Additives 2-Oxazolines

The additional oxazoline ligation is expected to deactivate the complexes in their Lewis acidity, as was shown in a theoretical study on (BOX)Cu catalysts [23]. The transformation of the resting state into the active (17e Cu ) species therefore necessitates the decoordination of an oxazoline unit and the opening up of the system (Scheme 15.3, top). The required hemilability is provided siereoe/ec-tronically by the strong dynamic Jahn-Teller effect of the d Cu" center. As a consequence of the threefold rotational symmetry of the system, all the possible dicoordinated catalytically active species (A-C) are equivalent (Scheme 15.3, bottom). 

Recently Desimoni et used the same bis(oxazoline) ligand in the magnesium(II) catalysed Diels-Alder reaction of the N-acyloxazolidinone depicted in Scheme 3.4. In dichloromethane a modest preference was observed for the formation of the S-enantiomer. Interestingly, upon addition of two equivalents of water, the R-enantiomer was obtained in excess. This remarkable observation was interpreted in terms of a change from tetrahedral to octahedral coordination upon the introduction of the strongly coordinating water molecules. 

Photochemical additions to give four-membered rings are known. Thus the reactions of imidazoles across the 4,5-bond with benzophenone and acrylonitrile are illustrated by (278) (279) and (280) (281), respectively (80AHC(27)24l). Oxazolin-2-one undergoes... 

In contrast to the above additions A-allyl- and substituted A-allyl-amides, -urethanes, -ureas and -thioureas undergo intramolecular cyclization only in 6(3-96% sulfuric acid to give the corresponding oxazolinium and thiazolinium salts. Treatment of these cations with base yields 2-oxazolines and 2-thiazolines in moderate to good yields. The reaction is illustrated by the conversion of A-2-phenylallylacetamide (342) into 2,5-dimethyl-5-phenyl-2-oxazoline (343) in 70% yield 70JOC3768) (see also Chapter 4.19). 

Cycloadditions of aziridines to diphenylcyclopropenone lead to 4-oxazolines (36) (70CJC89). A mechanism involving initial addition to the cyclopropenone carbonyl group followed by ring opening and recyclization was suggested. 

The photochemical addition of azirines to the carbonyl group of aldehydes, ketones, and esters is also completely regiospecific (77H(6)143). Besides the formation of the isomeric oxazolines (50) from (39) and ethyl cyanoformate, there is also formed the imidazole (51) from addition to C=N in the expected regioselective manner. Thioesters lead to thiazolines (52), while isocyanates and ketenes produce heterocycles (53). 

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. 

The mechanism of organolithium addition to naphthyl oxazolines is believed to occur via initial complexation of the alkyllithium reagent to the oxazoline nitrogen atom and the methyl ether to form chelated intermediate 17. Addition of the alkyl group to the arena 7t-system affords azaenolate 18, which undergoes reaction with an electrophile on the opposite face of the alkyl group to provide the observed product 4. The chelating methyl... 

Variations and Improvements on Alkylations of Chiral OxazoUnes Metalated chiral oxazolines can be trapped with a variety of different electrophiles including alkyl halides, aldehydes,and epoxides to afford useful products. For example, treatment of oxazoline 20 with -BuLi followed by addition of ethylene oxide and chlorotrimethylsilane yields silyl ether 21. A second metalation/alkylation followed by acidic hydrolysis provides chiral lactone 22 in 54% yield and 86% ee. A similar... 

Unsaturated chiral oxazolines have been employed in conjugate addition reactions... 

Chiral oxazolines have also been utilized for the synthesis of ehiral ketones bearing quaternary earbon stereoeenters. As shown below, reaetion of substituted oxazoline 30 with 2 equiv PhLi followed by treatment with benzyl bromide gives ketone 33 upon aeidie hydrolysis. This reaetion is believed to proeeed via addition of PhLi to keteneimine 31 to afford metalated enamine 32, whieh undergoes alkylation at the nueleophilie earbon to provide 33 after aqueous workup. ... 

Variations and Improvements on Asymmetric Additions to Naphthyl Oxazolines... 

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. 

The application of this strategy to the synthesis of chiral cyclohexadienes has been demonstrated by Kiindig. Addition of MeLi to the Cr(CO)3-complexed chiral phenyl oxazoline 43 followed by reaction with allyl bromide produced cyclohexadiene 44 in 69% yield and >98% de. ... 

The sesquiterpenoid hydrocarbons (5)-a-curcumene (59) and (5)-xanthorrhizol (60) were prepared by asymmetric conjugate addition of the appropriate aryllithium reagent to unsaturated oxazoline 56 to afford alcohols 57 (66% yield, 96% ee) and 58 (57% yield, 96% ee) upon hydrolysis and reduction. The chiral alcohols were subsequently converted to the desired natural products. ... 

Chiral Cu(ll)-complexes ofbis-oxazolines as Lewis acids for catalyzed cycloaddition, carbonyl addition, and conjugate addition reactions 99PAC1407. 

A similar influence of the lithium-magnesium exchange is documented for tetrahydroisoquino-lines, derived from chiral oxazolines (see Section 1.3.2.3.3.2 ). The tuning by magnesium bromide also serves well in the carbonyl addition of lithiated tetrahydro-2-isoquinolinecarboxy-late24, prepared by the Katritzky protection/activation method27,28. 

Conjugate addition of chiral amines to allenic and acetylenic sulfones has been reported73. The reaction 112 with (—)-ephedrine gives only one of the two possible diastereomeric oxazolines in high yield (equation 89). 

The search for the racemic form of 15, prepared by allylic cyclopropanation of farnesyl diazoacetate 14, prompted the use of Rh2(OAc)4 for this process. But, instead of 15, addition occurred to the terminal double bond exclusively and in high yield (Eq. 6) [65]. This example initiated studies that have demonstrated the generality of the process [66-68] and its suitability for asymmetric cyclopropanation [69]. Since carbon-hydrogen insertion is in competition with addition, only the most reactive carboxamidate-ligated catalysts effect macrocyclic cyclopropanation [70] (Eq. 7), and CuPF6/bis-oxazoline 28 generally produces the highest level of enantiocontrol. 

A variation of an approach developed by Meyers was used to prepare nifedipine-type 1,4-dihydropyridines 35 from pyridine 34 using an oxazoline-directed aryllithium 1,4-addition reaction <96H(43)2425>. 

A series of chiral phosphinous amides bearing pendant oxazoline rings (50, Ri=H,Tr R2=H,Tr, 51, Ri=H,Tr R2=H,Tr and 54, Ri=H,Tr R2=H,Tr in Scheme 41) have been used as ligands in the copper-catalyzed 1,4-addition of diethylzinc to enones. Two model substrates have been investigated, the cyclic 2-cyclohexenone and the acyclic trans-chalcone. The addition products are obtained quantitatively in up to 67% ee [171]. 

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