2-Oxazolines activating groups

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. 

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. 

The bidentate oxazoline ligands 85 and 86 (and derivatives thereof) are excellent reporter ligands, and several studies have used NOEs to determine the nature of their chiral pockets [61, 113, 114, 126]. NOESY studies on the cations [Ir(l,5-COD)(86)]+ and several cationic tri-nudear Ir(iii)(hydrido) compounds [110], e. g. [Ir3(p3-H)(H)5(86)3] +, 87, in connection with their hydrogenation activity, allowed their 3-D solution structures to be determined. In addition to the ortho P-phenyl protons, the protons of the oxazoline alkyl group are helpful in assigning the 3-D structure of both the catalyst precursors and the inactive tri-nudear dusters. Specifically, for one of these tri-nudear Ir(iii) complexes, 87 [110], with terminal hydride ligands at d -17.84 and d -21.32 (and a triply bridging hydride at 5 -7.07), the P-phenyl and oxazoline reporters define their relative positions, as shown in Scheme 1.5. 

The proton abstraction typically requires strong bases although weaker bases can be employed if the a-carbon is substituted with an additional activating group, such as an aryl group. " ° Deprotonation of chiral arylmethyloxazolines followed by alkylation gave modest levels of diastereoselection (up to 60% de). " Deprotonation of appropriately substituted 2-(allyloxymethyl)oxazolines resulted in... 

Ring closure of a 2-methoxyphenyl derivative of propanol to a chroman has also been achieved. Treatment of the aryloxazoline (259) with sodium hydride yielded the chroman (260) (81JOC783). The intramolecular nucleophilic displacement of the o-methoxy group is promoted through oxazoline activation and proceeds through an addition-elimination sequence. The initial attack involves coordination of the metal alkoxide to both the oxazoline moiety and the methoxy group, and aromatization follows with displacement of methoxide ion (Scheme 67). Hydrolysis of the oxazoline moiety to a carboxyl group has been accomplished. 

Our third example taken from a synthesis of the fully protected derivative 127,7 of Actinoidic Acid [Scheme 2.127], a constituent of Vancomycin, features the use of the oxazoline group as an activating group for an SNAr reaction, as a... 

Two further syntheses of Lactacystin also deployed a diastereoselective aldol reaction to create a quaternary centre.250-251 Smith and co-workers,250 protected the 1,2-amino alcohol 129.1 [Scheme 3.129] by heating with trimethyl orthobenzoate to give the oxazoline 129 2 in 82% yield. The oxazoline served the dual puipose of protecting and activating group in the subsequent aldol reaction... 

Furans and thiophenes normally undergo a-lithiation, but when substituted at the 2-position by an activating group, a competition arises between metalation at the 3-position (ortho lithiation) and the S-posi-tion (a-lithiation). 2-Oxazolinylthiophenes may be lithiated selectively at either the 3- or 5-position by adjusting the reaction conditions tertiary amides give little or no ortho selectivity, but secondary amides direct ortho lithiation reasonably well, as seen in Scheme 23. Both thiophenes and furans that are substituted with an oxazoline or tertiary amide at the 2-position may be dilithiated at the 3- and S-po-sitions. 76 Although secondary amides are less successful at directing ortho lithiation of furans than thiophenes, A, Af,M,lV -tetramethyldiamido phosphates work quite well. Subsequent hydrolysis affords access to butenolides. A typical example is shown in Scheme 24. 

Oxazolines (4) are easily prepared from benzoic acids and behave as activating groups in nucleophilic aromatic substitution. Thus, o-methoxy- or o-fluoro-substituents are replaced by the alkyl group of RLi. " The same oxazoline group in the 4-position of pyridine promotes 3-lithiation, whereas in the 3-position it induces nucleophilic alkylation to give 1,4-dihydropyridine derivatives. Benzyl alcohol is lithiated in the 2-position of the benzene nucleus. Solvent effects are suggested to be responsible for the quantitative syn selectivity in the alkylation of lithiated ketimines (5). ... 

These oxazolines have cationic surface-active properties and are emulsifying agents of the water-in-oil type. They ate acid acceptors and, in some cases, corrosion inhibitors (see Corrosion). Reaction to oxazoline also is useful as a tool for determination of double-bond location in fatty acids (2), or for use as a protective group in synthesis (3). The oxazolines from AEPD and TRIS AMINO contain hydroxyl groups that can be esterified easily, giving waxes (qv) with saturated acids and drying oils (qv) with unsaturated acids. 

Meyers has also reported the use of chiral oxazolines in asymmetric copper-catalyzed Ullmann coupling reactions. For example, treatment of bromooxazoline 50 with activated copper powder in refluxing DMF afforded binaphthyl oxazoline 51 as a 93 7 mixture of atropisomers diastereomerically pure material was obtained in 57% yield after a single recrystallization. Reductive cleavage of the oxazoline groups as described above afforded diol 52 in 88% yield. This methodology has also been applied to the synthesis of biaryl derivatives. 

Hie Leterocydic component in tlie leaving group offers possiLililies for introduction of diirality. Optically active oxazolin-2-yl and tliiazolin-2-yl allyl tliioetliers 7 were tlius diosen as suLstrales (Sdienie 8.8) [17]. 

The aza-bis(oxazoline) 14, bearing sterically hindering groups, led to very good results in terms of activity and selectivity, comparable to those obtained from corresponding aza-semicorins or bis(oxazolines). For the enantioselec-tive cyclopropanation of styrene, the trans isomer was obtained in 92% ee... 

The same group [97] studied the corresponding rhodium oxazoline complexes that led to very similar results in terms of activity (81% yield) and enantioselectivity (68%), however. 

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