A general and efficient method for the Suzuki-Miyaura coupling of 2-pyridyl nucleophiles

Article abstract of DOI:10.1002/anie.200801465

(Chemical Equation Presented) One of the most general systems for the cross-coupling of aryl and heteroaryl bromides and chlorides with 2-pyridyl-derived nucleophiles has been developed, for which catalysts comprising [Pd₂(dba)₃] and either diaryl (1) or dialkyl phosphine oxide (2) supporting ligands were found to be ideal (see scheme).

Full text of DOI:10.1002/anie.200801465

Angewandte
Chemie
DOI: 10.1002/anie.200801465
Cross-Coupling Reactions
A General and Efficient Method for the Suzuki–Miyaura Coupling of
2-Pyridyl Nucleophiles**
Kelvin L. Billingsley and Stephen L. Buchwald*
The Suzuki–Miyaura reaction has become one of the most
valuable synthetic processes for the construction of carbon–
carbon bonds,[1] and our laboratory has developed many
highly active catalyst systems that efficiently process chal-
lenging combinations of aryl halides and boronic acids.[2]
Recently, we have been able to extend our methodology to
the cross-coupling of heteroaryl boronic acids and esters,
Scheme 1. Effective phosphite and phosphine oxide ligands.
which serve as important building blocks for the assembly of
biologically active molecules.[3,4] However, 2-substituted
nitrogen-containing heteroaryl organoboranes, which are of
Table 1: The effects of the base and nucleophile.[a]
importance for the construction of numerous natural products
and pharmaceutically interesting compounds,[5] were not
effectively transformed by using our standard conditions.
Further examination of the literature indicated that only a
few reports of the Suzuki–Miyaura reaction of 2-pyridyl
nucleophiles with aryl halides have appeared, and in these
examples, only aryl iodides have been demonstrated as
À
Entry Ar BR3
Base
GC Yield [%] Conversion [%]
suitable coupling partners.[3,6–10] The difficulty can be attrib-
uted to several factors: 1) Electron-deficient heteroaryl boron
derivatives undergo transmetalation at a relatively slow rate,
and 2) these reagents rapidly decompose by a protodeboro-
nation pathway.The lack of an efficient method to process
this class of nucleophiles led us to develop a technique
specifically designed to accomplish this transformation.
We found that catalysts based upon phosphite or phos-
phine oxide ligands (1–4) were highly active for the Suzuki–
Miyaura reaction of 2-pyridyl boron derivatives with 1-
bromo-4-butylbenzene (Scheme 1).The use of these has
been pioneered by the work of Li, and elegant applications by
Ackermann and Wolf have appeared more recently.[11] How-
ever, the reaction remained sensitive to the nature of the
nucleophile and base.For example, the reaction of commer-
cially-available reagents, such as 2-pyridyl boronic acid,[6]
pinacol boronate ester,[7] or N-phenyl diethanolamine boro-
nate ester,[8] with 4-n-butylbromobenzene produced low
yields of the desired biaryl product (Table 1, entries 1–3).
Similarly, attempts to use organotrifluoroborates resulted in a
1
KF
NaOtBu
0
8
<10
36
2
3
KF
0
<10
73
NaOtBu 49
KF
6
43
100
NaOtBu 15
4
5
KF
NaOtBu 10
KF 85
NaOtBu 68
0
<10
37
100
100
low conversion of the aryl bromide (Table 1, entry 4).[9]
Although 2-pyridylborates have been used in Suzuki–
Miyaura reactions, the cross-coupling processes result in
only poor to modest yields of the desired biaryl product.[12]
However, when lithium triisopropyl 2-pyridylborate (A) was
employed as the nucleophile, the desired product could be
obtained in 85% yield with 100% conversion of the aryl
halide (Table 1, entry 5).Although A is not yet commercially
available, it is stable under an argon atmosphere for up to a
month, and it can be prepared in near quantitative yield from
2-bromopyridine by lithium–halogen exchange and immedi-
ate in situ quenching of the resulting anion with triisopro-
pylborate.[13] In addition, A can be prepared in multigram
quantities in excellent yield (Scheme 2).Lithium triisopropyl
2-(6-methoxypyridyl)borate (B) and lithium triisopropyl 2-(5-
fluoropyridyl)borate (C) were also prepared by employing
this protocol in 90% and 96% yield, respectively.Similarly,
under these conditions, 2-bromopyridines possessing a pro-
[*] K. L. Billingsley, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (GM 46059) for support
of this work. We are grateful to Merck, Amgen, and Boehringer
Ingelheim for additional support. The Varian NMR instruments
used in this work were purchased with funding from the NSF (CHE
9808061 and DBI 9729592).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801465.
Angew. Chem. Int. Ed. 2008, 47, 4695 –4698
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4695

Communications
Table 2: The reaction of A–D with aryl bromides.[a]
Entry
1
Borate
Ligand
Product
Yield [%][b]
85
A
1
2
3
4
A
A
A
1
1
1
82
74
87
Scheme 2. Synthesis of lithium triisopropyl 2-pyridylborates.
tected aldehyde (D) or a nitrile (E) could be efficiently
transformed to the corresponding borates.[14]
A catalyst based upon [Pd2(dba)3]/1 proved to be highly
effective for the Suzuki–Miyaura reactions of A with aryl and
heteroaryl bromides.For example, this system efficiently
combined 3,5-(bistrifluoromethyl)bromobenzene (Table 2,
entry 2) and 4-bromoanisole (Table 2, entry 3) with A to
furnish the desired biaryl in 82% and 74% yield, respectively.
In addition, ortho-substituted aryl bromides were coupled in
good to excellent yields (Table 2, entries 4 and 5).Heteroaryl
bromides were also suitable coupling partners as seen in the
reactions of A with 5-bromopyrimidine (Table 2, entry 6) and
4-bromoisoquinoline (Table 2, entry 7) which resulted in a
91% and 82% yield, respectively, of the desired heterobiaryl
compound.Utilizing a [Pd 2(dba)3]/2 catalyst, a range of
lithium triisopropyl 2-pyridylborates possessing functional
groups were successfully cross-coupled with aryl bromides.
Indeed, this catalyst system allowed the reaction of B and C
with a variety of electron-poor, -neutral, -rich, and ortho-
substituted aryl bromides (Table 2, entries 9–12).In addition,
the reaction of 4-bromobenzonitrile and D furnished the
desired biaryl in 63% yield (Table 2, entry 13).However, the
cross-coupling reactions utilizing E resulted in incomplete
conversion in its reaction with a variety of aryl bromides.We
attributed this difficulty to the relatively slow rate of trans-
metalation of the highly electron-deficient 2-pyridylborate.
Overall, however, this protocol still represents the most
general available method for the Suzuki–Miyaura reaction of
2-pyridyl nucleophiles with aryl or heteroaryl bromides.
Despite the efficacy of the [Pd2(dba)3]/1 catalyst system
for the reactions of lithium triisopropyl 2-pyridylborates with
aryl bromides, more modest yields of the desired biaryls were
obtained in the reactions of the corresponding aryl or
heteroaryl chlorides.Employing 2 as the supporting ligand,
however, provided a more active catalyst for this trans-
formation.For example, the reaction of A with 4-chloroben-
zonitrile furnished the desired product in 73% yield (Table 3,
entry 1).In addition, unactivated aryl chlorides were effi-
ciently coupled as the reactions of 4-n-butylchlorobenzene
(Table 3, entry 2) and 4-chloroanisole (Table 3, entry 4) with
A resulted in a 76% and 78% yield, respectively, of the
desired product.Similarly, under these conditions, ortho-
5
6
A
A
1
1
90
91
7
A
1
82
8
9
A
B
1
2
73
90[c]
10
11
B
C
2
2
61[c]
65[c]
12
13
C
2
1
40[c]
63[c]
D
[a] Reaction conditions: 1 equiv of aryl or heteroaryl bromide, 1.5 equiv
of 2-pyridylborate, 3.0 equiv of KF, dioxane (3 mLmmolÀ1 halide), cat.
[Pd2(dba)3], L:Pd=3:1. [b] Yield of isolated product based upon an
average of two runs. [c] 1.5% [Pd2(dba)3] used instead of 1.0%.
substituted aryl chlorides were suitable substrates; for exam-
ple, the reaction of 2-chloro-p-xylene and A gave the desired
product in 70% yield (Table 3, entry 3).In addition, a
heteroaryl chloride, 3-chloropyridine, was coupled with A in
an excellent yield to give o,m-bipyridine (Table 3, entry 6).
In summary, we have developed an efficient method for
the Suzuki–Miyaura reaction of lithium triisopropyl 2-pyr-
idylborates.The borates can be readily prepared in one step
from the corresponding 2-bromo- or 2-iodopyridine deriva-
4696 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4695 –4698

Angewandte
Chemie
Table 3: The reaction of A and B with aryl chlorides.[a]
À
Keywords: C C coupling · nitrogen heterocycles · palladium ·
Suzuki–Miyaura coupling
.
[1] Recent reviews: a) N.Miyaura, Top. Curr. Chem. 2002, 219, 11 –
59; b) F.Bellina, A.Carpita, R.Rossi, Synthesis 2004, 15, 2419;
c) N.Miyaura in Metal-Catalyzed Cross-Coupling Reaction
(Eds.: F. Diederich, A. de Meijere), Wiley-VCH, New York,
2004, chap.2.
Entry
1
Borate
Product
Yield [%][b]
73
[2] T.E. Barder, S.D. Walker, J.R. Martinelli, S.L. Buchwald,
J.
Am. Chem. Soc. 2005, 127, 4685 – 4696.
A
[3] For a review of the Suzuki–Miyaura reaction of heteroaryl
nucleophiles, see: E.Tyrell, P.Brookes, Synthesis 2004, 4, 469 –
483.
2
3
A
A
76
70
[4] K.L.Billingsley, S.L.Buchwald,
3358 – 3366.
J. Am. Chem. Soc. 2007, 129,
[5] a) CM. .Richardson, RJ..Gillespie, DS. .Williamson, AM. .
Jordan, A.Fink, A.R.Knight, D.M.Sellwood, A.Misra, Bioorg.
Med. Chem. Lett. 2006, 16, 5993 – 5997; b) F.Gellibert, A-.C.
De Gouville, J.Woolven, N.Mathews, V-.L.Nguyen, C.Bertho-
4
5
6
A
A
A
78
57
92
Ruault, A.Patikis, E.T.Grygielko, N.J.Laping, S.Huet,
J. Med.
Chem. 2006, 49, 2210 – 2221; c) I.Salama, C.Hocke, W.Utz, O.
Prante, F.Boeckler, H.Huebner, T.Kuwert, P.Gmeiner, J. Med.
Chem. 2007, 50, 489 – 500; d) K.M. Meyers, N. Kim, J.L.
Mendez-Andino, X.E. Hu, R.N. Mumin, S.R. Klopfenstein,
J.A.Wos, M.C.Mitchell, J.L.Paris, D.C.Ackley, J.K.Holbert,
S.W.Mittelstadt, O.Reizes, Bioorg. Med. Chem. Lett. 2007, 17,
814 – 818; e) D.R.Anderson, M.J.Meyers, W.F.Vernier, M.W.
Mahoney, R.G.Kurumbail, N.Caspers, G.I.Poda, J.F.Schin-
7
B
76[c]
dler, D.B.Reitz, R.J.Mourey,
2654.
J. Med. Chem. 2007, 50, 2647 –
[a] Reaction conditions: 1 equiv of aryl or heteroaryl chloride, 1.5 equiv of
2-pyridylborate, 3.0 equiv of KF, dioxane (3 mLmmolÀ1 halide), cat.
[Pd2(dba)3], L:Pd=3:1. [b] Yield of isolated product based upon an
average of two runs. [c] 1.5% [Pd2(dba)3] used instead of 1.0%.
[6] For examples of Suzuki–Miyaura reactions of 2-pyridyl boronic
acids, see: a) K.Deshayes, R.D.Broene, I.Chao, C.B.Knobler,
F.Diederich, J. Org. Chem. 1991, 56, 6787 – 6795; b) M.D.
Sindkhedkar, H.R.Mulla, M.A.Wirth, A.Cammers-Goodwin,
Tetrahedron 2001, 57, 2991 – 2996; c) S.D. Mandolesi, S.E.
Vaillard, J.C. Podestµ, R.A. Rossi, Organometallics 2002, 21,
4886 – 4888; d) A.Bouillon, J-.C.Lancelot, J.Sopkova de Oli-
tives.This represents the first relatively general Suzuki–
Miyaura cross-coupling reaction of these substrates with aryl
and heteroaryl bromides and chlorides.
veira Santos, V.Collot, P.R.Bovy, S.Rault,
Tetrahedron 2003,
59, 10043 – 10049; e) T.Shinozuka, K.Shimada, S.Matsui, T.
Tamane, M.Ama, T.Fukuda, M.Taki, Y.Takeda, E.Otsuka, M.
Yamato, S.Naito, Bioorg. Med. Chem. 2006, 14, 6807 – 6819.
[7] During the development of this work, we discovered unpub-
lished results from CombiPhos Catalysts, Inc.utilizing 2-pyridyl
pinacol boronate esters.Chlorodialkyl phosphines and dialkyl
phosphine oxides were used as supporting ligands.However, we
found that 2-pyridyl pinacol boronate ester was not effectively
coupled under our conditions as seen in Table 1.
[8] For examples of Suzuki–Miyaura reactions of 2-pyridyl N,N-
diethanolamine boronate esters, see: a) P.B. Hodgson, F.H.
Salingue, Tetrahedron Lett. 2004, 45, 685 – 687; b) P.Gros, A.
Doudouh, Y.Fort, Tetrahedron Lett. 2004, 45, 6239 – 6241.
[9] For work with 2-pyridyltrifluoroborates, see: G.A.Molander, B.
Biolatto, J. Org. Chem. 2003, 68, 4302 – 4314.
Experimental Section
General procedure for the Pd-catalyzed Suzuki–Miyaura reaction of
lithium triisopropyl 2-pyridylborates with aryl bromides: An oven-
dried re-sealable Schlenk tube with a Teflon screw valve was charged
with [Pd2(dba)3] (1.0–1.5%), 1 (6.0–9.0%), lithium triisopropyl 2-
pyridylborate (0.375 mmol), and anhydrous KF (43.5 mg, 0.75 mmol).
The Schlenk tube was capped with a rubber septum and then
evacuated and backfilled with argon (this sequence was carried out an
additional time).1,4 -Dioxane (0.75 mL) was added by syringe,
through the septum, followed by the addition of the aryl halide
(0.25 mmol) in a like manner (aryl halides that were solids were
added with the other solid reagents).The septum was then replaced
with a Teflon screw valve and the Schlenk tube was sealed.The
reaction mixture was heated to 1108C until the aryl halide had been
completely consumed (as determined by gas chromatography) and
was allowed to cool to room temperature.The reaction solution was
then filtered through a thin pad of silica gel (eluting with ethyl
acetate) and the eluent was concentrated under reduced pressure.
The crude material so obtained was purified by flash chromatography
on silica gel.
[10] Y.Yamamoto, M.Takizawa, X-.Q.Yu, N.Miyaura.
Angew.
Chem. 2008, 120, 942–945; Angew. Chem. Int. Ed. 2008, 47, 928 –
931; Angew. Chem. Int. Ed. 2008, 47, 928 – 931.
[11] For selected examples of phosphine oxides ligands in carbon–
carbon bond-forming cross-coupling processes, see: a) G.Y.Li,
Angew. Chem. 2001, 113, 1561 – 1564; Angew. Chem. Int. Ed.
2001, 40, 1513 – 1516; b) G.Y.Li, W.J.Marshall, Organometal-
lics 2002, 21, 590 – 591; c) C.Wolf, R.Lerebours, J. Org. Chem.
2003, 68, 7551 – 7554; d) C.Wolf, R.Lerebours, Org. Lett. 2004,
6, 1147 – 1150; e) R.Lerebours, A.Camacho-Soto, C.Wolf,
Org. Chem. 2005, 70, 8601 – 8604; f) L.Ackermann, R.Born,
J.
Received: March 28, 2008
Published online: May 19, 2008
J.H. Spatz, D. Meyer, Angew. Chem. 2005, 117, 7382 – 7386;
Angew. Chem. Int. Ed. 2005, 44, 7216 – 7219; g) L.Ackermann,
Angew. Chem. Int. Ed. 2008, 47, 4695 –4698
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4697

Communications
A.Althammer, Org. Lett. 2006, 8, 3457 – 3460; h) C.Wolf, K.
Ekoue-Kovi, Eur. J. Org. Chem. 2006, 1917 – 1925.
[12] a) “Substituted Pyridines as Selective Cyclooxygenase-2 Inhib-
itors”: D.Dube, R.Fortin, R.Friesen, Z.Wang, J.Gauthier
(Merck Frost Canada Inc.), WO 98/03484, 1998; b) B.T.OꢀNeill,
[13] The 2-pyridylborates are somewhat air-sensitive, so they were
stored in a benchtop desiccator to prolong the lifetime of the
reagents.However, during the setup of each reaction, these
reagents were weighed out on a bench open to the air.
[14] For a related protocol for the synthesis of 3-pyridine boronic
acid, see: W.Li, D.P.Nelson, M.S.Jensen, R.S.Hoerrner, D.
Cai, R.D. Larsen, P.J. Reider, J. Org. Chem. 2002, 67, 5394 –
5397.
D.Yohannes, M.W.Bundesmann, E.P.Arnold,
Org. Lett. 2000,
2, 4201 – 4204; c) “Process for the Production of Quinazolines”:
B.Ahman, P.Hodgson, S.Lewandowski, R.Walton (Pfizer Inc.),
WO 02/094815, 2002.
4698 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 4695 –4698