Reformatsky reagents with imines

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). 

In addition to aldehydes and ketones, organic compounds which are known to react with Reformatsky reagents include esters,nitriles, acid chlorides, organic halides,epoxides, nitrones, azirenes" and imines. This section describes the selectivity reported for Reformatsky reactions with functionally substituted aldehydes or ketones. 

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 reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

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. 

The condensation of an imine with a Reformatsky-type reagent and tandem reactions can result in asymmetric induction.3-207-484 87 The reaction of a ketene with an electron-rich alkene results in a [2+2] cycloaddition, although other systems can also be used,488 90 The stereochemistry of the adduct is cis, and functionalized ketenes can also be used. The ketene can be generated in situ (Scheme 26.21).491... 

Zinc enolates (Reformatsky reagents), generated finom a-bromo esters and zinc, react with imines derived finom aromatic amines to yield 3-lactams (Scheme 19).>40-142 -phe stereoselectivity of the reaction varies 4 >46 (jjg nature of ester substituents R and R the bulkier the groups, the more trans isomer is produced. 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

This chapter summarizes studies on the nature of the Reformatsky reagent as well as other, related, zinc enolates and outlines the synthetic aspects of the reaction with aldehydes and ketones. In addition, reactions of the Reformatsky reagent with imines and nitriles (the Blaise reaction) are described. 

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 . ... 

Addition of the Reformatsky reagent prepared from bromo ester 13 to imine 14 in benzene affords a 65% yield of trans jcis-fi-lactams 15 and 16 in 75 25 d.r. with trans-15 of d.r. [(3S,4R)/(3/f,4S)] 92 886. 

Reformatsky reaction. Reformatsky reagents are known to react with imines to afford P-lactams. The reaction can he applied to the synthesis of a,a-difluoro-p-lactams, and even chiral products. ... 

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