Reformatsky reagent condensation with

Gemcitabine (Gemzar ) is prepared from the 2,2-difluoro-2-deoxyribose, itself available by the addition of the Reformatsky reagent of ethyl bromodifluoroace-tate on the (R)-2,3-0-isopropylidene glyceraldehyde. The condensation of the corresponding mesylate with di(trimethylsilyloxy)pyrimidine provides gemcitabine [93]. The control of the stereoselectivity of the Reformatsky reaction is difficult (Fig. 30) [95]. Other approaches involving the fluorination of D-pyranoses have been proposed (Fig. 31) [96]. 

Condensation of the Reformatsky reagent of ethyl bromodifluoroacetate with an imine affords difluoroazetidinone. This latter compound is a precursor of 2,2-difluoro-2-deoxyaminopyranoses. ... 

Equations 36-39 suggest that fluorine substituents at the a position of the ester enolate play a role in favouring the formation of /J-arnino esters. This conclusion is supported by the condensation of the Reformatsky reagent deriving from 20 with imines, the only product being the open-chain adduct 63 (equation 40)123. 

There is a competition between alkoxymethylation and acylation in this reaction. Alkoxymethylation by cleavage of acetals is also applicable to alcoholates obtained by condensing Reformatsky reagents with aldehydes and ketones (98, 174a). 

Reformatsky reagent. Ethyl Irichloroacetate reacts with zinc in THE at -15° to form a stable chlorozinc cnolate (1). This reagent can be condensed with a number of... 

The Reformatsky reaction is the reaction of an a-halo ester with an aldehyde or ketone in the presence of zinc metal as shown in Scheme 1. The usual product of the reaction is a -hydroxy ester, which may be dehydrated in subsequent steps to give an unsaturated ester. A zinc ester enolate (1), the so-called Reformatsky reagent, is an intermediate in the reaction and the sequence is thus classified as an aldol condensation. Compared to the usual base-promoted aldol procedures, the distinguishing features of the Reformatsky reaction are the use of a metal-halogen redox reaction rather than an acid-base reaction to form the enolate, and the fact that the counterion of the enolate is zinc. 

It seems likely that many simple a-bromo esters can be reacted with zinc to produce the Reformatsky reagent nearly quantitatively, and that the reagent forms condensed ester primarily in a subsequent step. A successful synthesis of a Reformatsky reagent should then depend strongly on the time and temperature required for the preparation. Recently, a number of methods, including ultrasound promotion and the use of highly active forms of zinc, have allowed completion of the Reformatsky sequence in... 

Condensations conducted at low temperatures using preformed Reformatsky reagents gave P-amino esters that have almost exclusively the syn configuration (34 Scheme 16). These may be cyclized by forming the magnesium salt to give the pure cis-p-lactam. It was concluded that the first step of the reaction is reversible at reflux temperature and equilibration of syn and anti zinc salts, (35) and (36), is competitive with irreversible cyclization, as shown in Scheme 17. ... 

Condensation reactions of simple carboxylic acids with imines are of intense interest because of their applications to 3-lactam synthesis. Activation of the carboxylic acid derivative is accomplished by preforming the enolate in situ or by using a silyl ketene acetal derivative with Lewis acid catalysis. The first example of an enolate-imine condensation of this type can be attributed to Gillman and Speeter, who in 1943 reported the synthesis of 3-lactams from Reformatsky reagents and Schiff bases. Subsequently, other workers have investigated the mechanism and syn-anti selectivity of this reaction. A review of these studies by Evans et al. covering work through 1980 has appeared in their review, Stereoselective Aldol Condensations . ... 

The reaction of imines with Reformatsky reagents was first examined by Gilman and S pee ter82 in 1943 with benzalaniline. The product of the reaction was a (3-lactam, formed by cyclization of an intermediate zinc salt (Scheme IS). The stereoselectivity of the reaction of a-alkyl-substituted bromo esters with a variety of benzalanilines was examined by both Luche and Kagan,83 and Gaudemar and coworkers.84 Condensations conducted at reflux temperatures gave a mixture of cis and trans 3-lactams (equation 41). 

This reaction is believed to proceed by a mechanism analogous to that of the Reformatsky Reaction involving an initial condensation of the nitrile with the Reformatsky reagent the intermediate is finally transformed into 0-keto ester via acidic hydrolysis,as illustrated here. 

A synthesis of (313) from cycloheptanone and p-bromobenzoic acid which involved protection of the carboxylic acid function as its oxazoline derivative, has been described. Benzsuberone was converted into a mixture predominantly containing (314) by a Reformatsky reaction, and to (315 mixture of isomers) by condensation with the Grignard reagent of ethoxyacetylene followed by hydrolysis. 

The Reformatsky reagent from ethyl difluorobromoacetate is prepared with zinc under sonication (Ch. 5, p. 232). Its relative stability allows its condensation with aldehydes to be effected under sonication in a separate step (Eq. 14). This procedure gives cleaner products than with the traditional one-step process.ios... 

In 1887, the Russian chemist Sergei Reformatsky at the University of Kiev discovered that treatment of an a-haloester with zinc metal in the presence of an aldehyde or a ketone followed by hydrolysis in aqueous acid results in formation of a /3-hydroxyester. This reaction is similar to a Grignard reaction in that a key intermediate is an organo-metallic compound, in this case, a zinc salt of an ester enolate anion. Grignard reagents, however, are so reactive that they undergo self-condensation with the ester. 

The first step is considered to involve the condensation of the Reformatsky reagent with benzonitrile to yield the Zn-salt 5. C-alkylation by bromoacetate, followed by ring closure, is believed to lead to the hitherto elusive key intermediate 6A, a pyrrolinone ester. Condensation with a second molecule of benzonitrile and subsequent cyclization of intermediate 7, which could be isolated and was also mentioned by Famum, finally affords the DPP 2. 

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