ORGANIC
LETTERS
2003
Vol. 5, No. 20
3615-3617
Titanocene(III)-Promoted Reformatsky
Additions
J. D. Parrish, Daniel R. Shelton, and R. Daniel Little*
Department of Chemistry and Biochemistry, UniVersity of California-Santa Barbara,
Santa Barbara, California 93106-9510
Received July 9, 2003
ABSTRACT
A novel method for the promotion of Reformatsky-like reactions is presented. The technique employs titanocene(III) chloride as a mild and
homogeneous single-electron reductant. The reactions are rapid, operationally simple, and compatible with a wide range of functionalities.
These additions are also anti diastereoselective.
The Reformatsky reaction is a well-established method for
the formation of â-hydroxy esters.1 It offers the advantages
of regioselective enolate formation under nearly neutral
conditions. However, the classic method employing zinc dust
as a reductant can be plagued by extended reaction times
and/or byproduct formation. To address these concerns, many
other approaches have been developed employing either
alternative elemental reductants or low-valent organometallic
species.2 Unfortunately, several employ reagents that have
limitations of cost, availability, toxicity, and/or selectivity.
In this communication, we describe a novel system employ-
ing titanocene(III) chloride to promote Reformatsky-like
reactions that overcomes many of the aforementioned
complications.
Titanocene(III) chloride (Cp2TiCl, “Nugent’s reagent”) is
a mild and useful reductant. The most popular application
of this reagent is the single-electron opening of epoxides and
subsequent trapping of the resulting R-hydroxy radical.3 In
addition, Cp2TiCl has seen use in the reduction of aromatic
aldehydes,4 glycosyl halides,5 vicinal dihalides,6 sulfoxides,7
and nitroarenes.7 During our ongoing investigations using
this unique reagent,8 we noted the use of Cp2TiCl to success-
fully reduce R-halo carbonyl species.8,9 The substrate un-
dergoes a two-electron reduction to form an enolate, which
in the reported work was simply protonated upon workup
to afford the unsubstituted carbonyl. We reasoned that the
intermediate enolate could be trapped with electrophilic
reagents such as aldehydes, leading to Reformatsky-like aldol
products.
(2) For recent examples with various reducing systems, please see the
following. (a) Ge(0): Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo,
K. J. Org. Chem. 1998, 63, 691-697. (b) Sn: Shibata, I.; Suwa, T.;
Sakakibara, H.; Baba, A. Org. Lett. 2002, 4, 301-303. (c) SmI2: Fukuzawa,
S.; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000, 65, 1702-1706.
(d) Co(0): Orsini, F. J. Org. Chem. 1997, 62, 1159-1163. (e) In(0):
Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem.
Soc., Perkin Trans. 1 2000, 825-828. (f) Cr(II): Wessjohann, L.; Gabriel,
T. J. Org. Chem. 1997, 62, 3772-3774. TiCl4-Bu4NI: (g) Tsuritani, T.;
Ito, S.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2000, 65, 5066-5068.
(h) Mn*: Kakiya, H.; Nishimae, S.; Shinokubo, H.; Oshima, K. Tetrahedron
2001, 57, 8807-8815. (i) TiCl2: Kagayama, A.; Igarashi, K.; Shiina, I.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 2579-2585.
(3) (a) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103-2112.
(b) Gansa¨uer, A., Bluhm, H. Chem. ReV. 2000, 100, 2771-2788. (c)
Gansa¨uer, A.; Rinker, B. Tetrahedron 2002, 58, 7017-7026. (d) Li, J. J.
Tetrahedron 2001, 57, 1-24. (e) RajanBabu, T. V.; Nugent, W. A. J. Am.
Chem. Soc. 1994, 116, 986-997.
(4) Gansa¨uer, A.; Bauer, D. J. Org. Chem. 1998, 63, 2070-2071.
(5) Spencer, R. P.; Cavallaro, C. L.; Schwartz, J. J. Org. Chem. 1999,
64, 3987-3995.
(6) Qian, Y.; Li, G.; Zheng, X.; Huang, Y.-Z. Synlett. 1991, 489-490.
(7) Zhang, Y.; Yu, Y.; Bao, W. Synth. Commun. 1995, 25, 1825-1830.
(8) Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4, 1439-1442
(9) Qian, Y.; Li, G.; Huang, Y.-Z. J. Organomet. Chem. 1990, 381, 29-
34.
(1) For reviews, see: (a) Shriner, R. L. Org. React. 1942, 1, 1-37. (b)
Rathke, M. W. Org. React. 1975, 22, 423-460. (c) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando,
1984; Vol. 3, pp 111-212. (d) Fu¨rstner, A. Synthesis 1989, 571-590. (e)
Rathke, M. W.; Weipert, P. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 277-
299.
10.1021/ol035269c CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/06/2003