Site-specific phenylation of pyridine catalyzed by phosphido-bridged ruthenium dimer complexes: A prototype for C-H arylation of electron-deficient heteroarenes

Article abstract of DOI:10.1021/ja042510p

Direct and selective catalytic arylation of α-C-H bond in pyridine with iodobenzene was achieved in up to 70% yield. Phosphido-bridged bisruthenium complexes 6a and 6b arising from Ru₃(CO)₁₂ and PPh₃ were identified as active catalysts. The formation of complexes 6a and 6b was investigated, a sequence of C-H and C-P bond cleavage, cluster fragmentation, and disproportionation was established, and the intermediate ruthenium complexes lying on this pathway were isolated and fully characterized. Copyright

Full text of DOI:10.1021/ja042510p

Published on Web 02/25/2005
Site-Specific Phenylation of Pyridine Catalyzed by Phosphido-Bridged
Ruthenium Dimer Complexes: A Prototype for C-H Arylation of
Electron-Deficient Heteroarenes
Kamil Godula, Bengu¨ Sezen, and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, 3000 Broadway, New York, New York 10027
Received December 13, 2004; E-mail: sames@chem.columbia.edu
Table 1. Catalytic 2-Phenylation of Pyridinea
Functionalized azines (e.g., pyridine, pyrimidine, pyrazine) are
indispensable architectural units in the design of biologically active
compounds, pharmaceuticals, and other functional synthetics.
Although significant progress has been achieved in the development
of catalytic alkylation, alkenylation, and acylation reactions at the
pyridine nucleus,1 direct and selective C-H arylation of π-deficient
entry
catalyst
PPh3/mol %
time/h
yield/%
heteroarenes represents an unsolved challenge.2 Currently, the
preparation of aryl azines relies heavily on traditional cross-coupling
processes, such as the Suzuki3 and Stille4 couplings, which require
the establishment of proper functionalities on both coupling partners.
Herein we report a novel cross-coupling of iodobenzene and
pyridine, catalyzed by a phosphido-bridged binuclear ruthenium
complex.
1
2
3
4
5
6
7
8
Ru3(CO)12
1
2
3
4
4
2
0
0
0
0
0
18
18
18
18
18
18
18
66
36
36
41
39
32b
0
4
5a,b
6a,b
6a,b
55
70c
In the course of a systematic study, Ru3(CO)12 was identified as
a catalyst for the coupling of iodobenzene and pyridine, affording
2-phenylpyridine as the sole product in 36% yield (Table 1, entry
1). The choice of solvent and base as well as the presence of
phosphine ligand was essential for the success of this transformation.
Ru3(CO)12 has long been known to undergo the oxidative addition
of C-H bonds at the R-position of various azines5 to form hydride
clusters such as 1 (Figure 1). Recently, Moore and Murai success-
fully utilized this phenomenon to achieve catalytic acylation of
pyridine1b and other aza-heterocycles.1c However, no experimental
data were generated to gain better mechanistic understanding
beyond the intermediacy of 1. In contrast, we noted that in the
present arylation system neither Ru3(CO)12 nor complex 1 was the
catalytically active species. Consequently, we initiated a detective
effort to identify the active catalyst via both the isolation work and
independent synthesis.
a Conditions: Pyridine (1 equiv), iodobenzene (1 equiv), Cs2CO3
(1.2 equiv), catalyst (2 mol %), PPh3, t-BuOH, c ) 0.52 M, 100 °C 0.5 h,
110 °C 0.5 h, 150 °C 17 h. b 30% of catalyst recovered. c 5 mol % of catalyst
employed. Yields are an average of at least two trials with an error
within (3%.
Fast consumption of Ru3(CO)12 and formation of a set of new
ruthenium complexes were observed at temperatures ranging
between 80 and 110 °C, before the catalytic system reached the
reaction temperature of 150 °C. The stoichiometric experiments
with Ru3(CO)12 in the absence of iodobenzene revealed a series of
transformations, leading to the formation of bisruthenium species
4 and byproduct 5 (Figure 1). Initially, Ru3(CO)12 was converted
to hydride 2 in the presence of an excess of pyridine and 1 equiv
of PPh3 at 100 °C. This occurs through oxidative addition of the
pyridine C-H bond and the carbonyl-phosphine exchange,
presumably in either order. One sequence was illustrated by an
independent synthesis of complex 2 from 1 (Figure 1, conditions
b). Complex 2 was subsequently converted to a bisphosphine
complex 3 by the action of another equivalent of PPh3 with
concomitant release of CO. The latter complex underwent an
intriguing fragmentation in the presence of Cs2CO3 at 110 °C to
furnish phosphido-bridged bisruthenium complex 4, presumably via
P-C bond cleavage of one of the phosphine ligands, followed by
the loss of 1 equiv of benzene and double Ru-Ru bond cleavage.5b,6
The byproduct was identified as an inseparable mixture of bishy-
dride triruthenium cluster 5a and its C2 symmetrical isomer 5b, in
Figure 1. Generation of ruthenium dimer 4. All complexes were fully
characterized by NMR, IR, and MS spectroscopy and by elemental analysis.
X-ray crystallographic data were obtained for complexes 2, 4, and 5.
Conditions: (a) PPh3 (1 equiv), pyridine (8 equiv), t-BuOH, 100 °C, 95%.
(b) PPh3 (1 equiv), t-BuOH, 100 °C, 98%. (c) PPh3 (1 equiv), t-BuOH,
100 °C, 52%. (d) Cs2CO3 (1.5 equiv), t-BuOH, 110 °C, 36% of 4, and
10% of 5a,b. (e) PPh3 (1 equiv), Cs2CO3 (1.5 equiv), t-BuOH, 100 °C
(1 h) then 110 °C, 33% of 4 after two steps.
which the nitrogen atoms of both pyridine rings are coordinated to
the same ruthenium center.
Indeed, complexes 4, 5a, and 5b were detected under the catalytic
conditions and, hence, were tested separately for the catalytic
activity. While 4 catalyzed the cross-coupling of pyridine with
iodobenzene (Table 1, entry 5), the mixture of 5a and 5b was
inactive (entry 6). As complexes 1, 2, and 3 were also active, a
likely pathway toward 4, taking place in situ, may be constructed
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10.1021/ja042510p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
the dehydroiodination step (not shown). This simple model will
serve as the starting point for the future mechanistic and optimiza-
tion studies.
In conclusion, a novel protocol for site-specific phenylation of
pyridine was discovered, thus setting the precedent for the develop-
ment of new methodologies for direct arylation of π-deficient
heteroarenes. Formation of catalysts 6a and 6b involving a sequence
of C-H and C-P bond cleavage, cluster fragmentation, and
disproportionation has been uncovered. These crystalline, air, and
moisture stable complexes can be prepared in three steps in 30%
overall yield. This work also demonstrates the potential of bi- and
polynuclear metallic species in catalysis.10 The possibility of
facilitating processes requiring two consecutive oxidative addition
steps, through synergistic actions of multiple metal centers and the
incorporation of ligands such as phosphines to enable the transient
generation of a coordinately unsaturated polymetallic species, is
especially noteworthy. Rational design of such multifunctional
catalysts may lead to the development of new, thus far unforeseen,
chemical transformations.
Figure 2. Thermal disproportionation of complex 4.
Acknowledgment. This work was supported by the National
Science Foundation. D.S. is a recipient of the AstraZeneca
Excellence in Chemistry Award and the Unrestricted Grants in
Organic Synthesis Grant from Bristol-Myers Squibb. We also thank
GlaxoSmithKline and Merck Research Laboratories for their
support, Dr. Benjamin Lane (technical support and intellectual
contributions), Professor Gerard Parkin and Dr. Kevin Janak
(X-ray), and Dr. J. B. Schwarz (editorial assistance).
Figure 3. Proposed catalytic cycle.
(Figure 1). Further analysis of this complex system revealed the
formation of yet another complex which led us to suspect that
complex 4 was not the actual catalytic species but instead underwent
further transformation under the reaction conditions.
Heating complex 4 under the reaction conditions resulted in slow
conversion to a mixture of inseparable isomers, which were
identified as bisphosphine ruthenium dimers 6a and 6b (Figure 2).
The unsaturated ruthenium species resulting from this phosphine
disproportionation was not detected and presumably underwent
decomposition. The identical mixture of 6a and 6b may also be
prepared by treatment of 4 with 1 equiv of PPh3 at 150 °C.7 These
complexes provided a superior yield in comparison to other
catalytically active compounds (entries 7 and 8, Table 1); up to
70% of 2-phenylpyridine can be obtained in one step. Furthermore,
6a and 6b were detected as the principle ruthenium species in the
reaction mixture after 18 h. These observations strongly suggest
that the mixture of 6a and 6b represents the resting state of the
catalyst in this new process.
On the basis of these results, we propose the following model
of a catalytic cycle. A phosphine ligand is dissociated from complex
6, creating a coordinately unsaturated site at Ru(2), which undergoes
the oxidative addition with iodobenzene (Figure 3).8 The C-C bond
is formed by the subsequent reductive elimination, and the resulting
empty coordination site is filled by the free phosphine to afford
the putative complex 8. Coordination of pyridine (or replacement
of the product by pyridine), followed by C-H activation, and
elimination of hydrogen iodide would then complete the cycle. The
oxidative addition of iodobenzene may also occur at Ru(1), wherein
no direct pathway for the product formation is available and thus
a mechanism for the phenyl group transfer between the ruthenium
nuclei would have to be available.9 Labeling studies showed that
PPh3 is not the source of the phenyl group;7 it is more likely that
the oxidative addition is reversible, and thus the corresponding
product at Ru(1) lies outside the productive cycle. The choice of
base was also important, and presumably it is directly involved in
Supporting Information Available: Experimental procedures,
spectral data, elemental analyses, and tables and figures pertaining to
X-ray crystallographic studies of 2, 4, and 5 (CIF, PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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