Tetrahedron
Volume 60, Issue 42,
11 October 2004
, Pages 9325-9374
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Graphical Abstract
Introduction
The classical form of the well-known Reformatsky reaction, introduced for the first time in 1887,1 consists of the zinc-induced formation of β-hydroxyalkanoates from ethyl α-haloacetates in a reaction with aldehydes or ketones (Scheme 1).
The reaction was ultimately found to be applicable to alkyl 2-haloalkanoates in general as well as to ‘remote’ (3-, 4-, 5- or higher) haloalkanoates. The scope of the Reformatsky reaction was also extended beyond the use of aldehydes or ketones as electrophiles. In addition, a number of other metals and catalysts2 were found to promote the role analogous to that of zinc. These facts called for a broader, more comprehensive definition, and therefore, as stated in a previous review,3 “Reformatsky reactions are defined as those resulting from metal insertions into carbon–halogen bonds activated by carbonyl-, carbonyl-derived or carbonyl-related groups in vicinal or vinylogous positions with practically all kinds of electrophiles”. In a general sense, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt or complex into a carbon–halogen bond (or carbon–leaving group bond) activated by a vicinal carbonyl-derived group, followed by a reaction of the enolates thus formed with an appropriate electrophile (Scheme 2).4, 5 However, an aqueous metal-free electrochemical Reformatsky reaction, presumably proceeding via a radical mechanism, was reported recently.6
Several recent reviews have appeared, focusing on the structure and nature of the organozinc reagent (spectroscopically and theoretically),3, 7 substitution of zinc by other metals,2, 3 zinc activation,3, 4 experimental protocols,3, 4, 5 different precursors and electrophiles,3 and reactions and applications in organic synthesis.3, 4, 8
Reformatsky reactions have been recognized as among the most useful methods for the formation of carbon–carbon bonds, becoming a valuable tool in modern organic synthesis with a broad applicability and great versatility in numerous inter- and intramolecular reactions involving a great variety of electrophiles. As such, this methodology is considered a useful alternative to base-induced aldol reactions or, at the least, an important complement to other enolate reactions. A retro-Reformatsky reaction was recently reported and was used as one of the steps in the synthesis of heterocyclic enamines.9
One of the advantages of the Reformatsky reaction is that the reaction proceeds under neutral conditions, in contrast to the aldol reaction which, in general, requires a base to generate the enolate or an acid to activate the electrophile. Very important is the fact that in classical Reformatsky reactions no O-products are obtained, and even reagents with strong affinities for oxygen such as TMS–Cl afford only C-silylated products in most of the cases. Thus, the site of the reaction is strictly determined by the site of the halogen substituent, although some few exceptions to this rule are known (Scheme 3).10, 11, 12
Chloral 1 and other polyhalogenated carbonyl compounds react with phosgene 4 in the presence of zinc dust to afford 2,2-dihalovinyl chloroformate 6 clearly via an O-enolate reaction with the phosgene acting as the electrophile.10 Likewise, O-enolate attack of polyhalogenated compounds 2, 3 and 9 on acyl chlorides 5 in Reformatsky reactions led to vinyl compounds 7, 8 and 10 (Scheme 3).11, 12
However, several disadvantages of Reformatsky reactions have been recognized in the past. A problem encountered in many reactions is the unselective dehydration of the aldols initially formed, but this problem has been overcome either by substantially lowering the reaction temperature or by using silylated starting materials. Perhaps, the most serious limitation attributed to Reformatsky reactions has been the lower yields and stereoselectivities associated with them in comparison to those of aldol reactions.13 It is well known that base-induced aldolizations are readily stereocontrolled, and the low stereoselectivities associated with Reformatsky reactions have discouraged synthetic chemists from using them, particularly if asymmetric targets were desired. This perception has often limited the synthetic applications of the Reformatsky reaction, it being used largely for those syntheses that involve subsequent elimination or oxidation steps on the product aldol, as for example in the synthesis of (−)-oudemansins.14 Also, the Reformatsky condensation of benzyl α-bromopropionate with methyl 4-formylbenzoate 11 is conducted without stereochemical concerns because it is followed by dehydration of the diastereomeric products 12, to afford the respective α,β-unsaturated ester 13, which was used to prepare antifolate 9-alkyl-10-deazaminopterins 14 (Scheme 4).15 Similarly, β-substituted acrylates RCH=CHCO2Et (R=Ar, Cyhex, 3-Py) were synthesized via the reaction of the respective aldehydes with ethyl bromoacetate by way of one-pot Reformatsky/dehydration processes prompted by HMPT and zinc.16
In the total synthesis of (+)-10,10-difluorothromboxane A2, synthesis of the key aldehyde intermediate 18 was accomplished in 14 steps. Diastereoselectivity was high in all but the Reformatsky step with aldehyde 15 (Scheme 5).17 However, both epimers, 16 and 17, obtained in this reaction could be converted efficiently to key aldehyde 18. This is a good example of how a non-diastereoselective Reformatsky reaction was able to be useful in a stereo directed synthesis.
Sometimes the diastereomeric mixture resulting from Reformatsky reactions can be resolved by conventional chromatographic techniques, so that the subsequent synthetic steps can be performed on the specific diastereomer.18 However, such syntheses are obviously not convenient enough to have broad application.
Stereoselectivity in Reformatsky reactions has become a challenge of interest during the past decade, and a lot of recent progress has been made in this area. As will be illustrated later, there are now a number of examples of highly diastereo- and enantioselective Reformatsky reactions, deriving from the use of chiral ligands, thus circumventing the limitation mentioned above and rescuing the modern synthetic potential of this methodology. Therefore, the Reformatsky reaction is now suited for applications to the synthesis of complex target molecules, including being very applicable to intramolecular aldol processes, even when medium sized rings are desired. It is the intent of this review to summarize the most recent progress in the use of Reformatsky reactions in organic synthesis, including the latest developments in diastereo- and enantioselective reactions.
Section snippets
Zinc metal activation and catalysts
Previous reviews3, 5, 8 have summarized the most common methods of metal activation, which function to either remove the deactivating zinc oxide layer from the metal surface or to achieve a fine distribution of the metal. Such methods generally use procedures that involve simple washing of the zinc (in the form of dust, foil, pellets or turnings),3, 8 depassivating procedures employing reagents such as iodine,8, 19 chlorotrimethylsilane,20 iodine-chlorotrimethylsilane,21 1,2-dibromoethane,8, 22
Non-conventional reaction conditions
A Reformatsky reaction is run typically at temperatures ranging from room temperature to the boiling point of the solvent in which the reaction is carried out. However, there are numerous reports of Reformatsky reactions (as with a lot of other organic reactions) run under non-conventional reaction conditions involving ultrasound, high pressure and microwave heating.121 Solvent-free reactions122 or aqueous reactions123 offer obvious advantages which come from avoiding the need for flammable or
Reformatsky reactions involving non-fluorinated substrates
This section deals with application of the classical Reformatsky and Reformatsky-type reactions to a number of synthetic procedures involving non-fluorinated substrates. A lot of progress has been made in this field, particularly with regard to (a) the extension of the reaction to unconventional electrophiles and precursors, (b) the development of alternative methods that provided significant improvements in yields or stereocontrol, shortening of reaction times, simplification of work-up
Recent reports of Reformatsky reactions involving fluorinated substrates
The subject of Reformatsky reactions of fluorine-containing precursors and substrates has been recently reviewed.315 Classical reactions analogous to those of non-fluorinated systems lead to the synthesis of α,α-difluoro-β-hydroexyesters and α,α-difluoro-β-hydroxyketones, and the replacement of carbonyl compounds for imines269, 270, 316, 317 produces the anticipated α,α-difluoro-β-amino esters, for example, 302, or their respective α,α-difluoro-β-lactams, for example, 303 (Eq. 86).317 The
Concluding remarks
As seen throughout this review, much progress has been made on the asymmetric version of Reformatsky reactions, involving both fluorinated and non-fluorinated Reformatsky reagents. This significant progress has rescued Reformatsky methodology so that it is now even more useful than before for modern organic synthesis. When condensations are needed in planning organic synthesis, there are several factors which make the Reformatsky reaction a choice worth considering. Among those special factors
Rogelio Ocampo was born on July 9, 1962 in Marquetalia, Caldas (Colombia). He performed undergraduate studies of Education in Biology and Chemistry at Universidad de Caldas in Manizales (Colombia) where he obtained his degree in 1984. His graduated studies were performed at Universidad del Valle in Cali (Colombia) from where he obtained the MSc degree (1990) and PhD degree (1997). He received his doctoral training as a visitor scholar (partially granted by COLCIENCIAS) at University of Florida
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Rogelio Ocampo was born on July 9, 1962 in Marquetalia, Caldas (Colombia). He performed undergraduate studies of Education in Biology and Chemistry at Universidad de Caldas in Manizales (Colombia) where he obtained his degree in 1984. His graduated studies were performed at Universidad del Valle in Cali (Colombia) from where he obtained the MSc degree (1990) and PhD degree (1997). He received his doctoral training as a visitor scholar (partially granted by COLCIENCIAS) at University of Florida (1994–1996) from Professors William R. Dolbier, Jr. and Rodrigo Paredes (Universidad del Valle). His doctoral dissertation was graded Cum Laude, and he was awarded with the Colombian IV Prize of Chemistry (second place) in 2001. After his PhD degree he was back to Universidad de Caldas, where he is at present Professor of Organic Chemistry. His current interest is focused on synthesis and physical organic chemistry of fluorinated β-lactones and related compounds, working in collaborative projects of Universidad de Caldas-Universidad del Valle-University of Florida. At present, he is member of the research group SIMERQO granted by COLCIENCIAS (Colombia).
William R. Dolbier, Jr. Bill Dolbier is currently the Col. Allen R. and Margaret G. Crow Professor of Chemistry at the University of Florida. He received his BS in Chemistry from Stetson University in 1961 and obtained his PhD in organic chemistry from Cornell University in 1965, working with Mel Goldstein. After one and a half years of postdoctoral work with Bill Doering at Yale, he joined the faculty at UF in 1966, where he has been ever since, serving as Chairman from 1983 to 1988. Bill's research interests continue to be physical organic in nature, and he maintains long-term interests in thermal homolytic reactions, pericyclic reactions, and free radical reactivity. Since 1975, his efforts have mainly focused on the study of molecules containing fluorine. In recent years, his efforts have increasingly been devoted to development of new synthetic methods in organofluorine chemistry. Bill received the ACS award for Creative Work in Fluorine Chemistry in 2000, and is currently a member of the Executive Committee of the Fluorine Division of the ACS. When not immersed in such activities, Bill's main interests continue to be his wife, Jing, son, Stephen, three grandchildren, and a little handball.
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