ORGANIC
LETTERS
2010
Vol. 12, No. 10
2210-2213
KHMDS Enhanced SmI2-Mediated
Reformatsky Type r-Cyanation
Tobias Ankner, Maria Fride´n-Saxin, Nils Pemberton, Tina Seifert, Morten Grøtli,
Kristina Luthman, and Go¨ran Hilmersson*
Department of Chemistry, UniVersity of Gothenburg, KemiVa¨gen 10,
SE-412 96 Go¨teborg, Sweden
Received March 4, 2010
ABSTRACT
A novel combination of SmI2, KHMDS, and TsCN can be utilized to introduce a cyano group into structurally diverse and highly sensitive
2-alkyl-chroman-4-ones. Subsequent oxidation allows the formed 2-alkyl-3-cyanochromones to be isolated in yields ranging from 49 to 77%.
In addition, r-bromoketones and esters were found to undergo equally effective r-cyanation.
Carbon-carbon bond-forming reactions are central to chemi-
cal synthesis, and their development is of paramount
importance. The Reformatsky reaction, originally defined as
a zinc-promoted addition of R-halo esters to carbonyl
compounds, represents an important member of this family
of reactions.1 A major breakthrough in the Reformatsky
reaction came with the replacement of zinc with the mild
reducing agent SmI2 as a metal equivalent.2 The use of
divalent samarium-based reagents has seen a dramatic
increase during the last several decades both in functional
group reductions and various coupling reactions.3 The
reactivity of SmI2 can be adjusted with the addition of
additives or solvents,4 but to the best of our knowledge there
is no study on the effect of various additives on the SmI2-
mediated Reformatsky reaction. For some years we have
been interested in the synthesis of 2,3,6,8-tetrasubstituted
chromone derivatives and in exploring their properties, e.g.,
as scaffolds for peptidomimetics.5 As a part of this study,
we wished to install a cyano group in the 3-position of
2-alkyl-3-bromo-chroman-4-ones. Cyanation in an R-position
to a carbonyl may seem like a trivial transformation, but few
reliable methods exist.6 Examples of successful strategies
include formation of the enolate and reaction with various
electrophilic cyanide equivalents like tosyl cyanide.7 Unfor-
tunately, all attempts to introduce the nitrile using standard
conditions failed due to the high sensitivity of the chroman-
4-ones.8 Instead, a SmI2-mediated Reformatsky-type reaction
(3) (a) Lakshmy, K. V.; Trivedi, G. K. J. Sci. Ind. Res. 1984, 43, 200.
(b) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573. (c) Molander,
G. A. Org. React. 1994, 46, 211. (d) Urtimoto, K.; Matsubara, S. Organomet.
News 1995, 38. (e) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54,
3321. (f) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (g) Steel, P. G.
J. Chem. Soc., Perkin Trans.1 2001, 2727. (h) Kagan, H. B. Tetrahedron
2003, 59, 10351. (i) Procter, D. J.; Flowers, R. A.; Skrydstrup, T. Organic
Synthesis using Samarium Diiodide; RCS Publishing, 2009.
(4) (a) Kagan, H. B.; Namy, J.-L. Top. Organomet. Chem. 1999, 2, 155–
198. (b) Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. (c)
Flowers, R. A. Synlett 2008, 1427.
(1) (a) Furstner, A. Synthesis 1989, 571. (b) Ocampo, R.; Dolbier, W. R.
Tetrahedron 2004, 60, 9325.
(2) (a) Molander, G. A.; Etter, J. B. J. Am. Chem. Soc. 1987, 109, 6556.
(b) Inanaga, J.; Yokoyama, Y.; Handa, Y.; Yamaguchi, M. Tetrahedron
Lett. 1991, 32, 6371. (c) Aoyagi, Y.; Yoshimura, M.; Tsuda, M.; Tsuchibu-
chi, T.; Kawamata, S.; Tateno, H.; Asano, K.; Nakamura, H.; Obokata,
M.; Ohta, A.; Kodama, Y. J. Chem Soc., Perkin Trans. 1 1995, 689. (d)
Wei, H. X.; Wang, Z. M.; Shi, M. Chem. Pharm. Bull. 1999, 47, 909. (e)
Orsini, F.; Lucci, E. M. Tetrahedron Lett. 2005, 46, 1909. (f) Malapelle,
A.; Abdallah, Z.; Doisneau, G.; Beau, J. M. Angew. Chem., Int. Ed. 2006,
45, 6016. (g) Colobert, F.; Obringer, M.; Solladie, G. Eur. J. Org. Chem.
2006, 1455. (h) Lin, G. J.; Luo, S. P.; Zheng, X.; Ye, J. L.; Huang, P. Q.
Tetrahedron Lett. 2008, 49, 4007. (i) Nagano, T.; Motoyoshiya, J.; Kakehi,
A.; Nishii, Y. Org. Lett. 2008, 10, 5453.
(5) (a) Dahlen, K.; Wallen, E. A. A.; Grøtli, M.; Luthman, K. J. Org.
Chem. 2006, 71, 6863. (b) Wallen, E. A. A.; Dahlen, K.; Grøtli, M.;
Luthman, K. Org. Lett. 2007, 9, 389.
(6) See: Smith, M. March’s adVanced organic chemistry: reactions,
mechanisms, and structure, 6th ed; Wiley-Interscience: Hoboken, N.J., 2007;
Section 12-6
(7) Kahne, D.; Collum, D. B. Tetrahedron Lett. 1981, 22, 5011–5014.
10.1021/ol100424y 2010 American Chemical Society
Published on Web 04/29/2010