Oxazolines nucleophilic addition reactions

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

The first use of chiral oxazolines as activating groups for nucleophilic additions to arenes was described by Meyers in 1984. " Reaction of naphthyloxazoline 3 with phenyllithium followed by alkylation of the resulting anion with iodomethane afforded dihydronaphthalene 10 in 99% yield as an 83 17 mixture of separable diastereomers. Reductive cleavage of 10 by sequential treatment with methyl fluorosulfonate, NaBKi, and aqueous oxalic acid afforded the corresponding enantiopure aldehyde 11 in 88% yield. 

Addition of 2-Alkyl-2-Oxazolines All of the above mentioned reactions of nucleophilic addition of nitrones give the corresponding hydroxylamines. In this chapter, the reactions of nitrones and nucleophiles and their conversions to compounds of other structures are considered. 

Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. 

More recently, Meyers and Kolotuchin reported that nucleophilic addition to the 1-position of the 3-methoxy-(2-oxazolinyl)naphthalene 513 is preferred over methoxy group displacement." The reaction works well and as expected for RLi (R = m-Bu, iec-Bu, and Ph). However, 1,2-addition to 513 to give the oxazohdine 515 predominates for RLi (R = Me, fert-Bu, and PhMe2Si) (Scheme 8.167). When 513 contained a chiral oxazoline (Ri = fert-Bu, R2 = H), a single diastereomer of 514 was obtained in moderate yields (56 and 60% for R = n-Bu and Ph, respectively). Standard oxazoline chemistry and functional group manipulations were used to convert 514 to a variety of useful, chiral tetralones 516. 

Reviews on stoichiometric asymmetric syntheses M. M. Midland, Reductions with Chiral Boron Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 2, Academic Press, New York, 1983 E. R. Grandbois, S. I. Howard, and J. D. Morrison, Reductions with Chiral Modifications of Lithium Aluminum Hydride, in J. D. Morrison, ed.. Asymmetric Synthesis, Vol. 2, Chap. 3, Academic Press, New York, 1983 Y. Inouye, J. Oda, and N. Baba, Reductions with Chiral Dihydropyridine Reagents, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 4, Academic Press, New York, 1983 T. Oishi and T. Nakata, Acc. Chem. Res., 17, 338 (1984) G. Solladie, Addition of Chiral Nucleophiles to Aldehydes and Ketones, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 2, Chap. 6, Academic Press, New York, 1983 D. A. Evans, Stereoselective Alkylation Reactions of Chiral Metal Enolates, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 1, Academic Press, New York, 1984. C. H. Heathcock, The Aldol Addition Reaction, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 2, Academic Press, New York, 1984 K. A. Lutomski and A. I. Meyers, Asymmetric Synthesis via Chiral Oxazolines, in J. D. Morrison, ed., Asymmetric Synthesis, Vol. 3, Chap. 

The next phase of the synthesis was installation of the dimethylamino-oxazoline ring system. This was constructed from the oxazolidinone precursor 19. Oxazolidinone formation occurred when 25 was reacted with thionyl chloride. The more nucleophilic carbonyl of 19 was then O-alkylated with the Meerwein reagent to give an iminium ion that readily participated in a nucleophilic addition/elimination reaction with dime-thylamine to give 26. The final step of the synthesis was O-deacetylation of 26 with sodium methoxide to provide (—)-allosamizoline hydrochloride in 98% yield after acidification. 

Coordination of the oxazolidinone 9 with the zinc complex activated the electrophi-licity of the alkene moiety toward addition of the nucleophilic radicals, but the stereodetermining step was the subsequent addition-fragmentation reaction of the intermediate radical with an allyltin reagent. A transition state XVIII similar to FV was proposed for the bis(oxazoline)-Mg complex-catalyzed Diels-Alder reaction reported by Corey [13], As the conformation of the bound a-amidyl radical formed by reaction with tert-butyl radical is s-cis [29a], the back face of the prostereogenic radical in XVni is shielded by one of the phenyl substituents on the oxazoline rings. So, the addition reaction occurred from the front face to the radical intermediate XVIII to give the (/ ) product from the (R,R) ligand 12. 

Certain heterocycles, e.g. pyridines or quinolines, bearing of an electron-withdrawing group such as oxazoline, undergo the Michael-type nucleophilic 1,4-addition accompanied with loss of aromaticity to give the new C-C bond. Thus formed dihydropyridine or benzodihydropyridine can be oxidatively aromatized with conservation of chirality, primary induced by an influence of chiral oxazoline moiety. In this manner, Meyers and coworkers [27] described the Michael-type addition of 1-naphthyllithium (609) to the oxazoline 610 at low temperature to form 611 in 90% yield. The latter was oxidatively aromatized to the naphthylquinoline 612 in 87% yield with 88 12 ratio of two diastereomers. Diastereoselectivity in this reaction remained on the same level as obtained by the nucleophilic addition of 609 to 610 indicating the virtually complete conservation of chirahty, from sp -type in the compound 611 to the axially chiral compound 612, Scheme 11. 

Oxazolin-5-ones (azlactones, 1) in general undergo ring-opening addition reactions with a variety of nucleophiles including water, alcohols,... 

A powerful application of such chiral oxazolines is found in addition reactions to substituted naphthalenes (Scheme 3.14) [71-73]. Chiral oxazoline 82 undergoes conjugate addition reactions with carbanions and other nucleophiles to furnish a stabilized carbanion intermediate 83 [71]. This could be trapped with a variety of electrophiles to provide products such as 84 with 98 2 diastereoselectivity. Following auxiliary removal, the sequence provides... 

Reactions of the same substrate with several nucleophiles were also catalyzed by the water-soluble Pd-complex of a phosphinite-oxazoline ligand which was prepared from natural D-glucosamine (Scheme 6.23) [53]. The catalyst dissolves weU both in water and in CH3CN but not in diethyl ether. Therefore the reactions could be ran either in water/toluene biphasic systems or in homogeneous water/CHaCN solutions. In the latter case, phase separation could be induced by addition of diethyl ether upon which the catalyst moved quantitatively to the aqueous phase. The product was obtained from the organic phase by evaporation of the solvent(s) and the aqueous solution of the Pd-complex was recycled. In aqueous systems the... 

Coordination to strongly orf/zo-directing groups is responsible for the regiochemistry of some other reactions which do not involve ortholithiation. For example, while the electron-withdrawing nature of the oxazoline would be expected to direct the addition of the organolithium nucleophile to benzyne 11 towards the meta position, the major product that arises is the result of addition at the ortho position to give 12 (Scheme 1). ... 

Oxazoline-directed conjugate addition of nucleophiles to a naphthalene nucleus is one of the most useful methods to prepare dihydronaphthalenes. Since Meyers last comprehensive review, the focus has been directed to stereoselective synthesis of these important compounds. Meyers laboratory has continued their preeminence in this field and has expanded the scope and applications of this reaction. 

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