2-Oxazolines nucleophilic reactions

Hydrolysis is undoubtedly the most common nucleophilic reaction at the 2-position. It is generally used to unmask the hydroxy amide or amino alcohol after synthetic manipulations on the oxazoline ring are completed. Hydrolysis under... 

A donor-acceptor zwitterionic polymerization has been mentioned 2-ethyl-oxazoline nucleophilic monomer reacts with the electrophilic N-phenyl maleimide giving a 1 1 adduct which polymerizes upon heating (Fig. 20). A similar reaction was observed between bismaleimide and bis-oxazoline giving a crosslinked network stable up to 300 °C [72]. 

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. 

N-Acylaziridine-2-carboxylates readily rearrange to oxazolines under thennal, acidic, or nucleophilic conditions [91, 123-127]. Treatment of trans-aziridine-2-car-boxylate 176 (Scheme 3.63) with Nal in acetonitrile, for example, resulted in ring-expansion product 177 through the so-called Heine reaction. The reaction involves initial opening of the aziridine ring by iodide and subsequent oxazoline ring-closure by Sn2 displacement of the resultant iodide intermediate [127]. 

The reaction of difunctional nucleophiles with alkyl isocyanides under the influence of silver cyanide as catalyst has been described in an earlier section on imidazoles an example of the use of this simple approach in an oxazoline synthesis is shown in Scheme 107.169... 

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. 

Aldol reactions of isocyanides with aldehydes are catalyzed by cationic platinum complexes having P-C-P or N-C-N ligands in the presence of a catalytic amount of an amine base to give 2-oxazolines (Equation (126)) 48S>485a>485b Platinum-coordinated a-isocyano carbanions presumably serve as nucleophiles toward aldehydes. Low to moderate enantioselectivities were obtained by using chiral platinum complexes.485 4853... 

The success of bis(oxazoline)-copper(II) catalyzed Diels-Alder reactions involving acryloylimides as dienophiles has been extended to the Michael reaction, Eqs. 204 and 205. The observed enantiofacial discrimination in the Diels-Alder reactions was expected to translate well to Michael reactions involving enolsilanes as nucleophiles. Indeed, fumarate-derived imides afford Michael adducts of enolsilanes in high enantioselectivity (240). Diastereoselectivity in these reactions may be regulated by judicious choice of thioester and enolsilane geometry to provide either diastereomer in high selectivity (>99 1 syn or 95 5 anti). 

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... 

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. 

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). ... 

A note of warning both MOM acetals and methyl ethers ortho to electron-withdrawing groups—particularly oxazolines, aldehydes, imines and amides—are susceptible to nucleophilic aromatic substitution reactions involving loss of the alkoxy substituent ... 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

Yokozawa reported that the 2-substituent strongly affects the reactivity of a 2-substituted-oxazoline 360 with dimethyl 2,2-dicyano-3-ethoxy-l,l-dicarboxylate as shown in Scheme 8.115. Thus, oxazoline itself, 360 (R = H), gave the annulated bicyclic product 361 that resulted from collapse of the zwitterionic intermediate 362, whereas simple 2-alkyloxazolines, 360 (R = Me, Et), gave an alternating (1 1) copolymer. 2-Phenyloxazoline, 360 (R = Ph), was unreactive under the reaction conditions. The zwitterionic intermediate 362 (R = Me) was trapped by acetic acid to give the open-chain adduct 363 that resulted from nucleophilic ring opening at the 5-position of the oxazolinium zwitterion. 

However, a more exciting application of this reaction is the oxazoline-directed synthesis of axially chiral biaryls. The oxazoline system not only activates the ortho-methoxy group for nucleophilic displacement but also determines the stereochemical outcome of the reaction. This provides a convenient method for the introduction of axial-chirality. Meyers group continues their earlier lead on this subject with reports of the stereoselective synthesis of tetrasubstituted biphenyls 391,392 examples are shown in Table 8.29 (Scheme 8.154). The best... 

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. 

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. 

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