A versatile method for suzuki cross-coupling reactions of nitrogen heterocycles

Article abstract of DOI:10.1002/anie.200503479

(Chemical Equation Presented) A wide-ranging study of Suzuki reactions which use nitrogen-containing heterocycles is described (see scheme; dba = dibenzylideneacetone, Cy = cyclohexyl). This method is highly versatile (a single procedure was used for all substrates, including boronate esters and trifluoroborates), compatible with a variety of unprotected functionalities (e.g., NH₂-and OH-substituted substrates), and efficient even with unactivated aryl chlorides.

Full text of DOI:10.1002/anie.200503479

Communications
achieves Suzuki cross-couplings of an array of nitrogen-
containing boronic acids and aryl halides [Eq. (1); dba =
dibenzylideneacetone, Cy = cyclohexyl].
Since 1998, we and others have established that trialkyl-
phosphines, including P(tBu)3 and PCy3, serve as very
effective ligands for a variety of palladium-catalyzed coupling
processes.[1,5] In view of the low cost of PCy3 relative to many
of the other ligands that provide highly active cross-coupling
catalysts (e.g., P(tBu)3, aryldialkylphosphines, and carbenes),
we decided to examine the possibility of developing a
versatile PCy3-based catalyst for Suzuki reactions of nitrogen
heterocycles.
Homogeneous Catalysis
DOI: 10.1002/anie.200503479
In an earlier study, we employed Pd/PCy3/KF/THF as a
catalyst system for Suzuki cross-couplings of aryl halides.[6,7]
Unfortunately, when we applied these conditions to the
coupling of 3-pyridineboronic acid with 4-n-butylchloroben-
zene, we obtained essentially none of the desired biaryl
[Eq. (2)]. After considerable exploration of the reaction
parameters, we determined that Pd/PCy3/K3PO4/dioxane/
H2O achieves the desired cross-coupling in excellent yield
[Eq. (2)].[8,9]
AVersatile Method for Suzuki Cross-Coupling
Reactions of Nitrogen Heterocycles**
Noriaki Kudo, Mauro Perseghini, and Gregory C. Fu*
The Suzuki cross-coupling reaction is a powerful method for
carbon-carbon bond formation that has been applied in a
variety of settings, ranging from natural-products synthesis to
materials chemistry, including large-scale production.[1,2]
Among the attractive features of the Suzuki reaction are
the wide availability, stability to air and moisture, and low
toxicity of boronic acids, as well as the facile removal of the
boron-containing side products of the coupling process.
In recent years, tremendous progress has been described
in the discovery of more active catalysts for the Suzuki
reaction. Arguably the most important remaining challenge is
the development of a universal method for cross-coupling
substrates that include nitrogen heterocycles.[3] The presence
of such groups, which are particularly pervasive in medicinal
chemistry,[4] can lead to low reactivity in coupling reactions.
Herein, we describe an unusually versatile catalyst that
We were pleased to find that this standard protocol can be
applied directly to Suzuki reactions of an array of nitrogen
heterocycles. As illustrated in Table 1, a variety of hetero-
arylboronic acids can even be coupled with challenging aryl
halides. Thus, 3-pyridineboronic acid reacts with a range of
chlorobenzenes, including ortho-substituted and electroni-
cally deactivated substrates, in good yield (Table 1, entries 1–
4). As might be anticipated, the corresponding aryl bromides
and iodides also couple under these conditions (Table 1,
entries 5 and 6). In addition, substituted 3-pyridineboronic
acids are suitable cross-coupling partners (Table 1, entries 7–
9). The method is effective not only for 3-pyridineboronic
acids, but also for an array of other heteroarylboronic acids
(e.g., 4-pyridine, 5-pyrimidine, and indole; Table 1,
entries 10–13).
[*] Dr. N. Kudo, Dr. M. Perseghini, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
[**] We thank Frontier Scientific for boronic acids and Johnson Matthey
for [Pd2(dba)3]. Financial support was provided by the National
Institutes of Health (National Institute of General Medical Sciences,
R01-GM62871), Merck Research Laboratories, Novartis, Sankyo-
Agro Co. Ltd. (N.K.), and Novartis Stiftung (M.P.). Funding for the
MIT Department of Chemistry Instrumentation Facility was fur-
nished in part by the National Science Foundation (CHE-9808061
and DBI-9729592).
Although substrates that bear an indole NH group
undergo Suzuki cross-coupling smoothly with this procedure
(Table 1, entry 13), the catalyst appears to be sensitive to
pyrazole NH groups (Table 1, entries 14 and 16). However,
simple protection of the nitrogen atom leads to coupling with
useful efficiency (Table 1, entries 15 and 17).[10]
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Suzuki cross-couplings of heteroarylboronic acids with unac-
tivated aryl halides [for the reaction conditions, see Eq. (1)].
Table 2: Suzuki cross-couplings of heteroarylboronic acids with hetero-
aryl chlorides and bromides [for the reaction conditions, see Eq. (1)].
Entry
Heteroarylboronic acid
Aryl halide
Yield [%][a]
92
Entry
Heteroarylboronic acid
Heteroaryl halide
Yield [%][a]
1
1
97
2
3
92
95
88
90
91
83
87
85[b]
92
72
2
93
3
4
5
98
98[b]
75
4
5
6
6
7
87
88
7
8
8
9
97
95
97
77
9
10
11
10
11
12
13
14
85
78
8
12
13
14
89
69[c]
30[c]
15
64
15
16
<2
16
17
21
92
73
[a] Yield of isolated product (average of two experiments). [b] Double
Suzuki cross-coupling(2.2 equiv of the boronic acid, 2.0% [Pd (dba)3],
4.8% PCy3, and 3.4 equiv of K3PO4 were used). [c] The Boc protecting
group was removed during the Suzuki reaction.
2
[a] Yield of isolated product (average of two experiments). [b] The
product that results from the cross-couplingof the chloride was isolated
in 10% yield.
This catalyst system is also effective for Suzuki cross-
couplings in which both of the reaction partners are nitrogen
heterocycles, thus providing the desired products in generally
good yield (Table 2). Consistent with the example illustrated
in entry 13 of Table 1, the method tolerates indole NH groups
(Table 2, entries 2 and 12). In addition, pyridines that bear
hydroxy (Table 2, entry 6) and NH2 (Table 2, entries 8 and 9)
substituents are suitable substrates. tert-Butyloxycarbonyl
(Boc) protecting groups at pyrrole and indole nitrogen
atoms are cleaved under the cross-coupling conditions
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Communications
(entries 13 and 14, respectively).[11] Protection of the pyrazole
NH group is necessary for the coupling of a 4-bromopyrazole
with 3-pyridineboronic acid (entry 15 vs. 16; see also Table 1,
entries 14–17).
Keywords: cross-coupling· heterocycles ·
homogeneous catalysis · nitrogen · palladium
.
[1]For leading references, see: a) N. Miyaura in Metal-Catalyzed
Cross-Coupling Reactions (Eds.: A. de Meijere, F. Diederich),
Wiley-VCH, New York, 2004, chap. 2; b) A. Suzuki in Hand-
book of Organopalladium Chemistry for Organic Synthesis (Ed.:
E.-i. Negishi), Wiley Interscience, New York, 2002, chap. III.2.2.
[2]For an overview, see: A. M. Rouhi, Chem. Eng. News 2004, 82,
49 – 58.
In preliminary experiments, we determined that this Pd/
PCy3/K3PO4/dioxane/H2O-based method is effective not only
for Suzuki cross-couplings of heteroarylboronic acids, but also
for boronate esters and trifluoroborates [Eq. (3)]. Finally, we
[3]For recent reports that include Suzuki reactions of nitrogen
heterocycles, see: a) T. E. Barder, S. D. Walker, J. R. Martinelli,
S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685 – 4696;
b) T. E. Barder, S. L. Buchwald, Org. Lett. 2004, 6, 2649 – 2652;
c) I. Kondolff, H. Doucet, M. Santelli, Synlett 2005, 2057 – 2061;
d) A. E. Thompson, G. Hughes, A. S. Batsanov, M. R. Bryce,
P. R. Parry, B. Tarbit, J. Org. Chem. 2005, 70, 388 – 390, and
references therein.
[4]a) For a discussion of the widespread occurrence of nitrogen
heterocycles, particularly pyridines, in pharmaceutically active
compounds, see: V. Bonnet, F. Mongin, F. Trecourt, G. Breton, F.
Marsais, P. Knochel, G. Queguiner, Synlett 2002, 1008 – 1010
(footnote 1); b) A. F. Pozharskii, A. T. Soldartenko, A.
Katritzky, Heterocycles in Life and Society, Wiley, New York,
1997.
[5]For an overview, see: J. Tsuji, Palladium Reagents and Catalysts,
Wiley, New York, 2004.
[6]A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020 –
4028; see, also: A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110,
3586 – 3587; Angew. Chem. Int. Ed. 1998, 37, 3387 – 3388.
established that the procedure can be conducted on a
multigram scale (18 mmol of 4-n-butylchlorobenzenechloride
+ 20 mmol of 3-pyridineboronic acid, yield = 3.4 g (88%) of
product).
To the best of our knowledge, this is the most wide-
ranging study that has been described for Suzuki reactions of
nitrogen-containing cross-coupling partners. Attractive fea-
tures of this method include its versatility (a single procedure
was employed for all of the examples, including boronate
esters and trifluoroborates), its compatibility with a variety of
unprotected functionalities (e.g., NH2- and OH-substituted
pyridines and unprotected indoles), its convenience (com-
mercially available components), and its efficiency even with
inexpensive, unactivated aryl chlorides. We anticipate that
this catalyst system will find application in academia and, in
particular, in industry.
[7]For an early report of the use of Pd/PCy for palladium-
3
catalyzed Suzuki reactions, see: W. Shen, Tetrahedron Lett. 1997,
38, 5575 – 5578.
[8]For an overview of the use of water as a (co)solvent for Suzuki
reactions, see: N. E. Leadbeater, Chem. Commun. 2005, 2881 –
2902.
[9]For the application of a related system to the cross-coupling of
cyclopropylboronic acid with (hetero)aryl bromides, see: D. J.
Wallace, C.-y. Chen, Tetrahedron Lett. 2002, 43, 6987 – 6990.
[10]For the Suzuki cross-coupling illustrated in entry 15 of Table 1,
deboronation is a significant side reaction.
[11]For a previous example, see: C. N. Johnson, G. Stemp, N. Anand,
S. C. Stephen, T. Gallagher, Synlett 1998, 1025 – 1027.
Experimental Section
General procedure: The heteroarylboronic acid (1.10 mmol), [Pd2-
(dba)3](9.2 mg, 0.010 mmol), and PCy (6.7 mg, 0.024 mmol) were
3
added to a 25-mL Schlenk flask equipped with a stir bar in air. The
flask was evacuated and refilled with argon five times. Dioxane
(2.67 mL), the (hetero)aryl halide (1.00 mmol; if the halide was a
solid, it was added prior to the evacuation/refill cycle), and aqueous
K3PO4 (1.27m, 1.33 mL, 1.70 mmol) were added by syringe. The
Schlenk flask was sealed and heated in an oil bath at 1008C for 18 h
with vigorous stirring. The mixture was then filtered through a pad of
silica gel (washing with EtOAc), the filtrate concentrated under
reduced pressure, and the aqueous residue extracted three times with
EtOAc. The combined extracts were dried over anhydrous MgSO4,
filtered, and concentrated. The residue was then purified by column
chromatography on silica gel.
Received: October 1, 2005
Revised: December 12, 2005
Published online: January 19, 2006
1284
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Angew. Chem. Int. Ed. 2006, 45, 1282 –1284