Reactions Reformatsky

The Reformatsky reaction using sonication gave excellent yields compared to the traditional methods using activated zinc or trimethyl borate as a cosolvent. In the sonication procedure the metal zinc is activated by iodine and the reaction 

The Ramberg-Backlund reaction has been nsed for the preparation of strained nnsatnrated ring componnds that are difficnlt to obtain by other methods. A recent example is the synthesis of ene-diyne 5 that has been used as starting material 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and snbseqnent reaction with an aldehyde or ketone 3. Nowadays the name is nsed generally for reactions that involve insertion of a metal into a carbon-halogen bond and snbseqnent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

By reaction of an a-halo ester 1 with zinc metal in an inert solvent snch as diethyl ether, tetrahydrofnran or dioxane, an organozinc componnd 2 is formed (a Grignard reagent-like species). Some of these organozinc componnds are qnite stable even a strnctnre elncidation by x-ray analysis is possible in certain cases  

The reaction with a carbonyl snbstrate 3 is similar to a Grignard reaction. Hydrolytic workup then yields the /1-hydroxy ester 4. Sometimes product 4 easily eliminates water to yield directly an a,j6-unsatnrated ester. 

The organozinc compound 2 is less reactive than an organomagnesium compound the addition to an ester carbonyl group is much slower than the addition to an aldehyde or ketone. Nevertheless the addition of 2 to the carbonyl group of unreacted a-halo ester 1 is the most frequently observed side-reaction  

The a -halosulfone, required for the Ramberg-Backlund reaction, can for example be prepared from a sulfide by reaction with thionyl chloride (or with N-chlorosuccinimide) to give an a-chlorosulfide, followed by oxidation to the sulfone—e.g. using m-chloroperbenzoic acid. As base for the Ramberg-Backlund reaction have been used alkoxides—e.g. potassium t-butoxide in an etheral solvent, as well as aqueous alkali hydroxide. In the latter case the use of a phase-transfer catalyst may be of advantage.  

An intramolecular version of this reaction was used by Vedejs and Ahmad in a synthetic study of the cytochalasin ring system. 23 reaction, 578 was cyclized to give 579 as a 1 1 mixture of epimeric 

The selectivity of the Reformatsky reaction is apparent in Table 9.16, 26,327 taken from Heathcock s work, which shows the syn/anti selectivity for the hydroxy ester products (anti product 580 and syn product 581) resulting from reaction of a-haloesters with ketones and aldehydes. 27 Aldehydes generally show poorer selectivity than do ketones for formation of the anti product. 580. The bromozinc aldolate products from ketones were shown to equilibrate under reaction conditions but those from aldehydes did not. Generally, increasing the size of R in the a-halo-carbonyl derivative led to greater anti selectivity. 

In more recent work, germanium catalysts such as GeClq gave a highly diastereoselective Reformatsky reaction favoring the syn diastereomer.228 Another syn selective reaction was reported using TiCl2 and Cu.229 Enantioselective Reformatsky reactions have also used chiral amino alcohols as additives.220 

Spectroscopic and crystallographic studies of Reformatsky reagents derived from a-halo esters showed that the enoiate is present in the C-enolate form and in ether solvents they form dimers. Enolates derived from a-halo ketones prefer the O-metal enoiate form. It is assumed, based on theoretical calculation, that the zinc enoiate dimers are dissociated by the action of the carbonyl compound and converted to the corresponding O-zinc enolates. Subsequently, the reaction goes through six-membered chairlike transition state. 

Wessjohn and co-workers successfully applied the CrCl2-mediated Reformatsky reaction for the synthesis of C1-C6 fragment of epothilones. In their approach, they utilized the Evans (R)-4-benzyl-oxazolidinone chiral auxiliary to control the absolute stereochemistry. The chromium-Re/brmafsAy reaction between the (R)-4-benzyl-3-(2-bromoacetyl)-oxazolidinone and 2,2-dimethyl-3-oxo-pentanal occurred with complete chemoselection providing the product with 63% yield and as a single diastereomer. 

Pettit and co-workers used a novel fefraA/s(triphenylphosphine)cobalt(0)-promoted Reformatsky reaction for the synthesis of a dolastatin 10 unit, dolaproine in a Boc-protected form.  

Nucleophilic addition of organozinc reagents generated from a-haloesters to carbonyls. 

Furstner, A. In Organozinc Reagents Knochel, P. Jones, P. eds. Oxford University Press New York, 1999, pp 287-305. (Review). 

Until recently, the magnesium, lithium, and, to a lesser extent, cadmium compounds were the only organometallic systems of much use in organic synthesis. This situation has changed drastically in the last few years. Compounds of copper have proven to be especially valuable. One of the first examples of these compounds is a reagent prepared from methyllithium and cuprous iodide this reagent is referred to as lithium dimethylcuprate. The reagent adds selectively at the /3-carbon 

It has also been established that protected functional groups can be present in the organocopper species. For example. Fried and co-workers synthesized the alcohol 1, converted it to the methoxyisopropyl ether to prevent interference by the acidic hydroxyl group, and then formed the organocopper reagent. This intermediate 

Corey and Posner discovered that lithium dimethylcuprate could replace iodine or bromine by methyl in a variety of compounds, including aryl and vinyl halides. This method of replacement of halide by alkyl is much more satisfactory and general 

Saturated epoxides are opened in good yield by lithium dimethylcuprate. The methyl group is introduced at the less hindered carbon of the epoxide  

Epoxides having vinyl substituents undergo attack by the reagent at the double bond, with a concomitant shift of the double bond and ring-opening  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 212, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 227, Springer International Publishing Switzerland 2014 

13 Chao, L. Rieke, R.D. Synth. React. Inorg. Met.-Org. Chem. 1975, 5,165. 

15 Scanning Electronic Microscope, Model ETEC U-1 was used for surface study. 

17 Maeda, T. Tada, H. Yasuda, K. Okawara, R./. Organomet. Chem. 1971, 

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CH2Br COOH. White crystalline solid, m.p. 50"C, b.p. 208 C. Soluble in water and alcohol. Prepared by the action of dry bromine on dry ethanoic acid in presence of small amounts of red phosphorus. Produces sores upon the skin used in chemical syntheses. See Reformatski reaction. 

Reformatski reaction Aldehydes and ketones react with a-bromo- fatty acid esters in the presence of zinc powder to give -hydroxy-esters which may be dehydrated to give a-, 0-unsaturated esters. a-Chloroesters will react if copper powder is used in conjunction with the zinc. 

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... 

This preparation illustrates the Reformatsky reaction, which consists in the interaction of a carbonyl compound, an a-halogen ester (e.g., ethyl bromo-acetate) and zinc In the presence of ether or benzene, followed by hydrolysis. 

This 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 Section VI,8) ... 

By analogy with the Reformatsky reaction, the zinc derivative of a p-bromoester would do ... 

Knoevenagel, Dieckmann, Stobbe, and Reformatsky reactions to name just a few. 

Beckmann rearrangement, 3, 710 Pyran-4-carbaldehyde, 2,2-dimethyl-tetrahydro-Reformatsky reaction, 3, 732 4H-Pyran-4-carbaldehydes synthesis, 3, 760-761 Pyran-2-carbonitrile, 5,6-dihydro-reactions, 3, 732... 

Reformatsky reaction. Similar R2CU R2Cd R2CuLi... 

Reformatsky reaction is the formation of p-hydroxyesters by reaction of a-bromoacid ester and a carbonyl compound, usually in the presence of zinc... 

Conversion of androstans to pregnanes via the Reformatsky Reaction 17a-pregn-5-ene-3/3,17/3,21-triol and ethyl 3/3-acetoxy-17/3-hy droxy-17a-pregn-5-en-21-oate, 139... 

Rearrangement of a,/B-epoxy ketones to ftdicarbonyl isomers, 307 Reductive alkylation, 97 Reductive cleavage of halo ethers, 264 Reductive degradation of 19-substitutional steroids, 277, 278 Reformatsky reaction, 139 Removal of the C-10 substituent in steroids. 272... 

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)-... 

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. 

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]. 

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