Reformatsky products

Bieber reported that the reaction of bromoacetates is greatly enhanced by catalytic amounts of benzoyl peroxide or peracids and gives satisfactory yields with aromatic aldehydes. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, is proposed (Scheme 8.27).233 However, an alternative process of reacting aldehydes with 2,3-dichloro-l-propene and indium in water followed by ozonolysis provided the Reformatsky product in practical yields.234 An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported.235... 

Reformatsky product (46). Treatment of 46 with methanol and an acid ion-exchange resin afforded the methyl glycoside 47a, the product of partial hydrolysis (47b), and the 3,8-anhydro sugar 48. Synthetic transformations were performed on these products (52). 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

Albaiges et al. have continued their work on the synthesis of menthenols and menthadienols, preparing menth-3-en-8-ol (126), menth-l(7)-en-8-ol (127), and mentha-l(7),4(8)-dien-9-ol (128). These syntheses involve dehydrating the Reformatsky product (129) obtained from a 4-substituted cyclohexanone (130) and ethyl a-bromoproprionate with phosphorus oxychloride. Conventional treatment of the separated products [(131a), (131b), etc.] leads to the desired substances. 

Organic Syntheses 61, 122 (1983) non enolizabte aldehydes react differently, giving Reformatsky products (E. Nakamura, M. Shimuzu and I. Kuwajima, Tetrahedron Lett. 1699 (1976)),... 

Efficient Synthesis of Cardenolides. A general and efficient method has been described for the synthesis of cardenolides, consisting of (1) a-methylsulfenylation of pregnen-20-one, (2) Refor-matsky reaction, and (3) butenolide formation by alumina chromatography of the epoxy ester obtained from the S-methylated Reformatsky product (eq 4). ... 

Heating 1-phenyl-1-benzoylcyclopropane with excess ethyl bromo-acetate and 20-mesh zinc at reflux for 17 h gave a 47% yield of the Reformatsky product along with 55% recovered ketone [85]. What could be done to improve this reaction ... 

Dehydration of the /S-hydroxy ester Reformatsky products to the corresponding a,/3-unsaturated derivatives can be effected by heating with POCls-pyridine, p-TsOH or molten KHSO4 under acidic conditions. By this means the Reformatsky reaction has been used as an alternative to the Wittig-Homer method, especially in the synthesis of carbon-14-labeled steroids and terpenoids. 

Synthesis Control will be needed in the condensation as the ketone C is more reacfiye than the acid D both in enolisation and electrophilic power. The Reformatsky looks a good method. Again we don t know how this commercial product is actually made ... 

Likewise, a cis-2,6-disubstituted piperidine natural product, (-)-lobeline (98, Scheme 8.4.30) was synthesized from the chiral Af-alkyl pyridinium salt ent-80 via a sequence that included addition of a Reformatsky reagent to an intermediate oxazolidine. °... 

Bromination of the methyl group of (249) with A -bromosuccinimide, followed by reaction with excess secondary amine gave (250) which shows combined analgesic and antitussive properties. The Reformatsky reaction has also been used for the preparation of 2-amino-ethyl 3,3-diaryl-3-hydroxypropanates (251) as well as their dehydration products. The propene amides (252) have also been prepared for pharmacological evaluation. In l-methyl-3-bis (2-thienyl)-... 

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]. 

The Reformatsky reaction is a classical reaction in which metallic zinc, an a-haloester, and a carbonyl compound react to give a (i-hydroxyester.162 The zinc and a-haloester react to form an organozinc reagent. Because the carboxylate group can stabilize the carbanionic center, the product is essentially the zinc enolate of the dehalogenated ester.163 The enolate effects nucleophilic attack on the carbonyl group. 

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90).226,227 A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91).228 The combination of BiCl3-Al,229 CdCl2-Sm,230 and Zn-Et3B-Eb0231 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospecific and syn-diastereoselective (Eq. 8.92).232... 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

We felt the Reformatsky reaction was a worthwhile target because it is the most generally applicable method for converting aldehydes and ketones to ff-hydroxyesters(25). The improvements in yield and reaction time exceeded our expectations. Essentially quantitative conversion to the 0-hydroxyester was effected in a matter of a few minutes(26). The absence of other products, such as a, 0-unsaturated esters, resulting from dehydration, and dimers of the bromo ester and the carbonyl are probably the result of running... 

Reformatsky reagent 214 also reacted with cr-nitrostyrenes 215 to form the corresponding 1,4-addition products 216 in good yields (Scheme 121).320 The optimal conditions for the reaction were determined to be 48 h at 60 °C. A 3 1 mixture of C6H6-THF gave better yields than THF alone, although the latter is the most common solvent for this type of reaction. 

Higher-molecular-weight normal 2-alkenoic acids have been prepared in poor yields by the Doebner condensation of aldehydes with malonic acid,5-7 and by the Reformatsky reaction of aldehydes with ethyl bromoacetate followed by dehydration.8 The a-iodo acid, prepared from the bromo acid, has been dehydrohalogenated with potassium hydroxide in ethanol,9 but large quantities of the a-hydroxy acid are formed as a by-product which is difficult to separate in some instances. The present procedure is an adaptation of a published method.6... 

Moreover, Soai et al.53c found that the enantioselective addition of Reformatsky reagents to prochiral ketones proceeds well when N,N-dialkylnorephedine 59 is used as the chiral ligand. When (15, 2R)-59a is used, the //-hydroxyl ester is obtained in 74% ee and 65% yield with ( -configuration predominant. When (lR,25,)-59a is used, the product is obtained in 74% ee and at 47% yield with (R)-configuration prevailing. 

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. 

Asymmetric intramolecular Reformatsky reactions/ The bromoacetates (1) of (3-hydroxy ketones undergo a Reformatsky-type reaction when treated with Sml2 to give (3-hydroxy-8-valerolactones (2). These products are useful in their own... 

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

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