. 11a,b,12,21,22 Although such nanoparticles
are normally prepared through the premixing of a palladium
source and PEG at elevated temperatures, followed by the
introductionofsubstratesandbaseafteraninductionperiod,10d,12,23
we set out to verify the involvement of palladium nanoparticles
in our catalyst system.
Indeed, examination of the catalytic PEG 2000 cross-coupling
between 4-bromotoluene 1 and 4-methoxyphenylboronic acid
2 with transmission electron microscopy (TEM) revealed the
presence of in situ-generated palladium nanoparticles (Figure
1). At 23 °C, 1 min after combining the reaction components,
10-20 nm palladium nanoparticles embedded upon the surface
of a 200 nm PEG 2000 sphere were formed. At 5 min, the PEG
2000 sphere collapsed into well-dispersed 10-20 nm sized Pd-
PEG 2000 nanoparticles with high surface area. At 30 min and
2 h, the nanoparticles began to cluster, forming agglomerates,
with less surface area and presumably less catalytic activity.
a General reaction conditions: 4-bromoanisole (1 mmol), boronic acid
(1.3 mmol), Pd(OAc)2 (0.01 mmol), PEG 2000 powder (0.1 mmol),
K2CO3 (2.0 mmol), THF (1.6 mL), H2O (1.6 mL), reflux. b Isolated
yields. c 15% of the des-Boc coupled product was also isolated.
d Des-Boc 5v was isolated in 22% yield. e Des-Boc 5x was isolated in
21% yield with 51% and 47% recovery of 6 and N-Boc-5-indoleboronic
acid, respectively.
FIGURE 1. TEM imaging of the Pd-PEG 2000 catalyst at (A) 1 min,
(B) 5 min, (C) 30 min, (D) and 2 h.
during the course of the reaction. Heteroarylboronic acids have
had limited utility in the Suzuki-Miyaura coupling, primarily
due to their difficult preparation, poor solubility, and low
reactivity.19 Recently, the judicious choice of ligand, base, and
solvent have been shown to have a dramatic effect on the
reaction’s outcome.20 Evaluation of our Pd-catalytic PEG 2000
protocol against challenging heteroarylboronic acids revealed
encouraging results. Specifically, coupling of 3,4-methylene-
dioxyphenylboronic acid (entry 8), benzofuran 2-boronic acid
(entry 9), a substrate prone to proto-deborylation, and N-Boc-
pyrrole 2-boronic acid (entry 10) with 6 afforded the corre-
sponding products 5t, 5u, and 5v in good yield. Cross-coupling
of indoleboronic acid substrates, however, did not perform as
well (entries 11 and 12). Multiple products were observed in
the coupling of N-phenylsulfonyl-3-indoleboronic acid (entry
11), with no appreciable isolation of 5w. In the case of N-Boc-
To our knowledge, this represents the first observation of the
changing nanoparticle agglomeration landscape over the course
of a cross-coupling reaction. Interestingly, all reactions reported
herein turned black within 1 min, indicating the precipitation
of palladium from solution. Possibly, the larger chain length of
PEG 2000 is the cause of the palladium black precipitation as
the smaller PEG 400 has been reported to remain in solution
with no observable palladium black formation for months.11b
Currently, we are examining whether homogeneous or hetero-
geneous catalysis is operative with catalytic PEG 2000 and the
effect the Pd-PEG 2000 nanoparticle agglomeration has on the
reaction kinetics. In addition, evaluation of alternative cross-
coupling partners such as aryl and heteroaryl chlorides and
(21) For tetralkylammonium salt promoted Pd-nanoparticle formation see:
Reetz, M. T.; Westermann, E. Angew Chem., Int. Ed. 2000, 39, 165.
(22) Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44,
7852.
(23) References 11a and 11b describe one of the first examples of in situ-
generated nanoparticles.
(19) Tyrrell, E.; Brookes, P. Synthesis 2003, 4, 469.
(20) (a) Kudo, N.; Perseghini, M.; Fu, G. C. Angew Chem., Int. Ed. 2006,
45, 1282. (b) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484. (c) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3358.
J. Org. Chem. Vol. 74, No. 3, 2009 1383

black reaction mixture was cooled to rt, diluted with ethyl acetate
(10 mL), and introduced into a separatory funnel. The triphasic
solution was separated and the combined PEG 2000 and aqueous
phases were extracted with ethyl acetate (5 mL, 2×). The combined
organic extracts were washed with saturated aqueous sodium
chloride (10 mL, 2×), dried over sodium sulfate, filtered, and
concentrated under reduced pressure. The resulting crude material
was purified via silica gel chromatography (5% EtOAc/hexane) to
afford 4-methoxy-4′-(methyl)-1,1′-biphenyl 3 (0.28 g, 97%) as a
iodides as well as potassium trifluoroborate salts and boronate
esters is ongoing and will be reported in due course.
In summary, we have developed a practical reaction protocol
for the ligand-free, catalytic PEG 2000 Suzuki-Miyaura cross-
coupling. Advantages of our new method include the facile
isolation of polar cross-coupled products, low cost of PEG 2000,
and the ability to promote the cross-coupling of heteroaryl
bromides and heteroarylboronic acids. For the first time with
catalytic PEG-based Suzuki-Miyaura reactions, we have ob-
served the rapid formation (<1 min) of in situ-generated
palladium nanoparticles and their decreasing surface area over
the course of a reaction by TEM analysis.
1
white solid. Mp 105 °C; H NMR (400 MHz, CDCl3) δ 7.35 (dd,
J ) 6.6, 2.1 Hz, 2H), 7.29 (dd, J ) 6.4, 1.7 Hz, 2H), 7.07 (d, J )
7.9 Hz, 2H), 6.81 (dd, J ) 6.7, 2.1 Hz, 2H), 3.68 (s, 3H), 2.22 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 158.9, 137.9, 136.4, 133.7,
129.4, 127.9, 126.6, 114.2, 55.4, 21.0.
Experimental Section
Acknowledgment. We would like to thank Professors Barry
Trost (Stanford University) and Chulbom Lee (Seoul National
University) and Drs. Prashant P. Deshpande, Thorsten Rosner,
David A. Conlon, Rodney L. Parsons, Robert E. Waltermire,
and David R. Kronenthal (BMS) for helpful discussions.
General Procedure for the Catalytic PEG 2000 Mediated
Cross-Coupling of Aryl Bromides and Arylboronic Acids.
4-Bromotoluene 1 (0.171 g, 1 mmol) was added to a nitrogen-
purged 20 mL scintillation vial equipped with a stir bar. 2-Meth-
oxyphenylboronic acid 2 (0.197 g, 1.3 mmol) was then added,
followed by solid potassium carbonate (0.276 g, 2.0 mmol),
polyethylene glycol powder (PEG 2000, 0.199 g, 0.10 mmol), and
palladium acetate (0.002 g, 0.01 mmol). Tetrahydrofuran (1.6 mL,
0.6 M) followed by water (1.6 mL, 0.6 M) was added to the
scintillation vial via syringe and the vial was capped and brought
to reflux. After the reaction was deemed complete (5 h, TLC), the
Supporting Information Available: Experimental proce-
dures and 1H and 13C NMR spectra of the products. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO802277Z
1384 J. Org. Chem. Vol. 74, No. 3, 2009