Reformatsky reactions applications

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Non-Kolbe electrolysis of alicyclic p-hydroxy carboxylic acids offers interesting applications for the one-carbon ring extension of cyclic ketones (Eq. 35) [242c]. The starting compounds are easily available by Reformatsky reaction with cyclic ketones. Some examples are summarized in Table 13. Dimethylformamide as solvent and graphite as anode material appear to be optimal for this reaction. 

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... 

Application of the Reformatsky Reaction to Thiophene Aldehydes and Ketones. J. org. Chemistry 15, 89 (1950). 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

Two simple applications may be mentioned. With cyclohexene, 3-bromo-cyclohexene is obtained in a satisfactory yield (Expt 5.68), the latter upon dehydrobromination with quinoline affords an 80-90 per cent yield of cyclo-hexa-1,3-diene (Expt 5.13). Methyl crotonate yields the valuable synthetic reagent methyl y-bromocrotonate (Expt 5.69) this latter compound permits the introduction (in moderate yield) of a four-carbon atom chain at the site of the carbonyl group by the use of the Reformatsky reaction (compare Expt 5.170) ... 

Table 14.1 Some applications of the Reformatsky reaction in natural product synthesis...

Inanaga and coworkers [109] used a modified intramolecular Reformatsky reaction in the synthesis of the beetle aggregate phermone ferrulactone I (187). As shown in Scheme 61, precursor 185 was cyclized with Smij followed by acylation of the resulting unstable P-hydroxydecadienolide to afford the 11-membered lactone benzoate 186 in 47% yield. There are more applications of the Reformatsky reaction for macrocyclization [110]. 

Sonochemistry has been applied to acceleration of the Reformatsky reaction, Diels-Alder reactions, the arylation of active methylene compounds nucleophilic aromatic substitution of haloarenes, and to hydrostannation and tin hydride reduction. " Other sonochemical applications involve the reaction of benzyl chloride and nitrobenzene, a Sr I reaction in liquid ammonia at room temperature, and Knoevenagel condensation of aromatic aldehydes. lodination of aliphatic hydrocarbons can be accelerated, and oxyallyl cations have been prepared from ot,ot -diiodoketones using sonochemistry. Sonochemistry has been applied to the preparation of carbohydrate compounds.When sonochemistry is an important feature of a chemical reaction, this fact will be noted in the reactions presented in Chapters 10-19. 

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]. 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

Latouche, R., Texier-Boullet, R, and Hamelin, J., Reactivity of silylated compounds with active methylene under microwave irradiation in heterogeneous dry media. Application to the alkali metal fluoride-mediated silyl-Reformatsky reaction. Bull. Soc. Chim. Fr., 130, 535, 1993. 

Reactions exhibiting diastereofacial selectivity, which occur when the imine or the enolate contains an endogenous stereocenter or a chiral auxiliary, have important applications for the synthesis of optically active 3-l ctams and 3-amino carboxylic acid derivatives. Early work by Furukawa et al. has demonstrated the viability of preparing optically active 3-amino acids from chiral imines. For example, the Schiff base derived from (5)-a-methylbenzylamine (110) reacts with Reformatsky reagent (111) to give, after hydrolysis and removal of the chiral auxiliary, 3-amino-2,2-dimethyl-3-phenylpropionic acid (112) in 33% ee (Scheme 21). Similar Reformatsky reactions have been performed using (-)-menthyl esters but the enantiomeric excess values are lower. ... 

The most important organometallic reagents used for the carbon-carbon bond formation in carotenoid synthesis are the metal acetylides, metal alkenyls and the Gngnard reagents. However the Reformatsky reaction has also been applied and recently also transition metals such as Pd, Ni, Cu and especially low valent Ti have been used. The application of organometallic reactions for the synthesis of carotenoids and retinoids has recently been reviewed [39]. 

Zinc and Mercury. - New methods for the preparation of reactive forms of zinc broaden the synthetic applications of this metal. The use of a Zn/Ag- graphite reagent, prepared from CgK and ZnC /AgOCOCHg, allows the Reformatsky reaction to be carried out efficiently at low... 

Of the various organometallic reactions employed in carbon-carbon bond formation, the metal acetylide, Grignard, and Reformatsky reactions have been the most prevalent in the synthesis of vitamin A (7) and carotenoids [1]. However, there has been considerable interest in the applications of transition metals and, for the preparation of symmetrical carotenoids, low valent titanium. This article is divided according to the metals used in carbon-carbon bond formation, with further subdivisions based on reaction type and/or putative reactive intermediates. For multi-step syntheses, only the steps that employ metals in carbon-carbon bond formation are discussed and, whenever possible, the reaction conditions and yields are indicated on the reaction schemes. 

Rieke metal has broad application in organic synthesis that requires an active metal of low valence, such as the McMurry Coupling (Cr) and the Reformatsky Reaction (Zn). 

After the successful application of Zn/TMSCl in the Reformatsky reaction [82] (see also more recent work in this field [83-85]), the same combination was applied in Zn-Barbier reactions with allylic bromides in diethyl ether [86] ... 

The application of this type of activated zinc in a Reformatsky reaction was reported one year later [59]. 

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