Oxazoline anions addition reactions

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

OrganometaUic nucleophiles are also useful for MIRC cyclopropanation. The treatment of chloroalkyl oxazoline with LDA generated an oxazoline anion, which underwent cyclopropanation with alkenes through conjugate addition followed by intramolecular substitution [14]. The unsaturated Fischer carbene complex was also useful (Scheme 1.10) [15]. MIRC reactions to heterocyclic compounds have also been reported [16]. 

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. 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

In their synthesis of spirocyclopropanated oxazolines (see Section 2.1), the de Meijere group obtained initially unexpected cyclobutene-annelated pyrimidones 2-569 by reaction of the cyclopropylidene derivative 2-567 with the amidines 2-568. In this fourfold anionic transformation a Michael addition takes place to furnish 2-570, which is followed by an isomerization affording cyclobutenecarboxylates 2-572 and a final lactamization (Scheme 2.128) [294]. 

S-Ethenylsulfimines 287 react with amides to yield 2-substituted-oxazolines 28 9 304 reaction proceeds via initial Michael addition of an amide anion to 287 to give 288 that collapses to the oxazoline. The reaction is typically carried out at room temperature or 50 °C in THF, 1,2-dimethoxyethane (DME), or even MeCN using NaH as the base. Aryl, heteroaryl, and aliphatic amides can be used and the yields of 289 are modest to excellent (Scheme 8.82). 

The absolute configuration of 1 was set by conjugate addition to the oxazoline 3 followed by trapping of the product anion, following the precedent of Meyers. Reduction of the oxazoline to the alcohol, followed by thionocarbonate formation then set the stage for the key aryl transfer reaction. 

A. Barco, S. Benetti, C. De Risi, G. P. Pollini, G. Spalluto, and V. Zanirato, 4-Isopropyl-2-oxazolin-5-one anion as a new convenient formyl anion equivalent for conjugate addition and aldol reactions. Tetrahedron Lett. 34 3907 (1993). 

The thioacetal-/i fT-butylthio(2-pyridylthio)methane is deprotonated adjacent to sulfur on treatment with -BuLi and the anion undergoes diastereoselective and enantioselective addition to a range of aromatic and alkylaldehydes in the presence of the chiral bis(oxazoline) 122. For example, reaction with benzaldehyde proceeds to give anti- and syn-adducts 123 and 124 in 93% yield and 86 14 ratio, respectively <2004JOC1581> (Equation 89). 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

Insertion into Carbon-Carbon o-Bonds. First examples of this concept were reported with anionic nucleophiles in the context of the addition of a-lithioalkyl and a-lithioarylacetonitriles to arynes. In 1984, Meyers and Pansegrau proposed a cyclization rearrangement mechanism to account for the formation of products 77 in the reaction of a-lithioacetonitriles to 3-oxazolylbenzyne. Initial attack of the nucleophile takes place at C-2 probably due to chelation of the lithium atom from the lithiated nitrile to the oxazoline moiety (Scheme 12.40) [67]. 

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