Palladium-catalyzed Suzuki-Miyaura coupling of pyridyl-2-boronic esters with aryl halides using highly active and air-stable phosphine chloride and oxide ligands

Article abstract of DOI:10.1021/ol802642g

(Chemical Equation Presented) The palladium-catalyzed Suzuki-Miyaura coupling of pyridyl-2-boronic esters provided an efficient approach to useful biaryl building blocks containing a 2-pyridyl moiety. The convenient reaction protocol demonstrates its pote

Full text of DOI:10.1021/ol802642g

ORGANIC
LETTERS
2009
Vol. 11, No. 2
381-384
Palladium-Catalyzed Suzuki-Miyaura
Coupling of Pyridyl-2-boronic Esters
with Aryl Halides Using Highly Active
and Air-Stable Phosphine Chloride and
Oxide Ligands
David X. Yang,† Steven L. Colletti,† Kevin Wu,‡ Maoying Song,‡ George Y. Li,*,‡
and Hong C. Shen*,†
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065-0900, and CombiPhos Catalysts, Inc.
P.O. Box 220, Princeton, New Jersey 08542
george.y.li@combiphos.com; hong_shen@merck.com
Received November 15, 2008
ABSTRACT
The palladium-catalyzed Suzuki-Miyaura coupling of pyridyl-2-boronic esters provided an efficient approach to useful biaryl building blocks
containing a 2-pyridyl moiety. The convenient reaction protocol demonstrates its potentially wide applications in medicinal chemistry.
As one of the most powerful C-C bond formation methods,
the Suzuki-Miyaura coupling, has been routinely practiced
in medicinal and processs chemistry, leading to a wide range
of drugs and clinical candidates.1 Despite the tremendous
progress in this arena, Suzuki-Miyaura coupling reactions
of 2-substituted nitrogen-containing heteroaryl boronic acids
or esters with aryl or heteroaryl halides are extremely
challenging. The most prevalent side reactions are protode-
boronation and dimerization, thus prohibiting reasonable
yields of the desired coupling products. In the literature, aryl
iodides have been reported to couple with 2-pyridinyl boronic
acids/esters only leading to low yields of coupling products.2
Efforts to circumvent this problem have focused on utilizing
alternate C-B precursors, including the use of 2-pyridyl N,N-
diethanolamine boronate esters,3 cyclic triolborates,4 and
lithium triisopropyl 2-pyridylborates5 as nucleophiles to
construct biaryl systems containing a 2-pyridyl moiety. These
methods however are limited in terms of reaction scope and/
or the accessibility of the boron-containing reagent since they
must first be prepared from either the boronic acid or
halopyridine precursors, and in the case of halopyridine
(2) For selected examples, see: (a) Shinozuka, T.; Shimada, K.; Matsui,
S.; Tamane, T.; Ama, M.; Fukuda, T.; Taki, M.; Takeda, Y.; Otsuka, E.;
Yaato, M.; Naito, S. Bioorg. Med. Chem. 2006, 14, 6807. (b) Bouillon, A.;
Lancelot, J.-C.; Sopkova de Oliveira Santos, J.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2003, 59, 10043. (c) Mandolesi, S. D.; Vaillard, S. E.;
Podesta´, J. C.; Rossi, R. A. Organometallics 2002, 21, 4886. (d) Sind-
khedkar, M. D.; Mulla, H. R.; Wirth, M. A.; Cammers-Goodwin, A.
Tetrahedron 2001, 57, 2991. (e) Deshayes, K.; Broene, R. D.; Chao, I.;
Knobler, C. B.; Diederich, F. J. Org. Chem. 1991, 56, 6787.
(3) (a) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685.
(b) Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239.
(4) Yamamoto, Y.; Takiawa, M.; Yu, X.-Q.; Miyaura, N. Angew. Chem.,
Int. Ed. 2008, 47, 928.
† Merck & Co., Inc.
‡ CombiPhos Catalysts, Inc.
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV 1995, 95,
2457. (b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (c) Bellina, F.;
Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419. (d) Tyrell, E.; Brookes, P.
Synthesis 2004, 4, 469. (e) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(5) Billinsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
4695.
10.1021/ol802642g CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society

precursors conditions are required that are not compatible
with base-sensitive functional groups. In an attempt to
develop a convenient protocol that utilizes commercially
readily available 2-hetereoaryl boronic esters for the
Suzuki-Miyaura reaction, we were interested in exploring
the use of highly active and air-stable palladium phosphine
oxide and chloride complexes developed originally by
Dupont and currently commercially available from Combi-
phos (Figure 1).6
utility in various C-C, C-N, and C-S bond-forming
reactions.6 Using dioxane as the solvent, these catalysts
were found to give moderate yields of 4a (Table 1, entries
5-8). As advantageous water could be detrimental by
facilitating protodeboronation, aqueous base solutions
were therefore avoided for this type of reaction. The use
of i-PrOH to replace dioxane dramatically improved the
yield (Table 1, entry 9 vs entry 5) and turned out to be
the best solvent for this system in comparison with
methanol, tert-butanol, toluene, DME, or dioxane (data
not shown). Although KF, K2CO3, and K3PO4 all gave
moderate yields, CsF and Cs2CO3 are the best bases for
this transformation (Table 1, entries 9-13). In contrast,
the use of NaHCO3 or Na2CO3 led to only trace amounts
of product 4a (Table 1, entries 14 and 15). It should be
noted that solvents were used directly from commercial
sources without drying or degassing. All reagents were
weighed in air, and there is no need to degass the reaction
mixture. Typically a nitrogen-flushed reaction tube is
employed as the reaction vessel. Thus this appears to be
a very convenient procedure for the Suzuki-Miyaura
coupling of this type of 2-pyridyl nucleophiles.
Figure 1. Palladium phosphine chloride and oxide catalysts.
With optimized reaction conditions in hand for boronic
ester 3a, we then explored the scope of this reaction by using
a variety of aryl halides (Table 2).7 Reactions of both
electron-rich and electron-poor aryl halides proceeded
smoothly. More significantly, heteroaryl halides also par-
ticipated in the coupling reactions and gave moderate yields
of biheteroaryl products (Table 2, entries 5-7).
Utilizing bromobenzene 2a and 6-methoxypyridyl-2-
boronic ester 3a as substrates, only poor yields of the
desired coupling product 4a were obtained after a limited
survey of catalysts and bases that are commonly used in
the Suzuki-Miyaura reaction (Table 1, entries 1-4). The
Next we tested the Suzuki-Miyaura coupling reactions
of several pyridyl-2-boronic esters (Table 3). These
reactions generally gave moderate to good isolated yields.
It is worth noting that excellent conversions (90-100%)
were achieved for most reactions on the basis of LC/MS
data. Optimal reaction conditions are sometimes substrate-
dependent. For example, in the case of boronic esters 3b,
catalyst 1c afforded a better yield of 4j than catalyst 1a
(Table 3, entries 1 and 2). A profound additive effect was
observed in the reaction of 6-methylpyridine-2-boronic
ester 3d with bromide 2k, in which the use of 2 equiv of
lithium isopropoxide dramatically improved the yield
(Table 3 entry 5 vs entry 4).
Table 1. Effects of Catalyst, Base, and Solventa
entry
catalyst
Pd(PPh3)4
base
solvent
yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
dioxane
dioxane
n-BuOH
i-PrOH
dioxane
dioxane
dioxane
dioxane
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
11
5
Pd2dba3
Pd(OAc)2, S-Phosc K3PO4
27
17
30
25
29
27
62
64
47
48
22
<5
<5
Pd(OAc)2, S-Phos
CsF
1a
1b
1c
1d
1a
1a
1a
1a
1a
1a
1a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsF
For boronic ester 3e, dioxane appeared to be a better
solvent than isopropanol (yield <10%) by providing a 5-fold
higher yield (Table 3, entry 6). Pyridine boronic esters
containing a 6-substituted chloride or bromide underwent
chemoselective coupling reactions to give moderate yields
9
10
11
12
13
14
15
KF
K3PO4
K2CO3
Na2CO3
(6) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (b) Li, G. Y.;
Marshall, W. J. Organometallics 2002, 21, 590. (c) Wolf, C.; Lerebours,
R. J. Org. Chem. 2003, 68, 7551. (d) Wolf, C.; Lerebours, R. Org. Lett.
2004, 6, 1147. (e) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew.
Chem., Int. Ed. 2005, 44, 7216. (f) Ackermann, L.; Althammer, A. Org.
Lett. 2006, 8, 3457. (g) Wolf, C.; Ekoue-Kovi, K. Eur. J. Org. Chem. 2006,
1917.
NaHCO3 i-PrOH
a General procedure unless otherwise noted: To a resealable tube were added
aryl bromide (1 equiv), boronic ester (1.2 equiv), base (2 equiv), solvent, and
catalyst (3 mol %). The resealable tube was then heated at 90 °C over 18 h.
b Isolated yield. c S-phos ) 2-dicyclohexyl phosphino-2′,6′-dimethoxybiphenyl.
(7) General Procedure. To a sealed tube were added aryl bromide
(1 equiv), boronic ester (1.2 equiv), base (2 equiv), solvent, and catalyst
(3 mol %). The sealed tube was then heated at 90 °C over 18 h. After
1 h, to the mixture were added dichloromethane and water. The organic
layer was concentrated and purified by silica gel chromatography eluting
with ethyl acetate and hexanes to give the desired product.
palladium phosphine oxide and chloride complexes were
also tested because of their air-stability, good activity, and
382
Org. Lett., Vol. 11, No. 2, 2009

Table 2. Reactions of Aryl Halides with
6-Methoxypyridyl-2-boronic Ester 3aa
Table 3. Reactions of Pyridyl-2-boronic Estersa
a General procedure unless otherwise noted: To a resealable tube were
added aryl bromide (1 equiv), boronic ester (1.2 equiv), base (2 equiv),
solvent, and catalyst 1a (3 mol %). The sealed tube was then heated at 90
°C over 18 h. b Isolated yield. c 2 equiv of boronic ester and 3 equiv of
base were used.
of desired coupling products with 6-subsituted halides intact
(Table 3, entries 3 and 7).
As for the substrate scope of pyridine-2-boronic esters
lacking a 6-substituent, the reaction yields were low under
the conditions described in Table 1 (<10%). The addition
of lithium tert-butoxide (Table 3, entries 9 and 10) or
lithium isopropoxide (Table 3, entry 11) boosted the
reaction yield to a moderate range.8
As an example of a medium scale reaction, 1 g of
boronic ester 3b (1.2 equiv) coupled with aryl bromide
2k with a low loading of catalyst 1c (0.5 mol %) (Scheme
1). This reaction gave almost quantitative yield of 4r. To
our knowledge, this is the most efficient catalytic system
for this type of Suzuki-Miyaura reaction, regarding
catalyst loading.
a General procedure unless otherwise noted: To a resealable tube
were added aryl bromide (1 equiv), boronic ester (2 equiv), CsF (2 equiv),
solvent, and catalyst 1a (3 mol %). The resealable tube was then heated
at 90 °C over 18 h. b Isolated yield. c 1c (3 mol %) was used as the
catalyst. d Reaction was run in dioxane with 2 equiv of i-PrOLi and 3
equiv of CsF at 90 °C. e Reaction was run with 1c (3 mol %) in dioxane
at 105 °C for 18 h. f Reaction was run in dioxane with 2 equiv of
t-BuOLi, 3 equiv of CsF, and 1c (3 mol %) at 90 °C for 14 h. The
isolated yield of 4p is 36% using 50 mg of boronic ester and 60% using
1 g of boronic ester. g Reaction was run with 1.2 equiv of 3h in
isopropanol with 2 equiv of t-BuOLi and POPd-mix (3 mol %) at 90 °C
for 12 h.
In conclusion, we have developed a method for the
challenging cross-coupling reactions of pyridyl-2-boronic
esters with aryl halides using palladium phosphine chloride
and oxide catalysts (1a-d). The major advantage of these
catalysts is their air- and heat-stability, which make a low
catalyst loading possible. Bases and solvents were found
to play a profound role in the reaction outcome. Lastly,
(8) In ref 5, Buchwald and Billinsley utilized lithium triisopropyl
2-pyridylborates. Presumably similar lithium borate species were formed
in situ here from boronic esters and lithium alkoxides.
Org. Lett., Vol. 11, No. 2, 2009
383

The full scope and limitation of this chemistry, as well
as mechanistic studies, will be elaborated in due course.
Scheme 1
Acknowledgment. We thank Dr. Yongkui Sun for
helpful discussions.
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data or new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
the convenient benchtop procedures allow access to biaryl
systems containing one or two heteroaryl groups, which
can be readily incorporated into drug discovery programs.
OL802642G
384
Org. Lett., Vol. 11, No. 2, 2009