A new palladium precatalyst allows for the fast Suzuki-Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids

Article abstract of DOI:10.1021/ja1073799

Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki-Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow. With this precatalyst, Suzuki-Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2-thiophene, and 2-pyrroleboronic acids and their analogues proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.

Full text of DOI:10.1021/ja1073799

Published on Web 09/21/2010
A New Palladium Precatalyst Allows for the Fast Suzuki-Miyaura Coupling
Reactions of Unstable Polyfluorophenyl and 2-Heteroaryl Boronic Acids
Tom Kinzel, Yong Zhang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue, Cambridge,
Massachusetts 02139, United States
Received August 16, 2010; E-mail: sbuchwal@mit.edu
required for efficient coupling. Another solution, albeit limited to
Abstract: Boronic acids which quickly deboronate under basic
aryl bromides and iodides, allows the coupling of 2 and penta-
conditions, such as polyfluorophenylboronic acid and five-
membered 2-heteroaromatic boronic acids, are especially chal-
lenging coupling partners for Suzuki-Miyaura reactions. Never-
theless, being able to use these substrates is highly desirable
for a number of applications. Having found that monodentate
biarylphosphine ligands can promote these coupling processes,
we developed a precatalyst that forms the catalytically active
species under conditions where boronic acid decomposition is
fluorophenylboronic acid by using stoichiometric amounts of Ag2O
in addition to the palladium catalyst.12,13
Herein, we report the fast and efficient SMC of the free boronic
acids 1-8 at room temperature or 40 °C in short reaction times of
30 min to 2 h. Key to the success was the development of a new
precatalyst that generates the catalytically active LPd(0) species
quickly under mild conditions under which the deboronation of the
boronic acid is significantly slowed down.
In the course of mechanistic investigations, we prepared complex
slow. With this precatalyst, Suzuki-Miyaura reactions of a wide
range of (hetero)aryl chlorides, bromides, and triflates with
polyfluorophenyl, 2-furan, 2-thiophene, and 2-pyrroleboronic acids
SPhosPdPhCl (9) that results from oxidative addition of SPhosPd(0)
with chlorobenzene14 and treated it with 1 in the presence of
and their analogues proceed at room temperature or 40 °C in
aqueous K3PO4 (Scheme 1). Rapid formation of product 10
short reaction times to give the desired products in excellent
demonstrated that transmetalation and reductive elimination occur
yields.
with 1 at room temperature.15
Scheme 1. Initial Observation of the Coupling of 1 with a
Stoichiometric Amount of an Oxidative-Addition Complex 9
The Suzuki-Miyaura cross-coupling (SMC) reaction is arguably
the most important and widely used method for the construction
of sp2-sp2 carbon-carbon bonds.1 However, since SMCs are
typically performed at elevated temperatures and require several
hours reaction time, the scope of usable boronic acids is limited to
those that do not significantly decompose under standard conditions.
Consequently, the SMCs of quickly deboronating2 2,6-difluoro-
Using 2 mol % of 9 as precatalyst, 4-chloroanisole was coupled
phenylboronic acid (1) and analog 2 as well as the SMCs of five-
with 1 to give the desired product in 93% yield in less than 30 min
membered 2-heterocyclic boronic acids 3-8 (Chart 1) are
using a 1:2 mixture of THF and 0.5 M aqueous K3PO4. Kinetics
studies showed that product formation stopped abruptly, indicating
that the remainder of 1 was consumed by competing base- and/or
problematic.3-6 Being able to couple these boronic acids with
functionalized aryl and heteroaryl substrates would be of great
interest for the synthesis of pharmaceutical and agrochemical
metal-catalyzed deboronation.2 Increasing the temperature resulted
candidates, natural products, and materials.
in a lower conversion. However, full conversion of 4-chloroanisole
at room temperature was achieved by using the oxidative-addition
complex 11 in which the SPhos ligand is replaced by XPhos (Chart
Chart 1. Boronic Acids That Easily Undergo Protodeboronation in
Aqueous Base To Give the Parent Arene
2).
Chart 2. XPhos-Containing Precatalysts Used in This Study
One viable solution to this problem is the masking of the boronic
acids as MIDA boronates,7 cyclic triolborates,8 or trifluoroborate
salts9,10 which slowly hydrolyze11 to the free boronic acid under
the reaction conditions. The ratio of the concentration of catalyst
and the boronic acid is relatively high and, as a result, transmeta-
lation is favored over protodeboronation. Nevertheless, these
surrogates are typically prepared from the free boronic acids, and
often, high palladium loadings and/or long reaction times are
The syntheses of complexes 9 and 11 are difficult, and their use
as precatalysts for the SMC of 1 with any aryl halide necessarily
results in the formation of biaryl 10 in addition to the desired
product. The preparation and isolation of an individual oxidative-
addition complex for each substrate is clearly impractical and often
impossible. Because using Pd(OAc)2 or Pd(dba)2 with XPhos gave
unsatisfactory results, we sought another solution to provide the
9
10.1021/ja1073799  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14073–14075 14073

C O M M U N I C A T I O N S
catalytically active XPhosPd(0) species which undergoes oxidative
addition in situ.
Interestingly, we found that, while trisubstituted polyfluoro-
phenylboronic acids 2 and 14 could be employed to give products
16 and 17, very low conversion was observed with 2,3,6-trifluoro-
phenylboronic acid. To understand this result, we studied both the
deboronation rates19 and apparent transmetalation rates20 of (poly)-
fluorophenylboronic acids (Table 2). Transmetalation efficiency
increases with the number of fluorine substituents, with ortho
substitution having the greatest impact. Thus, 1 reacts about 150
times faster than simple phenylboronic acid, and almost 4 times
faster than 2-fluorophenylboronic acid. In the series of 1f2f14,
the loss in stability is counterbalanced by higher transmetalation
rates, thus allowing the coupling of 2 and 14 under essentially the
same reaction conditions. In contrast, the coupling of 2,3,6-
trifluorophenylboronic acid is more problematic because the de-
boronation rate is dramatically increased, whereas the transmeta-
lation rate does not change relative to that of 1.21
Previously, we developed precatalyst 12 which, upon deproto-
nation by a base, forms XPhosPd(0) and indoline via C-N reductive
elimination.16 While it is an excellent source of the catalytically
active Pd species, its activation with weak bases is slow and occurs
only at elevated temperatures. Moreover, its synthesis requires
several steps. In the process of addressing these issues, we found
that both drawbacks could be overcome with a new class of
precatalysts where the parent aliphatic amine in 12 is replaced by
2-aminobiphenyl in 13: First, the higher acidity of the palladium-
bound aromatic amine compared to the aliphatic amine allows
activation of 13 to occur almost instantaneously with weak base at
room temperature. Second, 13 is easily obtained in a one-pot
procedure by combining Pd(OAc)2 with 2-aminobiphenyl, followed
by addition of LiCl and the ligand (XPhos) (Scheme 2).17
Table 2. Deboronation Rates and Apparent Relative
Transmetalation Rates of Polyfluorophenylboronic Acids
Scheme 2. Synthesis of Precatalyst 13
relative
deboronation rate, t1/2 (min)a transmetalation rate, krel
entry
boronic acid
1
2
3
4
5
6
7
8
PhB(OH)2
2-F
3-F
4-F
2,6-F2 (1)
2,4,6-F3 (2)
2,6-F2-3-OnBu (14)
2,3,6-F3
1
42
2
5
28
10
6
155
202
536
156
For the SMC reaction between 4-chloroanisole and 1 in the
presence of aqueous 0.5 M K3PO4 as base, the use of precatalysts
12 and 13 was tested. As expected, only the latter promoted the
reaction, leading to full conversion to product.
2
a Deboronation due to the presence of base was measured via
calorimetry at room temperature in a mixture of THF and 0.5 M K3PO4.
The values in the column are the half-lives of the observed first-order
kinetic profiles.
Initially, several aryl halides or pseudohalides were subjected
to the SMC reaction with polyfluorophenylboronic acids. We
observed that aryl chlorides, bromides, and triflates are good
substrates for the coupling with 1, while only low conversions were
observed with aryl iodides18 (Table 1). Substrates with coordinating
groups in the ortho position, such as esters or ketones, could also
not be coupled efficiently. However, even large noncoordinating
ortho substituents, as in 15b, were well tolerated. Heteroaromatic
compounds readily underwent the SMC to form the desired products
in excellent yields, but five-membered chloro- or bromoheteroarenes
with multiple heteroatoms remained problematic.
It is important to note that the coupling of these polyfluoro-
phenylboronic acids proceeds by using established ligands (SPhos,
XPhos) that exhibited excellent results in other SMC reactions.
Thus, the previously reported unsuccessful attempts3 to couple 1
and 2 in the presence of these ligands were not due to their structure
but to the reaction conditions which were necessary to provide the
active catalytic species. Using precatalyst 13, the catalytically active
XPhosPd(0) species is formed rapidly at room temperature, thereby
allowing the successful coupling of these unstable boronic acids.
Next, we turned our attention to heteroaryl boronic acids and
found that, by using 2 mol % of 13, 2-heterocyclic boronic acids
3-8 could be coupled efficiently with a wide array of aryl and
benzyl halides, mostly within 30 min at room temperature or 40
°C (Table 3). The higher stability of the 2-heterocyclic boronic acids
relative to that of the polyfluorophenylboronic acids allowed the
transformations of challenging substrates that could not be used
with the latter. Therefore, performing the reaction at 40 °C for 2 h
allowed the conversion of 4- and 5-halopyrazoles, 2-chloro-
benzoxindole as well as 2-chloroacetanilide to give the coupled
products 19a, 20c, 22b, and 20b in excellent yields.
Table 1. Coupling of Polyfluoroboronic Acids to Aryl Chlorides,
Bromides, and Triflatesa
The fast generation of XPhosPd(0) from precatalyst 13 is a
prerequesite for the successful coupling of unstable boronic acids
1-8 but also increases the rate of reaction for other SMC reactions,
as illustrated by the fast coupling of 3-furan and 3-thiopheneboronic
acids to give 24 and 25.
In summary, we have developed a procedure for very fast SMC
reactions at room temperature or 40 °C that allows the coupling of
a wide range of (hetero)aryl halides and triflates with excellent
functional group tolerance. The fast catalytic process and the
extremely mild reaction conditions make the coupling of unstable
polyfluorophenyl and five-membered 2-heterocyclic boronic acids
a ArX (1 mmol), ArB(OH)2 (1.5 mmol), 13 (2 mol %), degassed THF
(2 mL), degassed 0.5 M aq K3PO4 (4 mL), rt, 30 min; isolated yields,
average of two runs. b 13 (3 mol %).
9
14074 J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010

C O M M U N I C A T I O N S
Table 3. Coupling of 2- and 3-Heterocyclic Boronic Acids to Aryl
(3) While 2,3- and 2,4-difluorophenylboronic acids could be coupled using
ligand SPhos at 80-90 °C, these conditions did not allow the efficient
coupling of 1 or 2: Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685.
and Benzyl Chlorides and Aryl Bromidesa
(4) For some examples for the coupling of 2,6-difluorophenylboronic acid with
vinyl triflates and aryl bromides, see: (a) Antonow, D.; et al. J. Med. Chem.
2010, 53, 2927. (b) Schmidt, D.; et al. Bioorg. Med. Chem. Lett. 2009, 19,
4768. (c) Palmer, B. D.; Smaill, J. B.; Rewcastle, G. W.; Dobrusin, E. M.;
Kraker, A.; Moore, C. W.; Steinkampf, R. W.; Denny, W. A. Bioorg. Med.
Chem. Lett. 2005, 15, 1931.
(5) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961. (b) Billingsley, K. L.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358. (c) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 3484. (d) Tyrell, E.; Brookes, P. Synthesis 2003,
469.
(6) For some representative examples of the coupling of five-membered
2-heteroaromatic boronic acids, see: (a) Kabri, Y.; Gellis, A.; Vanelle, P.
Eur. J. Org. Chem. 2009, 24, 4059. (b) Gill, G. S.; Grobelny, D. W.;
Chaplin, J. H.; Flynn, B. L. J. Org. Chem. 2008, 73, 1131. (c) Organ, M.;
C¸ alimsiz, S.; Sayah, M.; Hoi, K.; Lough, A. Angew. Chem., Int. Ed. 2009,
48, 2383. (d) Dang, Y.; Chen, Y. J. Org. Chem. 2007, 72, 6901. (e) Maeda,
H.; Haketa, Y.; Nakanishi, T. J. Am. Chem. Soc. 2007, 129, 13661. (f)
James, C. A.; Coelho, A. L.; Gevaert, M.; Forgione, P.; Snieckus, V. J.
Org. Chem. 2009, 74, 4094.
(7) 2-heterocyclic MIDA boronates were successfully employed for SMCs (see
ref 4a), but polyfluorophenyl MIDA boronates were not described. MIDA
) N-methyliminodiacetic acid.
(8) Yamamoto, Y.; Takizawa, M.; Yu, X.; Miyaura, N. Angew. Chem., Int.
Ed. 2008, 47, 928.
(9) Polyfluorophenyl BF3K salts were coupled to 4-bromobenzonitrile:
Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
(10) Coupling of 2-heterocyclic BF3K salts: Molander, G. A.; Canturk, B.;
Kennedy, L. E. J. Org. Chem. 2009, 74, 973.
(11) The hydrolysis of BF3K salts to the free boronic acid likely occurs prior to
cross-coupling: Butters, M.; Harvey, J. N.; Jover, J.; Lennox, A. J. J.; Lloyd-
Jones, G. C.; Murray, P. Angew. Chem., Int. Ed. 2010, 49, 5156.
(12) (a) Chen, J.; Cammers-Goodwin, A. Tetrahedron Lett. 2003, 44, 1503. (b)
Korenaga, T.; Kosaki, T.; Fukumura, R.; Ema, T.; Sakai, T. Org. Lett.
2005, 7, 4915. (c) Adonin, N. Y.; Babushkin, D. E.; Parmon, V. N.; Bardin,
V. V.; Kostin, G. A.; Mashukov, V. I.; Frohn, H. Tetrahedron 2008, 64,
5920.
(13) It should be mentioned that with copper or palladium catalysts, aryl bromides
and chlorides can be directly coupled to polyfluorobenzenes via C-H
activation processes, but high temperatures and long reaction times are
required. (a) Lafrance, M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097.
(b) Do, H.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
(14) Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics 2007, 26,
2183.
a Reagents and conditions: ArX (1 mmol), ArB(OH)2 (1.5 mmol), 13
(2 mol %), degassed THF (2 mL), degassed 0.5 M aq K3PO4 (4 mL), rt
or 40 °C, 30 min or 2 h; isolated yields, average of two runs.
(15) The reductive elimination of 4-methoxy-2′,6′-difluorobiphenyl from an
isolated Pd(II) complex has been reported: Osakada, K.; Onodera, H.;
Nishihara, Y. Organometallics 2005, 24, 190.
with a wide range of aryl (pseudo)halides possible. The rate increase
in comparison to that of typical SMC reactions relies on fast
generation of the catalytically active species from an easy-to-
prepare, air- and moisture-stable precatalyst.
(16) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130,
6686.
(17) Albert, J.; Granell, J.; Zafrilla, J.; Font-Bardia, M.; Solans, X. J. Organomet.
Chem. 2005, 690, 422.
Acknowledgment. We thank the NIH for financial support of
this project (GM46059) and BASF for a gift of palladium
compounds. T.K. thanks the Alexander von Humboldt Foundation
for a Feodor Lynen postdoctoral fellowship. We also thank Dr.
Jaclyn Henderson for assistance with some experiments. The Varian
NMR instrument used was supported by the NSF (Grants CHE
9808061 and DBI 9729592).
(18) The rate of the SMC reaction under the described conditions decreases in
the order ArCl > ArBr > ArI. This order is reproduced in stoichiometric
transmetalation studies starting from oxidative-addition complexes. Fur-
thermore, we found an inhibiting effect on the transmetalation rate by
additional halide ions, in the order I- > Br- > Cl-.
(19) The deboronation rates of some polyfluorophenylboronic acids in a D2O/
pyridine mixture at elevated temperatures were reported: Frohn, H.; Adonin,
N. Y.; Bardin, V. V.; Starichenko, V. F. Z. Anorg. Allg. Chem. 2002, 628,
2834.
(20) Apparent relative transmetalation rates were determined by competition
experiments using an excess of a mixture of 2-methoxyphenylboronic acid
and a second boronic acid with 4-chloroanisole as substrate in the presence
of 20 mol % 13. The obtained product ratios were normalized to the product
ratio found for the competition experiment between 2-methoxyphenylbo-
ronic acid and phenylboronic acid. To ensure that the measured values
reflect the transmetalation of the free boronic acids and not of boronic acid
anhydrides or boroxines present in the starting material, we modified the
experiment involving phenylboronic acid by premixing the boronic acid
mixture with aqueous K3PO4 solution prior to addition of the precatalyst
and aryl chloride, and we found the same ratio of products as before.
(21) The attempted coupling of 2,3,6-trifluorophenylboronic acid with 4-chlo-
roacetophenone under microwave irradiation led exclusively to the debo-
ronated compound, trifluorobenzene: Clarke, M. L.; France, M. B.; Fuentes,
J. A.; Milton, E. J.; Roff, J. R. Beilstein J. Chem. 2007, 3, 18.
Supporting Information Available: Complete refs 4a and 4b,
experimental procedures, and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3427.
(b) Miyaura, N. J. Organomet. Chem. 2002, 653, 54. (c) Miyaura, N. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., de Meijere, A.,
Eds.; Wiley-VCH: New York, 2004.
(2) Both base- and metal-catalyzed deboronation of boronic acids may occur
under typical SMC reactions. (a) Kuivila, H. G.; Reuwer, J. F.; Mangravite,
J. A. Can. J. Chem. 1963, 41, 3081. (b) Kuivila, H. G.; Reuwer, J. F.;
Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666.
JA1073799
9
J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010 14075