Zinc in Barbier-Type Reactions

Saytzeff, Reformatsky and Simmons-Smith Reactions. The metal zinc played an important role in organic synthesis at the end of the nineteenth century, after Frankland [39, 40] had opened up this field of organometallic chemistry and after Saytzeff and coworkers [41, 42] had introduced a considerable number of syntheses with the aid of zinc in that same period (see Sect. 1.2). 

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). 

However, in 1958, yet another powerful synthetic tool in which zinc plays a major role, was introduced to organic chemists i.e. the Simmons-Smith reaction [44, 45]. In this procedure, use is made of a carbenoid intermediate, formed by interaction of the metal (most commonly a zinc/copper alloy is used for this reaction) with diiodomethane  

This reagent adds readily to carbon-carbon double bonds forming cyclopropane derivatives. This reaction is also often executed in a one-step fashion. 

New Developments, A combination of new developments have recently stimulated a remarkable reintroduction of zinc as a coupling agent in traditional Barbier-type synthetic procedures. 

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The general tendency for the application of zinc in Barbier-type reactions has to be attributed to the decreased reactivity of the zinc-derivatives organometallic reagents of reduced reactivity have become of growing importance as modern organic chemistry tends to the synthesis of increasingly delicate targets. 

Zinc in Barbier-Type Reactions Table 3.15. Trifluoromethylation of Carbonyl Compounds [78], [79]... 

Activated Zinc in Barbier-Type Reactions. Throughout this Section the activation of zinc metal has been described in order to make Barbier-type reactions proceed in an improved fashion. 

The less stable trifluoromethyl zinc compounds [48] can be used as a source of nucleophilic trifluoromethyl fragments either in the isolated form or generated in situ by sonication of perfluoroalkyl iodides with zinc in DMF or THF. Zinc perfluoroorganyls find application in Barbier-type reactions [49], palladium-catalyzed cross-coupling reactions [50], or hydroperfluoroalkylations of acetylenes or olefins [51] (Scheme 2.119). 

After having started this monograph with one-step carbon-carbon bond formation reactions in which magnesium was the metallic reagent (chap. 2) and then having progressed on to the use of lithium and zinc, some attention will now be focussed on the application of numerous other metals in Barbier-type reactions. 

Yavari, I. Riazi-Kermani, F. (1995) Zinc-promoted Barbier-type reaction of propargyl bromide with aldehydes in aqueous media, Synth. Commun., 25,2923-8. 

In many cases, activation of the zinc dust is necessary to reach complete conversion or to accelerate the reaction. This activation can be achieved by treatment of zinc dust with an acid chloride267 but can be achieved also with liquid ammonia268 or by sonoelectrochemical methods.259,269,269a Activation can be achieved by adding metallic salts such as AICI3, CeCb, PbBr2, or Cul to the reaction mixture.2536,257,270 Sonication proved also to enhance the reactivity of Barbier-type reaction in aqueous media (Equation (157)).2S3 255 2S6 270 270a 271... 

In addition to serving as a useful replacement for lithium or magnesium in Barbier-type coupling reactions, SmI also provides advantages over zinc as a reductant in Reformatsky-type coupling reactions (equation 54).The latter only performs well when an activated form of zinc is utilized, and thus the homogeneous conditions afforded by SmI provide the advantage of enhanced reactivity under milder conditions. 

Of interest also is the aqueous Reformatsky cross-coupling reaction between a-halo ketones or aldehydes and carbonyl compounds in the presence of zinc, tin and indium. Like the Barbier-type reactions, indium was found to be the most efficient metal and it strongly reduced undesirable side reactions such as the reduction of the halide [134]. As usual in aqueous reactions implicating carbonyl compounds, lanthanum(III) triflate promoted the reaction [146]. 

Alkylation. Zinc-mediated reaction of cinnamyl chloride with aldehydes and ketones in aqueous THE" and Barbier-type reactions involving perfluoroalkyl... 

In that same period systematic studies [70] of the Barbier-type reaction of allylic bromides, benzaldehyde and zinc in ethanol as the solvent (see Sect. 3.4.4, p. Ill) also had led to the conclusion that the organometallic reagent was actually involved as an intermediate in these reactions. 

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. 

Kitazume and Ishikawa have published a number of communications on the regiospecific zinc mediated perfluoroalkylation of a variety of substrates [148-151]. A compilation of these results appeared in 1985 [152] (Scheme 71). Secondary alcohols are available in moderate yield by reaction of perfluoro-alkyl halides (RpX) with aldehydes as the result of a modified Barbier-type reaction [148-152]. However, reaction with ketones gave low yields of the expected tertiary alcohols, although the yields could be doubled by reaction in the presence of a bis[7i-cyclopentadienyl]titanium(II) catalyst, which was prepared in situ by reduction of the dichloride with zinc in the presence of ultrasound. 

More recently, a promising new technique based on the combined use of pulsed sonochemistry and electrochemistry was applied for the production of submicron crystalline metal powders. The first results showed that the zinc powder elaborated by such a method was about three times more reactive than the commercial one in an aqueous Barbier-type reaction excluding any organic cosolvent (Durant et al, 1995). 

The aqueous Barbier-Grignard-type reaction has also been used in the synthesis of natural products. Chan and Li used the zinc mediated allylation as a key step in a total synthesis of (+)-muscarine (Scheme 8.5).72 The strategy was based on the observation that the diastereoselectivity of the allylation reaction in water can be reversed through the protection of the a-hydroxyl group. 

In 1991, Li and Chan reported the use of indium to mediate Barbier-Grignard-type reactions in water (Eq. 8.49).108 When the allylation was mediated by indium in water, the reaction went smoothly at room temperature without any promoter, whereas the use of zinc and tin usually requires acid catalysis, heat, or sonication. The mildness of the reaction conditions makes it possible to use the indium method to allylate a methyl ketone in the presence of an acid-sensitive acetal functional group (Eq. 8.50). Furthermore, the coupling of ethyl 2-(bromomethyl)acrylate with carbonyl compounds proceeds equally well under the same reaction conditions, giving ready access to various hydroxyl acids including, for example, sialic acids. 

Iminium ions, generated in aqueous solution from secondary amines and formaldehyde, undergo a Barbier-type allylation mediated by tin, aluminum, and zinc. The reaction is catalyzed by copper and produces tertiary homoallylamines in up to 85% yield.67 The imines generated in situ from 2-pyridinecarboxaldehyde/2-quinolinecarboxaldehyde and aryl amines undergo indium-mediated Barbier allylation in aqueous media to provide homoallylic amines.68 Crotyl and cinnamyl bromides... 

Barbier-Grignard-type reactions in water (Li, 1996) between aUyl hahdes and carbonyl compounds can be mediated by metals of tin, zinc, or indium. Usually the generation of the organometalhc reagent takes place in anhydrous organic solvents, but using softer metals allows this reaction to take place in water. 

The oxidative insertion of zinc into a-halo carbonyl compounds and the subsequent reaction of the zinc enolates formed with various electrophiles can either be carried out in a one-pot Barbier-type fashion or in two consecutive steps.1-3 Zinc enolates exhibit a reasonably high stability over a wide temperature range (from -78°C to above 80°C for short periods of time) compared to other metal enolates. Although it has been reported that solutions of BrZnCH2COOtBu can be stored for several days without loss in activity,5 it is generally advisable to use freshly prepared reagents in order to avoid... 

Reformatsky reactions have a bad reputation as being difficult to entrain. To the authors experience, however, the reactive donors such as alkyl bromo-acetates do not pose particular problems even under rather conventional conditions. Commercial zinc dust activated by pre-treatment with either iodine of preferentially with cuprous chloride (i.e. Zn(Cu)) readily inserts into these halocarbonyl compound with formation of the corresponding zinc enolates. Protocols 1 and 2 describe prototype examples for Reformatsky reaction in the conventional two-step or Barbier-type set-up, respectively. 

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