Ruthenium-mediated regio- and stereoselective alkenylation of pyridine

Article abstract of DOI:10.1021/ja029829z

A novel alkenylation reaction of pyridine is developed. Heating a cationic ruthenium vinylidene complex [CpRu(C=C=HR)(PPh₃)₂]PF₆ in pyridine at 100-125 °C for 24 h affords (E)-2-alkenylpyridine. Initially, pyridine coordinates to ruthenium by displacement of one of the phosphine ligands. Then, [2 + 2] heterocycloaddition occurs to form a four-membered ruthenacyclic complex. Deprotonation of the β-hydrogen affords a neutral π-azaallyl complex. Protonolysis furnishes the product. As a result, a vinylidene group is inserted into the α C-H bond of pyridine. The alkenylation reaction is made catalytic in ruthenium by the use of (alkyn-1-yl)silane as the vinylidene source. Treatment of (alkyn-1-yl)trimethylsilane with pyridine in the presence of a cationic ruthenium complex [CpRu(PPh₃)₂]PF₆ affords the corresponding (E)-2-alkenylpyridine in good yield in a regio- and stereoselective manner. Copyright

Full text of DOI:10.1021/ja029829z

Published on Web 03/29/2003
Ruthenium-Mediated Regio- and Stereoselective Alkenylation of Pyridine
Masahiro Murakami* and Seiji Hori
Department of Synthetic Chemistry and Biological Chemistry, Kyoto UniVersity, Yoshida, Kyoto 606-8501, Japan
Received December 19, 2002; E-mail: murakami@sbchem.kyoto-u.ac.jp
Scheme 1. Possible Mechanistic Scheme for the Formation of 2a
Direct introduction of a carbon side chain on an aromatic ring
under mild conditions has been a challenging problem. Transition
metals participate in a variety of reactions for this purpose through
so-called C-H bond activation.1 Pyridine derivatives constitute an
important class of aromatic compounds because of their potent
biological activities. For the synthesis of substituted pyridines,
halopyridines are often used as the key starting materials.2 Direct
transformation of a pyridine core is more desirable, although the
examples have been limited.3 In this report, we describe a novel
alkenylation reaction of pyridines which occurs in a regio- and
stereoselective manner through mediation of ruthenium.4
Cationic ruthenium vinylidene complex 1a (Cp ) η5-cyclopen-
tadienyl) was heated in pyridine (20 equiv)5 at 125 °C for 24 h.
The cooled reaction mixture was filtered through a pad of florisil.
Chromatographic isolation of the filtrate afforded 1-phenyl-2-
pyridylethene 2a in 85% yield. The E isomer was formed
exclusively.
Therefore, it is also conceivable that the Z isomer 6 is initially
formed either selectively or nonselectively and then isomerizes to
2a, a thermodynamically more stable stereoisomer, under the
reaction conditions.
In contrast, ruthenium complex 1b having a bidentate ligand dppe
instead of the monodentate PPh3 failed to react with pyridine. It is
likely that dissociation of a phosphine ligand providing a coordina-
tion site for pyridine is an important step. No certain intemediate
was observed when a stoichiometric reaction of 1a with pyridine
was carried out in an NMR tube. Neutral alkynyl complex 3, which
is possibly generated from 1a by deprotonation,6 failed to react
with pyridine either.
Other ruthenium vinylidene complexes 1c-h also underwent an
analogous reaction with pyridine to afford alkenylated pyridines
2c-h in moderate to good yields. E isomers were obtained
selectively except the case of trisubstituted alkene 2h. Disubstituted
vinylidene complexes 1g and 1h, with which the rearrangement to
an η1 alkynyl or η2 alkyne complex is difficult, did react in an
analogous way, being supportive that the vinylidene complex
directly reacts with pyridine. On the other hand, ruthenium complex
1i having a bulky tertiary butyl group failed to react with pyridine,
probably due to steric conditions.
While vinylpyridine 2a formally results from insertion of the
vinylidene group of 1a into the R C-H bond of pyridine, the precise
mechanism of this transformation is unclear. Our working hypoth-
esis, which is similar to the one we proposed for the alkene-alkyne
coupling reaction,7 is shown in Scheme 1. Initially, pyridine
coordinates to ruthenium by displacement of one of the phosphine
ligands of the vinylidene complex 1a. Then, [2 + 2] heterocy-
cloaddition occurs to form four-membered ruthenacyclic complex
4. Deprotonation of the â-hydrogen8 affords neutral π-azaallyl
complex 5. Protonolysis furnishes 2a. As for the E-selectivity, we
independently prepared 1-phenyl-2-pyridylethene, having Z geom-
etry 6 by a literature procedure,9 and heated it in pyridine at 125
°C in the presence of CpRu(PPh3)2Cl and NaPF6.10 After 24 h,
complete isomerization of 6 to the E isomer 2a was observed.11
Apart from its precise mechanism, the reaction described above
is of great synthetic interest since an alkenyl group is directly
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J. AM. CHEM. SOC. 2003, 125, 4720-4721
10.1021/ja029829z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ruthenium-Catalyzed Alkenylation of Substituted
Table 1. Alkenylation of Pyridine with (Alkyn-1-yl)silanes
Pyridines
Multi-Element Cyclic Molecules” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental details (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
introduced on pyridine in a regio- and stereoselective way. With
the knowledge that vinylidene complexes are readily generated from
1-alkyne or from (alkyn-1-yl)trimethylsilane,12 we next attempted
the reaction of pyridine with these alkyne substrates in the presence
of catalytic amount of 1a. Although simple 1-alkynes underwent
self-dimerization rather than the desired alkenylation reaction,
(alkyn-1-yl)trimethylsilanes were converted into alkenylpyridine
derivatives under catalytic conditions. Thus, treatment of (2-
phenylethyn-1-yl)trimethylsilane 7a with pyridine (20 equiv) in the
presence of 1a (0.20 equiv) at 150 °C for 7 h stereoselectively
afforded 2a in 82% yield. Complex 1a initially alkenylates pyridine,
and the product 2a is liberated from 5 by protonolysis, as depicted
in Scheme 1. The resulting cationic ruthenium species then reacts
with 7a to regenerate 1a, completing the catalytic cycle. This
process was accompanied by protiodesilylation13 due to the presence
of water in the reaction medium.
References
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K.; Schottenberger, H.; Calhorda, M. J.; Veiros, L. F. Chem. Eur. J. 2002,
8, 3948-3961.
(5) A large excess of pyridine was needed for the success of the reaction. It
probably favors displacement of PPh3 with the weaker ligand, pyridine.
(6) Bruce, M. I.; Wallis, R. C. J. Organomet. Chem. 1978, 161, C1-C4.
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295.
More conveniently, CpRu(PPh3)2Cl (20 mol %) and NaPF6 (22
mol %) could be used as the source of cationic ruthenium species.10
(8) Slugovc, C.; Mereiter, K.; Schmid, R.; Kirchner, K. Eur. J. Inorg. Chem.
1999, 16, 1141-1149.
(9) Konakahara, T.; Takagi, Y. Synthesis 1979, 192-194.
(10) Blackmore, T.; Bruce, M. I.; Stone, F. G. A. J. Chem. Soc. (A) 1971,
2376-2382.
Thus, pyridine was alkenylated by (alkyn-1-yl)trimethylsilanes
7a-d to afford 2-alkenylpyridines in good yield (Table 1).14 Both
aromatic and aliphatic alkynes could be employed.
The reactions with substituted pyridines were also examined
(Table 2). Although 2-methylpyridine failed to react with 7a
probably due to steric reasons (entry 1), 3-methyl- and 4-meth-
ylpyridines were alkenylated with 7a (entries 2 and 3). In the case
of 3-methylpyridine, the 6-position on the less hindered side was
regioselectively alkenylated.
In conclusion, we have developed the direct alkenylation reaction
of pyridines.15 The ruthenium vinylidene intermediate, which
originates from (alkyn-1-yl)trimethylsilane, regio- and stereoselec-
tively inserts the vinylidene group into the R C-H bond of a
pyridine core. Application to other heterocyclic systems is the
subject of further investigation.
(11) No isomerization was observed in the absence of the ruthenium catalyst.
(12) (a) Schneider, D.; Werner, H. Angew. Chem., Int. Ed. Engl. 1991, 30,
700-702. (b) Katayama, H.; Ozawa, F. Organometallics 1998, 17, 5190-
5196 and references therein.
(13) Protiodesilylation is often observed during the formation of vinylidene
complexes: (a) Bruce, M. I.; Koutsantonis, G. A. Aust. J. Chem. 1991,
44, 207-217. (b) Bianchini, C.; Marchi, A.; Marvelli, L.; Peruzzini, M.;
Romerosa, A.; Rossi, R. Organometallics 1996, 15, 3804-3816. (c)
Kawata, Y.; Sato, M. Organometallics 1997, 16, 1093-1096. This lability
might be in conjunction with the relatively high acidity of HCdCdM.
(14) A representative experimental procedure: A mixture of (2-phenylethyn-
1-yl)trimethylsilane (7a, 52.3 mg, 0.30 mmol), pyridine (485 µL, 6.0
mmol), CpRu(PPh3)2Cl (43.6 mg, 60 µmol), and NaPF6 (11.1 mg, 66
µmol) was heated at 150 °C for 7 h. The cooled reaction mixture was
filtered through a pad of florisil, and the filtrate was purified by preparative
thin-layer chromatography on silica gel (hexane/AcOEt ) 3/1) to afford
2a (47.3 mg, 87%) as white crystals. The yield of 2a decreased to 24%
when 10 mol % of CpRu(PPh3)2Cl and 12 mol % of NaPF6 were used as
the catalyst precursors.
(15) Direct propargylation of aromatic compounds using a ruthenium complex
has recently been reported: Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.;
Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 11846-11847.
Acknowledgment. This research was supported by a Grant-in-
Aid for Scientific Research on Priority Areas (A) “Exploitation of
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