Reformatsky procedure

The procedure employed has been previously described by Cason and Rinehart,3 and is a modification of the standard Reformatsky procedure.9-10 The Reformatsky reaction, which has been reviewed elsewhere,9 has been widely employed with ketones, somewhat less frequently with aldehydes, and very seldom with a-alkyl aliphatic aldehydes. 

It was more recently shown that the stable and crystalline 2-pyridyl sulfide of Neu5Ac derivative 204 is also an excellent precursor of the anomeric organometallic species, in this samari-um-Reformatsky procedure [96] (O Scheme 42). 

In contrast to other reported methods of 1,3-asymmetric induction, the Sml2-mediated intramolecular Reformatsky procedure permits strict control of stereochemistry even in diastereomeric pairs of substrates bearing a-substituents (equations 58 and 59). ° Although the diastereoselectivity is somewhat lower for the syn diastereomeric substrate, where the a-substituent would be axially disposed in the proposed transition structure leading to the product, 1,3-asymmetric induction is still predominant and overwhelms other effects to an impressive extent. 

The two-stage Reformatsky procedure was originally devised to avoid the reduction of quinone substrates by zinc, which was observed in a single-stage sequence. A two-stage sequence also allows successful reaction with nitrobenzaldehydes (equation 20), although in this case the problem is a marked inhibition of the reaction of zinc with the bromo ester by nitro aromatics. 

In 1973, Baldwin and Walker [19] described the Claisen rearrangement of the allylic and acetylenic esters of a-bromo carboxylic acids with zinc at higher temperatures through the Reformatsky procedure. Though the method was better, it was severely restricted as it becomes mandatory to prepare the corresponding bromo-ester from the system of interest before the rearrangement could be effected (Scheme 5.1.7). 

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... 

This procedure is an adaptation of ones described by Dunna-vant and Hauser.2-4 Ethyl /3-hydroxy-/S,/3-diphenylpropionate has been prepared previously using the Reformatsky reaction by condensing ethyl a-bromoacetate with benzophenone by means of zinc metal.5... 

This procedure illustrates the use of lithio esters for the preparation of /3-hydroxy esters. Isopropyl and /-butyl /3-hydroxy-/8,/3-diphenylpropionate may be prepared in approximately 80% yields by using isopropyl or /-butyl acetates in place of ethyl acetate.2 This procedure is generally more convenient than the Reformatsky reaction for the preparation of such esters. Under similar conditions ethyl acetate may conveniently be condensed with various aldehydes or ketones to give the corresponding /8-hydroxy esters.4... 

Since the advent of the one step procedure for the preparation of various substituted thenaldehydes (44), the majority of the necessary starting materials were readily available. Consequently, the Reformatsky reaction was studied with these compounds. With the a-bromoesters the reaction was successfully carried out with four of the thenaldehydes and 2-acetothienone. The nature of the product seemed to depend on the degree of branching of the bromoester. In only one case, where ethyl bromoacetate was used, was a hydroxyester obtained. However, when the carbon atom adjacent to the carbethoxy group was substituted, the product usually contained a hydroxyl group. The dehydration by means of aqueous oxalic acid resulted in a nearly quantitative conversion to the unsaturated esters. 

Esters of cyclohexylideneacetic acid have been prepared by the Reformatsky reaction followed by acylation and pyrolysis, a laborious procedure giving low yields. The phosphonate car-banion procedure would appear to be the method of choice for preparation of these esters. 

The Reformatsky reactions are run following two basic procedures (i) a two-step Grignard-type protocol which first involves the formation of an organometallic zinc eno-late derivative followed by addition of the electrophile, and (ii) a Barbier-type protocol where the bromoester and the electrophile are simultaneously exposed to the action of zinc metal. 

To better compare modern protocols for the Reformatsky reactions, hereinafter discussed in this section, it is interesting to read, as an example, the experimental procedure reported by R. B. Woodward and coworkers in 1956 for the synthesis of the Lysergic acid precursor 3 (equation 2)14. The procedure adopted was a Barbier-like protocol, involving the addition of Zn and of methyl bromoacetate (la) in three portions to a solution of 2 in hot benzene. 

A nickel-catalysed electro-Reformatsky reaction has been previously presented (Section . . , Figure 5)57. Based on a formally related catalytic cycle, a nickel-catalysed 3-component route to /J-arnino esters and amides has been proposed (equation 41). To a CH2CI2 solution of an aldehyde and an aromatic amine are successively added dimethylz-inc, methyl bromoacetate (la) and bistriphenylphosphine nickel dichloride. After 1-3 h at rt, products were isolated in very high yield, and this procedure was exploited for the preparation of a chemical library of 64 members, using 4 aldehydes, 4 cr-haloesters and 4 substituted anilines58. 

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. 

Etiolates Type Anions. The well-known Reformatsky reaction allows the introduction of a functionalized two-carbon chain. Modified experimental procedures have now been proposed, such as the reaction of ethylbromoacetate with ketosugar 18 (Scheme 10) in the presence of zinc/silver graphite prepared from CgK, giving 19 in excellent yield [32]. 

A three-carbon unit can be introduced on ketosugars under Reformatsky conditions, as recently demonstrated by several groups [33,34], The analogous Dreiding-Schmidt procedure has also been applied in this case with successful double stereodifferentiation [35]. This is exemplified on ketone 18 which yields lactone 20 as a single isomer (see Scheme 10). The condensation on ketosugars of trimethylsilylacetate [36] or acrylate [33], in the presence of fluoride ion, has also been used with success for the synthesis of P-hydroxy acids or ra-methylene-y-lactones, respectively. 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

Many of the procedures given above have been utilized for the preparation of mevalonolactone labeled with isotopes of carbon, hydrogen, and oxygen.7-9 Mevalonolactone-14C has been prepared with the label at all six positions l-,7 29 2-,7 143 24 3-,llb 3 -, 203,30 4-,7,183 and 5-14C.19 Preparations of singly and doubly labeled meva-lonolactone-13C have been reported recently 2-,26,31 3-,32 4-,33 3, 4-,7,183 3,4-,26,33b and 4,5-13C.34 The procedure described here26 for the preparation of mevalonolactone-2-13C is both convenient and economical compared to the usual Reformatsky methods since acetic acid-2-13C is utilized directly in the condensation reaction, rather than methyl or ethyl bromoacetate. The overall yield of mevalonolactone-2-13C is 46-52% based on acetic acid-2-13C. 

A simple procedure for the preparation of trifluoromethylated vinyl- and dienyl-phosphonates with y-alkoxycarbonyl moiety of exclusively or predominantly (Z)-configuration (201) has been described. It involves acylation of ethyl-1,1-bisphosphonate (202) with trifluoroacetic anhydride, addition of selected Reformatsky reagents to the resulting 1-trifluoroacetyl-1,1-ethyl bisphos-phonates (203) and finally spontaneous Horner-Wadsworth-Emmons (HWE) olefination of the adducts (Scheme 55). " ... 

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