the pyridine ring. We were therefore very curious to learn
whether less electrophilic amides derived from other car-
boxylic acids would also be suitable substrates of the reaction
cascade leading to pyridinols. A successful extension would
dramatically increase the scope of our novel pyridine
synthesis.
Scheme 7
Gratifyingly, most of the carboxylic acids examined turned
out to be excellent components for the pyridine synthesis,
thus allowing installation of a variety of substituents in
position 6 of the pyridine ring. In Scheme 6 we assembled
Scheme 6
typical examples demonstrating that pentafluorobenzoic acid,
benzoic acid, 2-pyridinecarboxylic acid, and also simple
aliphatic carboxylic acids such as acetic acid furnish the
expected pyridine derivatives 11 or 12. In most cases, the
enamide intermediates with structures analogous to 5 (Scheme
2) were isolated as primary products after step 3 of our
sequence, thus clearly emphasizing the expected lower
tendency to undergo the intramolecular aldol condensation.
However, these enamides smoothly undergo the expected
cyclizations to pyridinols 11a-c by treatment with trimeth-
ylsilyl triflate and triethylamine. We also include two
examples where the unpurified pyridinols were directly
converted into the nonaflates 12a and 12b in good overall
yield. Of particular importance is the short synthesis of
specifically functionalized 2,2-bipyridyl derivatives such as
11c and 12a.
Selected examples demonstrate the potential of pyridyl
nonaflates in palladium-catalyzed reactions. Suzuki couplings
of dipyridyl derivatives 10a-c with 4-methoxyphenylboronic
acid provided the expected products 13a-c in good yields.
In compound 13c, six (hetero)aromatic rings are in conjuga-
tion, which makes compounds of type 13 to interesting
extended π-systems.9 They exhibit some similarity to pyri-
midine-phenylene oligomers which are known as blue-light-
emitting compounds.10
Not only Suzuki couplings but also Sonogashira, Stille, and
Heck reactions are easily possible employing our 4-pyridyl
and 3-pyridyl nonaflates.11
The pyridine ring constitutes a privileged structural motif
in compounds of importance for medicinal chemistry,
supramolecular chemistry, and material science.12 Our highly
flexible and fairly efficient method makes available a large
variety of new functionalized pyridine derivatives which
should be of interest for these applications.13 Not only can
perfluorinated substituents such as CF3 or C6F5 easily be
introduced,14 but most importantly, many other substituents
can be incorporated to the pyridine core at C-2 and C-6.
(11) Dash, J.; Lechel, T.; Reissig, H.-U. Unpublished results.
(12) Kleemann, A.; Engel, J.; Kutscher, B. Pharmaceutical Substances;
Thieme: Stuttgart, 2000. Lehn, J.-M. Supramolecular ChemistrysConcepts
and PerspectiVes; VCH: Weinheim, 1995. Mu¨ller, T. J. J.; Bunz, U. H. F.,
Eds. Functional Organic Materials; Wiley-VCH: Weinheim, 2007. Par-
ticularly useful are terpyridine derivatives: Schubert, U. S.; Hofmeier, G.
R.; Newkome G. R. Modern Terpyridine Chemistry; Wiley-VCH: Wein-
heim, 2006.
(13) For reviews on pyridine syntheses, see: McKillop, A; Boulton, A.
J. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984; Vol. 2, p 67. Newkome, G. R.,
Ed. Pyridine and its DeriVatiVes in Heterocyclic Chemistry; Wiley: New
York, 1984; Vol. 15, Part 5. Jones, G. In ComprehensiVe Heterocyclic
Chemistry II; McKillop, A., Ed. Pergamon Press: Oxford, 1996; Vol. 5, p
167. Spitzner, D. Science of Synthesis; Thieme: Stuttgart, 2004; Vol. 15,
pp 11-284. Henry, G. D. Tetrahedron 2004, 60, 6043-6061. Bagley, M.
C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459-2482. For selected recent
syntheses of pyridine derivatives, see: Abbiati, G.; Arcadi, A.; Bianchi,
G.; Di Guiseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959-
6966. Vasile´v, N. V.; Koshelev, V. M.; Romanov, D. V.; Lyssenko, K. A.;
Antipin, M. Y.; Zatonskii, G. V. Russ. Chem. Bull. 2005, 54, 1680-1685.
Dediu, O. G.; Yehia, N. A. M.; Oeser, T.; Polborn, K.; Mu¨ller, T. J. J. Eur.
J. Org. Chem. 2005, 1834-1848. Evdokimov, N. M.; Magedov, I. V.;
Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899-902. Emmerich, T.;
Reinke, H.; Langer, P. Synthesis 2006, 2551-2555. Ranu, B. C.; Jana, R.;
Sowmiah, S. J. Org. Chem. 2007, 72, 3152-3154. Andersson, H.; Almqvist,
F.; Olsson, R. Org. Lett. 2007, 9, 1335-1337 and references cited in these
publications.
In a similar fashion, pyridyl nonaflates 14a and 14b could
be coupled with boronic acids affording 4-aryl-substituted
pyridines 15a-c. Dealkylation of R1 under mild conditions,
conversion into nonaflates, and a second palladium-catalyzed
step allow introduction of a variety of substituents at C-3.
(9) Several of the compounds prepared show interesting photophysical
properties, which will have to be investigated in more detail.
(10) Wong, K.-T.; Hung, T. S.; Lin, Y.; Wu, C.-C.; Lee, G.-H.; Peng,
S.-M.; Chou, C. H.; Su, Y. O. Org. Lett. 2002, 4, 513-516.
Org. Lett., Vol. 9, No. 26, 2007
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