A versatile catalyst system for suzuki-miyaura cross-coupling reactions of C(sp2)-tosylates and mesylates

Article abstract of DOI:10.1021/ol9015892

Figure Presented A catalyst system for the Suzuki-Miyaura cross-coupling reactions of aryl and vinyl tosylates and mesylates has been developed. This catalyst displays excellent functional group tolerance and allows the coupling of heteroarylboronic acids

Full text of DOI:10.1021/ol9015892

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3954-3957
A Versatile Catalyst System for
Suzuki-Miyaura Cross-Coupling
Reactions of C(sp2)-Tosylates and
Mesylates
Brijesh Bhayana, Brett P. Fors, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received July 12, 2009
ABSTRACT
A catalyst system for the Suzuki-Miyaura cross-coupling reactions of aryl and vinyl tosylates and mesylates has been developed. This
catalyst displays excellent functional group tolerance and allows the coupling of heteroarylboronic acids with aryl tosylates and mesylates to
be performed in high yields. Moreover, reactions employing alkylboronic acids, as well as heteroaryl, vinyl, and allylic pinacol boronate esters,
were conducted with high efficiencies.
There has been a substantial increase in the utility of Pd-
catalyzed Suzuki-Miyaura cross-coupling reactions in the past
decade.1 Catalyst systems based on new ligands have allowed
reactions of aryl halides and arylboronic acids to be performed
at low catalyst loadings and with excellent functional group
tolerance.2 More recently, considerable attention has been
devoted to effectively coupling the less reactive aryl or vinyl
tosylates3 and mesylates.4 These substrates are more attractive
than the corresponding triflates and nonaflates because they are
cheaper and more stable.5
Figure 1. Biarylphosphine ligands.
In 2003, we reported a catalyst system, comprised of ligand
L1 (XPhos, Figure 1), for the cross-coupling of aryl-boronic
acids with aryl or vinyl tosylates.3d Although this system
provided good results in many instances, reactions involving
heteroarylboronic acids or electron-rich aryl tosylates were not
disclosed. More recently, Kwong has disclosed an active
catalyst, based on an indoyl phosphine ligand, for the
Suzuki-Miyaura cross-coupling reactions of aryl mesylates4b
and tosylates.3a This system showed good functional group
(1) (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (b)
Doucet, H. Eur. J. Org. Chem. 2008, 2013. (c) Corbet, J.; Mignani, G. Chem.
ReV. 2006, 106, 2651 .
(2) (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3358. (b) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101. (c) Zapf, A.; Beller, M.
Chem. Commun. 2005, 431. (d) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
10.1021/ol9015892 CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

tolerance and generally required e2 mol % Pd; however, no
examples using electron-deficient, heteroaryl, alkyl, or alkenyl-
boronic acids, as well as cross-couplings to form triortho-
substituted biaryls, were performed.
reaction; however, use of t-BuOH gave similar results as
with t-AmOH. We chose to use t-AmOH for the remainder
of our studies because it is a liquid at room temperature and
has a higher boiling point than t-BuOH.8 Furthermore,
carbonate and fluoride bases gave diminished yields com-
pared to K3PO4.
With our optimized reaction conditions we set out to explore
the scope of this catalyst system for the coupling of arylboronic
acids with aryl mesylates. Common functional groups such as
esters, nitriles, aldehydes, and ketones were all well tolerated
under these conditions (Figure 2, entries 1a-1c). A hindered
Herein, we report a catalyst for the Suzuki-Miyaura cross-
coupling of aryl tosylates and mesylates with boronic acids and
esters. This new system is highly active and general for these
reactions and, more importantly, extends the reaction scope to
substrates that had previously been ineffective coupling partners.
We began our study by examining the reaction of a
heteroarylboronic acid with an aryl mesylate. We hypothesized
that a catalyst based on L2, which we have previously shown
to be efficient for C-N cross-coupling reactions of aryl
mesylates,6 would be effective for these difficult Suzuki-Miyaura
reactions. Using Pd(OAc)2, L2, and K3PO4 in t-AmOH furan-
3-boronic acid was successfully combined with 4-tert-butylphe-
nyl methanesulfonate in a 98% GC yield (Table 1). With L1,
Table 1. Condition Screen for the Suzuki-Miyaura Reaction of
Furan-3-boronic Acid and 4-tert-Butylphenyl Methanesulfonatea
entry
ligand
solvent
base
yield (GC)
1
2
3
4
5
6
7
8
9
L2
L1
L2
L2
L2
L2
L2
L2
L2
t-AmOH
t-AmOH
DME
1,4-dioxane
toluene
t-BuOH
t-AmOH
t-AmOH
t-AmOH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
CsF
98%
71%
73%
79%
36%
99%
51%
71%
83%
Figure 2. Suzuki-Miyaura reactions of aryl mesylates using a
a Reaction conditions: ArOMs (1.0 mmol), ArB(OH)2 (2.0 mmol), base
(3.0 mmol), Pd(OAc)2 (2 mol %), ligand (4 mol %), solvent (2 mL), 110
°C, 2 h.
catalyst system based on L2. [a]Reaction conditions: ArOMs (1.0
mmol), ArB(OH)2 (2.0 mmol), K3PO4 (3.0 mmol), Pd(OAc)2 (2
mol %), L2 (4 mol %), t-AmOH (2 mL/mmol), 110 °C, 2 h. Isolated
yields based upon an average of 2 runs. [b] 0.5 mol % Pd(OAc)2
and 1 mol % L2 were used. [c] Used K3PO4•H2O as the base and
toluene as the solvent.
previously our best ligand for the coupling of aryl tosylates with
aryl boronic acids,3d,7 only 71% of the desired product was
obtained. Most other solvents that are commonly employed
for cross-coupling reactions gave reduced yields in this
substrate, 2,6-dimethylphenyl-boronic acid, was successfully
coupled to form a di-ortho-substituted biaryl in an excellent
yield with only 0.5 mol % Pd. This same substrate was also
successfully combined with 2,4-dimethylphenyl methane-
(3) (a) So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org.
Chem. 2008, 73, 7731. (b) Wilson, D. A.; Wilson, C. J.; Rosen, B. M.;
Percec, V. Org. Lett. 2008, 10, 4879. (c) Zhang, L.; Meng, T.; Wu, J. J.
Org. Chem. 2007, 72, 9346. (d) Nguyen, H. N.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 11818. (e) Brenstrum, T.; Gerristma,
D. A.; Adjabeng, G. M.; Frampton, C. S.; Britten, J.; Robertson, A. J.;
McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 7635.
(8) t-BuOH: mp ) 25 °C, bp ) 85 °C; t-AmOH: mp ) -12 °C, bp )
102 °C.
(9) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961. (b) Deng, J. Z.; Paone, D. V.; Ginnetti, A. T.; Kurihara,
H.; Dreher, S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org.
Lett. 2009, 11, 345. (c) Billingsley, K. L.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 4695.
(4) (a) Kuroda, J.; Inamota, K.; Hiroya, K.; Doi, T. Eur. J. Org. Chem.
2009, 2251. (b) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int.
Ed. 2008, 47, 8059.
(5) (a) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754. (b) Klapers, A.; Campos, K. R.; Chen, C.; Volante,
R. P. Org. Lett. 2005, 7, 1185.
(10) For Suzuki-Miyaura cross-coupling of secondary alkyl trifluo-
roborates with aryl chlorides, see: Dreher, S. D.; Dormer, P. G.; Sandrock,
D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257.
(11) (a) Yang, D. X.; Colletti, S. L.; Wu, K.; Song, M.; Li, G. Y.; Shen,
H. C. Org. Lett. 2009, 11, 381. (b) Billingsley, K. L.; Buchwald, S. L. J.
Org. Chem. 2008, 73, 5589.
(6) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(7) A catalyst comprised of L1 has also been used for other Pd-catalyzed
C-C cross-coupling reactions of aryl mesylates: (a) Zhang, L.; Qing, J.;
Yang, P.; Wu, J. Org. Lett. 2008, 10, 4971. (b) Ackermann, L.; Althammer,
(12) Tivola, P. B.; Deagostino, A.; Prandi, C.; Venturello, P. Org. Lett.
2002, 4, 1275.
A.; Fenner, S. Angew. Chem., Int. Ed. 2008, 121, 207
.
Org. Lett., Vol. 11, No. 17, 2009
3955

sulfonate in an 81% yield (Figure 2, entry 1e). This is the first
example of a Suzuki-Miyaura reaction of an aryl mesylate to
form a triortho-substituted biaryl.4b
Table 2. Suzuki-Miyaura Coupling of Mesylates and Tosylates
With Alkyl, Vinyl and Heterocyclic Nucleophiles Using L2a
Due to the ubiquity of heterocycles in biologically active
molecules we focused our attention on using heteroarylboronic
acids as substrates, which have not previously been coupled
with aryl mesylates. These substrates have often been difficult
partners for Suzuki-Miyaura reactions due to their instability;9
however, we postulated that with our new catalyst system the
desired reaction would be faster than the decomposition
pathway. Using a catalyst based on L2, 3-pyridyl, 3-furyl,
2-benzofuryl, 5-indolyl, and 3-thiophenylboronic acids were all
reacted with aryl mesylates in good to excellent yields (Figure
2, entries 1f-1p). It is worth pointing out that the 5-indolyl-
boronic acid was successfully coupled in a high yield without
the need for a protecting group on the nitrogen. In addition to
heteroarylboronic acids, heteroarylmesylates also proved to be
viable coupling partners. Mesylates derived from quinolines,
isoquinolines, and benzothiazoles were successfully utilized and
yielded the biaryl product in adequate yields (Figure 2, entries
1 g-1j, 1 L, 1m). Unfortunately, employing mesylates contain-
ing a nitrogen ortho to the sulfonate gave modest yields due to
competing hydrolysis to form the undesired phenol (Figure 2,
entries 1o and 1p).
Using a catalyst comprised of L2 and Pd(OAc)2, aryl
tosylates were coupled with an array of arylboronic acids
with higher efficiencies than in the reactions with the
corresponding aryl mesylates. Ortho substitution on both the
aryl tosylate and the arylboronic acid were well tolerated
(Figure 3, entries 2a-2f). For example, the diortho-sub-
Figure 3. Suzuki-Miyaura coupling of aryl and vinyl tosylates
using L2. [a] Reaction conditions: ArOTs (1.0 mmol), ArB(OH)2
(2.0 mmol), K3PO4 (3.0 mmol), Pd(OAc)2 (2 mol %), L2 (4 mol
%), t-AmOH (2 mL/mmol), 110 °C, 2 h. Isolated yields based upon
an average of 2 runs. [b]0.1 mol % Pd(OAc)2 and 0.2 mol % L2
were used. [c]Used K3PO4·H2O as the base and toluene as the
solvent.
a Reaction conditions: ArX (1.0 mmol), RB(OH)2 (2.0 mmol), K3PO4
(3.0 mmol), Pd(OAc)2 (2 mol %), L2 (4 mol %), t-AmOH (2 mL/mmol),
110 °C, 2 h. Isolated yields based upon an average of 2 runs. b ArOTs (1.0
mmol), RB(OH)2 (3.0 mmol), Pd(OAc)2 (4 mol %), L2 (8 mol %),
K3PO4·H2O (3.0 mmol), t-AmOH (1 mL/mmol), 120 °C, 4 h.
stituted 2,6-dimethylphenylboronic acid was successfully
reacted with an aryl tosylate in an excellent yield with only
0.1% Pd; 5 times less Pd than what was required for the
reaction of 2,6-dimethylphenylboronic acid with an aryl
mesylate. Heteroarylboronic acids were also successfully
3956
Org. Lett., Vol. 11, No. 17, 2009

employed in these reactions for the first time. The 3-thiophe-
nyl, 3-furyl, 3-pyridyl, and 5-indolylboronic acids were
coupled with aryl and heteroaryl tosylates in satisfactory
yields (Figure 3, entries 2c-2l). We also found that het-
eroaryl tosylates that contained a nitrogen ortho to the
sulfonate gave considerably higher yields in these reactions
than the corresponding heteroaryl mesylates. Hydrolysis to
give the phenol was not observed in these reactions (Figure
3, entries 2i-2l).
Alkylboronic acids were also viable coupling partners using
this new catalyst system; however, the scope was much more
limited than what we had seen with aryl-boronic acids (Table
2, entries 1-5). For example, methylboronic acid was reacted
with an aryl mesylate and an aryl tosylate in high yields. By
switching to a small secondary alkyl substrate, cyclopropylbo-
ronic acid, the efficiency of the coupling diminished and only
a 58% yield was obtained. When the larger cyclopentylboronic
acid was employed the reaction completely shut down and none
of the desired product was formed.10
be reacted with aryl mesylates and aryl tosylates in ap-
preciable yields.12 Further, 1-methylpyrazole-4-boronic acid
pinacol ester could be coupled with aryl or vinyl tosylates
and mesylates in high yields.
In summary, we have developed a versatile catalyst system,
based on L2, for the Suzuki-Miyaura cross-coupling reactions
of aryl or vinyl tosylates and mesylates. Using this catalyst an
array of aryl mesylates and boronic acids, which contained
sensitive functional groups, were successfully coupled in high
yields. This system also allowed the cross-coupling of het-
eroarylboronic acids with both aryl tosylates and aryl mesylates
for the first time. Finally, alkylboronic acids, as well as vinyl,
allylic, and heteroaryl pinacol boronate esters proved to be
proficient coupling partners in these reactions.
Acknowledgment. We thank the National Institutes of
Health (GM-46059) for financial support of this project.
We thank Merck, Boehringer Ingelheim, Amgen, BASF
(Pd(OAc)2), Nippon Chemical, and Chemetall (Cs2CO3) for
additional support. B.P.F. thanks Merck for a fellowship.
Finally, we were also able to couple pinacol boronate esters
with aryl tosylates and mesylates using a catalyst comprised of
L2 (Table 2, entries 6-14). These substrates are attractive
because they are more stable and more amenable to storage
than boronic acids.9b,11 Vinyl and allylic boronate esters could
Supporting Information Available: Procedural and spec-
tral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL9015892
Org. Lett., Vol. 11, No. 17, 2009
3957