Journal of the American Chemical Society
Communication
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Scheme 5. Preliminary Results with Other Nucleophiles
́
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that alkoxide, Grignard, organozinc, and malonate nucleophiles
react to form a diverse set of functionalized pyridines.
Furthermore, these results, along with those shown in Scheme
4D, reveal that changing the identity of the nucleophile leads to
the selective functionalization at either the 2- or 4-position.
Follow-up studies to investigate further reaction conditions with
a wide array of nucleophiles are ongoing and will be reported in
due course.
In summary, a novel bifunctional reagent has been designed
for the direct functionalization of pyridines. The reagent acts to
promote nucleophilic addition to pyridine, and as a mild two-
electron oxidant in the presence of a weak base. The utility of the
method is highlighted by the ability to carry out the cyanation of
pyridines bearing functional groups sensitive toward acid, base,
and oxidation. Preliminary results with other nucleophiles reveal
that this approach to pyridine functionalization will be broad
reaching. Work is ongoing to expand the scope to other
nucleophiles, and to explore further the application of these
bifunctional reagents in the development of new reactions.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Data for pyridinium salts from 2a (CIF)
Data for pyridinium salts from 2b (CIF)
Experimental details and characterization data for new
(11) For related anion exchange reactions, see: (a) Pabel, J.; Hosl, C.
E.; Maurus, M.; Ege, M.; Wanner, K. T. J. Org. Chem. 2000, 65, 9272.
(b) Yamaguchi, R.; Hatano, B.; Nakayasu, T.; Kozima, S. Tetrahedron
Lett. 1997, 38, 403. (c) Yamaguchi, R.; Omoto, Y.; Miyake, M.; Fujita,
K. Chem. Lett. 1998, 27, 547.
AUTHOR INFORMATION
Corresponding Author
ORCID
Notes
The author declares no competing financial interest.
■
(12) (a) Feely, W. E.; Beavers, E. M. J. Am. Chem. Soc. 1959, 81, 4004.
(b) Fife, W. K. J. Org. Chem. 1983, 48, 1375. (c) Vorbruggen, H.;
̈
Krolikiewicz, K. Synthesis 1983, 1983, 316. (d) Okamoto, T.; Tani, H.
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T. Heterocycles 1981, 15, 981. (f) Fife, W. K. Heterocycles 1984, 22, 93.
(g) Yamaguchi, K.; Xu, N.; Jin, X.; Suzuki, K.; Mizuno, N. Chem.
Commun. 2015, 51, 10034.
ACKNOWLEDGMENTS
■
(13) Reagent 2b was stored and handled on the benchtop without
precautions toward air or moisture. No degradation was observed over
the span of 2 months. Melting point, 84 °C; decomposition onset
temperature, 222 °C.
I thank Kevin Maloney, L. C. Campeau, and Ian Davies (all at
Merck) for their feedback. I thank Andy Brunskill (Merck) for
obtaining the crystal structures.
(14) Rewinkel, J.; Enthoven, M.; Golstein, I.; van der Rijst, M.;
Scholten, A.; van Tilborg, M.; de Weys, D.; Wisse, J.; Hamersma, H.
Bioorg. Med. Chem. 2008, 16, 2753.
(15) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books, 2006. (b) Simmons, E. M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066.
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D
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX