Benzaldehyde Reformatsky reactions

The Reformatsky Reaction consists of the interaction of an ester of an a-halogeno-acid with an aldehyde, a ketone or another ester in the presence of zinc. For example, if a mixture of ethyl bromoacetate and benzaldehyde is heated with zinc, the latter undoubtedly first combines with the ethyl bromoacetate to form a Grignard-like reagent (reaction A), which then adds on to the benzaldehyde Just as a Grignard reagent would do (reaction B). The complex so formed, on acidification gives ethyl p-phenyl-p-hydroxy-propionate (reaction C). Note that reaction A could not satisfactorily be carried out using... 

Kitazume and Kasai [55] have investigated the Reformatsky reaction in three ionic liquids. This reaction involves treatment of an a-bromo ester with zinc to give an a-zinc bromide ester, which in turn reacts with an aldehyde to give an addition product. An example is given in Scheme 5.1-26. Moderate to good yields (45-95 %) were obtained in ionic liquids such as [EDBU][OTf] for the reactions between ethyl bro-moacetate or ethyl bromodifluoroacetate and benzaldehyde [55]. 

Fluorine-containing compounds can also be synthesized via enantioselective Reformatsky reaction using bromo-difluoroacetate as the nucleophile and chiral amino alcohol as the chiral-inducing agent.86 As shown in Scheme 8-41, 1 equivalent of benzaldehyde is treated with 3 equivalents of 111 in the presence of 2 equivalents of 113, providing a,a-difluoro-/ -hydroxy ester 112 at 61% yield with 84% ee. Poor results are observed for aliphatic aldehyde substrates. For example, product 116 is obtained in only 46% ee. 

In the first reports on the use of esters of 4-bromo-2-butenoic acid (191a and b, crotonic acid) and of 4-bromo-3-methyl-2-butenoic acid (191c, senecioic acid), the corresponding Reformatsky reactions with benzaldehyde were performed with the old-fashioned procedure, which required heating the haloester, the aldehyde and granulated zinc in benzene/ether mixtures at reflux temperature. 

Homo-Reformatsky reaction.1 The reaction of 1-ethoxy-1-trimethylsilyloxy-cyclopropane (1) with an aldehyde in the presence of ZnCl2 results in y-silyloxy esters via a zinc homoenolate (a) of ethyl propionate (equation I). Znl2 is the preferred catalyst in the case of reactions with acetophenone and benzaldehyde dimethyl acetal and in reactions of l-isopropoxy-l-(t-butyldimethylsilyl-oxy)cyclopropane with aromatic aldehydes. 

An enantioselective one-pot, three-component imino-Reformatsky reaction has been reported.20 Combining a benzaldehyde, an aniline, and an alkyl bromoacetate ester, (g) ees of up to 92% have been achieved in the /i-amino ester product, using a recyclable A-methylcphedrinc as auxiliary. A nickel(II) salt and dimethylzinc are employed the latter serves as dehydrating agent, reductant, and coordinating metal. 

More recently, Concellon has reported a stereoselective method for the formation of ( )-a,p-unsaturated esters that exploits a Sml2 Reformatsky reaction followed by an elimination.141 For example, ethyl dibromoacetate reacts with benzaldehyde in the presence of Sml2 to form samarium alkoxide 126, which is reduced further to give a second Sm(III) enolate 127. Elimination then affords ( )-a,p-unsaturated ester 128 in good yield (Scheme 5.90).141... 

Chiral Modification of Achiral Organometallic Reagents. The addition of n-Butyllithium or Ethylmagne-sium Bromide to aldehydes or ketones in the presence of (—)-sparteine resulted in the formation of optically active secondary or tertiary alcohols with 20% ee or lower. Optically active acyl sulfoxides (<15% ee) were obtained by acylation of p-Tolylsulfinylmethyllithium. The asymmetric Reformatsky reaction of ethyl bromoacetate with benzaldehyde proceeds with 95% ee, in an exceptional case (eq 1). ... 

Because of conflicting reports or inadequate controls, the question of kinetic or thermodynamic control of stereochemistry for reported Reformatsky reactions often has no satisfactory answer. Jacques and co-workers have concluded that Reformatsky reactions of benzaldehyde in refluxing benzene can be completed with kinetic stereoselection. The relatively high syn.anti ratios they observed, at least with small R groups (equation 36 and Table 4), are not those expected for equilibrated zinc chelates. 

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. 

Details have been given of the partial asymmetric syntheses of j -hydroxy-esters by the Reformatsky reaction in the presence of (— )-sparteine, reported in brief earlier. The optical purity of the products was occasionally very high, particularly when the carbonyl component was benzaldehyde, and reached 95 3 % in the reaction between benzaldehyde, zinc, sparteine, and ethyl bromo-... 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

The Reformatsky reaction, the zinc-mediated reaction of a-halo esters with aldehydes or ketones, may be considered an alternative to the aldol addition. As far as enantioselective versions are concerned, this method was much less developed than the aldol protocols [155]. In an early approach, Guette and coworkers explored the Reformatsky reaction of ethyl bromoacetate in the presence of stoichiometric amounts of sparteine although a high enantiomeric excess was observed with benzaldehyde (94% ee), the method was much less satisfactory for other carbonyl compounds [156]. According to a report of Yamano and coworkers, high enantioselectivity (up to 97% ee) was obtained when the Reformatsky reagent generated from ethyl bromoacetate was allowed... 

Treatment of a-iodo ketone and aldehyde with an equimolar amount of Et3B yielded the Reformatsky type adduct in the absence of PhaSnH (Scheme 21), unlike ot-bromo ketone as shown in Scheme 15 [22], Ethyl radical abstracts iodine to pro-duee carbonylmethyl radical, which would be trapped by EtsB to give the corresponding boron enolate and regenerate an ethyl radical. The boron enolate reacts with aldehyde to afford the adduct. The three-component coupling reaction of tert-butyl iodide, methyl vinyl ketone and benzaldehyde proceeded to give the corresponding adduct 38, with contamination by the ethyl radical addition product 39. The order of stability of carbon-centered radical is carbonylmethyl radical > Bu > Pr > Ef > Me . 

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