A solution to the 2-pyridyl organometallic cross-coupling problem: Regioselective catalytic direct arylation of pyridine N-oxides

Article abstract of DOI:10.1021/ja056800x

Direct arylation reactions of pyridine N-oxides occur in excellent yield with complete selectivity for the 2-position with a wide range of aryl bromides. This reactivity permits the use of inexpensive, commercially available, and bench-stable pyridine N-oxides as replacements for problematic 2-metallapyridines in palladium-catalyzed cross-coupling reactions. Copyright

Full text of DOI:10.1021/ja056800x

Published on Web 11/30/2005
A Solution to the 2-Pyridyl Organometallic Cross-Coupling Problem:
Regioselective Catalytic Direct Arylation of Pyridine N-Oxides
Louis-Charles Campeau, Sophie Rousseaux, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received October 5, 2005; E-mail: keith.fagnou@science.uottawa.ca
Table 1. Regioselective Direct Arylation of Pyridine N-Oxidesa
While transition metal catalyzed cross-couplings have been
successfully employed with a wide range of halides and organo-
metallics,1 some substrate classes still pose significant challenges.
This is the case with 2-pyridyl organometallics, whose frequent
instability and difficult synthesis severely limits their application.
For example, while the coupling of 2-halopyridines with aryl
boronic acids is well precedented,2 the inherent instability of
2-pyridyl boronic acid makes successful cross-couplings with this
nucleophile rare.3 Given the importance of 2-arylpyridines in
materials4 and medicinal chemistry,5 the development of a readily
available, bench-stable replacement for 2-pyridyl organometallics
in cross-coupling reactions would find significant use in the
preparation of this class of molecule.
In recent years, direct arylation has emerged as an attractive
alternative to typical cross-coupling reactions.6 In direct arylation,
one of the preactivated cross-coupling partners (typically the
organometallic species) is replaced by an unfunctionalized arene.
Consistent with an electrophilic aromatic substitution (SEAr)
pathway, electron-rich heterocyclic arenes have been featured
prominently in recent developments.7 While some simple arenes
can now be used,8,9 direct arylation reactions with π-electron-
deficient heteroarenes, such as pyridine, remain a challenging goal.10
Herein we report the use of pyridine N-oxides as commercially
available (or easily prepared),11 inexpensive, bench-stable replace-
ments for problematic 2-metallapyridines. Direct arylation reactions
of pyridine N-oxides occur in excellent yield with complete
selectivity for the 2-position with a wide range of aryl bromides
(eq 1).
a Conditions: aryl halide (1 equiv), pyridine N-oxide (4 equiv), K2CO3
(2 equiv), Pd(OAc)2 (0.05 equiv), and PtBu3-HBF4 (0.15 equiv) in toluene
(0.3 M) at 110 °C overnight. b Isolated yields. c With 3 equiv of 1a. d With
2 equiv of 1a. e With 1 equiv of 1a.
Reaction development was carried out with pyridine N-oxide and
4-bromotoluene. From these studies, palladium acetate in combina-
tion with tri-tert-butylphosphine (added to the reaction mixture as
the commercially available and air-stable HBF4 salt) emerged as
the optimal metal-ligand combination. Potassium carbonate was
deemed the optimal base, and toluene the optimal solvent.12 The
reactions are run under quite concentrated conditions (0.3 M), with
2-4 equiv of pyridine N-oxide. Under these conditions (4-
bromotoluene, 2-4 equiv of pyridine N-oxide, 5 mol % of Pd-
(OAc)2, 15 mol % of PtBu3‚HBF4, 2 equiv of K2CO3 in toluene at
110 °C), 2-tolylpyridine N-oxide is obtained in 91% isolated yield
exclusively as one regioisomer (Table 1, entry 1).13 While 4 equiv
of the N-oxide are not required, under the present conditions, a
decrease to 1 equiv leads to diminished yields (entries 2-8).
Importantly, when 1 equiv of 1a is employed, greater than 95% of
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C O M M U N I C A T I O N S
Table 2. Deoxygenation of 2-Arylpyridine N-Oxidesa
reduced to the free pyridine via palladium-catalyzed hydrogenolysis.
Preliminary mechanistic probes indicate that an SEAr mechanism
is not operative. Given the ready availability and low cost associated
with the use of pyridine N-oxides, these reactions should find
significant use in the preparation of these types of molecules and
provide a useful alternative to the problematic use of 2-pyridyl
organometallics in cross-coupling reactions.
R
R
′
yield (%)
R
R
′
yield (%)
H
H
4-CH3
3-OMe
95
87
4-OMe
H
4-CH3
4-CO2CH3
84
87
Acknowledgment. We thank NSERC, the Canada Foundation
for Innovation, the Ontario Innovation Trust, and the University
of Ottawa, the Ontario government (PREA, K.F.), and the Research
Corporation (Cottrell Scholar Award, K.F.) for support of this work.
L.-C.C. thanks the Canadian government for a NSERC-PGS D
scholarship. S.R. thanks NSERC for a summer undergraduate
scholarship.
a Conditions: pyridine N-oxide (1 equiv), Pd/C (0.1 equiv), HCOONH4
(10 equiv), MeOH (0.2 M), room temperature.
the unreacted N-oxide can be recovered by silica gel chromatog-
raphy, demonstrating that oxide decomposition is not occurring.
Illustrative examples of the reaction scope are included in Table
1. (Caution: Pyridine N-oxides have been shown to exothermically
decompose at very high temperature.14 Uncontrolled heating of the
reaction media should be avoided.) A variety of substitution types
and positions can be employed in these transformations. Both
electron-rich (entries 6-8 and 11) and electron-poor (entries 12
and 13) aryl bromides are compatible, as are more sterically
encumbered ortho-substituted arenes (entries 9 and 10).15 The effect
of substitution on the pyridine N-oxide has also been examined.
The presence of both electron-donating and -withdrawing groups
is tolerated, as exemplified by the successful coupling of both
4-methoxy and 4-nitropyridine N-oxide (entries 14 and 15). In
contrast to reactions performed with many types of organometallics,
these reactions are completely insensitive to the presence of water
since 5 equiv of water added at the reaction outset has no deleterious
impact on the reaction outcome. The 2-arylpyridine N-oxide
products can easily be converted to the corresponding 2-aryl
pyridines under mild conditions and in high yield via palladium-
catalyzed reduction with ammonium formate (Table 2).16
The SEAr mechanism has the strongest experimental support in
direct arylation reactions.7 Since pyridine N-oxides are known to
react via SEAr in other reactions,17 a competition experiment was
performed to determine if this pathway was operative. Under the
standard conditions, 4-bromotoluene was reacted in the presence
of both electron-deficient 4-nitropyridine N-oxide 3 and electron-
rich 4-methoxypyridine N-oxide 4 (eq 2). In stark contrast to direct
arylation reactions, which typically react preferentially with the
more electron-rich substrate,7 the only product detected by 1H NMR
analysis of the crude reaction mixture was 5, arising from reaction
of the more electron-deficient pyridine N-oxide. In another reaction,
3 equiv of pyridine and pyridine-d5 N-oxides was reacted in one
pot, revealing an intermolecular primary KIE of 4.7. These results
are incompatible with an SEAr mechanism, and we are currently
working to elucidate the mode of direct arylation of these molecules.
Supporting Information Available: Experimental procedures and
spectroscopic characterization of all new products (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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