Magnesium Reformatsky reactions

Two further methods for the preparation of p-ketoesters consist of the Reformatsky reaction of pyrazolides[67] (a) and the magnesium bromide-induced Claisen condensation of pyrazolides[68] (b). 

Reaction XLIII. (c) Condensation of a-Halogen Fatty Acid Esters with Aldehydes and Ketones by means of Zinc or Magnesium (Reformatsky-Grignard). (C., (1901), I., 1196 II., 30 (1902), I., 856.)—This is an extension of the Grignard and zinc alkyl reactions which enables a-halogen esters to be condensed with carbonyl compounds as if they were simple alkyl halogen compounds. The zinc or magnesium alkyl derivative is neither prepared beforehand nor isolated in the reaction, but there is little doubt that some such compound is transitorily formed. Zinc is the metal... 

One of the main issues with the use of magnesium and zinc as inexpensive co-reductants is their reactivity with alkyl halides. Also, additives such as TMSOTf are relatively expensive. In an attempt to address these limitations, Namy utilised mischmetal (La 33%, Ce 50%, Nd 12%, Pr 4%, Sm and other lanthanides 1%) as the stoichiometric reductant for the regeneration of the Sm(II).31,32 This reagent system provides an important alternative since it does not require the use of additives and mischmetal is relatively inexpensive. This system has been utilised successfully in Barbier and Reformatsky reactions, halide reductions and pinacol couplings (Scheme 7.7).31,32... 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

In the last 10 years, the Barbier reaction method has been utilized more with other metals than with magnesium. The number of papers published on the lithium-Barbier reaction is three to four times that of magnesium [149-157]. Reactions can be carried out at lower temperatures than possible with Mg-Barbier reactions and yields are often very high with fewer by-products. Other metals of note are samarium, in the form of its diiodide [158-165], and zine [166-169], the metal of choice for the pre-Barbier one-step reaction, and the classic Reformatsky reaction. In situ reactions have been reported for A1 [170], Ce [171], Cd [172,173], Ga [174], Hg [175], In [176], Mn [177], Pb [178-180], Sb [181-183], Sn [184,185], and Ti [186]. An excellent paper by Li reviews the Barbier reactions of many metals in aqueous media [187]. 

Reformatsky reaction. This reaction can be carried out conveniently and with improved yield with magnesium in place of the less reactive zinc provided that the /-butyl halo ester is used to retard self-condensation of the a-halo ester. ... 

Several workers have observed aldol reactions with enolates prepared by reductive removal of an o-heteroatom from a carbonyl compound. The classic example is the Reformatsky reaction, which is reviewed in Volume 2, Chapter 1.8. Dubois and coworkers have employed this method for the preparation of magnesium enolates. An important example from this study, which stimulated much of the subsequent work on aldol stereoselectivity, is shown in equation (21). 

As would be expected, very shortly after Barbier s and Grignard s discovery of the effective replacement of zinc by magnesium in the synthesis of alcohols, publications appeared regarding the use of magnesium in the Reformatsky reaction. 

As early as 1901, two years after Barbier s introduction of magnesium in organic synthesis, the successful use of magnesium in the Reformatsky reaction was reported [5]. 

A few years later superior results were also reported when using magnesium in the Reformatsky reaction with acetophenone and ethyl 2-haloethanoate, with benzene as the solvent [7]. 

Claims were refuted [9] that in Reformatsky reactions with ethyl bromo-ethanoate and acetophenone (or benzophenone), magnesium gave results inferior to those obtained with zinc [10]. 

Much more recently a comparison between the results obtained from Reformatsky reactions with zinc and magnesium in which sterically hindered a-bromo esters were used was published [12]. 

It can be said therefore that some remarkable results have been reported when magnesium was used in Reformatsky reactions. In general, however, the use of this metal leads to undesired products due to the high reactivity of the intermediate organomagnesium compound as demonstrated in the following two examples ... 

In that same period, identical problems were encountered when ethyl oxalate was used in Reformatsky reactions [16] with zinc the expected hydroxy acid ester was obtained whereas magnesium yielded the keto acid ester. 

Neither Shriner [17] in 1942, nor Rathke [18] in 1974, in their review articles on the Reformatsky reaction have come to the conclusion that zinc could in general be replaced by magnesium in this synthetic procedure. 

After Barbier [6] introduced magnesium in the Saytzeff reaction , zinc lost its predominant position in this field of synthesis, although it remained the preferred metal in the Reformatsky reaction [43] (see Sect. 1.2.5). 

With Iodine. As is the case with magnesium (see Sect. 5.3.1) iodine has been applied [58] in a Barbier-type reaction with propargyl bromide and cyclohexanone. More recently, in a Reformatsky reaction under sonication [59], use was made of iodine-activated zinc. In the absence of iodine the sonicated mixture of zinc, ethyl 2-bromo-ethanoate and acetophenone reacted slowly and gave no addition product recovery of the ester and the ketone were quantitative. 

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