In the Reformatsky reaction

This result is similar to that obtained in the Reformatsky reaction (16-31), but this is more general since no ester or other group is required to be a to the halogen. Another important advantage of the Wittig reaction is that the position of the new double bond is always certain, in contrast to the result in the Reformatsky reaction and in most of the base-catalyzed condensations (16-38-16-46). Examples of this are given below. 

Highly reactive zinc can be prepared by reduction of anhydrous ZnC with potassium/THF or sodium/DME(l 7,29). This zinc has been shown to undergo rapid oxidative additions with alkyl bromides to produce near quantitative yields of the corresponding dialkylzinc. It also underwent oxidative addition with phenyl iodide and bromide. Moreover, the zinc was found to be useful in the Reformatsky reaction. Reactions could be carried out in diethyl ether at room temperature to generate near quantitative yields of the 3-hydroxyester. 

Carbohydrate lactones have been used as the carbonyl reagent in the Reformatsky reaction. Thus, 2,3 5,6-di-O-cyclohexylidene-D-mannono-1,4-lactone [44, obtained by oxidation of the mannofuranose derivative (49)] reacted with ethyl bromoacetate and zinc to give the protected 2-deoxy-3-octulosonic acid ethyl ester (45a) in 69% yield (50). Ketonic hydrolysis with potassium hydroxide in aqueous methanol, followed by acidification and heating, afforded the 1-deoxyheptulose derivative 45b. Similarly, starting from compound 44, the 1-C-substituted allyl and propar-gyl lactols were prepared on reaction with allyl or propaigyl bromides in the presence of zinc (51). 

In the example given in Scheme 3j18 the primary step in the Reformatsky reaction is the addition of the halide reagent and zinc to the protected peptide 12 in THF hydrolysis of the intermediate formed results in the corresponding difluoroalkyl alcohol 13. Since compound... 

Methyl 4-bromobut-2-enoate (BrCH2-CH=CH,C02Me, a vinyl analogue of ethyl bromoacetate, Expt 5.69) can also be used in the Reformatsky reaction, and its use permits an analogous four-carbon atom chain extension process. 

Even unreactive alkenes undergo the Simmons-Smith reaction (cyclopropanation) in high yield with dibromomethane and this zinc powder. Almost quantitative yields are obtained in the Reformatsky reaction of ethyl a-bromoacetate and this zinc powder. Ethyl a-chloroacetate can also be used if the reaction is conducted at higher temperatures for a longer period. 

Reformatsky reaction.6 Ultrasonic radiation is beneficial in the Reformatsky reaction. Yields are > 90%, and the rate is enhanced. Specially activated zinc is not necessary. However, iodine and potassium iodide are effective additives, possibly by suppressing enolization. The solvent of choice in this variation is dioxane. 

A. Fiirstner, Recent Advancements in the Reformatsky Reaction, Synthesis 1989, 8, 571-590. 

Orsini reported the use of a 10 mol % Sml2-Mg reagent system in the Reformatsky reactions of a-halocarbonyl compounds, nitriles and phospho-nates with ketones, aldehydes and imines.29... 

The bicyclic core of the targets was constructed using a Sml2-mediated Reformatsky reaction (Scheme 7.26). Shiina found that the use of HMPA in the Reformatsky reaction had a dramatic effect on its outcome. When a-bromo ester 58 was treated with Sml2 in the absence of HMPA, alcohol 60 (containing the incorrect stereochemistry required for the natural products) was obtained... 

N,N-Dialkyl-oi.-halo amides may be substituted for a.-halo esters in the Reformatsky reaction. The yields of N,N-dialkyl-/3-hydroxyamides compare favorably with those of the corresponding hydroxy esters (cf. method... 

Dialkylzinc compounds are an alternative source of zinc in the Reformatsky reaction. When an a-bromo ester, an aldehyde, and diethylzinc were reacted in THE with a rhodium catalyst, the p-hydroxy ester was formed. ... 

Application of zinc as a sacrificial anode often overcomes the difficulties with activation of zinc in the Reformatsky reaction and the problems with uncontrolled exothermic reactions. When zinc or indium is employed for the reaction, the amount of electricity used is less than the theoretical, and this suggests that the anode acts as activated metal and reacts with the bromo compound [175]. 

Leaving groups on the a-carbon of carbonyl compounds (e.g., Br and OR) are reduced away by one-electron reducing agents. a-Bromocarbonyl compounds are reduced to the corresponding enolates by Zn in the Reformatsky reaction (Chapter 2). After the initial electron transfer, several pathways are possible, but all lead to the enolate. The enolate is usually allowed to react immediately with an electrophile such as another carbonyl compound. Before the advent of strong, non-nucleophilic bases, the Reformatsky reaction was the only way to prepare enolates of simple carbonyl compounds quantitatively. 

In the Reformatsky reaction, an ester with an a-halogeno substituent is treated with zinc, and so forms a masked carbanion, which in turn can react with a carbonyl compound to form a 3-hydroxyester. In the Darzens condensation, an a-halogenoester, on treatment with a base, reacts with a carbonyl compound to form an a,P-epoxyester. 

Cure and Gaudemar5 report that yields in the Reformatsky reaction are generally improved if the reaction is carried out in two steps. First, the a-bromo ester (1) is converted into an organozinc bromide (2) by reaction with zinc in pure and dry dimethoxymethane.6 This derivative is apparently formed in almost quantitative yield. The aldehyde or ketone is then added at 0°. The /3-hydroxy ester is obtained in about 60-90% yield. 

The optimum approach to kinetic stereoselection in the Reformatsky reaction would appear to be the use of two-stage procedures, which allows the zinc aldolates to be formed at the lowest possible temperature. Gaudemar-Bardone and Gaudemar prepared a variety of zinc ester enolates in dimethoxymethane at 40 C which were then reacted at lower temperatures with benzaldehyde or with acetophenone (equation 38). Selected data from their study are shown in Table 5. If these data are the result of total kinetic control, as concluded by the authors, it is clear that the reactions exhibit only a modest kinetic stereoselectivity. 

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