ORGANIC
LETTERS
2008
Vol. 10, No. 24
5589-5591
Highly Regioselective Fluorination and
Iodination of Alkynyl Enolates
Han Yang, Bo Xu, and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille, Kentucky 40292
gb.hammond@louisVille.edu
Received October 23, 2008
ABSTRACT
A simple yet efficient approach to various functionalized quaternary r-alkynyl r-fluoro esters and γ-iodoallenoates from readily available
allenoates through an alkynyl enolate intermediate generated by LDA is presented. Reaction of this alkynyl enolate with NFSI gives the
r-product (r-alkynyl-r-fluoro ester), whereas the reaction of the silyl ether of alkynyl enolate with I2 gives solely the γ-product (iodoallenoate).
The regioselective synthesis of substituted γ-iodoallenoates
or R-fluoropropargyl esters from a common, readily available
precursor is a sought after strategy because the resulting
products are either useful synthons or possess important
biological properties. An example of the former is the recent
surge of interest in the synthetic applications of γ-iodoal-
lenes.1 Examples of the latter are the extensive therapeutical
ramifications of R-fluoro esters,2 used in the synthesis of
fluorinated amino acids,3 anticancer reagents,4 antiviral
agents,5 antibiotics,6 and other pharmaceutically attractive
molecules.7 Because of the versatility of the triple bond,8
an alkyne-substituted R-fluoro ester would enhance the range
of R-fluoro carboxylic acids and derivatives. But unlike their
nonfluorine counterpart, which is easy to obtain and has
found numerous applications in synthesis,9 the synthesis of
R-alkyne-substituted R-fluoro esters10 has a limited scope
and utilizes CHCl2F, an ozone-depleting reagent.
Recently, we reported the regioselective synthesis of
carbinol allenoates,11 R,R-disubstituted R-alkynyl esters,12
(1) (a) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in,
A. V.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440–1452. (b) Trost,
B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117–2120. (c) Sromek, A. W.;
Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500–10501.
(d) Shen, L.; Hsung, R. P.; Zhang, Y.; Antoline, J. E.; Zhang, X. Org. Lett.
2005, 7, 3081–3084. (e) Ohno, H.; Ando, K.; Hamaguchi, H.; Takeoka,
Y.; Tanaka, T. J. Am. Chem. Soc. 2002, 124, 15255–15266. (f) Xia, Y.;
Dudnik, A. S.; Gevorgyan, V.; Li, Y. J. Am. Chem. Soc. 2008, 130, 6940–
6941.
(4) (a) Burchardt, A.; Takahashi, T.; Takeuchi, Y.; Haufe, G. J. Org.
Chem. 2001, 66, 2078–2084. (b) Haufe, G.; Burchardt, A. Eur. J. Org.
Chem. 2001, 450, 1–4507.
(5) Lee, K.; Choi, Y.; Hong, J. H.; Schinazi, R. F.; Chu, C. K.
Nucleosides, Nucleotides Nucleic Acids 1999, 18, 537–540.
(6) Ihara, M.; Satoh, K.; Ishida, Y.; Taniguchi, N.; Tokunaga, Y.;
Takemura, M.; Fukumoto, K. Heterocycles 1996, 42, 437–443.
(7) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. Angew. Chem., Int. Ed. 2008, 47, 164–168.
(2) (a) Bellezza, F.; Cipiciani, A.; Ricci, G.; Ruzziconi, R. Tetrahedron
2005, 61, 8005–8012. (b) Fujisawa, H.; Fujiwara, T.; Takeuchi, Y.; Omata,
K. Chem. Pharm. Bull. 2005, 53, 524–528. (c) Polla, M. O.; Tottie, L.;
Norden, C.; Linschoten, M.; Musil, D.; Trumpp-Kallmeyer, S.; Aukrust,
I. R.; Ringom, R.; Holm, K. H.; Neset, S. M.; Sandberg, M.; Thurmond,
J.; Yu, P.; Hategan, G.; Anderson, H. Bioorg. Med. Chem. 2004, 12, 1151–
1175.
(8) Diederich, F.; Stang, P.; Tykwinski, R. R. Acetylene chemistry:
chemistry, biology, and material science; Wiley-VCH: Weinheim, 2005.
(9) (a) Just, Z. W.; Larock, R. C. J. Org. Chem. 2008, 73, 2662–2667.
(b) Lin, G.-Y.; Yang, C.-Y.; Liu, R.-S. J. Org. Chem. 2007, 72, 6753–
6757. (c) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2006, 128, 9705–9710. (d) Choi, K. S.; Akiyama, I.; Hoshino, M.;
Nakayama, J. Bull. Chem. Soc. Jpn. 1993, 66, 623–9.
(3) Edmonds, M. K.; Graichen, F. H. M.; Gardiner, J.; Abell, A. D.
Org. Lett. 2008, 10, 885–887.
(10) Xu, B.; Hammond, G. B. J. Org. Chem. 2006, 71, 3518–3521.
10.1021/ol802451e CCC: $40.75
Published on Web 11/18/2008
2008 American Chemical Society