Reformatsky reaction with imines

An enantioselective difluoro Reformatsky reaction with imines was disclosed recently by Ando and coworkers. According to this valuable procedure, , -difluoro-P-lactams are obtained directly due to an in situ condensation following the addition of the zinc enolate. For this purpose, ethyl bromodifluoroacetate 324b was allowed to react with Af-benzyl-protected imines 391 that are derived from aromatic aldehydes. Diethyl zinc was used to generate the zinc enolate. When the reaction was mediated by the amino alcohol 323, required in equimolar amounts, P-lactams 392 were obtained in fair chemical yields and remarkably... 

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. 

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. 

Reformatsky reaction with nitriles leads to the formation of imine, which readily hydrolyse to the ketones. Using appropriate nitrile, keto-y-butyrolactone is obtained in good yield (Scheme 31). 

The condensation reaction of an imine derived from an aldehyde with ethyl bromoacetate under Reformatsky53 conditions led to a mixture of amino-esters and P-lactams. When acetaldehyde was condensed with methylamine, Schiff base 4.116 was the product A Reformatsky reaction with ethyl bromoacetate gave a mixture of the P-lactam (4.117) and the amino-ester (4.118). Acid hydrolysis and hydrogenation led to the P-amino acid N-methyl-3-aminobutanoic acid (4.119). When benz-aldehyde was the aldehyde starting material, 3-(N-methylamino)-3-phenylpropanoic acid (4.120) was the final product. ... 

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... 

Reformatsky reaction has covered aspects of this topic (20b). If analogous pericyclic transition states are involved in these condensations, the added stereochemical control element imposed on the condensation by the imine geometry should provide a more well-defined set of transition states than for the analogous aldehyde condensations. The four diastereomeric chair and boat transition states for ( )- and (Z)-enolates with ( )-imines are illustrated in Scheme 15. 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

Reformatsky reactions of Af-(2-bromoalkanoyl)-l,3-benzoxazin-4-ones 267 and 272 and imines derived from aniline or /)-substituted anilines gave fra j -/3-lactams 273 with complete diastereoselectivity, and the l,3-benzoxazin-4-one auxiliary 269 could also be recycled. However, in the similar transformations of imines containing an o-methoxyphenyl substituent on the nitrogen, no cyclization to azetidinone occurred and /r -/3-aminocarboxamide derivatives 274 were the only products formed (Scheme 51) <2005S725>. 

Inspired by a bright report from Katritzky and coworkers on the use in Reformatsky reactions of a variety of benzotriazolyl aminals121, which in solution are in equilibrium with the corresponding imines, the formaldehyde aminal 61122 was reacted with lc, Zn and TMSC1 to give adducts 62 (equation 39), which can be successively converted into /3-lactams upon treatment with f-BuMgCl. 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

The joint effect of substituents and of temperature is clearly evident in imino-Reformatsky reactions of zinc dienolates197. At —78 °C, imines 194a-d react with crotonate derived zinc-dienolate 195, affording the products listed in Table 4. Imine substituents play a fundamental role in controlling the reaction regiochemistry. 

The indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates with ketones or aldehydes gives di-, tri-, and tetrasubstituted /3-lactones (Table 21).327-329 A similar reaction of imines with ethyl bromoacetate gives 3-unsubstituted /3-lactams (Equation (83)).330 331... 

Orsini reported the use of a 10 mol % Sml2-Mg reagent system in the Reformatsky reactions of a-halocarbonyl compounds, nitriles and phospho-nates with ketones, aldehydes and imines.29... 

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. 

For the preparation of chiral nonracemic dipeptide isosteres, Otaka and Fujii also reported the use of camphorsultam derivative 49, which was prepared in optically pure form through the Reformatsky reaction of BrCF2C02Et with a chiral imine (see Scheme 10.15) [25]. 

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]. 

Attempts to prepare homochiral -lactams using chiral reactants under Reformatsky conditions described above gave poor results.Good diastereoselectivities are observed in the reaction of lithium enolates with imines bearing a chiral group on either a nitrogen (equation 46)or carbon atom (equation 47). Esters derived from isobomeol-lO-diisopropylsulfonamide give enolates which condense with cinnamaldimines to yield cis -lactams with excellent enantioselectivity (equation 48). ... 

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 . ... 

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 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). 

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