SCHEME 1
A Simple and Efficient Procedure of Low Valent
Iron- or Copper-Mediated Reformatsky Reaction
of Aldehydes
Angshuman Chattopadhyay* and Akhil Kr. Dubey
Bio-Organic DiVision, Bhabha Atomic Research Centre,
Mumbai-400 085, India
ReceiVed May 29, 2007
ment of practically viable methodologies to carry out these
reactions.4,6 Hence, a variety of strategies have emerged until
recently to perform this reaction using metal mediators like Zn,6a
Ge,6b In,6c Sn,6d Zn-Cu couple,6e ultrasound approach,6f,i
catalyzed with Co(I),6j Fe,6k Ni,6l etc.
An operationally simple and very efficient procedure of
Reformatsky reaction of aldehydes has been carried out in
THF in the presence of low valent iron or copper which were
prepared in situ employing a bimetal redox strategy through
reduction of FeCl3 or CuCl2-2H2O with magnesium.
Earlier, we developed a useful procedure for zinc-mediated
Reformatsky reaction of aldehydes where active metal was
produced by surface erosion on treatment with a Lewis acid.7
Recently, we have developed a practical method of crotylation
of aldehydes in distilled THF through mediation of metals like
Fe, Cu, and Co in their low valent form.8 The metals were
prepared in an active form in situ following a bimetal redox
strategy (step a, Scheme 1) by stirring a mixture of the
corresponding metal salt and a reducing metal (zinc dust) in
THF in the presence of the reactants. It is well-known that, for
all such metal-mediated additions of organic halides, the prime
requisite is the ability of a metal in its active form to insert into
the carbon-halogen bond to produce the organometallic (as in
step b, Scheme 1), which then undergoes nucleophilic addition
to carbonyls (as in step c, Scheme 1). Our next venture was to
explore the viability and efficacy of this strategy to perform
Reformatsky reaction of aldehydes taking into account the fact
that zinc Reformatsky reagents derived from R-halo esters exist
as C-metalated structures.9 In this pursuit, our aim was to attempt
this reaction with a variety of aldehydes using similar combina-
tions of metals/metal salts.
Metal-mediated carbon-carbon bond formation is an impor-
tant strategy in organic synthesis. In this regard, considerable
attention has been focused over the ages toward exploring the
potentials of various metals in promoting varieties of Barbier
type addition of organic halides to electrophiles.1 It is well-
known that to mediate any reaction a metal needs to be in an
active form under the reaction conditions.2 Nevertheless, for
all metal-promoted additions the electronic configuration and
the active state of a metal contribute significantly regarding the
efficacy and operational procedure of the reactions, in addition
to its role in directing the stereoselectivity in the case of
asymmetric additions. In this perspective, there is a scope for
exploring the potential of metals of various active forms to
participate in Barbier type additions to carbonyls and simulta-
neously investigating the mechanism of such reactions.
Reformatsky reaction is a classic example of Barbier type
carbon-carbon bond forming reactions in organic synthesis
producing a synthetically exploitable structural unit, â-hydroxy
propionic acid esters Via the reaction of a R-bromoester with
an aldehyde.3 The scope of this reaction has been reviewed over
the ages.4 Because of the importance of â-hydroxy esters, the
Reformatsky products, as useful components for the synthesis
of natural products such as macrolides and polyether antibiotics,5
there has been continuous effort until recently for the develop-
Based on the encouraging results we encountered for croty-
lation8 of aldehydes with FeCl3 (97%, Aldrich) and CuCl2-
(6) (a) Rieke, R. D.; Uhm, S. J. Synthesis 1975, 542. (b) Kagoshima,
H.; Hashimoto, Y.; Oguro, D.; Saigo, K. J. Org. Chem. 1998, 63, 691 and
references cited therein. (c) Chao, L.; Rieke, R. D. J. Org. Chem. 1975,
40, 2253. (d) Harda, T.; Mukaiyama, T. Chem. Lett. 1982, 161. (e)
Santanielo, E.; Manzocchi, A. Synthesis 1977, 698. (f) Han, B.; Boudjouk,
P. J. Org. Chem. 1982, 47, 5030. (g) Bieber, L. W.; Malvestiti, I.; Storch,
E. C. J. Org. Chem. 1997, 62, 9065 and references cited therein. (h) Tanaka,
K.; Kishigami, S.; Toda, F. J. Org. Chem. 1991, 56, 4333. (i) Ross, N. A.;
Bartsch, R. A. Org. Chem. 2003, 68, 360. (j) Lombardo, L.; Gualandi, A.;
Pasi, F.; Trombini, C. AdV. Synth. Catal. 2007, 349, 465. (k) Durandetti,
M.; Perichon, J. Synthesis 2006, 1542. (l) Durandetti, M.; Gosmini, C.;
Perichon, J. Tetrahedron 2007, 63, 1146.
(1) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 164. (b) Rieke,
R. D. Science 1989, 246, 1260. (c) Erdik, E. Tetrahedron 1987, 43, 2203.
(2) ActiVe Metals; Fu¨rstner, A. Ed.; VCH Publishers: Weinheim,
Germany, 1996.
(3) Reformatsky, S. Chem. Ber. 1887, 20, 1210.
(7) Chattopadhyay, A.; Salaskar, A. Synthesis 2000, 561.
(8) Chattopadhyay, A.; Goswami, D.; Dhotare, B. Tetrahedron Lett. 2006,
47, 4701.
(9) (a) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron Lett. 1982, 23,
3945. (b) Orsini, F.; Pelizzoni, F.; Ricca, G. Tetrahedron 1984, 40, 2781.
(c) Dekker, J.; Budzelaar, P. H. M.; Boersma, J.; van der Kerk, G. J. M.
Organometallics 1984, 3, 1403. (d) Dekker, J.; Boersma, J.; van der Kerk,
G. J. M. J. Chem. Soc., Chem. Commun. 1983, 553.
(4) (a) Fu¨rstner, A. Synthesis 1989, 571. (b) Rathke, M. W. Org. React.
1975, 22, 423. (c) Shriner, R. L. Org. React. 1942, 1, 1. (d) Ribeiro, C. m.
R.; de Farias, F. M. C. Mini-ReV. Org. Chem. 2006, 3, 1-10. (e) Ocampo,
R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325 and references cited
therein.
(5) Recent Progress in the Chemical Synthesis of Antibiotics; Lukacs,
G., Ohno, M., Eds.; Springer-Verlag: Berlin, 1990.
10.1021/jo0710984 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/31/2007
J. Org. Chem. 2007, 72, 9357-9359
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